Vernakalant Injection for Conversion of Recent Onset Atrial Fibrillation
CRDAC Briefing Document – Vernakalant injection
VERNAKALANT INJECTION FOR CONVERSION OF RECENT ONSET ATRIAL FIBRILLATION
BRIEFING DOCUMENT FOR THE CARDIOVASCULAR AND RENAL DRUGS ADVISORY COMMITTEE
Correvio International Sàrl
MEETING DATE: 10 December 2019
Advisory Committee Briefing Materials: Available for Public Release
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CRDAC Briefing Document – Vernakalant injection
TABLE OF CONTENTS TABLE OF CONTENTS ...... 2 LIST OF TABLES ...... 6 LIST OF FIGURES...... 8 LIST OF ABBREVIATIONS AND TERMS ...... 9 1 EXECUTIVE SUMMARY ...... 12 2 INTRODUCTION ...... 26 2.1 Proposed Indication and Contraindications for Use ...... 27 2.2 Regulatory History ...... 27 3 DISEASE BACKGROUND AND MEDICAL NEED ...... 29 3.1 Epidemiology ...... 29 3.2 Impact on Patients ...... 30 3.3 Guidelines for Treating AF ...... 30 3.4 Current Treatment Strategies ...... 31 3.4.1 Pharmacological Cardioversion ...... 31 3.4.2 Electrical Cardioversion ...... 34 3.4.2.1 Limitations of Electrical Cardioversion ...... 35 3.4.2.2 Review of Risks Associated with Electrical Cardioversion ...... 35 3.4.2.3 ECV Safety Data from Vernakalant Clinical Program ...... 36 3.4.3 Watchful Waiting for Spontaneous Conversion ...... 36 3.5 Vernakalant to Address Medical Need ...... 36 4 NONCLINICAL ...... 38 4.1 Nonclinical Overview ...... 38 4.2 Nonclinical Pharmacokinetics/Pharmacodynamics ...... 38 4.2.1 Pharmacodynamics ...... 38 4.2.1.1 Primary Pharmacodynamics and Efficacy ...... 38 4.2.1.2 Mechanism of Action for Vernakalant-Induced Hypotension ...... 39 4.3 Nonclinical Safety and Toxicology ...... 41 4.3.1 Safety Pharmacology ...... 41 4.3.2 Toxicology Studies ...... 41 5 CLINICAL PHARMACOLOGY ...... 42 5.1 Overview ...... 42 5.2 Pharmacokinetics ...... 42 5.3 Influence of Intrinsic and Extrinsic Factors on Vernakalant Injection ...... 44 5.4 Pharmacodynamics ...... 45 5.4.1 Electrophysiological Study ...... 45 5.4.2 Pharmacokinetic/Pharmacodynamic Modelling ...... 45 5.4.2.1 QTcF PK/PD Model ...... 45 5.4.2.2 Systolic Blood Pressure PK/PD Model ...... 46 6 CLINICAL DEVELOPMENT PROGRAM ...... 47
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6.1 Original NDA Submission ...... 47 6.1.1 Efficacy Endpoints and Safety Monitoring ...... 48 6.2 NDA Resubmission ...... 50 6.2.1 Overview of New Clinical Studies ...... 50 6.2.2 Study Oversight ...... 53 6.2.3 Analysis Populations, Demographics, and Exposure ...... 53 6.2.3.1 Efficacy Analyses ...... 54 6.2.3.2 Safety Analyses ...... 54 6.3 Post-Authorization Safety Study (SPECTRUM) ...... 56 6.3.1 Endpoint Selection and Assessments ...... 57 6.3.2 Patient Selection ...... 58 6.3.2.1 Baseline Characteristics ...... 58 6.3.2.2 Patient Disposition ...... 60 6.3.3 Study Oversight and Data Reporting ...... 61 6.4 Other Post-marketing Data ...... 61 7 EFFICACY RESULTS ...... 62 7.1 Original NDA Submission ...... 62 7.1.1 Disposition ...... 63 7.1.2 Primary Efficacy ...... 63 7.1.3 Secondary and Exploratory Efficacy Endpoints ...... 64 7.1.4 Comparison of Efficacy Results in Subpopulations (ACT I/III) ...... 65 7.2 NDA Resubmission ...... 67 7.2.1 Conversion to Sinus Rhythm ...... 67 7.2.2 Secondary and Exploratory Efficacy Endpoints in All Phase 2 and 3 Trials ...... 67 7.2.3 Target Patient Population ...... 70 7.3 Post-Authorization Safety Study (SPECTRUM) ...... 70 7.3.1 Study Results ...... 70 7.4 Other Post-marketing Efficacy Data ...... 70 7.5 Efficacy Conclusions ...... 71 8 SAFETY ...... 72 8.1 FDA Approvable Letter ...... 73 8.2 NDA Resubmission ...... 74 8.3 Eight Cases of Interest ...... 74 8.4 Death Resulting in Clinical Hold ...... 78 8.5 Overview of Adverse Events ...... 79 8.6 Adverse Events of Special Interest ...... 79 8.6.1 Ventricular Arrhythmia ...... 80 8.6.1.1 Sponsor’s Events of Interest Analysis ...... 80 8.6.1.2 FDA Adverse Events of Special Interest...... 83 Correvio International Sàrl 04 November 2019 Page 3 of 166
CRDAC Briefing Document – Vernakalant injection
8.6.1.3 SAEs and Study Drug Discontinuations due to Ventricular Arrhythmia . 84 8.6.1.4 Ventricular Arrhythmia Events within 0-2 and 2-24 Hours Following Vernakalant, Placebo, and ECV ...... 86 8.6.1.5 1 vs 2 doses ...... 86 8.6.1.6 Subpopulation Analysis ...... 87 8.6.1.7 Analysis of AEs Using Risk Mitigation Strategies ...... 87 8.6.2 Bradycardia ...... 89 8.6.2.1 Pharmacology of conversion ...... 89 8.6.2.2 Correvio Events of Interest Analysis ...... 89 8.6.2.3 FDA Adverse Events of Special Interest...... 92 8.6.2.4 SAEs and Study Drug Discontinuations due to Bradycardia ...... 92 8.6.2.5 Sinus Pause Events within 0-2 and 2-24 Hours Following Vernakalant, Placebo, and ECV ...... 95 8.6.2.6 1 vs 2 doses ...... 95 8.6.2.7 Subpopulation Analysis ...... 96 8.6.2.8 Analysis of AEs Using Risk Mitigation Strategies ...... 96 8.6.3 Hypotension ...... 98 8.6.3.1 Mechanism of vernakalant-induced hypotension ...... 98 8.6.3.2 Correvio Events of Interest Analysis ...... 98 8.6.3.3 FDA Adverse Events of Special Interest...... 99 8.6.3.4 SAEs and Study Drug Discontinuations due to Hypotension ...... 100 8.6.3.5 Hypotension Events within 0-2 and 2-24 Hours Following Vernakalant, Placebo, and ECV ...... 103 8.6.3.6 1 vs 2 doses ...... 103 8.6.3.7 Subpopulation Analysis ...... 103 8.6.3.8 Analysis of AEs Using Risk Mitigation Strategies ...... 104 8.6.4 Other Adverse Events of Interest ...... 105 8.6.4.1 Atrial Flutter ...... 105 8.7 Other Adverse Events ...... 107 8.7.1 Overview of AEs ...... 107 8.7.2 Common TEAEs ...... 107 8.7.3 SAEs ...... 107 8.7.3.1 Serious Adverse Events over Time ...... 107 8.7.3.2 Serious Adverse Events by Dose ...... 110 8.7.4 Discontinuations due to Adverse Events ...... 112 8.7.5 Deaths ...... 113 8.7.5.1 Overview of Deaths...... 113 8.8 SPECTRUM ...... 114 8.8.1 Events of Interest ...... 114 8.8.2 FDA Events of Interest ...... 118
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8.8.3 Overdose ...... 119 8.9 Post-Marketing Safety Experience ...... 120 8.9.1 Risk Management Activities in the Post-Marketing Setting ...... 120 8.9.2 Spontaneous Adverse Reports ...... 121 8.9.2.1 Overdose ...... 123 8.9.2.2 Post-Marketing Reports of Death ...... 123 8.9.3 Literature Reviews ...... 127 8.9.3.1 Vernakalant Safety ...... 127 8.10 Safety Summary and Conclusions ...... 127 9 BENEFIT-RISK EVALUATION ...... 130 9.1 Benefits Summary ...... 131 9.2 Risks Summary ...... 132 9.2.1 Risk Mitigation ...... 134 9.2.1.1 Product Labeling ...... 134 9.2.1.2 Pre-Infusion Checklist ...... 135 9.3 Conclusions ...... 136 10 REFERENCES ...... 137 APPENDIX 1 ...... 143 Table of Clinical Efficacy Endpoints by Study ...... 143 APPENDIX 2 ...... 146 Summary of Excluded Populations in the Pivotal Phase 3 Studies ...... 146 APPENDIX 3 ...... 147 Narratives: Eight Adverse Events of Significant Concern Identified by FDA and Deaths . 147 Eight Adverse Events of Significant Concern Identified by FDA ...... 147 Narratives of Deaths ...... 155 APPENDIX 4 ...... 161 FDA AEs of Special Interest Groupings ...... 161 APPENDIX 5 ...... 164 Tables of Most Common Treatment Emergent Adverse Events ...... 164 APPENDIX 6 ...... 165 Preinfusion Checklist ...... 165
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LIST OF TABLES Table 1. Conversion of Short Duration AF (>3 Hours to ≤7 Days) SR within 90 Minutes of First Exposure to Study Drug ...... 17 Table 2. AF Symptomatic Relief and Maintenance of Sinus Rhythm after AF Conversion ...... 17 Table 3. Summary of Incidence of Ventricular Arrhythmia Events from 0-2 Hours and 2-24 Hours Post-Dosea (Safety Set, All Patients Population Excluding CRAFT) ...... 19 Table 4. Summary of Incidence of Bradycardia Events from 0-2 Hours and 2-24 Hours Post- Dosea (Safety Set, All Patients Population Excluding CRAFT) ...... 20 Table 5. Summary of Incidence of Hypotension Events from 0-2 Hours and 2-24 Hours Post-Dose (Safety Set, All Patients Population Excluding CRAFT) ...... 20 Table 6. SAEs and Discontinuations for Ventricular Arrhythmia, Bradycardia and Hypotension in the 0-24 hour following Infusion ...... 21 Table 7. Incidence of Ventricular Arrhythmia, Sinus Pause and Hypotension From 0-2 Hours From Start of Study Drug Infusion and 0-2 Following ECV (All Patients, Excluding CRAFT) ...... 22 Table 8. SAEs and Discontinuations and Treatments, Target Patient Population ...... 23 Table 9. FDA Approved Antiarrhythmic Agents for Pharmacological Cardioversion of Atrial Fibrillation to Sinus Rhythm ...... 33 Table 10. Cardiac effects and serious extracardiac toxicities of select AF converting agents ..... 34 Table 11. Summary of Clinical Safety and Efficacy Study Designs in Original NDA Submission ...... 48 Table 12. Overview of Primary and Secondary Endpoints and Safety Monitoring ...... 49 Table 13. Summary of New Clinical Safety and Efficacy Study Designs in NDA Resubmission ...... 51 Table 14. Primary Populations Used for Integrated Safety Analyses for Vernakalant Injection . 55 Table 15. Summary of Demographics and Baseline Characteristics (All Patients Population and Target Patient Population) ...... 55 Table 16. Enumeration of Subjects in SPECTRUM ...... 57 Table 17. Demographics and Baseline Characteristics of Subjects in SPECTRUM ...... 59 Table 18. Conversion of Short Duration AF (>3 Hours to ≤7 Days) SR within 90 Minutes of First Exposure to Study Drug ...... 63 Table 19. Termination of AF within 90 Minutes of First Exposure to Study Drug ...... 64 Table 20. Secondary and Exploratory Endpoints in Short Duration AF Subjects Who Converted to Sinus Rhythm within 90 Minutes of First Study Drug Exposure ...... 65 Table 21. Time to Conversion and Maintenance of Sinus Rhythm in Short Duration AF Subjects who Converted to SR within 90 Minutes and Symptom Relief in All Subjects in All Phase 2 and Phase 3 Clinical Studies ...... 69 Table 22. Overview of Requests from FDA Approvable Letter ...... 73 Table 23. Summary of Eight Patient Cases of Interest Identified by FDA ...... 76 Table 24. Incidence of Subjects Reporting FDA Requested and Sponsor Assessments of Events of Interest (All Patients Population) ...... 80 Table 25. Incidence of Ventricular Arrhythmia Events from 0-2, 2-24, and 0-24 Hours Post- Dose (Safety Set, All Patients Population Excluding CRAFT) ...... 81
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Table 26. Differences in Change from Baseline in QTcF Interval Through Follow-up (All Patients, excluding CRAFT) ...... 82 Table 27. Number (%) of Patients with Shifts in QTcF Interval from Baseline to Outliers of ≥500, ≥550 msec (Safety Set, All Patients Population Excluding CRAFT) ...... 83 Table 28. Incidence of FDA Adverse Events of Special Interest of Ventricular Arrythmias by Time Period (Safety Set, All Patients Population) ...... 84 Table 29. Ventricular Arrhythmia Events Reported as Serious Adverse Events and/or Adverse Events Leading to Discontinuation of Study Drug Within 24 Hours of Study Drug Administration ...... 84 Table 30. Incidence of Ventricular Arrhythmia From 0-2 and 2-24 Hours from Start of Study Drug Infusion for Vernakalant-Treated Patients and 0-2 and 2-24 Hours Following ECV for Placebo-Treated Patients (All Patients, Excluding CRAFT) ...... 86 Table 31. Incidence of SAEs of Ventricular Arrythmias from 0-2 and 2-24 hours by Number of Doses Administered (Safety Set, All Patients Population) ...... 87 Table 32. SAEs and Discontinuations and Treatment for Ventricular Arrhythmia in the Target Patient Population ...... 89 Table 33. Incidence of Bradycardia Events from 0-2, 2-24, and 0-24 Hours Post-Dose (Safety Set, All Patients Population Excluding CRAFT)...... 90 Table 34. Bradycardia and Conversion to Sinus Rhythm from 0-2 Hours and 2-24 Hours Post- Dose (All Patients Population Excluding CRAFT) ...... 91 Table 35. Incidence of FDA Adverse Events of Special Interest of Bradycardia by Time Period (Safety Set, All Patients Population) ...... 92 Table 36. Bradycardia Events Reported as a Serious Adverse Event and/or an Adverse Event Leading to Discontinuation of Study Drug Within 24 Hours of Study Drug Administration ...... 93 Table 37. Incidence (%) of Sinus Pause From 0-2 and 2-24 Hours From Start of Study Drug Infusion for Vernakalant-Treated Patients and 0-2 and 2-24 Hours Following ECV for Placebo-Treated Patients (All Patients, Excluding CRAFT) ...... 95 Table 38. Incidence (%) of SAEs of Bradycardia from 0-2 and 2-24 hours by Number of Doses Administered (Safety Set, All Patients Population) ...... 96 Table 39. SAEs and Discontinuations and Treatment for Bradycardia in the Target Patient Population ...... 98 Table 40. Incidence of Hypotension Events from 0-2, 2-24, and 0-24 Hours Post-Dose (Safety Set, All Patients Population Excluding CRAFT)...... 99 Table 41. Incidence of FDA Adverse Events of Special Interest of Hypotension by Time Period (Safety Set, All Patients Population) ...... 100 Table 42. Hypotension Events Reported as a Serious Adverse Event and/or Adverse Event Leading to Discontinuation of Study Drug Within 24 Hours of Study Drug Administration ...... 101 Table 43. Incidence of Hypotension Events 0-2 and 2-24 Hours from the Start of Study Drug Infusion and 0-2 and 2-24 Hours Following Electrical Cardioversion (All Patients, Excluding CRAFT) ...... 103 Table 44. Incidence of SAEs of Hypotension from 0-2 and 2-24 hours by Number of Doses Administered (Safety Set, All Patients Population) ...... 103 Table 45. SAEs and Discontinuations and Treatment for Hypotension in the Target Patient Population ...... 105
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Table 46. Incidence of Atrial Flutter Events from 0-2, 2-24, and 0-24 Hours Post-Dose (Safety Set, All Patients Population) ...... 105 Table 47. Atrial Flutter Events Reported as a Serious Adverse Event and/or Adverse Event Leading to Discontinuation of Study Drug Within 24 Hours of Study Drug Administration ...... 106 Table 48. Overview of Treatment-Emergent AEs (Safety Set, All Patients Population) ...... 107 Table 49. All Serious Treatment-Emergent AEs from 0-2 hours, 2-24 hours, and 0-24 hours (Safety Set, All Patients Population) ...... 108 Table 50. Incidence of Overall SAEs from 0-2 and 2-24 hours by Number of Doses Administered (Safety Set, All Patients Population) ...... 110 Table 51. Treatment-Emergent Adverse Events Resulting in Discontinuation of Study Drug (Safety Set, All Patients Population) ...... 112 Table 52. Incidence of Health Outcomes of Interest ...... 115 Table 53. SPECTRUM – HOIs and SAEs ...... 116 Table 54. Incidence of FDA AEs of Special Interest (Safety Set, SPECTRUM Population) .... 119 Table 55. Numbers of Serious Adverse Drug Reactions in >1 Patient from Post-Marketing Data Sources ...... 122
LIST OF FIGURES Figure 1. Plasma vernakalant concentration in extensive and poor metabolizers versus time ..... 43 Figure 2. SPECTRUM Patient Disposition ...... 60 Figure 3. Patient Disposition in Pivotal Studies of Vernakalant Injection ...... 63 Figure 4. Treatment Difference (Vernakalant Injection Minus Placebo) in Conversion of AF to SR in Short-Duration AF Population Subgroups with Intrinsic Factors – ACT I/III Pooled Pivotal Data ...... 66 Figure 5. Conversion Rates of Short-Duration AF across Studies ...... 67 Figure 6. Post-Marketing studies of vernakalant in patients with AF < 48 hours duration ...... 71
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LIST OF ABBREVIATIONS AND TERMS ACC American College of Cardiology ACT Atrial arrhythmia Conversion Trial ADR Adverse drug reaction AE adverse event AERP atrial effective refractory period AF atrial fibrillation AFL atrial flutter AHA American Heart Association Amio Amiodarone APD action potential duration AUC Area under the curve AV Atrioventricular BP blood pressure bpm beats per minute CABG coronary artery bypass graft CAD Coronary artery disease CCS Canadian Cardiovascular Society CEC clinical events committee CHF congestive heart failure CI confidence interval Cmax Maximum plasma concentration COPD chronic obstructive pulmonary disease Cplasma concentration of drug in plasma CPR Cardiopulmonary resuscitation CRDAC Cardiovascular and Renal Drugs Advisory Committee CRT Serum creatinine CYP Cytochrome P450 DB Double-blinded DC Discontinued dP/dtmax maximum positive value of the first derivative of left ventricular pressure over time dP/dtmin maximum negative value of the first derivative of left ventricular pressure over time DSMB Data Safety Monitoring Board EAD early afterdepolarizations ECG Electrocardiogram ECV electrical cardioversion ED emergency department EF ejection fraction EM extensive metabolizer EMA European Medicines Agency EU European Union EHRA European Heart Rhythm Association EP electrophysiology ERP Effective refractory period ESC European Society of Cardiology FDA Food and Drug Administration GI Gastrointestinal GLP Good Laboratory Practice HCP Health care provider HEK human embryonic kidney HFrEF Heart failure with reduced ejection fraction HOI Health Outcome of Interest HR heart rate Correvio International Sàrl 04 November 2019 Page 9 of 166
CRDAC Briefing Document – Vernakalant injection
HRS Heart Rhythm Society HCTZ hydrochlorothiazide HTN hypertension ICH International Conference on Harmonisation IHD Ischemic heart disease IIS Investigator Initiated Studies IK1 inward rectifier potassium current IKACh acetylcholine activated potassium current IKr rapid activating delayed rectifier potassium current IKs slow activating delayed rectifier potassium current IKur ultra-rapid delayed rectifier potassium current INa sodium current Ito transient outward potassium current IND Investigation New Drug ISS Integrated Summaries of Safety IV intravenous(ly) LAH Left anterior hemiblock LLOQ Lower limit of quantitation LOC Loss of consciousness LV left ventricular LVD Left ventricular dysfunction LVH Left ventricular hypertrophy LVEDP left ventricular end diastolic pressure MAH Marketing authorization holder MedDRA Medical Dictionary of Regulatory Activities MI Myocardial infarction msec millisecond MTD maximum tolerated dose NA Not available NDA New Drug Application NE Norepinephrine NEDS Nationwide Emergency Department Sample NR Not reported NYHA New York Heart Association OL Open label P Prospective PAF paroxysmal atrial fibrillation Pat patient PASS post-authorization safety study PBRER Periodic Benefit-Risk Evaluation Report PBO placebo PCV pharmacological cardioversion PD Pharmacodynamic PE Physical examination PEA Pulseless electrical activity PI Package insert PIL Patient information leaflet PK Pharmacokinetic PM poor metabolizer PT Preferred term R Randomized; retrospective RBBB Right bundle branch block RCA Right coronary artery RCT Randomized controlled trial Correvio International Sàrl 04 November 2019 Page 10 of 166
CRDAC Briefing Document – Vernakalant injection
RI Renal impariment S screening SAE serious adverse event SBP systolic blood pressure SD Standard deviation SE standard error SHF Systolic heart failure Sig significant SmPC Summary of Product Characteristics SPA Special Protocol Assessment SR sinus rhythm SRC Safety Review Committee SSS Sick sinus syndrome SVT supraventricular tachycardia TdP torsade de pointes TEAE treatment-emergent adverse event TEE transesophageal echocardiography TPR Total vascular resistance UDP Uridine 5'-diphosphate UGT Uridine 5'-diphospho - glucuronosyltransferase US United States Vd volume of distribution VF ventricular fibrillation VKT vernakalant injection VS Vital signs VT ventricular tachycardia
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CRDAC Briefing Document – Vernakalant injection
1 EXECUTIVE SUMMARY
Background Vernakalant injection is an intravenous antiarrhythmic agent developed to rapidly convert recent onset atrial fibrillation (AF) to sinus rhythm (SR). Vernakalant exerts its activity in the atria by the concentration-, voltage- and frequency-dependent blockade of sodium channels, combined with preferential atrial specific blockage of potassium currents. The net results are prolonged atrial refractoriness and rate-dependent slowing of atrial conduction which are the mechanisms by which vernakalant converts AF effectively to SR. Correvio International Sàrl (“Correvio”) is seeking approval of vernakalant injection in the United States for the rapid conversion of recent onset AF to sinus rhythm (SR): • For non-cardiac surgery patients: AF ≤ 7 days duration; • For post-cardiac surgery patients: AF ≤ 3 days duration In the United States, the New Drug Application (NDA) for vernakalant injection was originally submitted by Astellas in December 2006. Following a favorable meeting of the Cardiovascular and Renal Drugs Advisory Committee (CRDAC) on 11 December 2007, the Food and Drug Administration (FDA) issued an Approvable Letter on 8 August 2008. The Agency concluded that vernakalant was effective in converting patients with recent AF to normal sinus rhythm; however, the Agency indicated that the potential risks of vernakalant, including the mechanism of such risks, should be well characterized prior to approval. Further, the Agency identified 8 adverse events of concern, primarily related to hypotension and arrhythmias, and requested that the company conduct an additional study to define the safety and efficacy of vernakalant. The ACT V study was developed in collaboration with the FDA to address the Agency’s concerns. The trial was initiated in October 2009 and, in November 2010, the vernakalant injection development program was placed on IND Clinical Hold following a case of cardiogenic shock in an ACT V patient. Since 2010, Correvio (and former Sponsors Astellas and Merck) have had ongoing discussions with the Agency, however, these did not result in the FDA lifting the clinical hold. In 2018, Correvio proposed an NDA resubmission as we believed that the significant new data available since the original NDA submission, provided a thorough characterization of the risks of vernakalant and supported a positive benefit-risk conclusion for the drug. The FDA agreed to the resubmission and this resulted in a pre-NDA meeting in October 2018 where plans for resubmission were discussed and the subsequent submission in June 2019. Eight studies were included in the original NDA comprising 872 patients with AF or atrial flutter (AFL) ≤ 45 days. Since that time, an additional 776 recent onset AF patients have been studied in 4 Phase 3 efficacy and safety clinical studies (ACT IV, ACT V, AVRO, and the Asia-Pacific Study). In addition, 5 pharmacokinetic studies have been completed since the original NDA. Further, the development program is also now supported by data from a new European post- authorization safety study (PASS) which enrolled 1778 unique patients (2009 treatment episodes) as well as worldwide post-marketing safety data from an estimated 58,298 treatment courses, including the 2009 treatment episodes in the PASS and approximately 2,000 patients in Investigator Initiated Studies (IIS). The proposed US PI has been revised to reflect the known risks of vernakalant and to describe the appropriate monitoring and treatment of a target patient population based on these additional clinical data and over 9 years of experience in the post-marketing setting.
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CRDAC Briefing Document – Vernakalant injection
The PASS, SPECTRUM, which was conducted as part of follow-up measures with the EU approval, provides supportive data describing the practical implementation of the proposed US label. These additional data taken together address the following key points from the Approvable Letter (Section 8.1) including: • Vernakalant risks have been well characterized in the development program and are supported by the post-marketing experience; • Of the 8 cases of concern identified by the FDA, 4 patients would be identified as having contraindications for vernakalant use. Three other patients experienced bradyarrhythmias at the time of cardioversion which can occur irrespective of conversion modality used1,2,3. The eighth patient, with undiagnosed idiopathic cardiomyopathy, experienced an event 12 hours after receiving vernakalant injection that the sponsor considers unrelated to vernakalant (Section 8.3). • Vernakalant is an important and effective addition to the pharmacological treatment options currently available for cardioversion. A Target Patient Population has been identified, consistent with the European SmPC and the proposed US PI, that is at low risk for serious adverse events with a demonstrable benefit to these patients. The positive risk/benefit assessment and appropriate use in the target population has been supported by the PASS. • Preclinical and clinical data explain the mechanism of action for vernakalant-induced hypotension and show that it occurs in the setting of decreased myocardial reserve or is associated with transient bradyarrhythmias that occur at the time of cardioversion • The FDA expressed concern over the use of vernakalant in “the outside-trial environment”. Labeling guidance for the appropriate use of vernakalant has been used in this environment in Europe, Canada, and Rest of World for 9 years with an estimated 58,298 treatment courses. Post-marketing data provide further characterization of safety and strongly support a favorable benefit/risk profile for vernakalant.
Outside of the United States, the first marketing approval for vernakalant was received from the European Union in September 2010. Since then, the drug has been approved in 62 countries worldwide, is currently registered in 41 countries, and is marketed in 25 countries. No registrations of vernakalant have been withdrawn due to safety concerns. Vernakalant is included in the European Society of Cardiology Guidelines with a Class IA recommendation4 for the treatment of recent onset AF patients with no relevant structural heart disease, with a Class IIbB recommendation for patients with mild heart failure (NYHA Class I or II), including those with coronary artery disease, provided they do not present with hypotension, severe aortic stenosis or severe Heart Failure with reduced Ejection Fraction (HFrEF). There is also a class IIbB recommendation for cardioversion of postoperative AF in patients without severe heart failure, hypotension, or severe structural heart disease (especially aortic stenosis). In Canada, vernakalant is also included in the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation5 for acute pharmacological rhythm control in patients who are eligible for cardioversion. This Briefing Document summarizes the clinical, nonclinical and post-marketing data on vernakalant and outlines the complete response to the Agency’s requests in the Approvable Letter of 2008. Vernakalant injection, at an initial intravenous (IV) dose of 3 mg/kg over 10 minutes with an efficacy-dependent second 10-minute dose of 2 mg/kg, has consistently demonstrated its effectiveness in converting recent onset AF to sinus rhythm and providing rapid relief of AF Correvio International Sàrl 04 November 2019 Page 13 of 166
CRDAC Briefing Document – Vernakalant injection symptoms in 8 Phase 3 studies. The safety profile of vernakalant, has been well characterized from both extensive preclinical investigations and clinical experience and confirmed in the post- marketing setting, including in a large PASS. Vernakalant injection is administered in a clinical setting where the identified risks and the risks associated with cardioversion can be appropriately managed.
Unmet Medical Need (Section 3) Atrial fibrillation is the most common cardiac rhythm disturbance encountered in the adult and elderly population and accounts for more than 467,000 hospitalizations annually in the United States.6,7,8 Conversion to SR normalizes ventricular rate, improves cardiac function, hemodynamics, and exercise capacity. Conversion alleviates the symptoms associated with AF, such as fatigue, palpitations, dyspnea, hypotension, and syncope, and importantly could reduce the need for hospitalization.6,9,10 Moreover, early conversion of AF mitigates the development of atrial electrical and structural remodeling associated with untreated AF and may reduce the progression of AF to a permanent condition. 6,10,11 Recent observations show that even a short delay to cardioversion of 12 hours or longer from AF symptom onset may increase the risk of thromboembolic complications in patients with a high risk of stroke.12,13 Early conversion to sinus rhythm reduces the need for weeks of anticoagulation before treatment in select patients and shorter duration of AF is associated with a lower stroke risk. The AHA/ACC/HRS guideline recommends both pharmacological and electrical cardioversion when pursuing a rhythm control strategy. 14 For pharmacological therapy, the following agents are recommended: oral and intravenous (IV) amiodarone, oral dofetilide, oral flecainide, IV ibutilide and oral propafenone.14 (Table 9). Of these, only dofetilide and ibutilide are FDA approved for the conversion of AF to SR.
Both ibutilide and dofetilide, as Class III agents, exert significant effects on QT and are attended with an increased risk of sustained polymorphic VT. Dofetilide must be administered to patients in a monitored setting in a facility for a minimum of 3 days. 15,16 Conversely, vernakalant has a unique ion channel targeting profile. It does not block the slow delayed rectifier potassium current [IKs] or the inward rectifier potassium current (IK1), which are important currents in ventricular repolarization. To date, clinical data (and supported by post-marketing data) have not shown an increased risk of torsade de pointes with the use of vernakalant.
Electrical cardioversion is also used for the conversion of AF to SR and is more effective than pharmacological conversion, particularly when AF has been present for more than 7 days. However, ECV is not appropriate for all patients with AF, such as patients who have not fasted or those with impaired respiratory function or morbid obesity; it is also undesirable in the immediate post-cardiac surgery population. ECV also requires sedation and anesthesia with their own set of potential complications and, which may delay access to treatment if an anesthesiologist is not readily available.4,17 It is common practice for people with AF who are targeted for ECV to receive anticoagulant and rate controlling therapy and be discharged to return weeks later for their scheduled ECV. In order to use ECV earlier, transesophageal echocardiography is recommended prior to cardioversion to reduce the risk of embolizing a left atrial thrombus. Vernakalant is a rapidly-acting, quick-offset, effective AF converting agent with a positive risk- benefit profile in a target patient population of stable patients without conditions that may impair
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CRDAC Briefing Document – Vernakalant injection myocardial reserve and have symptomatic recent onset AF, including post-cardiac surgery AF. Vernakalant has been shown to have a low risk of significant hypotension in the appropriate patient population and the bradycardias post cardioversion are similar to those associated with any other forms of cardioversion. Further, there are no data to suggest that vernakalant is torsadogenic. The availability of vernakalant to US physicians and their patients would provide a valuable, rapidly-acting pharmacological option for patients who are hemodynamically stable and do not have clinically evident significant underlying structural heart disease.
Nonclinical (Section 4) A comprehensive nonclinical program was conducted including a wide range of nonclinical pharmacology, safety pharmacology, pharmacokinetic, and toxicology studies.
In vitro and in vivo pharmacodynamic studies showed that vernakalant has several properties that differentiate it from other antiarrhythmic drugs:
• Vernakalant’s INa blocking actions are potentiated in the atria during AF with only limited activity in the ventricle; • Class III antiarrhythmic drugs cause prolongation of action potential duration (APD) in both the atria and ventricles, whereas vernakalant has greater net effects on repolarization in the atria versus ventricle; • Class III agents are associated with early afterdepolarizations (EADs), which lead to TdP. Vernakalant suppresses EADs induced by Class III antiarrhythmic drugs in in vitro Purkinje fiber assays • Class III agents do not block late INa and, indeed, the Class III agent ibutilide has been shown to increase late INa. Vernakalant blocks late INa and suppresses Class III antiarrhythmic drug-induced TdP in animal models; • Vernakalant has more rapid on/off binding kinetics to sodium channels than Class Ic agents such as flecainide allowing for a rapid onset and shorter duration of action; • Class Ic agents have demonstrated ischemia-related proarrhythmia in nonclinical models. Vernakalant is not proarrhythmic in these models.
These properties clearly differentiate vernakalant from selective Class I and Class III antiarrhythmic agents and suggest safety advantages over existing agents for the conversion of AF to SR.
Clinical Pharmacology (Section 5) The maximum concentration of vernakalant is achieved at the end of the infusion and rapidly declines as vernakalant is extensively and rapidly metabolized (primarily by cytochrome P450 2D6 [CYP2D6]). The elimination half-life of vernakalant in CYP2D6 extensive metabolizers is 3 hours (increasing to ~5.5 hours in poor metabolizers). Dose adjustments are not necessary for age, serum creatinine, CYP2D6 expression, hepatic or renal impairment. Pharmacokinetic/pharmacodynamic modeling have shown the median predicted increases in QTcF interval after the 1st and 2nd doses are 20.0 and 20.8 msec, respectively. Doubling the observed exposure after the 2nd dose would theoretically increase the QTcF interval to 29.8 msec. The same model indicated that vernakalant concentrations contribute to an increased risk of
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CRDAC Briefing Document – Vernakalant injection hypotension, but the 1.4-fold increased risk only becomes important when baseline systolic blood pressure is lower than 105 mmHg. The nonclinical data demonstrating vernakalant’s atrial selectivity are supported by data from a study in patients who were undergoing electrophysiological testing for supraventricular/ventricular arrhythmia. These clinical data showed that vernakalant prolongs atrial effective refractory period (AERP) with no significant effects on ventricular refractoriness, or repolarization.
Clinical Development Program (Section 6) A thorough global clinical development program has been conducted for vernakalant injection. Eight clinical studies were included in the original NDA submission, including 3 pivotal Phase 3 studies. The pivotal Phase 3 studies included the Atrial arrhythmia Conversion Trial (ACT) I, conducted in patients with AF, the ACT III trial, conducted in patients with AF or atrial flutter (AFL), and the ACT II trial, conducted in patients who developed AF or AFL subsequent to cardiac surgery. Since the original NDA submission, 4 additional Phase 3 efficacy and safety studies have been completed adding 536 vernakalant patients to the clinical database; a total of 1648 subjects have now been enrolled in the clinical development program, of whom 1073 received vernakalant injection and 575 received comparators including placebo. Across all clinical studies, a broad, representative patient population was enrolled with common AF co-morbidities and typical background medications. The PASS study was conducted in Western Europe from 2011 to 2018 and provides supportive data from a further 2009 treatment episodes (1778 unique patients, of whom 1580 were prospectively enrolled). This NDA resubmission supports the use of vernakalant injection for the rapid conversion of recent-onset AF to SR. Though some trials enrolled subjects with longer duration AF (duration 8- 45 days) and subjects with AFL, efficacy was not demonstrated in these settings, thus the proposed indication excludes these subjects. Also, in a separate clinical program, an additional 694 patients with sustained symptomatic AF (duration >72 hours and <6 months) who were eligible for cardioversion received the oral formulation of vernakalant with dosing of up to 3 months. There are no plans to continue development of oral vernakalant and this program is not further discussed in this Briefing Document.
Efficacy Results (Section 7) In the two randomized, double-blind placebo-controlled pivotal trials, ACT I and ACT III, the proposed dosing regimen for vernakalant injection was shown to be effective in non-surgery patients with recent-onset AF (> 3 hours and ≤ 7 days). A significantly greater percentage of patients receiving vernakalant injection experienced conversion of AF to SR for a minimum of 1 minute within 90 minutes of first exposure to study drug compared to patients receiving placebo (Table 1). In the pivotal trial in AF or AFL patients after cardiac surgery, ACT II, vernakalant injection was shown to be effective in patients who developed short duration AF (> 3 hours and ≤ 72 hours) within 24 hours to 7 days after surgery. A significantly greater percentage of patients receiving vernakalant injection experienced conversion of AF to SR for a minimum of 1 minute within 90 minutes of first exposure to study drug compared to patients receiving placebo (Table 1).
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Table 1. Conversion of Short Duration AF (>3 Hours to ≤7 Days) SR within 90 Minutes of First Exposure to Study Drug ACT I ACT III ACT IId PBO Vkt PBO Vkt PBO Vkt Conversion to SR 3/75 74/145 3/84 44/86 7/50 47/100 (4.0%) (51.0%) (3.6%) (51.2%) (14.0%) (47.0%) % Differencea (95% CI) 47.0 (37.8, 56.3) 47.6 (36.3, 58.9) 33.0 (19.3, 46.7) P-value <0.0001b <0.0001b 0.0001b Odds Ratio (95% CI) 24.0 (6.9, 83.6) 38.3 (9.2, 129.5) 3.25 (1.61, 6.57)c Abbreviations: AF=Atrial fibrillation; SR=sinus rhythm; CI=Confidence interval, Vkt=vernakalant injection; PBO=placebo Definitions: Conversion of AF or AFL to sinus rhythm, minimum 1-minute duration within 90 minutes of first exposure to study drug. a Difference in percentage of successful conversions between vernakalant injection and placebo groups; missing values counted as failed conversions b Cochran-Mantel-Haenszel test c Relative risk (95% CI) presented d AF Duration 3-72 hr In patients with recent-onset AF in the ACT I and III pivotal studies who converted to SR within 90 minutes, vernakalant injection demonstrated a rapid onset of action (median time to conversion of AF to SR in vernakalant responders was 11 and 8 minutes from the start of the first infusion respectively). For the 6 patients who received placebo and converted to sinus rhythm within 90 minutes, the median was 29 minutes and 34 minutes in ACT I and ACT III respectively. In the ACT II study, the median time to conversion for AF patients who converted to sinus rhythm within 90 minutes was 12 and 30 minutes in the vernakalant and placebo groups respectively. Vernakalant injection provided both rapid relief of symptoms to patients and conversion was durable when measured at 7 days (Table 2).
Table 2. AF Symptomatic Relief and Maintenance of Sinus Rhythm after AF Conversion Endpoint ACT I ACT III ACT IIa PBO Vkt PBO Vkt PBO Vkt Any AF symptom n, (%) N 75 145 84 86 54 107 Baseline 61 (81.3) 125 (86.2) 71 (84.5) 64 (74.4) 48 (88.9) 98 (91.6) 90 min 57 (76.0) 75 (51.7) 59 (70.2) 41 (47.7) 43 (79.6) 71 (66.4) p-value* P<0.0001 0.004 0.099 24 hr 23 (30.7) 57 (39.3) 24 (28.6) 18 (20.9) 28 (51.9) 57 (53.3) p-value 0.886 0.289 0.869 Life Table Estimate of Maintenance of Sinus Rhythm, % N 3 75 3 44 8 48 2 hr 66.7% 98.6% 100% 97.6% 62.5% 93.6% 24 hr/discharge 66.7% 97.0% 100% 97.6% 50.0% 59.5% 7 Days 66.7% 92.0% 100% 94.8% 50.0% 56.9% *Fisher’s exact test a includes patients with AF or AFL
The efficacy demonstrated in the remaining safety and efficacy studies (CRAFT, Asia Pacific, AVRO, ACT IV and SPECTRUM) was consistent with that demonstrated in ACT I, ACT II and ACT III. The Scene 2 study, conducted in the early development program, did not show that vernakalant was effective at converting typical atrial flutter. Correvio International Sàrl 04 November 2019 Page 17 of 166
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Vernakalant injection was effective across a broad range of subgroups: sex, age, region (including the US), renal or hepatic impairment, use of CYP2D6 inhibitors or substrates, use of QT prolonging medications, and implanted rate control devices. Further, vernakalant injection was effective in the presence of typical background medications for the target patient population, including rhythm and rate control medications. The PASS, SPECTRUM, was an observational study that was conducted as a follow up measure after the approval of vernakalant injection by the European Commission. The study was designed with input from the European Medicines Agency (EMA) to quantify and characterize medically significant health outcomes of interest (HOI) with the use of vernakalant injection in clinical practice. Efficacy data were also collected. In this study, conversion of AF to SR occurred in 70.2% of patients within the first 90 minutes after vernakalant administration. This higher efficacy rate is likely due to a shorter duration of the index atrial fibrillation episode in SPECTRUM relative to the Clinical Phase 2 and 3 trials (median duration of 17.7 to 48.7 hours in the clinical phase 2 and phase 3 studies, compared to 11.9 hours in SPECTRUM).
Safety (Section 8) FDA Approvable Letter and Eight Cases of Concern The safety review in this Briefing Document firstly addresses the 8 cases of concern identified by the FDA in the Approvable Letter. Of these 8 cases, 4 patients would be identified as having contraindications for vernakalant use based on a history of symptomatic heart failure (NYHA Class III or IV or those with known moderate or severe left ventricular dysfunction) or, evidence of clinically significant aortic stenosis prior to vernakalant dosing. Three other patients, one of whom would also have been contraindicated prior to treatment due to a baseline systolic blood pressure <100 mmHg, experienced bradyarrhythmias at the time of cardioversion (2 with sinus pauses and one who developed complete heart block following ECV at 158 minutes after initiation of vernakalant). Bradyarrhythmias can occur irrespective of conversion modality used 1,2,3 and are typically transient and self-limited requiring no treatment, or, on occasion may be symptomatic, requiring atropine or isoproterenol and rarely, external pacing. The eighth patient, with undiagnosed idiopathic cardiomyopathy, experienced cardiogenic shock 12 hours after receiving vernakalant injection, 10 hours after ECV and proximate to multiple doses of sedatives and a respiratory depressing and sedating anti-psychotic, which resulted in hypotension. The Sponsor considers this event unrelated to vernakalant. Deaths (Section 8.7.5) There has been a total of 9 deaths in the vernakalant development program; 8 patients who received vernakalant injection and 1 patient who received placebo. Six deaths occurred without a common pathophysiological cause and were unlikely to be related to vernakalant. There were two deaths where vernakalant may have played a causative role: One death was in a hemodynamically unstable patient with severe aortic stenosis in whom the product would be contraindicated (Section 8.3) and one in a patient with known reduced myocardial reserve, which resulted in the US FDA clinical hold. This patient is discussed in detail in Section 8.4. Serious Adverse Events (Section 8.7.3) The analyses of safety in the clinical development program focused on events occurring within 2 and 24 hours immediately following vernakalant administration. Vernakalant has a short elimination half-life of about 3 hours in CYP2D6 Extensive Metabolizers (EMs) and 5.5 hours
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CRDAC Briefing Document – Vernakalant injection in CYP2D6 Poor Metabolizers (PM)s, thus the 24-hour monitoring period would have captured any drug-related side effect. The 0- to 2-hour time period captures the time of Cmax (end of infusion) and the time when the drug’s effects (efficacy and safety) were generally observed. After 2 hours, other antiarrhythmic converting agents and electrical cardioversion were permitted in the clinical trials, which potentially confound interpretation of events in the later time period. From 0-2 hours post dose, the incidence of SAEs was higher in patients who received vernakalant (3.0%) compared with placebo (0.7%), but from 2-24 hours post dose, the incidence of SAEs was higher in the placebo group (3.3%) compared with vernakalant (2.0%). The most frequent SAEs (occurring in more than 0.1%) reported in the first 24 hours in AF patients who received vernakalant injection were hypotension (0.7%) and bradycardia (0.4%). Ventricular Arrhythmia, Bradycardia and Hypotension Events of interest associated with antiarrhythmic drugs, including ventricular arrhythmia, bradycardia and hypotension, were prospectively identified for close scrutiny at the beginning of the clinical development program. A thorough and systematic assessment of the safety database was conducted to evaluate the incidence of these events. Analyses were conducted to examine the incidence across multiple sources of data (ECGs, Holter findings, and vital sign data), in addition to AEs identified by multiple associated preferred terms. Table 3, Table 4, and Table 5 provide summaries of the incidence of ventricular arrhythmia, bradycardia and hypotension respectively across these multiple sources of data. In all events of interest, the incidence was higher in the vernakalant group than placebo in the 0-2 hour time period post dose and the incidence was higher in the placebo group than vernakalant in the 2-24 hour time period post-dose. Full tables showing the nature and frequency of the ventricular arrhythmia, bradycardia and hypotensive events can be found in Sections 8.6.1.1, 8.6.2.2, and 8.6.3.2 respectively. Table 3. Summary of Incidence of Ventricular Arrhythmia Events from 0-2 Hours and 2-24 Hours Post-Dosea (Safety Set, All Patients Population Excluding CRAFT) 0-2 hours 2-24 hours Placebo Vernakalant Placebo Vernakalant (N=439) (N=1037) (N=439) (N=1037) Source Event n (%) n (%) n (%) n (%) All Sourcesa Any ventricular arrhythmia event 11 (2.5%) 39 (3.8%) 43 (9.8%) 72 (6.9%) AE Databaseb Any ventricular arrhythmia event 2 (0.5%) 15 (1.4%) 9 (2.1%) 14 (1.4%) CEC assessment of 12- Any ventricular arrhythmia event 1 (0.2%) 2 (0.2%) 0 0 lead ECG Holter device Any ventricular arrhythmia event 8 (1.8%) 22 (2.1%) 38 (8.7%) 61 (5.9%) cardiologist over-read Abbreviations: AE, adverse event; CEC, Clinical Events Committee; ECG, electrocardiogram. a “All Sources” row represents total from all data sources. b AEs are defined as any non-serious event starting or worsening after the start of the first dose through 10 days after the last dose in addition to all serious events starting or worsening after the start of the first dose through 30 days after the last dose.
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Table 4. Summary of Incidence of Bradycardia Events from 0-2 Hours and 2-24 Hours Post- Dosea (Safety Set, All Patients Population Excluding CRAFT) 0-2 hours 2-24 hours Placebo Vernakalant Placebo Vernakalant (N=439) (N=1037) (N=439) (N=1037) Source Event n (%) n (%) n (%) n (%) All Sourcesa Any bradycardia event 12 (2.7%) 53 (5.1%) 56 (12.8%) 78 (7.5%) AE Databaseb Any bradycardia event 3 (0.7%) 41 (4.0%) 11 (2.5%) 24 (2.3%) CEC assessment of 12- Any bradycardia event 0 3 (0.3%) 2 (0.5%) 4 (0.4%) lead ECG Holter device Any bradycardia event 0 2 (0.2%) 2 (0.5%) 1 (0.1%) cardiologist over-read Abbreviations: AE, adverse event; AV, atrioventricular; CEC, Clinical Events Committee; ECG, electrocardiogram. a “All Sources” row represents total from all data sources b AEs are defined as any non-serious event starting or worsening after the start of the first dose through 10 days after the last dose in addition to all serious events starting or worsening after the start of the first dose through 30 days after the last dose.
Table 5. Summary of Incidence of Hypotension Events from 0-2 Hours and 2-24 Hours Post- Dose (Safety Set, All Patients Population Excluding CRAFT) 0-2 hours 2-24 hours Placebo Vernakalant Placebo Vernakalant (N=439) (N=1037) (N=439) (N=1037) Source Event n (%) n (%) n (%) n (%) All Sourcesa Any hypotension event 21 (4.8%) 59 (5.7%) 26 (5.9%) 35 (3.4%) AE Databaseb Any hypotension event 6 (1.4%) 44 (4.2%) 13 (3.0%) 18 (1.7%) Vital signs Any hypotension event 21 (4.8%) 47 (4.5%) 19 (4.3%) 26 (2.5%) Abbreviations: AE, adverse event. a “All Sources” row represents total from all data sources b AEs are defined as any non-serious event starting or worsening after the start of the first dose through 10 days after the last dose in addition to all serious events starting or worsening after the start of the first dose through 30 days after the last dose.
SAEs and Discontinuations for Ventricular Arrhythmia, Bradycardia and Hypotension Table 6 summarizes the incidence of SAEs and drug discontinuations for the events of interest in the 0-2 and 2-24 hour time period following start of infusion. There was a total of 7 SAEs or discontinuations for a ventricular arrhythmia event in the vernakalant group plus an additional ventricular fibrillation adverse event (not reported as a separate SAE) in the 0-2 hour time period following infusion (0.7%, 8/1073) and 2 ventricular arrhythmia SAEs or discontinuations in the placebo group in the 2-24 hour time period (0.4%, 2/459). There were two events of ventricular tachycardia (VT) in the vernakalant group; one discontinuation due to VT and right bundle branch block (RBB); subsequently adjudicated by the core laboratory cardiologist as AF with RBBB, which required no intervention. The second VT was an SAE that continued for 3 minutes and resolved spontaneously. There were 2 SAEs and one AE of ventricular fibrillation (VF) discussed further below. Twelve SAEs or discontinuations for bradycardia occurred in the vernakalant group within 2 hours of infusion (1.1%) and 3 in the 2-24 hour period. Of the 3 bradycardias that occurred in the 2-24 hour period in the vernakalant group; one occurred about 5 hours after vernakalant and 3 hours after receiving amiodarone; a second developed complete heart block 158 minutes after initiation of vernakalant, and immediately following ECV; and the third occurred in a patient who converted after one dose of vernakalant and an SAE of sinus arrest began 4 hours after conversion which required no treatment. Two SAEs of bradycardia occurred in the placebo group in the 2-24 hour Correvio International Sàrl 04 November 2019 Page 20 of 166
CRDAC Briefing Document – Vernakalant injection period (0.4%). There were 6 uses of atropine, one of which was administered with a pressor, in the vernakalant group in hours 0-24 and one use of atropine in the placebo group. One post-surgical vernakalant patient received external pacing. A total of 11 SAEs or discontinuations for hypotension occurred in the 24 hours following the start of vernakalant infusion, of which 10 occurred in the first 2 hours (0.9%); one event occurred in the same period in the placebo group (0.2%). In the 2-24 hour period there was an incidence of 0.4% and 0.1% hypotensive SAEs or discontinuations in placebo and vernakalant groups respectively. The 1 SAE in the vernakalant group that occurred in the 2-24 hour period occurred approximately 6 hours after vernakalant exposure and was associated with abdominal pain and possible cholecystitis. Most hypotensive events resolved quickly without intervention or with simple supportive care, 3 patients required pressors; one of the 3 patients also required CPR and (b) (6) defibrillation (patient discussed below). Table 6. SAEs and Discontinuations for Ventricular Arrhythmia, Bradycardia and Hypotension in the 0-24 hour following Infusion 0-2 hours 2-24 hours Placebo Vernakalant Placebo Vernakalant (N=459) (N=1073) (N=459) (N=1073) n (%) n (%) n (%) n (%) SAEs and discontinuations due to ventricular arrhythmia Total, n (%) 0 8 (0.7) 2 (0.4) 0 Use of defibrillation, n 0 3 0 0 SAEs and discontinuations due to bradycardia Total, n (%) 0 12 (1.1) 2 (0.4) 3 (0.3) Use of atropine/pressor, n 0 5 1 1 Use of CPR, n 0 1 0 0 Use of external pacing, n 0 1 0 0 SAEs and discontinuations due to hypotension Total 1 (0.2) 10 (0.9) 2 (0.4) 1 (0.1) Use of atropine/pressor, n 0 3 2 0 Use of saline/Trendelenburg 1 5 1 0 Unknown 0 2 0 0
Three of the ventricular arrhythmia events in the vernakalant group were ventricular fibrillation: (b) (6) • Patient in the ACT III study experienced an SAE of ventricular fibrillation 47 minutes after the start of the first infusion and 12 minutes after completion of the second infusion of vernakalant. This patient presented with known severe aortic stenosis (known 120mmHg gradient) and AF and had findings suggestive of acute coronary syndrome (chest pain and ST segment elevation on the ECG) and was hemodynamically unstable at baseline. The arrhythmia occurred in the setting of hypotension. This patient is discussed in more detail in Section 8.3 and Appendix 3. (b) (6) • Patient in the CRAFT Phase 2 study received the low dose of vernakalant injection (0.5 mg/kg 10-minute infusion followed by 1.0 mg/kg 10-minute infusion 30 minutes later). The subject did not convert to sinus rhythm and 1 hour after completion of second infusion, an unsynchronized shock was delivered (a loose monitor lead was identified) which caused VF and then was immediately defibrillated.
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(b) (6) • Patient in the ACT V study had an SAE of cardiogenic shock and experienced ventricular fibrillation during the resuscitation. Two defibrillations resulted in the return of AF. The VF was not recorded as an SAE. This patient is discussed in more detail in Section 8.4 and Appendix 3. There were no TdP SAEs within 24 hours of dosing in either treatment group. One case of TdP (not classified as an SAE or AE but identified in Holter recordings) occurred in a patient with AFL who did not convert to sinus rhythm after receiving vernakalant. The patient received ibutilide 1 hour and 45 minutes after the second vernakalant injection and soon after a nine-beat run, classified as TdP was noted. Incidence of Events of Interest Following Vernakalant, Placebo and ECV The incidence of ventricular arrhythmia, sinus pause, and hypotension in the 0-2 hours following start of study treatment infusion (placebo or vernakalant) was analyzed and compared to the incidence of the same events of interest in the 2 hours from start of electrical cardioversion in both treatment groups in the Phase 3 population. Electrical cardioversion was allowed, per protocol, at any time >2 hours after vernakalant or placebo administration, if patients had not converted. In the first 2 hours following study drug infusion there was a higher incidence of all events of interest in the vernakalant group compared to placebo (Table 7). In the 0-2 hour period following ECV the event rate was higher in those patients in the placebo group who received ECV. Table 7. Incidence of Ventricular Arrhythmia, Sinus Pause and Hypotension From 0-2 Hours From Start of Study Drug Infusion and 0-2 Following ECV (All Patients, Excluding CRAFT) Time Period Treatment Placebo Vernakalant Ventricular arrhythmia n, (%) 0-2 hrs following first infusion 11/439 (2.5) 39/1037 (3.8) 0-2 hrs following first ECV attempt 6/261 (2.3) 6/404 (1.5) Sinus Pause, n, (%) 0-2 hrs following first infusion 2/439 (0.5) 11/1037 (1.1) 0-2 hrs following first ECV attempt 11/261 (4.2) 7/404 (1.7) Hypotension n, (%) 0-2 hrs following first infusion 21/439 (4.8) 59/1037 (5.7) 0-2 hrs following first ECV attempt 16/261 (6.1) 12/404 (3.0) Abbreviations: ECV, electrical cardioversion Ventricular arrhythmia, sinus pause and hypotension defined as events of interest including AEs, 12-lead ECG, Holter and vital sign data
Sub-Group Analyses by Clinical History and Extrinsic Factors Analyses of the events of interest (ventricular arrhythmia, bradycardia, and hypotension) described above were also performed for subgroups based on intrinsic and extrinsic factors and the following were found; however, conclusions based on these assessments should be interpreted with caution due to the small number of patients in certain subgroups. • No clinically relevant or significantly increased risk of ventricular arrhythmia, hypotension, or bradycardia events was observed with vernakalant injection compared to placebo in subgroups based on duration of the current episode of AF, age, sex, history of hypertension, history of ischemic heart disease, history of myocardial infarction, and background use of any rate control Correvio International Sàrl 04 November 2019 Page 22 of 166
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medication, calcium channel blockers, digoxin, all rhythm control medications, CYP2D6 inhibitors, CYP2D6 substrates, and QT prolonging medications. • The risk of hypotension events is increased in the first 2 hours post dose in vernakalant patients with a history CHF (% risk difference [95% CI]: 9.1 [0.8, 17.4]) or background use of beta blockers (% risk difference [95% CI]: 4.4 [0.8, 8.0]), although there was no indication of increased risk for all rate control medications. Nonclinical studies characterizing the mechanism of action for vernakalant-induced hypotension would suggest increased risk for patients with severely depressed cardiac function. These risks will be mitigated by proposed labeling with a contraindication for the use in patients with reduced myocardial function and a recommendation (in the Warnings and Precautions section) against the use of IV beta-blockers for 2 hours before and after treatment in the proposed label. • Patients with valvular heart disease had an increased incidence of ventricular arrhythmia and bradycardia with vernakalant injection from 0-2 hours post-dose, however the number of patients with valvular heart disease was small (n=192) to make comparative risks. All but one of the bradycardia events from 0-2 hours was associated with acute cardioversion. Use in patients with clinically significant aortic stenosis will be contraindicated as myocardial reserve may be reduced in such patients. Use of intravenous Class I and Class III antiarrhythmics will also be contraindicated within 4 hours prior or 4 hours after vernakalant injection because of the absence of safety data in these patients and to be consistent with pharmacokinetic considerations for FDA-approved acute use of intravenous rhythm control agents. Target Patient Population When the patient population of the Phase 3 clinical studies of vernakalant injection is restricted to the Target Patient Population, i.e., excluding those subjects with contraindications in the proposed US package insert, the risk of SAEs or discontinuations of ventricular arrhythmias, bradycardia, and hypotension was 0.6% (including AE of VF), 0.9% and 0.9% respectively in the first 2 hours post dose in vernakalant patients, the time period during which patients would be monitored following treatment. Table 8 shows the treatments these patients received. Of note, the patient who (b) (6) received defibrillation (and also received pressors) was patient . Table 8. SAEs and Discontinuations and Treatments, Target Patient Population 0-2 Hours 2-24 Hours Placebo Vernakalant Placebo Vernakalant SAEs and discontinuations N=259 N=668 N=259 N=668 Ventricular arrhythmia, n (%) 0 4 (0.6) 0 0 Use of defibrillation, n 0 1 0 0 No treatment, n 0 3 0 0 Bradycardia, n (%) 0 6 (0.9) 0 2 (0.3) Use of atropine, n 0 3 0 0 No treatment, n 0 3 0 2 Hypotension, n (%) 0 6 (0.9) 1 (0.4) 0 Use of pressors, n 0 2 0 0 Use of saline/Trendelenburg, n 0 2 1 0 No treatment, n 0 1 0 0 Unknown, n 0 1 0 0
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Comparative analyses of events of interest in the All Patients Population and Target Patients Population are provided in Section 8.6.
Post-Marketing Safety Experience (Section 8.8 and 8.9) Vernakalant has been marketed since its first approval in the EU in 2010, cumulative exposure to vernakalant injection post marketing is estimated to be 58,298 treatments to August 31, 2019. A total of 463 adverse drug reactions have been received in 252 individual case safety reports cumulatively. A PASS, SPECTRUM, was conducted following the approval of vernakalant in the EU. The SPECTRUM study evaluated 2,009 treatment episodes in 1,778 patients. The primary objective of the study was to estimate the incidence of medically significant “health outcomes of interest” (HOIs) i.e., events which were likely to require treatment, of hypotension, ventricular arrhythmia, AFL, and bradycardia, that were reported during treatment and during the first 24 hours after last infusion or until discharge/end of medical encounter. The study also investigated the potential risk of overdose and medication error and evaluated the effectiveness of risk minimization activities. A total of 19 HOIs (defined by the investigator, study-defined criteria, and/or the Safety Review Committee- SRC) were reported in 17 patients. The cumulative incidence of patients with HOIs was 0.8% (17/2009) (95% CI: 0.5% to 1.4%). In the 2 hours following vernakalant infusion, significant bradycardia was the most common HOI, occurring in 0.7% of the treatment episodes (15/2009; 95% CI: 0.4% to 1.2%). Two of these transient events occurred simultaneously with significant hypotension. Therefore, the cumulative incidence of significant bradycardia with significant hypotension within the first 2 hours from the start of vernakalant infusion was 0.1% (2/2009) (95% CI: <0.1% to 0.4%). There were two episodes of AFL with 1:1 conduction; both converted to sinus rhythm following ECV. One AFL event occurred within 2 hours of infusion, the second occurred in the 2-4 hour period and was characterized as a ventricular arrhythmia by the Investigator but confirmed as AFL by the Safety Review Committee. There were an additional 9 SAEs that did not meet HOI criteria. All patients with an HOI or SAE recovered, and there were no deaths, TdP, or ventricular fibrillation. Atrial flutter with 1:1 atrioventricular conduction has emerged as a risk during post-marketing surveillance. Of 21 serious AFL events reported from spontaneous reports, 10 were with 1:1 atrioventricular conduction. Most of these converted after ECV treatment and none had a fatal outcome. The risk of AFL with or without 1:1 atrioventricular conduction is identified in the proposed label and will continue to be monitored as part of the pharmacovigilance plan.
Benefit-Risk Evaluation (Section 9) Vernakalant has shown consistent efficacy in a broad range of subjects with AF, with the efficacy being similar to, or potentially better than, existing pharmacologic agents used for acute conversion of AF. This is a point with which the Agency previously agreed, stating in the Approvable Letter dated August 2008) that vernakalant is “clearly effective in promptly converting patients with recent atrial fibrillation (AF) to normal sinus rhythm (NSR).” This was also the case made during the advisory committee discussion in 2007. Conversion occurred rapidly; the median time to conversion in the clinical trials ranged from 8 to 14 minutes. Conversion rates ranged from 45.7 to 52.9% in non-surgery and cardiac surgery patients. In the SPECTRUM study, the conversion rate was even higher, i.e., 70.2% conversion. Almost all patients with recent-onset AF (in the ACT I/III pivotal studies) who converted to SR after receiving vernakalant injection remained in SR Correvio International Sàrl 04 November 2019 Page 24 of 166
CRDAC Briefing Document – Vernakalant injection during the study observation period (97% maintenance at 24 hours; 93% at 7 days). Further, vernakalant provided rapid relief of the AF symptoms causing discomfort and concern that prompted these patients to seek care for treatment (46.3% asymptomatic at 90 minutes compared with 28% on placebo).
The anticipated benefits of rapid conversion of AF to SR include the following: • Rapid reduction of related symptoms and a return to normal heart rate4,18; • Shorter hospital stays4; • Reduced need for weeks of anticoagulation prior to delayed cardioversion12; • May reduce progression of AF6. Current pharmacological agents have limitations related to both efficacy, onset of action, and safety, resulting in a treatment gap that leads to hospitalization of most US patients. Vernakalant addresses this treatment gap by offering an additional treatment option because of its rapid onset of action and reduced need for prolonged monitoring. Unlike ECV, the need for anesthesia and its attendant complexity in providing treatment, can be avoided in some patients. The safety profile of vernakalant has been well characterized based on a clinical development program together with post-marketing experience estimated to reflect include >58,000 cumulative treatment episodes (as of 31 August 2019). The potential risks of ventricular arrhythmias, bradycardia, and hypotension are well characterized. Proposed labeling and use of the pre-infusion checklist (see Section 9.2.1.2 and Appendix 6) will mitigate these risks by guiding physicians in appropriate patient selection. Further, vernakalant will be administered in a clinical setting where any of the risks associated with cardioversion can be appropriately managed. The Sponsor will provide physician education to support appropriate patient selection and monitoring. These additional measures were evaluated as part the SPECTRUM study, the results of which suggest physicians are treating the appropriate population.
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2 INTRODUCTION
Summary: • The proposed indication for vernakalant injection is for the rapid conversion of recent onset atrial fibrillation (AF) to sinus rhythm (SR) in
o non-cardiac surgery patients with AF ≤7 days duration o post-cardiac surgery patients with AF ≤3 days duration. • The proposed dosing regimen is an initial infusion of 3 mg/kg over 10 minutes. If conversion to SR does not occur within 15 minutes after the end of the initial infusion, a second 10-minute infusion of 2 mg/kg may be administered. • Nine Phase 2 and 3 clinical studies have been conducted with 1073 adults exposed to vernakalant injection to fully characterize the efficacy and safety profiles of vernakalant injection. • Vernakalant injection was approved in 62 countries, is currently registered in 41 countries, and marketed in 25 countries.
This briefing document provides background information for the members of the Cardiovascular and Renal Drugs Advisory Committee (CRDAC) for a meeting on 10 December 2019. This document provides the scientific foundation for the following conclusions: • There is a treatment gap in the current standard of care. Pharmacologic cardioversion is part of the AHA/ACC/HRS Guideline recommended standard of care for AF, but each of the currently approved and other agents used have limitations regarding efficacy and safety (Section 3.4, Current Therapies). Only two medications, dofetilide and ibutilide, are FDA approved for the conversion of AF to SR and, as Class III agents, exert significant effects on QT with associated risk of sustained polymorphic VT and require extensive ECG monitoring following administration. • Vernakalant addresses the treatment gap by offering an alternative option, with a unique mechanism of action that focuses largely on atrial repolarization, with rapid onset and offset of action (Section 3.5, Vernakalant to Address Medical Need). Within the indicated patient population, the vernakalant clinical development program to date has shown a low risk of ventricular arrhythmia comparable to placebo over the first 24 hours. Rapid, durable, and effective conversion of AF to SR reduces symptoms associated with AF, results in a shorter stay in hospital, may reduce the need for anticoagulation prior to delayed cardioversion, and may reduce the risk of early recurrence of AF. • Efficacy of vernakalant, rapid conversion, reduction in symptoms, and maintenance of effect has been demonstrated in the target population (Section 7.5, Efficacy Conclusions). The Phase 3 clinical studies consistently demonstrated efficacy of vernakalant injection for rapid conversion (median time of 8 to 14 minutes) of recent onset AF (≤ 7 days) to SR within 90 minutes of injection in 45.7 to 52.9% of patients. Further, vernakalant resulted Correvio International Sàrl 04 November 2019 Page 26 of 166
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in a significant improvement in AF symptoms at 90 minutes and the majority of patients maintained SR at 24 hours and 7 days (97% and 93%, respectively). • Risks of vernakalant treatment have been well characterized (Section 8.10, Safety Summary and Conclusions) and the mechanisms for these risks are understood. Some risks are associated with cardioversion to sinus rhythm irrespective of modality, and some are vernakalant-related. The appropriate Target Patient Population has been identified, and the risks of these events are mitigated by appropriate patient selection, as well as appropriate monitoring during and after the infusion. • Proposed labeling and the Pre-Infusion Checklist will mitigate safety risks associated with cardioversion and the risk of clinically serious hypotension (Section 8.9.1, Risk Management Activities in the Post-Marketing Setting).
2.1 Proposed Indication and Contraindications for Use
The Sponsor, Correvio International Sàrl, is seeking approval for the use of vernakalant injection for the rapid conversion of recent onset AF to SR in adults. • For non-surgery patients: AF ≤ 7 days duration • For post-cardiac surgery patients: AF ≤ 3 days duration The proposed dosing regimen is an initial infusion of 3 mg/kg (up to a maximum of 339 mg) over 10 minutes. If conversion to SR does not occur within 15 minutes after the end of the initial infusion, a second 10-minute infusion of 2 mg/kg may be administered (up to a maximum of 226 mg). The proposed contraindications for use of vernakalant injection include patients with the following, which are also highlighted in the proposed pre-infusion checklist: • Systolic blood pressure < 100 mmHg (or having received fluid resuscitation or inotropes to maintain BP > 100mmHg); • Severe heart failure (including NYHA class III and IV or with known moderate or severe left ventricular dysfunction); • Clinically significant aortic stenosis; • Severe bradycardia, sinus node dysfunction or second degree or third degree heart block in the absence of a pacemaker; • Prolonged QT at baseline (uncorrected > 440 msec); • Acute coronary syndrome (including myocardial infarction) within the last 30 days; • Use of intravenous rhythm control antiarrhythmics (class I and class III) within 4 hours prior to, as well as in the first 4 hours following, vernakalant administration is contraindicated.
2.2 Regulatory History
The NDA for vernakalant injection was originally submitted by the previous sponsor, Astellas, in December 2006. Following a favorable CRDAC meeting on 11 December 2007, in which the panel voted 6-2 in favor of approval of vernakalant for conversion of AF, the FDA issued an Approvable Letter on 8 August 2008. The Agency concluded that vernakalant was clearly effective in converting patients with recent AF to normal SR. However, in the Agency’s opinion, electrical cardioversion (ECV) constituted a relatively safe and very effective alternative, so vernakalant Correvio International Sàrl 04 November 2019 Page 27 of 166
CRDAC Briefing Document – Vernakalant injection needed to be ‘extremely’ safe and its risks better characterized prior to approval. The FDA identified 8 specific patient events described in the Approvable Letter as the basis of their concern that the benefit of the drug may not outweigh its risks in some patients (see Section 8.3). FDA also requested that the company identify the mechanism underlying the uncommon cases of severe hypotension observed after vernakalant administration. Following this decision, a Phase 3B trial, ACT V, was developed in collaboration with the FDA to address the Agency’s concerns. The trial was initiated in October 2009 and, in November 2010, the vernakalant injection development program was placed on IND Clinical Hold following a case of cardiogenic shock in an ACT V patient. This patient subsequently died. Since 2010, Correvio (and former Sponsors Astellas and Merck) have met or had calls with the Agency on nine occasions to discuss the vernakalant injection program. Additional nonclinical pharmacology studies have been conducted with FDA consultation to ascertain the mechanism and characterize the risk for vernakalant-induced hypotension. However, neither the studies, nor the discussions, resulted in the FDA lifting the clinical hold. In 2018, Sponsor proposed an NDA resubmission as we believed that the significant new data available since the original NDA submission, provided a thorough characterization of the risks of vernakalant and supported a positive benefit-risk conclusion for the drug. The FDA agreed to the resubmission and this resulted in a pre-NDA meeting in October 2018 where plans for resubmission were discussed and the subsequent submission in June 2019. This US NDA resubmission follows regulatory approvals in the EU, Canada, Hong Kong, the Middle East, South Africa, and Switzerland. Vernakalant has been approved in 62 countries, is currently registered in 41 countries and marketed in 25 countries. In all instances, it is approved, for the rapid conversion of recent-onset AF to SR in adults (for non-cardiac surgery patients: AF ≤7 days duration; for post cardiac surgery patients: AF ≤3 days duration). No registrations of vernakalant have been withdrawn due to safety concerns.
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3 DISEASE BACKGROUND AND MEDICAL NEED
Summary: • There is a medical need for safe and efficacious pharmacological treatments for symptomatic recent onset AF • Patients with recent onset AF present to the Emergency Department (ED) with symptoms and want immediate cardioversion to alleviate symptoms. Physicians want a safe and effective option to rapidly convert their patients to SR. • Pharmacologic cardioversion is part of recommended standard of care for recent onset AF. • There are significant risks and limitations associated with each of the current pharmacological treatments used for conversion of AF to SR (e.g., slow acting, high rates of proarrhythmia, prolonged periods of ECG monitoring). The most commonly treatment is not approved for the indication and has both significant risks and limitations and requires prolonged periods of monitoring. • There are risks associated with the use of ECV for conversion of AF to SR: it is not ideal for all patients with AF, requires a fasting state, sedation and anesthesia, and is difficult to provide at the time of initial assessment in most US hospitals. • Vernakalant demonstrated robust and consistent efficacy across the clinical development program. • When used in the target patient population, vernakalant has a favorable safety profile relative to other pharmacologic cardioversion therapies as described in their package inserts.
3.1 Epidemiology
AF is the most common cardiac rhythm disturbance encountered in the adult population and accounts for more than 467,000 hospitalizations annually in the United States and this number is increasing.6,7,8 It is estimated that as many as 6.1 to 9.3 million Americans have been diagnosed with AF; a number that has been steadily increasing over the past decade and is expected to double by 2050.7,19 In the most recent American Heart Association (AHA) Health Disease and Stroke Statistics – 2019 Update,20 the lifetime risk of AF has been estimated to be approximately 1 in 3 among whites and 1 in 5 in blacks in the United States. The prevalence of AF increases with patient age, as less than 1% of AF patients are under 60 years old, 12% of AF patients are aged 75 to 84 years, and approximately one third of AF patients are 80 years or older.6 Reported frequencies of pharmacologic cardioversion range from 1.2% to 12-14% in large US registries, national inpatient, outpatient, and insurance databases, much lower than in many other countries.21,22,23,24,25
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This low use of pharmacologic cardioversion in the US and the inability to provide ECV in the emergency department, given its need for anesthesia, in turn results in a much higher rate of hospitalization for patients initially seen with AF. In an analysis of the US Nationwide Emergency Department Sample (NEDS) comprising 1,320,123 ED visits with a primary diagnosis of AF, 69.3% of patients were admitted to the hospital.26 In a survey of the American College of Emergency Physicians, approximately 26% of physicians report attempting to convert patients with symptomatic recent-onset AF to SR while in the Emergency Department (ED) “always” or “most of the time.” Among physicians with a preference of initially attempting cardioversion, 65% treated first with drugs and 35% initially used ECV. The factors influencing choice were not studied.27
3.2 Impact on Patients
Recent onset AF commonly causes discomfort and is associated with a number of symptoms and signs, such as fatigue, palpitations, dyspnea, hypotension, and syncope.6 AF limits physical activities for many; patients who are in AF can be fatigued, sometimes light-headed, and are often unable to enjoy simple physical activities like riding a bike or walking. Atrial fibrillation is a relatively common cause of stroke, and when permanent can lead to congestive heart failure (CHF), an independent risk factor for mortality, and has been recognized as a risk factor for dementia.6,28,29 It is AF symptoms that bring most patients into the emergency department within a few hours. Of these patients, some will not be candidates for pharmacologic conversion because of the need for anticoagulation, the duration of the AF or the identification of significant underlying cardiac or other medical conditions. However, for the remaining patients-those with persistent symptoms, new onset AF, and with no serious underlying cardiac dysfunction- prompt conversion is a desirable option to relieve symptom, stabilize heart rate, and allay concerns of risk of stroke. Being admitted to a hospital or returning for additional procedures weeks later that require anesthesia is inconvenient, expensive, invasive, and interferes with their lives. These patients want to be treated and return home.
3.3 Guidelines for Treating AF
There are a number of reasons to convert AF to SR early after AF onset. Conversion to SR normalizes ventricular rate, improves cardiac function, hemodynamics, and exercise capacity. Importantly, it alleviates associated symptoms, and along with anticoagulation reduces the risk of stroke.6,9,10 In addition, early conversion of AF instead of a long delay may reduce the progression of AF.6,10,11 Electrophysiologic and structural remodeling increases rapidly with time, e.g., progressive dilatation and disruption of normal flow makes it more difficult to terminate AF after 7 days and promotes thrombus formation, the risk for which increases quickly after 2 days.6,30,31,32 Recent observations in individuals at high risk for stroke show that even a short delay to cardioversion of 12 hours or longer from AF symptom onset may increase the risk of thromboembolic complications by as much as 4-fold.12,13 If AF remains untreated for 48 hours or more, current US guidelines recommend either 3 weeks or more of therapeutic anticoagulation or the use of transesophageal echocardiography (TEE) prior to cardioversion in order to minimize the risk of a thromboembolic event.33
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Similar recommendations are made by the European Society of Cardiology (ESC) and European Heart Rhythm Association (EHRA) and the Canadian Cardiovascular Society (CCS).4,5 Patients with recent onset AF (less than 48 hours duration) and a low thromboembolic risk can be converted to SR either pharmacologically or with ECV without the need for prior anticoagulation.33 The AHA Task Force on Clinical Practice Guidelines, American College of Cardiology (ACC), and the Heart Rhythm Society (HRS) guideline for the management of patients with AF (2014) recommend a rhythm-control strategy, as opposed to a rate-control and watchful waiting strategy for patients with persistent symptoms associated with AF. Additionally, a rhythm-control strategy may be favored in patients who have difficulty achieving adequate rate control, in younger patients, and in patients with possible tachycardia-mediated cardiomyopathy.6,7 Cardioversion is also recommended for the first episode of AF, in patients with AF precipitated by an acute illness, and to prevent progression to paroxysmal AF and to persistent AF, which results in structural remodeling that can become irreversible. The guideline also notes that pharmacological cardioversion is most successful when initiated within 7 days of AF onset.34
3.4 Current Treatment Strategies
Pharmacological cardioversion has practical advantages over ECV. Electrical cardioversion requires a fasting state, and usually the presence of an anesthesiologist to accomplish deep sedation or anesthesia and to manage the airway, and adequate staffing to monitor the patient until the effects of anesthesia are negligible. An important benefit of pharmacological conversion is to provide a logistically simpler alternative to ECV that avoids the safety risks related to anesthesia. However, the currently available drugs are either slow acting or require prolonged periods of close observation, thus limiting their usefulness in patients who are appropriate candidates for early cardioversion and discharge. In the US, a common practice is to provide anticoagulation and rate control treatment for subjects with new onset AF and discharge them to return weeks later for a scheduled ECV; however, for most in whom early cardioversion is desired, they are admitted to hospital. Watchful waiting is the strategy of administering rate control and anticoagulants per physician discretion and delaying cardioversion attempts to observe whether the patent spontaneously converts to sinus rhythm without additional intervention. It is not a strategy that is typically used in emergency departments nor cardiology wards, since it requires a patient (and physician) to accept continuing symptoms and risks and requires an effective follow-up system to follow and manage the patient who may need to return to hospital 1 and 2 days later for additional examinations and treatment if needed. 3.4.1 Pharmacological Cardioversion Pharmacological therapies for arrhythmia are commonly classified by their primary electrophysiologic effects in the ventricle, according to the original Vaughan Williams Classes I through IV, which recently have been revised to allow capturing of multiple drug targets/actions and of adverse, sometimes actually proarrhythmic, effects.35,36 The most commonly used AF converting agents are the Class III and Class Ic agents. Class III agents, including ibutilide, amiodarone, sotalol, and dofetilide, are potassium channel blockers that primarily prolong ventricular repolarization. Class Ic agents, such as flecainide and propafenone, neither of which are approved for the intended indication, are sodium channel blockers which have limited effects Correvio International Sàrl 04 November 2019 Page 31 of 166
CRDAC Briefing Document – Vernakalant injection on ventricular repolarization, but slow conduction in both atria and ventricle.36 Both of these drug classes have a number of limitations associated with their use; e.g., several are slow acting, most with significant risks of ventricular proarrhythmia, and most requiring prolonged periods of monitoring, including electrocardiogram (ECG), blood pressure, etc.35,36 In the US, there are only two pharmacological agents which are FDA-approved for conversion, IV ibutilide and oral dofetilide. Ibutilide was approved by the FDA in 1996 and dofetilide in 1999, since then there have been no new pharmacological treatments approved for AF conversion.
Both ibutilide and dofetilide, as Class III agents, exert significant effects on QT with associated risk of VT. Rates of sustained polymorphic VT requiring cardioversion were reported in 1.7% of patients in the ibutilide registration trials. In the dofetilide registration trials, 3% of the patients had their dose down-titrated due to increased QT or QTc interval and 3% of patients discontinued therapy due to increased QT or QTc interval. In the supraventricular arrhythmia population (AF or other supraventricular arrhythmias) the overall incidence of TdP was 0.8%. To minimize the risk of these arrhythmias, dofetilide must be administered to patients in a monitored setting in a facility for 3 days and ibutilide patients should be monitored with continuous ECG monitoring for at least 4 hours following infusion or until QTc has returned to baseline. This facility must be able to provide creatinine clearance calculations, continuous ECG monitoring and cardiac resuscitation. From the time of its approval in 1999 until 2016, dofetilide was available only to hospitals and prescribers that had received appropriate dofetilide dosing and treatment initiation education. This REMS has now been removed. Further details on the indication, reported efficacy, black box warnings, and contraindications of ibutilide and dofetilide are shown in Table 9 below.
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Table 9. FDA Approved Antiarrhythmic Agents for Pharmacological Cardioversion of Atrial Fibrillation to Sinus Rhythm Drug Indication Efficacya Contraindications and Boxed Warnings statement Dofetilide- • Conversion of 6-30% b • Congenital or acquired long QT syndrome oral AF/AFL 29-30%c • Creatine clearance <20 mL/min o Dofetilide has 70% converted • Concomitant use of verapamil, cimetidine, trimethoprim, or not been within 24 to 36 ketoconazole shown to be hours • Concomitant use of other known inhibitors of the renal cation effective in transport system such as prochlorperazine, dolutegravir and patients with megestrol paroxysmal • Concomitant use of hydrochlorothiazide (HCTZ) AFc • Known hypersensitivity to dofetilide • Maintenance of • To minimize the risk of induced arrhythmia, patients normal SR initiated or reinitiated on dofetilide should be placed for a (delay in minimum of 3 days in a facility that can provide creatinine AF/AFL clearance calculations, continuous ECG monitoring and recurrence) cardiac resuscitation. Ibutilide- Rapid conversion 43%d • Hypersensitivity to ibutilide fumarate or any of the other product IV of AF or AFL of Within 70-90 components recent onset to SR minutes • Can cause potentially fatal arrhythmias, particularly sustained polymorphic ventricular tachycardia, usually in association with QT prolongation (torsades de pointes), but sometimes without documented QT prolongation. • These arrhythmias can be reversed if treated promptly. It is essential that ibutilide be administered in a setting of continuous ECG monitoring and by personnel trained in the identification and treatment of ventricular arrhythmias, particularly polymorphic VT. Source: US approved product labels Note: Bolded text is to highlight the boxed warning a Savelieva et al, 2014 (unless otherwise noted).37 b Singh et al, 200038; efficacy varies based on dose (125 to 500 µg twice daily). c Dofetilide US approved label. d Ibutilide US approved label.
Perhaps due to the dearth of effective and well tolerated FDA-approved treatment options, other AF converting agents are used in the US that have not been approved for this indication. In fact, the most commonly used AF converting agent in the US is amiodarone, an antiarrhythmic approved for treatment of ventricular arrhythmia38. The AHA/ACC/HRS guideline for pharmacological conversion of AF recommends the following agents; flecainide and propafenone (Class IA recommendation), oral amiodarone (Class IIA recommendation), ibutilide and oral dofetilide (Class IA)6. The efficacy of these antiarrhythmic drugs varied widely across clinical studies, however efficacy was usually greatest for short duration AF (≤ 48 to 72 hours). To summarize some of the risks associated with the current pharmacologic treatments for AF, Table 10 presents the cardiac effects and serious extracardiac toxicities of these AF converting agents.
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Table 10. Cardiac effects and serious extracardiac toxicities of select AF converting agents Drug Cardiac Effects Extracardiac Labeled Cardiac Adverse Reactionsa Toxicities Class III Ibutilide Polymorphic VT/TdP, slows Hypotension, IV (Feb 2017; n=586 AF/AFL patients): AV ventricular rateb nauseaa block (1.5%), bradycardia (1.2%), bundle branch block (1.9%), hypertension (1.2%), nonsustained monomorphic VT (4.9%), nonsustained polymorphic VT (2.7%), palpitations (1.0%), QTC prolongation (1.2%), sustained polymorphic VT (1.7%), ventricular extrasystoles (5.1%), tachycardia (2.7%) Dofetilide TdPc Headache, chest Oral (Oct 2018; n=38-703 AF patients): AV pain, dizzinessa block (0-1.5%), heart block (0-0.5%), ventricular fibrillation (0-2.6%), ventricular tachycardia (2.6-13.2%), TdP (0-10.5%) Amiodarone TdP (infrequent)c Phlebitis, IV (Nov 2016; n=1836 patients with life- Delayed conversion to sinus hypotensionb threatening VT/VF): bradycardia (4.9%), rhythm 8-12 hrsb IV: Liver function CHF (2.1%), heart arrest (2.9%), hypotension tests abnormala (15.6%), ventricular fibrillation (<2%), ventricular tachycardia (2.4%) Oral (Nov 2018; n=241 patients): cardiac arrhythmias (>1%), congestive heart failure (>1%), SA node dysfunction (>1%) Class IC Flecainide Atrial flutter 1:1 conduction, Hypotensionb Oral (Nov 2018; n=429 ventricular QT prolongationb arrhythmia patients): chest pain (5.4%), VT; 2:1 AV conduction; CHF; palpitations (6.1%) negative inotropic effectsc Propafenone Atrial flutter 1:1 conduction, Hypotensionb Oral (Feb 2019; n=480 SVT patients): QRS prolongationb bradycardia (2%), congestive heart failure VT; 2:1 AV conduction; CHF; (2%), palpitations (2%), wide complex negative inotropic effectsc tachycardia (2%) Abbreviations: AV, atrioventricular; CHF, congestive heart failure; LVH, left ventricular hypertrophy; NR, not reported; TdP, Torsade de Pointes. a From FDA-approved product labeling. b Kirchof et al., 201639 c Camm et al., 200816
As described in the table, drug-induced torsade de pointes (TdP) and other ventricular arrhythmias may occur with all of these agents, some of which lead to the need for in-hospital monitoring during their initiation and short-term follow up.4,15,16
3.4.2 Electrical Cardioversion Electrical cardioversion is useful for the conversion of AF to SR and is more effective than pharmacological conversion, particularly when AF has been present for more than 7 days. Electrical cardioversion is the recommended treatment for hemodynamically unstable AF patients and for patients who do not respond to pharmacological therapies.6 Studies of ECV show conversion rates of ~90% in clinical practice although there is a high rate of both immediate and early recurrence, particularly in those who have had AF for 7 days or longer.13 Use of ECV to convert AF to SR is not advisable in some settings, as described below.
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3.4.2.1 Limitations of Electrical Cardioversion ECV is not appropriate for all patients with AF, such as patients who are not fasted, or those with impaired respiratory function and/or morbid obesity. ECV is also undesirable in the immediate post-cardiac surgery population because the chest wall is still healing from surgery. The most significant impediment to the acute use of ECV is the requirement for sedation and anesthesia, which in itself has risks and also may delay access to treatment if an anesthesiologist is not readily available, which is often the case in Emergency Departments in the US.4,17 3.4.2.2 Review of Risks Associated with Electrical Cardioversion As part of the evaluation of cardioversion risks, and in response to a request from FDA, Correvio conducted a detailed assessment of the risk of ECV and AEs associated with the deep sedation/anesthesia required for ECV or the procedure itself, based on a systematic review of the published literature. This review of AEs, from a mixture of controlled studies, cohort studies and case reports, shows that ECV is associated with a risk of SAEs, including ventricular arrhythmias and ventricular fibrillation, the occurrence of significant bradyarrhythmias including complete heart block, sinus pauses requiring pacing, respiratory distress requiring ventilation support, aspiration pneumonia, hypotension, as well as uncommon events such as pulmonary edema, cardiogenic shock, and death.2,40,41,42,43,44,45,46,47,48,49 Determining the real incidence of these events from these studies is difficult because of the heterogenous populations, the varied definitions of what constitutes a serious event and the lack of continuous ECG recordings. However, the larger studies provide an estimate. Large studies have reported incidences of ventricular fibrillation and ventricular tachycardia ranging from 0.29% to 0.8% after ECV2,44,50 and have indicated that these can occur following both monophasic and biphasic waveform shocks. Delivery of nonsynchronous shocks, which may cause serious ventricular arrhythmias, have also been reported in up to 4% of patients.2,47 Serious bradycardia, typically reported as that which requires an intervention such as complete heart block, long sinus pauses (>10 sec), or need for isoproterenol or pacing, ranged from 0.13% to 1.5% in the largest studies. 2,3,41,47,48,49,51,52 Apnea and respiratory distress, along with aspiration, are among the more common AEs that relate to sedation and anesthesia, and in some cases are serious and require ventilation support.41,47,53,54 In the large study by Niebauer et al,47 6/4695 of patients with cardioversions (0.13%) required aggressive ventilation support, and 6/388 patients (1.5%) required ventilator support in the study by Burton et al,.54 These complications are unique to ECV. The incidence of hypotension varies, and when not associated with bradyarrhythmias post cardioversion, hypotension is most often attributed to the anesthetic / sedation agents used. Propofol is the most common agent used today and has a high incidence of hypotension that is usually managed by fluid replacement and close monitoring. Significant hypotension or hemodynamic instability, sometimes requiring treatment with pressors, are known complications. 47, 54,55,56 Serious pulmonary edema, cardiogenic shock, and death are uncommon with ECV, but have occurred.41,43,44,48,51,57,58,59,60 Other adverse effects of ECV include prolonged recovery of normal atrial contraction (“atrial stunning”) which, though reported with both electrical and pharmacological conversion of AF to SR, occurs more commonly following ECV.50,62,63,64 Correvio International Sàrl 04 November 2019 Page 35 of 166
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Pacemaker malfunction has also been reported.65,66 The most common complications are chest wall skin burns and irritation which are uncomfortable and painful and sometimes a reason for refusal to have the procedure. The majority of significant AEs associated with ECV in the reviewed studies occur, as might be expected, in those patients with the most extensive underlying heart disease or most comorbidity. The same has been true for most of the currently available drugs used for cardioversion. 3.4.2.3 ECV Safety Data from Vernakalant Clinical Program The incidence of ventricular arrhythmia, bradycardia and hypotension in the periods 0-2 and 2-24 hours from the start of the infusion (vernakalant and placebo groups), and 0-2 and 2-24 hours following ECV attempt (vernakalant and placebo groups) were analyzed. In summary, 3.8% of patients receiving vernakalant experienced a ventricular arrhythmia event within 2 hours of infusion and 2.3% of patients receiving placebo experienced a ventricular arrhythmia event within 2 hours of ECV. The incidence of sinus pause was 1.1% within 2 hours of receiving vernakalant infusion and 4.2% in placebo patients within 2 hours of ECV. The incidence of hypotension was 5.7% within 2 hours of vernakalant infusion and 6.1% in placebo patients within 2 hours of ECV. Further details can be found in Section 8.6. 3.4.3 Watchful Waiting for Spontaneous Conversion Although given time a subset of patients with AF will spontaneously convert, watchful waiting is not an option that physicians typically choose for patients with recent onset symptomatic AF. In a recently published study of adults who presented to the Emergency Department with hemodynamically stable, symptomatic, recent onset (<36 hours) AF, 437 patients (171 of 3706 that were screened and 266 from centers without screening logs) were randomized to either watchful waiting or active treatment. The “delayed” group returned at 48 hours and two-thirds had spontaneously reverted to sinus rhythm67. The delayed group of patients must be willing to tolerate continued symptoms and to return for possibly more care. Implementation of such a strategy of delaying cardioversion for one or two days, for which only a small subset of patients is eligible, in addition to the requirement for a second hospital visit, is too complex and unwieldy to practice in most hospitals in the US except in the setting of a clinical trial.
3.5 Vernakalant to Address Medical Need
The availability of vernakalant to US physicians and their patients would address a medical need for an additional treatment option for pharmacologic cardioversion, targeting patients with recent onset AF, who want treatment for symptom relief, or who are concerned about electrical cardioversion or complications and/or inconvenience due to delay of cardioversion. Vernakalant is a rapid and effective conversion agent; 51% of patients converted within 90 minutes of infusion and of those patients who converted, the median time was approximately 11 minutes, which compares favorably with the current FDA-approved pharmacologic treatments: • Dofetilide - 29-30% of patients converted, 70% converted within 24 to 36 hrs. Further, the US PI states that dofetilide has not been shown to be effective in patients with paroxysmal AF; • Ibutilide - 43% of patients converted within 70-90 minutes.
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There are potentially serious risks associated with the FDA-approved pharmacological treatments for AF. • The ibutilide product label contains a boxed warning for life threatening arrhythmias and appropriate treatment environment to manage the potentially fatal arrhythmias that may occur with ibutilide treatment. • The dofetilide product label contains a boxed warning that patients should be placed for a minimum of 3 days in a facility that can adequately monitor creatinine clearance, provide continuous electrocardiographic monitoring and cardiac resuscitation. The most commonly used drug for the treatment of AF, amiodarone, is slow acting and requires hospitalization for infusion and monitoring. Furthermore, it is important to have other treatment options for patients who have impaired respiratory function, patients who have recently undergone cardiac surgery, and patients who are not fasting or for other clinical situations where ECV may not be appropriate.6 The 2018 Canadian Cardiovascular Society Guidelines, along with the European Society of Cardiology Guidelines support a rhythm control strategy, which may include the use of vernakalant, for managing hemodynamically stable, symptomatic AF patients in the emergency department (ED); vernakalant has a Class 1A recommendation in the ESC Guidelines.4,5 Vernakalant allows for rapid and effective conversion of AF with early improvement of symptoms, a low and manageable risk of hypotension and a comparable risk of bradycardia to that seen with other forms of cardioversion. The results of the clinical development program have provided important information in the proposed product label to guide physicians in appropriate patient selection to minimize risks. Furthermore, vernakalant is administered in a controlled environment by caregivers with expertise in the management of adverse events associated with cardioversion. The totality of data support making vernakalant injection available to healthcare providers and patients in the US to manage recent onset AF.
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4 NONCLINICAL
Summary • Vernakalant is a multi-ion channel blocker which preferentially delays atrial repolarization and slows conduction in a frequency- and voltage-dependent manner. • Efficacy has been demonstrated in canine and goat models of atrial fibrillation. • Proarrhythmia is lower than with other antiarrhythmic drugs in nonclinical models. • Hypotension observed in anesthetized animals is due to a decrease in cardiac output. • Vernakalant has a short elimination half-life and large volume of distribution such that it is rapidly cleared from the plasma.
4.1 Nonclinical Overview
A total of 63 pharmacology studies were performed by the Sponsor for the vernakalant development program. These studies included primary pharmacodynamics studies evaluating the in vitro and in vivo mechanisms of action of vernakalant and its metabolites, secondary pharmacodynamic/safety pharmacology studies, and pharmacodynamic interaction studies with other antiarrhythmic agents and warfarin. In consultation with the FDA, eight of these studies were conducted to ascertain the mechanism and characterize the risk for vernakalant-induced hypotension, discussed in Section 4.2.1.2.
4.2 Nonclinical Pharmacokinetics/Pharmacodynamics
4.2.1 Pharmacodynamics 4.2.1.1 Primary Pharmacodynamics and Efficacy At therapeutic concentrations, vernakalant acts on the heart by blocking potassium channels that affect repolarization in the atria combined with voltage-, and frequency-dependent blockade of sodium channels.68 The net result is preferential prolongation of atrial refractory period and rate-dependent slowing of atrial conduction. These attributes translate into more atrial versus ventricular refractory period prolongation in animals and in humans,69 and greater slowing of atrial conduction at faster pacing rates in dogs. Vernakalant has antiarrhythmic efficacy in both canine and goat models of AF at dose levels that slow conduction and delay repolarization in the atria. With respect to cardiac safety, vernakalant is antiarrhythmic in nonclinical models of cardiac ischemia/reperfusion where flecainide is proarrhythmic and in models where IKr blockers can elicit 70 the arrhythmia, torsades de pointes (TdP). Inhibition of the late INa at the same concentration as inhibition of IKr prevents excessive delays in ventricular repolarization (QT interval prolongation) and reduces the proarrhythmic risk associated with IKr inhibition. Also, there were no incidences Correvio International Sàrl 04 November 2019 Page 38 of 166
CRDAC Briefing Document – Vernakalant injection of drug-induced ventricular arrhythmias in dog and goat models of AF, conscious dogs with left ventricular dysfunction, or anesthetized dogs with chronic left bundle branch block.71 There were no pharmacodynamic interactions between vernakalant and verapamil, propranolol or warfarin in in vivo studies in rats. In summary, vernakalant has efficacy in AF with atrial targeted actions that do not fit readily into the Vaughan Williams antiarrhythmic drug classification. Vernakalant is a unique cardiac ion channel blocker with inhibitory effects on peak INa, late INa, IKr, IKur, IKACh and Ito. This combination of activities confers efficacy and a favorable safety profile in converting AF to SR. Vernakalant has a number of properties that differentiate it from other antiarrhythmic drugs:
• The potency of vernakalant’s INa blocking action is greater in the atria during AF compared to the ventricle due to its voltage- and frequency-dependence of INa block; • Class III antiarrhythmic drugs prolong the APD in both the atria and ventricle, whereas vernakalant has a greater effect on repolarization in the atria versus ventricle due to inhibition of IKur and IKACh as well as IKr; • Class III agents can elicit EADs, which underlie the polymorphic ventricular arrhythmia, Torsade de Points. Vernakalant suppresses EADs induced by Class III antiarrhythmic drugs in in vitro Purkinje fiber assays; • Class III agents do not block late INa and, indeed, the Class III agent ibutilide has been shown to increase late INa. Vernakalant blocks late INa within the therapeutic range and this explains its ability to suppress Class III antiarrhythmic drug-induced Torsade de Pointes in rabbit and dog models; • Vernakalant has more rapid on/off binding kinetics to sodium channels than the Class Ic agent flecainide; • Class Ic agents are proarrhythmia in nonclinical cardiac ischemia/reperfusion models. Vernakalant is antiarrhythmic in these models. • Vernakalant injection has a rapid onset of action and shorter duration of action than currently available drugs used for AF. This profile ensures prompt exposure to convert AF to SR while minimizing the time required to monitor for adverse effects following dosing.
4.2.1.2 Mechanism of Action for Vernakalant-Induced Hypotension Uncommon events of severe hypotension have been observed in the vernakalant injection clinical program and in the post-authorization setting. Dose-dependent, decreases in blood pressure and heart rate are observed at supra-therapeutic dose levels of vernakalant in anesthetized rats, guinea pigs, dogs, and pigs, but hypotension is not observed in conscious animals. Anesthetized animal models provided the opportunity to determine mechanisms for hypotension with vernakalant. In anesthetized dogs, hypotension was only observed at the highest dose level of vernakalant tested, 16 mg/kg (Cplasma: 23,122 ng/mL), where there were decreases in cardiac output and left ventricular contractility (LV +dP/dt) and increases in vascular resistance and heart rate. At a lower dose level, 8 mg/kg (Cplasma: 13,886 ng/mL), there was a significant decrease in left ventricular contractility and increases in left ventricular end diastolic pressure (LVEDP) and total vascular resistance (TPR) with no hypotension. Therefore, vernakalant decreases cardiac contractility and there are compensatory increases in LVEDP and TPR which maintained blood pressure with 8 mg/kg but not with 16 mg/kg vernakalant.
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At clinically relevant plasma levels of vernakalant in conscious dogs (Cplasma: ~ 4,300 ng/mL), mild increases in blood pressure, peripheral resistance and LVEDP, and a nonsignificant decrease in left ventricular contractility were observed with no changes in heart rate, cardiac output or left ventricular ejection volume. In two other hemodynamic studies in conscious dogs, vernakalant transiently decreased LV +dP/dt while blood pressure and cardiac output were stable. These results from these three studies demonstrate that, at therapeutic levels, the transient negative inotropic effect of vernakalant infusion is accompanied by a compensatory, reflex-mediated increase in vascular resistance that maintains cardiac output and blood pressure in conscious dogs. An identical hemodynamic profile was observed with flecainide in conscious dogs, anesthetized dogs with left bundle branch block71 and anesthetized pigs. At clinically-relevant plasma levels in conscious dogs with left ventricular dysfunction induced via ventricular pacing (~50% decrease in cardiac output and contractility prior to dosing) or atrial pacing (~ 25% decrease in cardiac contractility prior to dosing), the profile of hemodynamic responses to vernakalant was similar to that in normal dogs. There was a transient decrease in LV +dP/dt with tachycardia, slight decreases in mean cardiac output and no hypotension. Therefore, these dogs with left ventricular dysfunction were not more sensitive to the negative inotropic effect of vernakalant and there was no hypotension. One dog from the first study (ventricular pacing) with very severe cardiac dysfunction (~ 70% lower cardiac output prior to dosing) and higher vernakalant plasma levels (5,645 ng/ml) displayed abrupt hypotension and profound bradycardia which culminated in cardiogenic shock and death. In these two studies, hypotension was only observed in this one dog where there was very severe cardiac dysfunction prior to dosing. Vernakalant had no effect on peripheral or systemic vascular resistance in a rat hind-limb model at supra-therapeutic plasma levels (< 10 μg/mL) and there were no effects on peripheral blood flow in multiple vascular beds measured with microspheres in anesthetized dogs at a dose level (16 mg/kg) that decreased blood pressure. In isolated, precontracted human subcutaneous resistance artery rings, vernakalant (1–10 μM) produced no vasorelaxation. The mechanism for the decrease in cardiac contractility with vernakalant is sodium channel inhibition, i.e., it is a mechanism-based activity, as with flecainide.72 There are no other on-target or off-target mechanisms associated with vernakalant that can account for the negative inotropic activity. In isolated, perfused guinea pig hearts, vernakalant (1 – 30 µM) produced a concentration– related decrease in LV +dP/dt. Negative inotropic effects have been less evident in isolated guinea pig atria, human ventricular trabecular muscle strips, and in rabbit atria and papillary muscle; however, the sensitivity of these preparations is low since the effects of vernakalant on ERP were also not observed or were of limited magnitude in these studies. In conclusion, 1) the mechanism for hypotension with vernakalant in anesthetized animals is decreased cardiac output, 2) hypotension with vernakalant was only observed in animal models with anesthesia and/or severely depressed cardiac function; conditions where cardiac reserve and autonomic reflexes cannot fully compensate for reduced cardiac contractility, and 3) an identical profile of negative inotropic activity and hypotension was observed with flecainide.
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4.3 Nonclinical Safety and Toxicology
4.3.1 Safety Pharmacology
Vernakalant injection was evaluated in the standard battery of GLP safety pharmacology studies, as well as in a non-core battery supplemental study in mice. In these studies, there were no vernakalant-related adverse effects on indices of neurobehavioral, pulmonary and cardiovascular function at clinically-relevant dose levels. 4.3.2 Toxicology Studies Dose-limiting toxicity with vernakalant was consistent with noncardiac sodium channel inhibition and included salivation, tremors, ataxia and convulsions in the dog and rat as well as respiratory depression and mortality in the rat at a higher dose level. The therapeutic indices based upon plasma exposure levels from the GLP, 28-day repeat-dose toxicity studies were 2.6 and 2.5 in dog and rat, respectively.
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5 CLINICAL PHARMACOLOGY
Summary • Cmax is achieved at the end of the vernakalant infusion and concentrations rapidly decline contributing to the quick onset of action and rapid offset. • Vernakalant is extensively and rapidly metabolized (primarily by CYP2D6) and distributed in the body, with a typical clearance of 0.41 L/hr/kg, volume of distribution of ~2 L/kg and a half life in CYP2D6 extensive metabolizers of 3 h (increasing to ~5.5 h in poor metabolizers). • Vernakalant is not highly bound (<50%) to serum proteins. • Significant covariates affecting vernakalant pharmacokinetics were age, serum creatinine (CRT), subject status (patient versus healthy subject), and CYP2D6 expression, however effects of these covariates on Cmax and AUC are not clinically meaningful and dose adjustments are not necessary. • Based on pharmacodynamic modeling, the median predicted increases in QTcF interval after the 1st and 2nd doses were 20.0 and 20.8 msec, respectively. Doubling the observed exposure after the 2nd dose would theoretically increase the QTcF interval to 29.8 msec. • Based on pharmacodynamic modeling, vernakalant concentrations contribute to an increased risk of hypotension, but the 1.4-fold increased risk only becomes important when SBP baseline is lower than 105 mmHg. • Vernakalant prolongs atrial effective refractory period (AERP) with no significant effects on ventricular refractoriness, or repolarization.
5.1 Overview To date, 17 clinical trials have been completed in the development of vernakalant injection, all of which (except AVRO) have provided pharmacokinetic (PK) data. The overall PK evaluation for vernakalant injection incorporates data from 7 volunteer studies (with doses ranging from 0.1 to 5 mg/kg or 500 mg in one study); one study in patients undergoing electrophysiology evaluation (doses ranging from 2 to 4 mg/kg loading dose+ 0.5 to 1 mg/kg/hr over 35 minutes); and 8 studies in AF and/or AFL patients (doses ranging from 0.5 to 5 mg/kg total dose). All Phase 3 studies were performed with the proposed dosing regimen of 3 mg/kg infused over 10 minutes, followed by a 15-minute observation period and then if conversion to SR did not occur, a second dose of 2 mg/kg was infused over 10 minutes. Pharmacodynamics (PD) studies were also performed and are briefly summarized below.
5.2 Pharmacokinetics
In healthy volunteers, the maximum plasma concentration (Cmax) and area under the curve (AUC) have been demonstrated to be dose proportional between 0.1 mg/kg and 5 mg/kg. Peak plasma concentrations typically occur at the end of vernakalant infusions. In patients, average peak plasma concentrations of vernakalant were 3.9 mcg/mL following a single 10-minute infusion of 3 mg/kg Correvio International Sàrl 04 November 2019 Page 42 of 166
CRDAC Briefing Document – Vernakalant injection vernakalant, and 4.3 mcg/mL following a second dose of 2 mg/kg with a 15-minute interval between doses.
Vernakalant is extensively and rapidly metabolized and distributed. Cytochrome P450 (CYP) 2D6 was identified as the primary isozyme responsible for the metabolism of vernakalant and the formation of the major metabolite (4-O-demethylated vernakalant). As CYP2D6 is a polymorphic enzyme, individuals may be classified as extensive or poor metabolizers. In subjects identified as CYP2D6 poor metabolizers, metabolism is slower and less extensive, with direct glucuronidation of vernakalant being more important.
While population PK modelling suggests that CYP2D6 poor metabolizers have 50% lower vernakalant clearance compared to CYP2D6 extensive metabolizers and prolonged half-life (5.5 versus 3 hours), plasma profiles for vernakalant are similar between poor metabolizer and extensive metabolizer patients over the 2-hour period (from start of the first dose to ~90 minutes post last dose). The similarity in acute exposure (Cmax and AUC0-90min) between extensive metabolizers and poor metabolizers is likely a result of the fact that vernakalant is rapidly and extensively distributed into the tissue. Vernakalant concentrations decrease by > 40% in both CYP2D6 extensive metabolizers and CYP2D6 poor metabolizers within 5 minutes after the end of infusion.
Figure 1. Plasma vernakalant concentration in extensive and poor metabolizers versus time
The lines are simulations based on the “typical” pharmacokinetic parameters derived from the overall patient population, and the data points are the average + SEM (standard error of the mean) of the plasma concentrations at selected nominal time points.
Distribution Vernakalant is extensively and rapidly distributed in the body, with a volume of distribution of approximately 2 L/kg. Vernakalant is not highly bound (<50%) to serum proteins and in vitro evidence suggests a low potential for protein binding related drug interactions.
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Metabolism Vernakalant injection is extensively and rapidly metabolized. The main metabolic route for vernakalant is 4-O-demethylation, by CYP2D6, to the major metabolite, most of which is then rapidly converted to the inactive glucuronide conjugate. In subjects identified as CYP2D6 poor metabolizers, metabolism is slower and less extensive. Direct glucuronidation of vernakalant is more important in CYP2D6 poor metabolizers, in whom vernakalant glucuronide is the primary plasma metabolite. No metabolism associated with any other CYP isozyme has been observed. UDP-glucuronosyltransferase (UGT) 1A1 is not involved in the glucuronidation of vernakalant or its metabolites. While the major metabolite was found to react with UGT2B15, the low rate of glucuronide formation suggests that the metabolite is a poor substrate.
Studies in healthy volunteers and patients with AF or AFL confirm that the major plasma metabolite occurs primarily in the glucuronidated form. Increases in Cmax and AUC for the major metabolite have been shown to be dose proportional in healthy subjects and patients and achieved peak concentrations in plasma at 35-50 minutes and decreased to levels generally below the lower limit of quantitation (LLOQ) by 24 hours after infusion.
Vernakalant is a moderate inhibitor of CYP2D6.
Elimination / Excretion In patients, the typical total body clearance of vernakalant was estimated to be 0.41 L/hr/kg in CYP2D6 extensive metabolizers and ultra-rapid metabolizers, as compared to 0.20 L/hr/kg in poor metabolizers. Corresponding population estimates for mean elimination t½ of vernakalant were 3 hours and 5.5 hours, respectively. Higher concentrations of unchanged vernakalant are found in the systemic circulation and a higher proportion is excreted unchanged in the urine in poor metabolizers (24%), as compared to extensive metabolizers (7 – 11%).
5.3 Influence of Intrinsic and Extrinsic Factors on Vernakalant Injection Special Populations and Intrinsic Factors A population PK model was created to describe vernakalant exposure using data pooled from 5 studies in AF or AFL patients from 1 study in healthy volunteers. This model was later validated using data from 2 additional Phase 3 studies, ACT V and Asia Pacific. Typical clearance and volume of distribution were 0.35 L/hr/kg (or 28 L/hr for an 80 kg patient) and 1.55 L/kg (124 L for an 80 kg patient), regardless of CYP2D6 status. Significant covariates affecting vernakalant pharmacokinetics were age, serum creatinine (CRT), subject status (patient versus healthy subject), and CYP2D6 expression. CYP2D6 poor metabolizers were found to have 50% lower vernakalant clearance (0.20 L/hr/kg or 16.4 L/hr for 80 kg patient) compared to CYP2D6 extensive metabolizers (0.41 L/hr/kg or 32.7 L/hr for 80 kg patient). Poor metabolizers and extensive metabolizers have similar Cmax while poor metabolizers have higher AUC compared to extensive metabolizers. The lower clearance in poor metabolizers led to an increase in half-life from 3 to 5.5 hours compared to extensive metabolizers.
Sensitivity analysis indicates that the differences in Cmax and AUC0-90 with age and serum creatinine are small. For example, Cmax values would be approximately 0.5% higher in an 81 year old subject relative to a 60 year old subject. In the case where serum creatinine doubles, there is a predicted 3% increase in the Cmax value. Therefore, a dose adjustment on the basis of the age and CRT values is not deemed necessary. Correvio International Sàrl 04 November 2019 Page 44 of 166
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CYP2D6 expression, a significant covariate for vernakalant clearance had little effect on Cmax in a manner similar to age and CRT, however, CYP2D6 PMs would be expected to have approximately 15% higher AUC values than CYP2D6 EMs. Since vernakalant acts acutely, a dose adjustment on the basis of CYP2D6 expression is not deemed necessary.
Drug Interactions No formal clinical drug interaction studies with vernakalant injection were conducted. The effect of CYP2D6 inhibitor medications on the pharmacokinetics of vernakalant injection were evaluated in the population pharmacokinetic analysis. Concomitant use of CYP2D6 inhibitors and medications that are beta-blockers (or any other concomitant medications tested, including warfarin, metoprolol, furosemide and digoxin) were not significant covariates affecting the pharmacokinetics of vernakalant.
Vernakalant is a substrate but not an inhibitor of P-glycoprotein and is therefore not expected to perpetrate any drug interaction mediated by this transporter.
Vernakalant is not highly bound to human serum proteins and in vitro evidence suggests a lack of competition/interaction with warfarin, propranolol, acebutolol, diltiazem, verapamil, or quinidine for binding sites. Furthermore, clinical data demonstrate that vernakalant injection has been safely administered to subjects receiving concomitant antithrombotics.
5.4 Pharmacodynamics 5.4.1 Electrophysiological Study A Phase 2B, open-label, electrophysiology (EP) study in patients undergoing EP testing for ventricular or supraventricular arrhythmias or radiofrequency ablation for supraventricular arrhythmias (AV re-entry or atrial tachycardia) was conducted to assess the effect of vernakalant on the AERP, and other EP parameters. The doses evaluated were a 2.0 mg/kg loading dose infused over 10 minutes followed by a 0.5 mg/kg/hr maintenance dose administered over 35 minutes or 4.0 mg/kg infused over 10 minutes followed by 1.0 mg/kg/hr over 35 minutes. Vernakalant prolonged AERP in a dose-dependent manner. Vernakalant exhibited a small conduction slowing effect in the atrium and AV node at the higher dose level. Vernakalant, at the doses studied, had no significant effects on ventricular refractoriness, or repolarization. The dosing regimen successfully maintained median vernakalant plasma levels during EP testing at concentrations that approached those demonstrated to convert AF to sinus rhythm in patients.
5.4.2 Pharmacokinetic/Pharmacodynamic Modelling 5.4.2.1 QTcF PK/PD Model A PK/PD model was developed to evaluate the exposure-response relationship for QTcF interval using data collected in 5 studies in AF or AFL patients and refined using data from ACT V and the Asia Pacific studies. The influence of patient covariates on QTcF, including age, sex, race, body weight, CYP2D6 expression, study, history of congestive heart failure (CHF), New York Heart Association (NYHA) class, history of coronary artery disease (CAD), history of hypertension, arrhythmia duration (short vs. long), arrhythmia type (AF vs. AFL), conversion status (converted vs. non-converted), use of class I and III antiarrhythmics, beta-blockers, calcium channel blockers, and the four most commonly used concomitant medications (warfarin, metoprolol, furosemide, and Correvio International Sàrl 04 November 2019 Page 45 of 166
CRDAC Briefing Document – Vernakalant injection digoxin) were investigated. The influence of diurnal variation on QTcF was also investigated and incorporated into the model. The final model conservatively overpredicts the median effect for concentrations greater than 4000 ng/mL by up to approximately 8.7 msec. Using this model, the median predicted increases in QTcF interval after the 1st and 2nd doses were 20.0 and 20.8 msec, respectively. Doubling the observed∼ exposure after the 2nd dose would theoretically increase the QTcF interval to 29.8 msec. It is important to note that following administration of vernakalant for the current indication, patients are to be monitored closely for at least 2 hours after dosing and the proposed labelling states: “BRINAVESS should be administered by intravenous infusion in a monitored clinical setting appropriate for cardioversion which includes all the necessary items used for resuscitation. Only a qualified healthcare professional should administer BRINAVESS and the patient should be carefully observed for signs and symptoms of a sudden decrease in blood pressure or heart rate, during infusion and for at least 2 hours after cessation of BRINAVESS treatment, and until clinical status and ECG parameters are stable.” Thus, the expected changes in QTcF are appropriately monitored and any associated risks of QT prolongation can be managed in the clinical setting of cardioversion.
5.4.2.2 Systolic Blood Pressure PK/PD Model A PK/PD model was developed to evaluate the exposure-response relationship for systolic blood pressure (SBP) using data collected in Phase 3 trials. Hypotension was defined as SBP ≤ 90 mmHg and the cut-off times were 0-60 minutes and 0-120 minutes. The influence of patient covariates on SBP, including age, sex, race, patient status, creatinine clearance, arrhythmia type, arrhythmia duration, history of CHF, history of CAD, history of hypertension, conversion status, plasma concentration of vernakalant, baseline SBP, and four most commonly used background medications (warfarin, metoprolol, furosemide, and digoxin), clinically relevant CYP2D6 inhibitors, antihypertensives, and beta-blockers on the probability of a patient becoming hypotensive was investigated. Predicted vernakalant plasma concentration was found to be related to variation of SBP. A low baseline SBP (<105 mmHg) and a history of CHF are the most important factors that correlate to approximately a 3-fold and 1.8-fold increased risk of hypotension, respectively. Male gender and patients who take furosemide and digoxin also contributed to an increased risk of hypotension, but to a much lesser extent than SBP baseline. Hypotension is related to peak plasma levels (with an increased risk of approximately 1.4-fold at plasma levels of 4000 ng/mL). Vernakalant concentrations contribute to an increased risk of hypotension, but the 1.4-fold increased risk only becomes important when SBP baseline is lower than 105 mmHg. Vernakalant concentrations contribute to an increased risk of hypotension, but the 1.4-fold increased risk only becomes important when SBP baseline is lower than 105 mmHg.
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6 CLINICAL DEVELOPMENT PROGRAM
Summary • Five clinical studies of safety and efficacy were included in the original NDA (n=537 subjects treated with vernakalant injection), including 3 pivotal Phase 3 studies (ACT I, ACT III and ACT II). • In the resubmission, an additional four Phase 3 clinical studies conducted to further support the safety and efficacy in recent onset AF patients (n=536 additional subjects treated with vernakalant injection) are included (ACT IV, ACT V, AVRO, and the Asia-Pacific Study). • Across all clinical studies, a broad, representative patient population was enrolled including AF and AFL (initially) patients with common AF co- morbidities and typical background medications. • Potential adverse events of interest were proactively characterized and monitored in the clinical studies through collection and analysis of 24-hour Holter, 12-lead ECG, vital sign and adverse event data. • One new post-authorization safety study (SPECTRUM) which enrolled 1778 unique patients (2009 treatment episodes) has been conducted to further support the safety of vernakalant injection. • The estimated cumulative exposure to vernakalant injection since first marketing approval (10 September 2010) is approximately 58,298 treatment courses and includes approximately 2,000 patients in Investigator Initiated Studies.
6.1 Original NDA Submission As described in Section 2.2, the basis for the clinical efficacy and safety in the original NDA submission was five Phase 2 and 3 clinical studies. Of these, vernakalant injection was assessed in the following 3 pivotal randomized, double-blind, placebo-controlled, studies, all of which used the proposed dose regimen (3.0 mg/kg, + 2.0 mg/kg if required): • Atrial arrhythmia Conversion Trial (ACT) I: Phase 3 study in patients with AF; • ACT III: Phase 3 study in patients with AF or AFL; • ACT II: Phase 3 study in patients who developed AF or AFL subsequent to cardiac surgery. Efficacy and safety information from two randomized, double-blind, placebo-controlled, Phase 2/3 studies were also included in the original NDA submission: • CRAFT: Phase 2 study in patients with AF using a dosing regimen of 0.5 + 1.0 mg/kg if required or 2.0 mg/kg, + 3.0 mg/kg if required; • Scene 2: Phase 2/3 study in patients with AFL (3.0 mg/kg + 2.0 mg/kg if required). An overview of the study designs of these five studies is provided in Table 11. Correvio International Sàrl 04 November 2019 Page 47 of 166
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Table 11. Summary of Clinical Safety and Efficacy Study Designs in Original NDA Submission Clinical Study Population/Disease Study Design Dose Time Course (Post Dose) (Phase) Duration Regimen 1235-0703 AF short duration 0-10 min: 1st dose (ACT I) (> 3 hr to ≤ 7 days) and R, DB, 3.0 mg/kg, + 25-35 min: 2nd dose PIVOTAL long-duration Pbo-controlled 2.0 mg/kga,b 2 hrd: ECV/PCV permitted Phase 3 (> 7 days to ≤ 45 days) 24 hr: Discharge AF or AFLc 7 days: Follow-up visit 04-07-010 short duration 30 days: Phone follow-up (ACT III) R, DB, 3.0 mg/kg, + (> 3 hr to ≤ 7 days) and PIVOTAL Pbo-controlled 2.0 mg/kga,b long-duration Phase 3 (> 7 days to ≤ 45 days) 0-10 min: 1st dose 1235-0104 AF or AFL 25-35 min: 2nd dose (ACT II) (duration ≥3 hr to ≤ 72 R, DB, 3.0 mg/kg, + 2 hrd: ECV/PCV permitted PIVOTAL hr) occurring 1-7 days Pbo-controlled 2.0 mg/kga,b 24 hr: Discharge Phase 3 after cardiac surgeryc 14 days: Follow-up visit 30 days: Phone follow-up 0-10 min: 1st dose 1235-1001 0.5 mg/kg + 30-40 min: 2nd dose (CRAFT) R, DB, 1.0 mg/kgb or AF > 3 hr to ≤ 72 hours 2 hrd: ECV/PCV permitted SUPPORTIVE Pbo-controlled 2.0 mg/kg, + 24 hr: Discharge Phase 2a 3.0 mg/kgb 7 days: Follow-up visit 0-10 min: 1st dose 1235-0703B 25-35 min: 2nd dose (Scene 2) R, DB, 3.0 mg/kg, + 2 hrd: ECV/PCV permitted AFL > 3 hr to ≤ 45 days SUPPORTIVE Pbo-controlled 2.0 mg/kga,b 24 hr: Discharge Phase 2/3 7 days: Follow-up visit 30 days: Phone follow-up Abbreviations: AF=atrial fibrillation; AFL=atrial flutter; DB=double blind; ECV=electrical cardioversion; hr=hour; Pbo=placebo; PCV=pharmacological cardioversion; R=randomized; T=time aDosage regimen selected based on minimally effective dose of 2.0 mg/kg, + 3.0 mg/kg if required established in CRAFT study as well as PK modelling demonstrating increased time at therapeutic plasma concentrations without additional risk of potential adverse events bThe second dose of vernakalant injection or placebo was administered if the patient was in AF or AFL at the end of the observation period following the first dose c Studies included small numbers of patients with AFL. After these studies were initiated, results from a phase 2/3 study showed vernakalant injection to be ineffective for conversion of AFL at the doses studied. The indication for this application is conversion of AF to sinus rhythm. d The 0-to 2-hour time period captures the time of Cmax and the time where the drug’s effects (efficacy and safety) were generally observed. After 2 hours, other antiarrhythmic converting agents and electrical cardioversion were permitted, which potentially confound interpretation of events in the time period after 2 hours.
6.1.1 Efficacy Endpoints and Safety Monitoring In all 3 pivotal studies, efficacy was assessed as conversion from AF (or AFL) to SR by Holter monitoring or 12-lead electrocardiogram (ECG) and confirmed by a blinded clinical events committee (CEC). Holter monitoring was performed from baseline until 24 hours post dose. If Holter monitor data were not available, deemed unusable, or did not indicate SR had been achieved, ECG data were then reviewed. If SR was captured on 2 consecutive 12-lead ECG recordings or ECG monitor leads recorded at least 1 minute apart, these data were used to document that the study endpoint was achieved.
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The time course of treatment, primary efficacy endpoint, and time course of safety monitoring in the Phase 2/3 clinical studies included in the original NDA submission are provided in Table 12 followed by a list of secondary and key exploratory endpoints. Table 12. Overview of Primary and Secondary Endpoints and Safety Monitoring Clinical Study Time Course (Post Dose) Primary Efficacy Safety Monitoring (Phase) Endpoints 1235-0703 0-10 min: Dose 1 Proportion of patients PE: S, 24 hr, 7 days (ACT I) 25-35 min: Dose 2 (optional) with treatment- AEs: continuous to 30 days PIVOTAL 2 hrc: ECV/PCV permitted induced conversion VS and ECG: S, -1 hr, 0 min, every Phase 3 24 hr: Discharge to SR for ≥ 1 min 5 min from 0 min to 50 min, 90 min, 7 days: Follow-up visit within 90 min of first 2 hr, 4 hr, 8 hr, 24 hr, 7 days, upon 30 days: Phone follow-up exposure to study SAE, upon conversion 04-07-010 drugd Holter: continuous to 24 hr (ACT III) (short-duration AFa) Telemetry: 0 min to 2 hr PIVOTAL Chemistry: -1 hr, 24 hr, 7 days (S Phase 3 for ACT I) Hematology: -1 hr, 24 hr, 7 days Urinalysise: -1 hr, 24 hr, 7 days 0-10 min: Dose 1 Proportion of patients PE: S, 14 days 25-35 min: Dose 2 (optional) with treatment- AEs: continuous to14 days 2 hrc: ECV/PCV permitted induced conversion SAEs: continuous to 30 days 24 hr: Discharge to SR for ≥ 1 min VS: S, -1 hr, 0 min, 10 min, 25 min, 14 days: Follow-up visit within 90 min of first 35 min, 50 min, 90 min 2 hr, 4 hr, 6 1235-0104 30 days: Phone follow-up exposure to study hr, 24 hr, 14 days (ACT II) drugd ECG: S, -10 min, 0 min, 10 min, 25 PIVOTAL (short-duration min, 35 min, 50 min, 90 min 2 hr, 4 Phase 3 AF/AFLa) hr, 6 hr, 24 hr, 14 days Holter:0 min to 24 hr Telemetry: 0 min to 2 hr Chemistry: -1 hr, 24 hr Hematology, Urinalysis: -1 hr, 24 hr 1235-1001 0-10 min: Dose 1 Termination of AFb PE: S, 7 days (CRAFT) 30-40 min: Dose 2 (optional) during infusion or in AEs: 0 min to 24 hr, 7 days SUPPORTIVE 2 hrc: ECV/PCV permitted the 30 min post- VS: S, every 2 min from 0 min to 5 Phase 2a 24 hr: Discharge infusion period min, 15 min, 30 min, 60 min, every 7 days: Follow-up visit following either dose 2 hr from 2-8 hr, 7 days ECG: S, every 1 min from 0 min to 5 min, 15 min, 30 min, 60 min, every 2 hr from 2 hr to 8 hr, upon SAE, upon termination, 7 days Holter: S, 0 min, 15 min, 30 min, 60 min, every 2 hr from 2 hr to 8 hr, termination of AF, 24 hr Chemistry and Hematology: S, 60 min, 7 days Urinalysis: S, 60 min, 2 hr, 4 hr, 8 hr, 24 hr, 7 days 1235-0703B 0-10 min: Dose 1 Proportion of AFL PE: S, 24 hr, 7 days (Scene 2) 25-35 min: Dose 2 (optional) patients with AE: continuous to 30 days SUPPORTIVE 2 hrc: ECV/PCV permitted treatment-induced VS and ECG: S, -1 hr, 0 min, every Phase 2/3 24 hr: Discharge conversion to SR for 5 min from 0 min to 50 min, 90 min, 7 days: Follow-up visit ≥ 1 min within 90 2 hr, 4 hr, 8 hr, 24 hr, 7 days, upon 30 days: Phone follow-up min of first exposure SAE, upon conversion to study drugd Holter: continuous to 24 hr Correvio International Sàrl 04 November 2019 Page 49 of 166
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Telemetry: -1 hr to 2 hr Chemistry: S, -1 hr, 24 hr, 7 days Hematology and Urinalysis: -1 hr, 24 hr, 7 days Abbreviations: AE=adverse event; AF= atrial fibrillation; AFL=atrial flutter; hr=hours; ECG=electrocardiogram; ECV=electrical cardioversion; PCV=pharmacological cardioversion; PE=physical examination; S=screening; SR=sinus rhythm; VS=vital signs; SAE=serious adverse event a AF duration >3 hours and ≤7days b Defined as the absence of AF or AFL for a duration of one minute. c The 0-to 2-hour time period captures the time of Cmax and the time where the drug’s effects (efficacy and safety) were generally observed. After 2 hours, other antiarrhythmic converting agents and electrical cardioversion were permitted, which potentially confound interpretation of events in the time period after 2 hours. d Determined by Holter monitoring or 12-lead electrocardiogram (ECG) and confirmed by a blinded clinical events committee (CEC). e Urinalysis done for ACT I only.
Key secondary and exploratory efficacy endpoints collected in one or more of the pivotal studies included the following: • Time to conversion of AF to sinus rhythm for ≥1 min within 24 hours of first study drug exposure (overall population and short-duration AF) • The proportion of subjects who had a treatment-induced termination of AF (or AFL) for ≥1 min within 90 min after first exposure to study drug (overall population, short-duration AF, long-duration AF/AFL). • Symptoms associated with AF at 90 minutes after first infusion dose (overall population, short-duration AF, and long-duration AF). • Proportion of patients reporting AF symptoms at each timepoint (screening, baseline, 90 min, 24 hours, 7 days, and 30 days). • Maintenance of SR at 24 hours and 7 days, and/or hospital discharge (short-duration AF). A breakdown of the efficacy endpoints by study is provided in Appendix 1. 6.2 NDA Resubmission 6.2.1 Overview of New Clinical Studies As described in Section 2.2, an additional four clinical studies of efficacy and safety have been conducted and are discussed along with the five studies included in the NDA resubmission. These four Phase 3 studies are: • ACT V: Phase 3b study in patients with AF; • AVRO: Phase 3 active-controlled (amiodarone) study in patients with AF; • Asia-Pacific: Phase 3 study in Asian patients with AF; • ACT IV: Phase 3 open-label study in patients with AF. An overview of the study designs of these four additional studies is provided in Table 13. Additional clinical studies of vernakalant injection in healthy volunteers, subjects with renal impairment, subjects with hepatic impairment as well as studies of oral vernakalant have been conducted. They are not discussed further in this document, as the focus of this document will be clinical studies in proposed indication.
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Table 13. Summary of New Clinical Safety and Efficacy Study Designs in NDA Resubmission Population/ Clinical Study Study Dose Primary Efficacy Disease Time Course (Post Dose) Safety Monitoring (Phase) Design Regimen Endpoints Duration 6517-CL-0020 0-10 min: Dose 1 Conversion to SR PE: S, 24 hr ACT V 25-35 min: Dose 2 (optional) or a paced rhythm AEs: 0 min to 7 days (Phase 3b) 2 hr: ECV permitted for ≥ 1 min within VS: S, -1 hr, every 5 min from 0 min to 60 4 hr: Discharge 90 min of first min, every 30 min from 60 min to 4 hr, 24 R, DB, 3.0 mg/kg, AF >3 hr to ≤7 7 days: Follow-up visit exposure to study hr, 7 days Pbo- + 2.0 days 30 days: Phone follow-up drug ECG: S, -1 hr, 0 min, 10 min, 25 min, 35 controlled mg/kga,b min, every 30 min from 60 min to 4 hr, 24 hr, 7 days Holter: -30 min to 24 hr Telemetryc: 0 min to 2 hr VERI-305-AMIO 0-10 min: Dose 1 Proportion of PE:S, dischargee AVRO 25-35 min: Dose 2 (optional) subjects with AEs:0 min to 7 days (Phase 3) 2 hr ECV permitted conversion of AF VS: S, -1 hr, 5 min, 20 min, 30 min, 40 R, DB, 3.0 mg/kg, AF ≥3 hr to 6 hr: Discharge to SR for ≥1 min min, 90 min, 4 hr, dischargee, 7 days Pbo- + 2.0 ≤48 hours 7 days: Follow-up visit within 90 min of ECG: S, -1 hr, 20 min, 90 min, 4 hr, controlled mg/kga,b 30 days: Phone follow-up first exposure to dischargee study drug Holter: -1 hr to 4 hr Telemetry: -1 hr to dischargee 6621-010-04 0-10 min: Dose 1 Proportion of PE: -1 hr, 24 hr, 7 days Asia-Pacificd 25-35 min: Dose 2 (optional) patients with AEs: daily from 0 min to 7 days. 30 days (Phase 3) 24 hr: Discharge treatment-induced VS: S, -10 min, 0 min, 10 min, 20 min, 25 7 days: Follow-up visit conversion of AF min, 35 min, 45 min, 65 min, 90 min, 2 hr, Asian patients R, DB, 3.0 mg/kg, 30 days: Phone follow-up to SR for ≥1 min 4 hr, 24 hr, 7 days with AF >3 Pbo- + 2.0 within 90 min after ECG, S, -10 min, 10 min, 25 min, 35 min, hrs to ≤7 days controlled mg/kga,b first exposure to 45 min, 65 min, 90 min, 2 hr, 4 hr, 24 hr, 7 study drug days Holter: continuous to 24 hr Telemetryc: -1hr to 2 hr
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Population/ Clinical Study Study Dose Primary Efficacy Disease Time Course (Post Dose) Safety Monitoring (Phase) Design Regimen Endpoints Duration 05-7-012 0-10 min: Dose 1 Rate of conversion PE: S, 8 hr or 24h, 7 days ACT IV 25-35 min: Dose 2 (optional) of atrial fibrillation AEs: continuous to 30 days (Phase 3) 8-24 hr: Discharge to SR for ≥1 min VS: S, -10 min, 0 min, 10±2 min, 25±2 7 days: Follow-up visit within 90 min of min, 35±2 min, 45±2 min, 60±10 min, OL, 3.0 mg/kg, 30 days: Phone follow-up first exposure to 90±10 min, 8 hr±10 min, 24 hr±10 min. AF > 3 hr to ≤ single + 2.0 study drug ECG: S, -10 min, 0 min, 10±2 min, 25±2 45 days arm mg/kga,b min, 35±2 min, 45±2 min, 60±10 min, 90±10 min, 8 hr±10 min, 24 hr±10 min., 7 days Holter: continuous to 24 hr Telemetryc: 0 min to 2-8 hr Abbreviations: AF=atrial fibrillation; AFL=atrial flutter; DB=double blind; hr=hour; OL=open label; Pbo=placebo; R=randomized; ECV=electrical cardioversion; PCV=pharmacological cardioversion; SR=sinus rhythm; PE=physical examination; S=screening; AE=adverse event; VS=vital signs; ECG=electrocardiogram; SAE=serious adverse event aDosage regimen selected based on minimally effective dose of 2.0 mg/kg, + 3.0 mg/kg if required established in CRAFT study as well as PK modelling demonstrating increased time at therapeutic plasma concentrations without additional risk of potential adverse events bThe second dose of vernakalant injection or placebo was administered if the patient was in AF or AFL at the end of the observation period following the first dose c The 0-to 2-hour time period captures the time of Cmax and the time where the drug’s effects (efficacy and safety) were generally observed. After 2 hours, other antiarrhythmic converting agents and electrical cardioversion were permitted, which potentially confound interpretation of events in the time period after 2 hours. d Study terminated early by sponsors. ACT V was terminated after clinical hold (Section 2.2). The Asia-Pacific study was terminated due to sponsor reprioritization. e Discharge occurred at the discretion of the investigator, no sooner than 6 hours after initiation of dosing.
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Secondary efficacy endpoints in one or more of the Phase 3 studies in the NDA resubmission included the following: • Time to conversion of SR within 90 min after start of infusion • Time to conversion to SR within 24 hours of first infusion • Proportion of subjects with no AF symptoms at 90 min • Change in EQ-5D quality of life assessment Visual Analogue Scale at 2 hours (AVRO only) • Proportion of converted patients maintained in SR at 24 hours and at 7 days 6.2.2 Study Oversight The clinical studies were overseen by both a CEC and DSMB as outlined below. • Clinical Events Committee (CEC): The CEC which was composed of four external cardiologists with a special interest in clinical studies and arrhythmias was blinded to treatment allocation and used to confirm efficacy endpoints of conversion of AF or AFL to sinus rhythm and termination of AF. The CEC was also responsible for determination of the baseline rhythm. If there was a discrepancy between the investigator reported rhythm and the CEC interpretation, the CEC interpretation took precedence. A CEC was in place for the ACT I, II, III, Scene 2, ACT V, AVRO and Asia Pacific studies. The same CEC committee was used for the three pivotal clinical studies (ACT I, ACT II and ACT III) and for Scene 2. A CEC was not used in the open-label ACT IV study, nor in the Phase 2 study, CRAFT. • Data Safety Monitoring Board (DSMB): A DSMB composed of at least four external members who were experienced in DSMB-related activities in clinical trials was used in the ACT I, ACT II, ACT III and ACT V studies. The DSMB was responsible for monitoring the overall conduct of the studies, receiving and reviewing SAE reports, reviewing periodic unblinded safety data, establishing study “stopping” rules for safety reasons, and making recommendations to the co-sponsors and the steering committee. 6.2.3 Analysis Populations, Demographics, and Exposure A total of 1073 AF or AFL patients have received vernakalant injection across 9 Phase 2 and 3 safety and efficacy clinical studies. The pivotal Phase 3 registration studies are the ACT I (Study 1235-0703), ACT III (Study 04-7- 010) and ACT II (Study 1235-0104) studies. All clinical studies were conducted in compliance with local regulations and guidance, the ICH Guidelines, and GCP regulations. Study populations in the clinical trials were similar, with the exception of patients in the ACT II study who were enrolled 1 to 7 days following cardiac surgery (coronary artery bypass graft and/or valvular surgery) upon occurrence of AF or AFL. Patients with pacemakers were included in the pivotal studies, as were patients with a history of a variety of cardiac conditions. A list of patient characteristics excluded from the Phase 3 pivotal studies is provided in Appendix 2. The other Phase 2/3 clinical studies had inclusion/exclusion criteria that were generally similar to these described above. ACT V excluded all patients with a history, or evidence, of heart failure (or presented with symptoms of heart failure) or documentation of left ventricular dysfunction (ejection fraction <40%).
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6.2.3.1 Efficacy Analyses For the purposes of this briefing document, all efficacy results are presented separately by study, with the exception of secondary efficacy endpoints and subgroup analyses in ACT I and ACT III, which have been pooled. The primary efficacy endpoint will be presented separately for these studies. The primary and secondary endpoints are also presented for the Target Patient Population, which includes patients with no contraindications per the current approved European Summary of Product Characteristics (SmPC) and proposed US package insert (PI) in placebo-controlled Phase 3 studies in patients with AF ≤ 7 days duration (for proposed Contraindications, see Section 2.1).
6.2.3.2 Safety Analyses Safety data have been pooled across studies with similar patient populations and design elements (dose, duration of exposure, and safety data collection methods). Pooling of safety data in this manner improves precision of estimates and sensitivity to differences. Additionally, individual patient data are presented and discussed for SAEs and AEs leading to discontinuation. The “All Patients Population” includes all Phase 2 and 3 studies and therefore includes both AF and AFL patients. This population represents all the studies for which efficacy results are also discussed in this document. Special analyses were conducted to further examine the incidence of ventricular arrhythmias, bradycardia, and hypotension (i.e., events of interest) across multiple sources of data. The data sources include the AE database (with multiple preferred terms within each of the events of interest), cardiologist over-read of ECGs, Holter device cardiologist assessments, CEC over-read of ECGs, and vital sign data, as appropriate for the event of interest. These analyses were performed for the All Patients Population excluding patients from the CRAFT study and for the Target Patient Population. CRAFT patients were excluded from these analyses because ECG and Holter data were not collected at the same time points for this study and therefore these patients could not be pooled for these analyses. Further, dosing was different for CRAFT patients. In pre-NDA discussions (October 2018), the FDA requested a separate analysis of AEs of special interest (“FDA AEs of Special Interest”) and Post-Dose Resuscitation Measures. The FDA provided groupings of preferred terms (Appendix 4). The datasets described in Table 14 were used for the safety analyses presented in this briefing package.
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Table 14. Primary Populations Used for Integrated Safety Analyses for Vernakalant Injection Population Clinical Studies Safety Analyses Number of Pts Pbo Vkt All Patients CRAFT, Scene 2, ACT • Demographic and baseline characteristics 459 1073 Populationa I, ACT II, ACT III, • AEs and SAEs ACT IV, ACT V, • FDA AEs of Special Interest, AVRO, and AP • Post-Dose Resuscitation Measures, • Events of interest and subgroup analyses All Patients Scene 2, ACT I, ACT • FDA AEs of Special Interest 439 1037 Population II, ACT III, ACT IV, • SAEs b Excluding CRAFT ACT V, AVRO, and • Events of interest and subgroup analyses AP Target Patient ACT I, ACT II, ACT • Demographic and baseline characteristics 259 668 Populationb III, ACT IV, ACT V, • AEs and SAEs AVRO and AP • Events of interest (AF ≤ 7 days) a This population includes both AF and AFL patients, patients exposed to non-standard dosing in the CRAFT study, and patients in the active controlled study AVRO. Data from the amiodarone arm of the AVRO study are not included in the integrated safety analysis. b AF patients only
A summary of the demographics, baseline characteristics and background medication use for the safety pools is provided in Table 15. Table 15. Summary of Demographics and Baseline Characteristics (All Patients Population and Target Patient Population) Demographics and Baseline All Patients Target Patient Population Characteristics Placebo Vernakalant Placebo Vernakalant (N=459) (N=1073) (N=259) (N=668) Baseline diagnosis, n (%) Atrial fibrillation 430 (93.7%) 1011 (94.2%) 259 (100.0%) 666 (99.7%) Atrial flutter 28 (6.1%) 59 (5.5%) 0 0 Unknown/not done 1 (0.2%) 3 (0.3%) 0 2 (0.3%) Duration of the current episode, n (%) 3 hours to 7 days 373 (81.3%) 876 (81.6%) 259 (100.0%) 668 (100.0%) 8 days to 45 days 86 (18.7%) 196 (18.3%) 0 0 Unknown/not done 0 1 (0.1%) 0 0 Demographics Gender (M/F), n 303/156 714/359 172/87 451/217 Age (yrs), Mean (SD) 62.1 (12.37) 63.1 (12.89) 60.9 (13.01) 61.7 (13.16) Race, n (%) White 391 (85.2%) 977 (91.1%) 207 (79.9%) 602 (90.1%) Black or African-American 2 (0.4%) 15 (1.4%) 0 8 (1.2%) Asian 62 (13.5%) 64 (6.0%) 49 (18.9%) 47 (7.0%) Other/unknown 4 (0.9%) 17 (1.6%) 3 (1.2%) 11 (1.6%) Medical history, n (%) Congestive heart failure 73 (15.9%) 167 (15.6%) 21 (8.1%) 57 (8.5%) Hypertension 229 (49.9%) 599 (55.8%) 126 (48.6%) 373 (55.8%) Myocardial infarction 42 (9.2%) 111 (10.3%) 18 (6.9%) 60 (9.0%) Ischemic heart disease 117 (25.5%) 231 (21.5%) 61 (23.6%) 129 (19.3%) Valvular heart disease 67 (14.6%) 131 (12.2%) 22 (8.5%) 63 (9.4%) Structural heart diseasea 191 (41.6%) 408 (38.0%) 84 (32.4%) 211 (31.6%) Coronary artery disease 119 (25.9%) 237 (22.1%) 62 (23.9%) 134 (20.1%)
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Demographics and Baseline All Patients Target Patient Population Characteristics Placebo Vernakalant Placebo Vernakalant (N=459) (N=1073) (N=259) (N=668) Background useb of rate control medication, n (%) Any rate control medication 299 (65.1%) 685 (63.8%) 144 (55.6%) 385 (57.6%) Beta-blockers 241 (52.5%) 539 (50.2%) 113 (43.6%) 300 (44.9%) Calcium channel blockers 79 (17.2%) 185 (17.2%) 41 (15.8%) 109 (16.3%) Digoxin 71 (15.5%) 138 (12.9%) 26 (10.0%) 38 (5.7%) Background useb of rhythm control medication, n (%) Any rhythm control medication 72 (15.7%) 169 (15.8%) 33 (12.7%) 94 (14.1%) Class I antiarrhythmics 16 (3.5%) 59 (5.5%) 10 (3.9%) 40 (6.0%) Class III antiarrhythmics 59 (12.9%) 111 (10.3%) 25 (9.7%) 51 (7.6%) Concomitant or background usecof 185 (40.3%) 444 (41.4%) 80 (30.9%) 239 (35.8%) QT prolonging medications, n (%) Concomitant or background usec of 101 (22.0%) 242 (22.6%) 43 (16.6%) 117 (17.5%) CYP2D6 inhibitors, n (%) Concomitant or background usec of 248 (54.0%) 550 (51.3%) 117 (45.2%) 311(46.6%) CYP2D6 substrates, n (%) Abbreviations: CYP, cytochrome P450 a Includes patients with history of ischemic heart disease and/or history of valvular heart disease and/or history of heart failure and/or history of myocardial infarction. b Background use is defined as medication used during the 7-day period prior to study drug infusion. c Concomitant or background use is defined as medication used during the 7-day period prior to study drug infusion up to 24 hours post infusion
6.3 Post-Authorization Safety Study (SPECTRUM) A post-authorization safety study of vernakalant injection (SPECTRUM) was conducted in Austria, Denmark, Finland, Germany, Sweden, and Spain. This study was required as a follow up measure after the approval of vernakalant injection (BRINAVESS) by the European Commission for rapid cardioversion of recent onset AF (≤3 days duration for post-cardiac surgery patients and ≤7 days duration for nonsurgical patients with AF) and was conducted from 2011 until 2018. The study was designed with input from the EMA to quantify and characterize medically significant health outcomes of interest (HOI) with the use of vernakalant injection in clinical practice. SPECTRUM was conducted with the primary objective of estimating the incidence of cases of pre-specified health outcomes of interest (HOIs) consisting of significant cases of hypotension, ventricular arrhythmia, AFL, and bradycardia in a post marketing setting. The study initially included only prospectively identified patients. Prospective patients were to be selected for enrollment in SPECTRUM after the decision was made by the investigator to administer vernakalant. To support timely completion of the study, after receiving the approval of the EMA, the study was amended (2016) to allow enrollment of retrospective subjects as long as the retrospectively identified patients met the same eligibility criteria, informed consent was obtained and the demographic, clinical history, treatment and follow up data were available. A total of 1778 unique patients with 2009 treatment episodes were enrolled in this study of which 1580 treatment episodes were prospective.
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Table 16. Enumeration of Subjects in SPECTRUM Study Number Phase Population/ Disease Vernakalant Design Number of Subjects or Patients (Acronym)a Duration Dose Receiving Treatment Submission Prosp Retro Total 6621-049-00 4 AF ≤3 days post 3.0 mg/kg Post-authorization 1580 429 2009b SPECTRUM cardiac surgery and + 2.0 mg/kg safety study SUPPORTIVE ≤7 days non-surgery if requiredf Resubmission Abbreviations: AF, atrial fibrillation; Prosp, prospective; Retro, retrospective; Vkt, vernakalant a In general, study acronyms are used when referencing individual studies throughout the Summary of Clinical Efficacy. b 2009 treatment episodes in a total of 1778 unique patients.
6.3.1 Endpoint Selection and Assessments As specified by the EMA during the course of the protocol development, the primary objectives of this study were as follows: • Estimate the incidence of medically significant HOIs reported during treatment and during the first 24 hours after last infusion of vernakalant injection or until discharge/end of medical encounter. Pre-specified medically significant HOIs included the following: • Significant hypotension (symptomatic hypotension with systolic blood pressure <90 mmHg and requiring treatment with vasopressors). • Significant ventricular arrhythmia defined as: sustained ventricular tachycardia with a ventricular heart rate >120 bpm and with a duration >30 seconds or ventricular tachycardia that required intervention with either electrical shock or antiarrhythmic drugs, or TdP with a duration of >10 seconds or ventricular fibrillation of any duration. • Significant AFL defined as: AFL with 1:1 atrioventricular conduction of >1 second duration and having a ventricular rate >200 bpm. • Significant bradycardia defined as: bradycardia requiring electrical pacing (temporary or permanent) or any other SAE reports involving bradycardia. Note: this list was supplemented by a list of predefined MedDRA preferred terms to be considered as significant bradycardia HOIs as part of study-defined criteria. • Investigate potential risk of overdose and medication error. • Evaluate the effectiveness of risk minimization activities by: • Describing the appropriateness of selection and treatment of patients consistent with the label and risk minimization activities. • Monitoring for the occurrence and incidence of both SAEs and HOIs.
Amongst others, one of the secondary endpoints was to describe the rate of successful cardioversion to sinus rhythm for at least one minute within 90 minutes of start of first vernakalant administration and time until discharge/end of medical encounter. Patients who received vernakalant injection and who provided informed consent were enrolled and followed up for 24 hours after the last vernakalant infusion or until end of medical encounter, whichever occurred first, in order to obtain information on medically significant HOIs and SAEs. Data on concomitant medications and therapies for restoration and/or maintenance of SR for patients with hospital stays exceeding 24 hours following last infusion of vernakalant were recorded up to 7 days following the last vernakalant infusion. Correvio International Sàrl 04 November 2019 Page 57 of 166
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Data collection was performed prospectively during and shortly following vernakalant administration, with abstraction of required data elements from patient medical charts as well as supplemental, prospective data collection of study-specific data elements. Retrospective data collection was performed through chart review. 6.3.2 Patient Selection Patients presenting with recent-onset AF and for whom their physician had selected treatment with vernakalant according to their usual practice, were screened by the site personnel prior to receiving treatment. This would happen in the emergency department, upon hospital admission to another ward, or, following cardiac surgery. If the patient met the inclusion criteria; chosen as a candidate for use of vernakalant and provided informed consent and had no exclusion criteria (i.e. no enrolment in an investigational drug or device trial within the previous 30 days) then the patient could be enrolled. Prospective patients were selected for enrollment by the investigator physician. Investigators were instructed to include consecutive eligible patients, to maintain a screening log and to document reasons for non-participation. The primary reason (94%) for non- enrollment in the study was due to refusal/lack of informed consent. Retrospective patients were identified by chart review using prescription records and, if informed consent was provided, then the patient was enrolled if the study’s same eligibility criteria were met and if the demographic, clinical history, treatment and follow up data were available. To reflect the current clinical practice, retrospective data were only collected from patients who received vernakalant injection after the additional risk minimization measures were implemented in April 2013. These measures included addition of the pre-infusion checklist to the vernakalant package and delivery directly to the point of care (see Section 9.2.1.2). Collection of data regarding use of risk minimization materials (the Pre-Infusion Checklist and HCP Educational Card) began in August 2014 for prospective patients. A patient could be enrolled in the study more than once if she/he presented more than once for treatment of different AF episodes. Each treatment episode was assigned a different patient identification number and was treated independently. In total, 2009 treatment episodes were evaluated for 1778 unique patients. All medical treatment delivered was solely at the discretion of the physician in accordance with their usual practice and within the guidelines set out in the protocol. 6.3.2.1 Baseline Characteristics Patient baseline characteristics are presented in Table 17. Characteristics are presented by treatment episode (n=2009) not unique patients (n=1778).
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Table 17. Demographics and Baseline Characteristics of Subjects in SPECTRUM Characteristic All Treatments (N=2009) Prospective (N=1580) Retrospective (N=429) Current Episode of AF Lone AF 851 (42.4%) 749 (47.4%) 102 (23.8%) First Diagnosed 477 (23.7%) 393 (24.9%) 84 (19.6%) Paroxysmal 1191(59.3%) 906 (57.3%) 285 (66.4%) Persistent 259 (12.9%) 201 (12.7%) 58 (13.5%) Post-operative 69 (3.4%) 69 (4.4%) 0 (0%) Duration of AF, hrs (Median [Q1, 11.1 (5.44, 27.03) 11.9 (5.8, 29.7) 8.2 (4.8, 18.3) Q3]) Demographics Gender (M/F) 1222/787 998/582 224/205 Age (yrs), Mean (SD) 62.3 (13.04) 61.9 (13.48) 63.6 (11.21) Racea, n, (%) 2007 1579 428 White 1931 (96.2%) 1560 (98.8%) 371 (86.7%) Black 5 (0.2%) 5 (0.3%) 0 Hispanic 6 (0.3%) 6 (0.4%) 0 Asian 2 (0.1%) 2 (0.1%) 0 Other 65 (3.2%) 8 (0.5%) 57 (13.3%) Medical History, n (%) Heart failureb 63 (3.1%) 59 (3.7%) 4 (0.9%) Hypertension 1103 (54.9%) 884 (55.9%) 219 (51.0%) Angina 118 (5.9%) 82 (5.2%) 36 (8.4%) Clinically meaningful valvular 261 (13.0%) 240 (15.2%) 21 (4.9%) stenosis Valve replacement 50 (2.5%) 47 (3.0%) 3 (0.7%) Cardiomyopathy 33 (1.6%) 31 (2.0%) 2 (0.5%) Constrictive pericarditis 0 0 0 Left ventricular hypertrophy 203 (10.1%) 174 (11.0%) 29 (6.8%) Pacemaker implanted 32 (1.6%) 21 (1.3%) 11 (2.6%) Background use of rate control medicationsc, n (%) Beta blocking agents, selective 994 (49.5%) 746 (47.2%) 248 (57.8%) Beta blocking agents, non- 61 (3.0%) 54 (3.4%) 7 (1.6%) selective Calcium channel blockersd 22 (1.1%) 20 (1.3%) 2 (0.5%) Digitalis glycosidese 22 (1.1%) 18 (1.1%) 4 (0.9%) Background use of rhythm control agents, n (%) Class IA 1 (0.1%) 1 (0.1%) 0 Class IC 84 (4.2%) 70 (4.4%) 14 (3.3%) Class III 98 (4.9%) 89 (5.6%) 9 (2.1%) Abbreviations: NYHA, New York Heart Association; SD, standard deviation Note: Total n for each variable includes non-missing observations. Percentages, where applicable, were calculated with non- missing observations in denominator unless otherwise noted. a Patients may select more than one race category b NYHA heart failure functional Class at presentation was physician’s assessment of patient’s status at the time of the index hospitalization or medical encounter prior to administration of vernakalant injection. Class 0 was added to allow identification of patients with “no heart disease with unexplained manifestation.” History of heart failure as recorded in the baseline medical history CRF. These values may differ. c Within 24 hours prior to hospitalization or medical encounter admission. d Selective calcium channel blockers with direct cardiac effects, includes diltiazem and verapamil e Includes digitalis/digoxin for AF and non-AF indications
In comparing the SPECTRUM baseline characteristics (Table 17) to those of the All Patients Population and the Target Patient Population (Table 15), it is apparent that although the Correvio International Sàrl 04 November 2019 Page 59 of 166
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SAE assessment. Additional analyses were also performed for the FDA AEs of Special Interest and Post-Dose Resuscitation Measures. 6.3.3 Study Oversight and Data Reporting An external Safety Review Committee (SRC) composed of 2 external cardiologists with clinical experience in treatment of AF and an epidemiologist with specialization in cardiovascular disease provided expert medical input and advice, reviewed the interim and final reports of safety data, and monitored the overall study progress during scheduled or ad hoc meetings. For prospectively enrolled patients, reporting of all SAEs and HOIs that occurred during the study follow-up period (24 hours after the last vernakalant IV infusion or until end of medical encounter, whichever came first) was mandatory and study investigators were required to report the event within 24 hours of identification. All patients with SAEs were followed up for outcome of the event. Follow-up information on the SAE was provided by the investigator within 24 hours of identification. Reporting of SAEs and HOIs of retrospective patients occurred within 24 hours of awareness by the physician based on the chart review. All information on the medical history and follow up study period was based on the medical chart. All SAEs and HOIs were confirmed for source verification through review of patient records at the treating medical center and/or direct follow-up with the treating physician. All clinical information including the event narrative and relevant source documentation regarding each SAE and HOI event was reviewed by the SRC and the SRC collectively adjudicated the events. The adjudication included characterization of the event and assessment of whether the event fulfilled the criteria for an HOI. 6.4 Other Post-marketing Data The estimated cumulative exposure to vernakalant injection in the marketed setting from 01-Sep- 2010 until 31-Aug-2019 is 58,298 treatment courses. This includes the patients enrolled in the SPECTRUM study. Post-marketing exposure was estimated using marketed product distribution data of the 500 mg vial, with the assumption that one vial corresponded to one course of treatment.
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7 EFFICACY RESULTS
Summary • In the short duration AF cohorts in the pivotal Phase 3 studies, a significantly (P<0.0001) greater percentage of patients receiving vernakalant injection compared to placebo achieved the primary endpoint, conversion of AF to SR for a minimum of 1 minute within 90 minutes of first exposure to study drug:
o ACT I (non-surgery patients): 51.0% vernakalant injection, 4.0% placebo;
o ACT III (non-surgery patients): 51.2% vernakalant injection, 3.6% placebo.
o ACT II (post-cardiac surgery patients): 47.0% vernakalant injection, 14.0% placebo. • Similar rate of conversion to sinus rhythm (45.7% to 52.9%) were observed in the other supportive studies (CRAFT, ACT IV, ACT V, Asia Pacific, and AVRO). • Conversion was rapid; median time to conversion in the short duration AF cohorts was 8 to 12.4 minutes. • Vernakalant provided rapid relief of symptoms in the short duration AF cohorts compared to placebo (P<0.0001) at 90 minutes after first exposure to study drug. • Of the non-surgery patients with short duration AF who converted to SR within 90 minutes following vernakalant injection, sinus rhythm was maintained by ≥97.0% at 24 hours and ≥92.0% at 7 days. Of the post-cardiac surgery patients with AF who converted to SR within 90 minutes following vernakalant injection, SR was maintained by 59.5% at 24 hours and 56.9% at 7 days. • High rates of conversion following treatment of vernakalant (70%) were also reported in the post-authorization safety study, SPECTRUM. • In the post-marketing setting, overall conversion rates to sinus rhythm of 52.8% to 86% (median=77.6%) have been reported in investigator published literature after vernakalant treatment in non-surgery patients.
7.1 Original NDA Submission Efficacy claims for vernakalant injection are primarily based on the results of 3 pivotal placebo-controlled studies that were designed to allow reasonable assessment of benefit, specifically the rapid conversion of symptomatic recent-onset AF to sinus rhythm: ACT I, ACT III, and ACT II. Descriptions of study design are included in Section 6.1; these studies were submitted in the original NDA submission. Correvio International Sàrl 04 November 2019 Page 62 of 166
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7.1.1 Disposition ACT I was conducted from August 2003 through November 2004. This study enrolled 356 patients in Europe and North America, 34 (10.1%) of which were in the United States. ACT III was conducted from June 2004 through August 2005, with 276 patients (239 AF patients) in Europe, North America, and South America including 38 AF patients in the United States. ACT II was conducted from June 2004 through February 2007 in 190 patients in Argentina, Canada, Denmark, India, Italy, Poland, and the United States. Five patients were enrolled in ACT II in the United States. Patient disposition in the three pivotal studies is presented in Figure 3. Figure 3. Patient Disposition in Pivotal Studies of Vernakalant Injection ACT I ACT III ACT II
7.1.2 Primary Efficacy A summary of the conversion of AF to SR for at least 1 minute within 90 minutes after the first exposure to study drug (primary endpoint) in the short-duration AF cohort in each study is presented in Table 18. Table 18. Conversion of Short Duration AF (>3 Hours to ≤7 Days) SR within 90 Minutes of First Exposure to Study Drug AF duration ACT I ACT III ACT IId PBO Vkt PBO Vkt PBO Vkt Conversion to SR 3/75 74/145 3/84 44/86 7/50 (14.0%) 47/100 (4.0%) (51.0%) (3.6%) (51.2%) (47.0%) % Differencea (95% CI) 47.0 (37.8, 56.3) 47.6 (36.3, 58.9) 33.0 (19.3, 46.7) P-value <0.0001b <0.0001b 0.0001b Odds Ratio (95% CI) 24.0 (6.9, 83.6) 38.3 (9.2, 159.5) 3.25 (1.61, 6.57)c Abbreviations: AF, Atrial fibrillation; SR, sinus rhythm; CI, Confidence interval, Vkt, vernakalant injection; PBO, placebo a Difference in percentage of successful conversions between vernakalant injection and placebo groups; missing values counted as failed conversions b Cochran-Mantel-Haenszel test c Relative risk (95% CI) presented d AF Duration 3-72 hr Correvio International Sàrl 04 November 2019 Page 63 of 166
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In the short-duration AF cohorts, a higher percentage of patients receiving vernakalant injection experienced conversion of AF to SR for a minimum of 1 minute within 90 minutes of first exposure to study drug. 7.1.3 Secondary and Exploratory Efficacy Endpoints There was no statistically significant difference between the two treatment groups in the proportion of subjects with long-duration AF (> 7 days and ≤ 45 days) who had treatment-induced AF termination (as defined by AF termination to any rhythm other than AF or AFL for a minimum duration of one minute) within 90 minutes of first exposure to study drug in ACT I or ACT III. Of note, long-duration AF patients (AF >3 days) were not enrolled in ACT II. Table 19. Termination of AF within 90 Minutes of First Exposure to Study Drug ACT I ACT III AF duration (cohort) PBO Vkt PBO Vkt Termination of AF Overall population (>3 hr, ≤45 d) 3/115 (2.6%) 83/221 (37.6%) 5/121 (4.1%) 47/118 (39.8%) Long duration (8d, ≤45 d) 0/40 6/76 (7.9%) 1/37 (2.7%) 3/32 (9.4%) % Differencea (95% CI) Overall population (>3 hr, ≤45 d) 34.9 (27.9, 42.0) 35.7 (26.2, 45.2) Long duration (8d, ≤45 d) 7.9 (1.8, 14.0) 6.7 (-4.7-18.0) P-value Overall population (>3 hr, ≤45 d) <0.0001b <0.0001b Long duration (8d, ≤45 d) 0.0918c 0.3303c Odds Ratio (95% CI) Overall population (>3 hr, ≤45 d) 21.3 (6.5, 69.6) 20.6 (6.8, 62.4) Long duration (8d, ≤45 d) N/A N/A Abbreviations: AF, Atrial fibrillation; AFL, Atrial flutter; CI, Confidence interval, N/A, not applicable Note: Values in Act I and Act III overall population and long-duration relate to Termination of AF instead of Conversion of AF to SR a Difference in percentage of successful conversions between vernakalant injection and placebo groups; missing values counted as failed conversions b Cochran-Mantel-Haenszel test c Fisher’s exact test
Other secondary and exploratory efficacy endpoints in the target population in the three pivotal studies are presented in Table 20. ACT I and ACT III pooled efficacy results are presented for these endpoints alongside the results from ACT II. In patients with recent-onset AF in the ACT I/III pivotal studies who converted to SR within 90 minutes, vernakalant injection demonstrated a rapid onset of action (median time to conversion of AF to SR in responders was 10 minutes from the start of the first infusion), compared with 31.5 minutes in the 6 patients who converted spontaneously in the placebo group. A post-hoc analysis was performed for the ACT I study to determine the rate of conversion from AF to SR for patients with AF duration of less than 48 hours. This analysis could be performed for the ACT I study because continuous data on AF duration was collected. The rate of conversion of AF to SR for patients with AF duration <48 hours was 61.2% in the vernakalant injection group compared with 4.9% in the placebo group, a difference of 56.2% that was statistically significant (P<0.0001). A large proportion of patients with recent-onset AF in the ACT I/III pivotal studies who converted to SR after receiving vernakalant injection remained in SR (97% maintenance at 24 hours; 93% at 7 days). Correvio International Sàrl 04 November 2019 Page 64 of 166
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Vernakalant injection provided significantly more symptomatic relief to patients with a reduction of AF symptoms from baseline to 90 minutes of; 81.8% to 50.2% in vernakalant-treated patients and, 83.0% to 73.0% in placebo-treated patients. AF symptom reduction included relief of chest tightness/pains, and palpitations due to rapid heart beat and irregular pulse. There was no significant difference in symptoms between the two treatment groups at 24 hours and 30 days; however, after 2 hours, ECV and other conversion agents were permitted.
Table 20. Secondary and Exploratory Endpoints in Short Duration AF Subjects Who Converted to Sinus Rhythm within 90 Minutes of First Study Drug Exposure Endpoint ACT I/III ACT II PBO Vkt PBO Vkt Time to Conversion from AF to SR (min) n 6 118 7 47 Median 31.5 10.0 29.7 12.4 Range (Min-Max) (3.0 – 60) (1.0 – 90) 2.8 – 52.0 0.5 – 57.1 Range (25% - 75%) NR NR NR NR p-value NR <0.001 Life Table Estimate of Maintenance of Sinus Rhythm (SR / SE) n 6 118 8 48 2 hr 83.3% / 15.21% 98.2% / 1.235% 62.5% / 1.71% 93.0% / 0.36% 4 hr 83.3% / 15.21% 98.2% / 1.235% 62.5% / 1.71% 89.2% / 0.46% 6 hr NR NR 62.5% / 1.71% 82.4% / 0.56% 8 hr 83.3% / 15.21% 98.2% / 1.235% NR NR 24 hr/discharge 83.3% / 15.21% 97.2% / 1.59% 50.0% / 1.77% 59/5% / 0.74% 7 Days 83.3% / 15.21% 93.0% / 2.57% 50.0% / 1.77% 56.9% / 0.78% Symptom Relief n 159 231 54 107 Any AF symptom Baseline 132 (83.0%) 189 (81.8%) 48(88.9%) 98(91.6%) 90 min 116 (73.0%) 116 (50.2%)b 43(79.6%) 71(66.4%) p-value <0.0001 0.099 24 hr 47 (29.6%) 75 (32.5%) 28(51.9%) 57(53.3%) Follow upa 63 (39.6%) 97 (42.0%) 16(29.6%) 35(32.7%) p-value 0.5780 0.869 Abbreviations: Hr, AF, atrial fibrillation; hour; min, minute; Pbo, placebo; SR, sinus rhythm; SE, standard error; Vkt, vernakalant a Follow up visit was day 7 in ACT I/III studies and anytime from discharge to 14 days in ACT II b Statistically significant reduction compared with placebo (P<0.001) . 7.1.4 Comparison of Efficacy Results in Subpopulations (ACT I/III) Subpopulation analyses were performed using the ACT I/III pooled pivotal data. Vernakalant injection was effective across a broad range of subgroups: sex, age, region (including the US), renal or hepatic impairment, use of CYP2D6 inhibitors or substrates, use of QT prolonging medications, and implanted rate control devices. The results are generally consistent across the subgroups, noting that such comparisons are limited by sample size and multiplicity considerations. Forest plots of treatment difference in key subgroups are presented in Figure 4. No difference in treatment effect was observed for these groups. In sub-group analyses of extrinsic factors, including use of rate and rhythm control medication and CYP2D6 inhibiting drugs, patients with a background use of Class I antiarrhythmics (n=39) and patients with a background use of digoxin (n=57) showed generally lower conversion rates than patients without either medication; although vernakalant was still statistically different from placebo. Correvio International Sàrl 04 November 2019 Page 65 of 166
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Figure 4. Treatment Difference (Vernakalant Injection Minus Placebo) in Conversion of AF to SR in Short-Duration AF Population Subgroups with Intrinsic Factors – ACT I/III Pooled Pivotal Data Gender, Age and Race Medical History
HISTORY OF CHF
NO (n = 348) YES (n = 42)
HISTORY OF HYPERTENSION
NO (n = 232) YES (n = 158)
HISTORY OF MYOCARDIAL INFARCTION
NO (n = 365) YES (n = 25)
HISTORY OF ISCHAEMIC HEART DISEASE
NO (n = 340) YES (n = 50)
HISTORY OF VALVULAR HEART DISEASE
NO (n = 354) YES (n = 36)
HISTORY OF STRUCTURAL HEART DISEASE
NO (n = 281) YES (n = 109)
-100 -75 -50 -25 0 25 50 75 100 Treatment Difference (Vernakalant - Placebo) With 95% Confidence Interval
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7.2 NDA Resubmission The analysis of the totality of the efficacy data, including the studies submitted in the original NDA as well as those in the NDA resubmission, are presented in this section. The efficacy demonstrated in the supportive safety and efficacy clinical trials (CRAFT, Scene 2, Asia Pacific, AVRO, and ACT IV) was consistent with that demonstrated in ACT I, ACT III, and ACT II. 7.2.1 Conversion to Sinus Rhythm A comparison of conversion rates of AF of ≤ 48 hours (AVRO), ≤ 72 hours (ACT II), or ≤ 7 days to SR across the Phase 2 and 3 studies is shown in Figure 5. All controlled trials demonstrated a statistically significant difference in conversion to sinus rhythm at 90 minutes between vernakalant and control. In the active-controlled trial, AVRO, significantly more patients treated with vernakalant injection met the primary endpoint of conversion to SR within 90 minutes compared with those treated with amiodarone. Efficacy was generally consistent across all studies and ranged from 46% to 53% and rates of conversion were statistically different from placebo across all studies. Figure 5. Conversion Rates of Short-Duration AF across Studies
Abbreviations: AF, atrial fibrillation; CABG, coronary artery bypass graft; CHF, congestive heart failure; SR, sinus rhythm. CRAFT: dosing was 2 mg/kg + 3 mg/kg; data represents % in SR at 1hour post dosing. AF duration >3 to 72 hours. ACT I, III and IV: AF >3 hours to ≤7 days; ACT IV: a placebo group was not included in this open-label study; ACT II: AF post CABG and/or valvular surgery; AF duration >3 to <72 hours. ACT V: AF >3 hours to ≤7 days in patients with no history of CHF (study terminated early). Asia Pacific Study: AF >3 hours to ≤7 days (study terminated early) AVRO: AF ≥3 hours to ≤48 hours, active comparator study with amiodarone.
7.2.2 Secondary and Exploratory Efficacy Endpoints in All Phase 2 and 3 Trials A comparison of secondary and exploratory efficacy endpoints in short-duration AF patients across all Phase 2 and Phase 3 studies is presented in Table 21. Treatment with vernakalant resulted in a statistically significantly greater proportion of patients reporting no AF symptoms at 90 minutes and, in the AVRO trial, a greater improvement in a patient’s perception of their state of health (based on the EQ-5D Quality of Life VAS) at hour 2 compared to amiodarone. In the vernakalant Correvio International Sàrl 04 November 2019 Page 67 of 166
CRDAC Briefing Document – Vernakalant injection group, a mean adjusted change of 10.9 points was seen compared to a mean adjusted change of 5.6 points in the amiodarone group (P=0.0006). While amiodarone is not approved by the FDA for the conversion of AF, it is recommended for use by current treatment guidelines and is commonly used for this indication in US emergency departments, as described in Section 3.4.1.
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Table 21. Time to Conversion and Maintenance of Sinus Rhythm in Short Duration AF Subjects who Converted to SR within 90 Minutes and Symptom Relief in All Subjects in All Phase 2 and Phase 3 Clinical Studies Pivotal Studies Supportive Studies Parameter ACT I/III ACT II CRAFT ACT V Asia Pacific AVRO ACT IV Pbo Vkt Pbo Vkt Pbo Vkt Pbo Vkt Pbo Vkt Amio Vkt Vkt Time to Conversion from AF to SR in Patients who met Primary Endpoint (min) nb 6 118 7 47 5 11 1 59 7 29 6 60 85 25th percentile NR NR NR NR NR NR NR 11 11.3 7.6 21 6 NR Median 31.5 10.0 29.7 12.4 162.0 14.0 NRa NR 19.2 11.0 25.5 11 14.0 75th percentile NR NR NR NR NR NR NR NR 41.2 25.0 58 19 NR Range (min-max) 3 – 60 1 – 90 2.8 – 52.0 0.5 – 57.1 NR NR NR NR 9 – 75 3 – 79 2 – 81 1 – 60 3 – 87 95% CI NR NR NR NR NR NR >90, >90 36.32, >90 >90, >90 25, >90 NR NR NR Maintenance of Sinus Rhythm nb 7 125 8 48 NR NR 1 59 7 29 6 60 85 4 hr 86% 98% 63% 89% NR NR NR NR NR NR 100% 98.3% NR 8 hrc 86% 98% 63% 82% NR NR NR NR NR NR NR NR 98.8% 24 hr/ discharge 86% 97% 50% 60% NR NR 100% 94.9% 57% 89% NR NR 97.4% 7 days 86% 92% 50% 57% NR NR NR NR 57% 82% 83.3% 91.7% 91.0% 30 days NR NR NR NR NR NR NR NR NR NR 66.7% 88.3% NR AF Symptoms Present nd 159 231 54 107 N/A N/A 68 129 56 55 116 116 N/A Baseline 83.0% 81.8% 88.9% 91.6% NR NR 78% 88% 95% 91% NR NR NR 90 mins 73.0% 50.2% 79.6% 66.4% NR NR 30.9% 47.3% 57% 38% 67.2% 46.6% NR p-value <0.0001 0.099 N/A 0.0264 N/A 0.0012 N/A 24 hr 29.6% 32.5% 51.9% 53.3% NR NR NR NR 21% 20% NR NR NR 7 days 39.6% 42.0% 29.6% 32.7% NR NR NR NR 29% 26% NR NR NR 30 days 39.0% 39.0% 22.2% 30.8% NR NR NR NR 20% 15% NR NR NR Abbreviations: Amio., amiodarone; CI, confidence interval; N/A, not applicable; NR, not reported; Pbo, placebo; Vkt, vernakalant CRAFT: dosing was 2 mg/kg + 3 mg/kg; data represents % in sinus rhythm 1 hour post dosing. ACT IV: open label study, no placebo group included AVRO: active-comparator study vs amiodarone AF durations by study: CRAFT (>3 to 72 hours), ACT I, III, V, IV and Asia-Pacific (>3 hours to ≤7 days), ACT II (>3 to <72 hours post CABG and/or valvular surgery), AVRO (≥3 hours to ≤48 hours) a One placebo subject converted to SR at minute 84. b Results presented for subjects with short-duration AF who converted to sinus rhythm for at least 1 minute in the first 90 minutes after exposure to study drug c Maintenance of sinus rhythm was 6 hrs in Act II. d Results presented for all short-duration AF subjects exposed to study drug
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7.2.3 Target Patient Population In patients with AF duration ≤7 days and no contraindications per current approved European SmPC and proposed US PI, 51.7% (345/668) of the patients receiving vernakalant injection converted to sinus rhythm within 90 minutes of start of infusion and 6.6% of placebo patients (17/259). Maintenance of sinus rhythm was consistent with that described in the short duration AF population (Table 21) with 96.2%, 100%, 58.3%, 94.4% and 100% maintaining sinus rhythm at 24 hours in the ACT I, ACT III, ACT II, ACT V and Asia-Pacific studies respectively (contraindicated patients censored). Similarly, there was a statistically significant reduction (p <0.001) in AF symptoms at 90 minutes; 47.5% (221/465) reporting AF symptoms in the vernakalant group and 70.0% (161/230) reporting AF symptoms in the placebo group, in the target patient population in a pooled analysis of ACT I, ACT III, ACT V, AVRO and Asia-Pacific studies. 7.3 Post-Authorization Safety Study (SPECTRUM) 7.3.1 Study Results Overall, 72.1% (1,448/2,009) of the patients converted to SR at any point, 70.2% (1359/1936) in the efficacy population, which excluded patients who received ECV or intravenous Class I/III antiarrhythmic drugs within 90 minutes of vernakalant administration. Data for 1580 prospective vernakalant injection treatment episodes and 429 retrospective vernakalant injection treatment episodes were also analyzed separately in this study. Prospective patients converted to SR in 70.1% (1062 /1515) of treatment episodes and retrospective patients converted to SR in 70.5% (297 /421) of treatment episodes (effectiveness population). The reported conversion rate in SPECTRUM is numerically higher than those reported in the phase 2 and 3 studies. The higher rate of conversion observed for AF in SPECTRUM (70.1% compared to 45.7-53.0% in the Phase 2/3 studies) is associated with a shorter duration of AF prior to treatment (median 11.9 hours compared to 17.7 to 48.7 hours for other studies [median duration of AF episode not reported for ACT II or ACT III]). 7.4 Other Post-marketing Efficacy Data In a recent systematic review of post-marketing studies comparing vernakalant treatment to other pharmacological cardioversion therapies with data from a total of 2822 participants treated with vernakalant it was found that overall, 52.8% to 86% (median=77.6%) of patients converted to sinus rhythm after vernakalant treatment (12 observational, one RCT, n=1524). Median time to conversion after vernakalant treatment ranged from 8 to 18.4 minutes (median=10 minutes) in 8 observational studies and one RCT (n=875) in which it was measured. There was consensus that time to conversion was shorter with vernakalant than comparator treatments (flecainide 162 minutes, propafenone 151 minutes, amiodarone 350 minutes, ibutilide 26 minutes) across five studies (four observational, one RCT, n=393). Figure 6 shows a summary of post-marketing studies in AF < 48 hours duration in the emergency department setting.
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Figure 6. Post-Marketing studies of vernakalant in patients with AF < 48 hours duration
1. Costabel, 201573; 2. Juul-Moller, 201374; 3. Simon, 201775; 4. Simon, 201976; 5. Pohjantähti-Maaroos, 201977; 6. Stoneman, 201778; 7. Cosin Sales, 201679; 8. Carbajosa Dalmau, 201780; 9. Kriz, 201681; 10. Manolis, 201982; 11. Vogiatzis, 201783; 12. Sigmund, 201484.
7.5 Efficacy Conclusions Five randomized double-blind placebo-controlled Phase 3 trials, one active comparator-controlled Phase 3 trial, and a single-arm Phase 3 study have consistently demonstrated efficacy of vernakalant injection for rapid conversion of recent onset AF (≤ 7 days) to SR within 90 minutes of injection in 45.7 to 52.9% of non-surgery and cardiac surgery patients. Conversion of recent onset AF to SR within 90 minutes was much lower in placebo-treated patients in these same studies (1.5 to 14%). Conversion occurred rapidly; for vernakalant patients who converted to sinus rhythm within 90 minutes, the median time to conversion ranged from 8 to 14 minutes. The majority of patients with recent-onset AF (in the ACT I/III pivotal studies) who converted to SR after receiving vernakalant injection remained in SR during the study observation period (97% maintenance at 24 hours; 93% at 7 days). Further, in subjects who converted to SR for 1 minute within 90 minutes after exposure to study drug, vernakalant provided rapid relief of the AF symptoms causing discomfort and concern that had driven these patients to the hospital for treatment (48.9% with no AF related symptoms at 90 minutes compared with 18.2% at baseline). Vernakalant has shown consistent efficacy in a broad range of subjects with AF with no clinically relevant effect of sex, age, region (including the US), use of CYP2D6 inhibitors or substrates, use of QT prolonging medications, and implanted rate control devices. Vernakalant injection has also been shown to be effective in the presence of typical background medications for the target patient population, including rhythm and rate control medication.
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8 SAFETY
Summary • The most frequent TEAEs reported from 0-2 and 0-24 hours post dose in AF patients who received vernakalant injection were dysgeusia (22.0%), sneezing (14.0%), and paraesthesia (8.8%). • The most frequent treatment-emergent SAEs reported from 0-24 hours post dose in AF patients who received vernakalant injection were hypotension (0.7%) and bradycardia (0.3%). • AEs of special interest were identified prospectively and include; ventricular arrhythmia, bradycardia, and hypotension. The rates of AEs of special interest are higher in the vernakalant group during 0-2 hours post dose; however, the risk of events is higher in the placebo group after 2 hours. • From 0-2 hours post dose, the incidence of ventricular arrhythmia was higher in patients treated with vernakalant compared to placebo (3.8% vs. 2.5%, respectively) but from 2-24 hours post dose, the incidence was higher for placebo than vernakalant (9.8% vs. 6.9% respectively). o In the 0-2 hour time period 0.7% (8/1073) of patients receiving vernakalant and 0 patients receiving placebo experienced either an SAE or discontinued drug due to ventricular arrhythmia. Of these 8 patients, 3 received defibrillation or cardioversion. • From 0-2 hours post dose, the incidence of the bradycardia events was greater for vernakalant patients than placebo patients (5.1% vs. 2.7%, respectively); however, from 2-24 hours post dose, the incidence was greater for placebo than vernakalant (12.8% vs 7.5%, respectively). o In the 0-2 hour time period 1.2% (12/1073) of patients receiving vernakalant and 0 (0/459) patients receiving placebo experienced either an SAE or discontinued drug due to bradycardia. Of these 12 patients, 5 received atropine (none received a pressor), 1 received CPR, and 1 post cardiac surgery patient received temporary external pacing. In the 2-24 hour post dose period, 3 patients receiving vernakalant experienced either an SAE or discontinued drug due to bradycardia. Of these 3 patients, 1 resolved without treatment, 1 was treated with flecainide, and 1 was treated with atropine and isoproterenol. • From 0-2 hours post dose, the incidence of hypotension events was greater for vernakalant patients than placebo patients (5.7% vs 4.8%, respectively); however, 2-24 hours post dose the incidence was greater for placebo than vernakalant (5.9% and 3.4%, respectively). The risk of hypotension events is increased in vernakalant patients with CHF or background use of beta blockers. These risks will be mitigated by proposed labeling. o In the 0-2 hour time period 1.0% (10/1073) of patients receiving vernakalant and 0.2% of patients receiving placebo experienced either an SAE or discontinued drug due to hypotension. Of the 10 vernakalant patients, 5 were treated with saline and/or Trendelenberg and 3 were treated with atropine and 2 with pressors. • SPECTRUM, which employed more restrictions to its use when compared to the early development trials, showed a 0.1% incidence of significant hypotension, a 0.4 % risk of significant bradycardia and no significant ventricular arrhythmias. There were no cases of ventricular fibrillation and no deaths in 2009 uses. Additional postmarketing data further characterized and quantified important clinical events identified in clinical trials. In addition, AFL with 1:1 atrioventricular conduction has emerged as a new risk during post-marketing surveillance.
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8.1 FDA Approvable Letter In the Approvable Letter issued on 8 August 2008 in response to the initial NDA submission, FDA identified several items that needed to be addressed prior to approval of the application. Table 22 below provides a summary of the FDA requests and indicates where the responses may be found within this Briefing Book. Table 22. Overview of Requests from FDA Approvable Letter FDA Approvable letter request Location of discussion in Briefing Book 1) Vernakalant’s risks need to be well characterized The risks associated with vernakalant treatment based on data from 9 Phase 2/3 studies, a PASS and postmarketing experience are discussed in Sections 8 and 9.2. 2) FDA identified eight specific cases of significant The 8 cases are described in Section 8.3 and Appendix 3. concern related to hypotension, arrhythmias, and/or sinus pause and requested additional information and a discussion of these cases. 3) If, after submission of items listed above, FDA ACT V was conducted but placed on clinical hold due to a believed a further study to be indicated, an death (see Section 8.4). Safety data from ACT V is additional clinical study should be conducted to integrated in safety analyses of the All Patients Population, define the safety and efficacy of vernakalant; Target Patient population and individual analyses of events with submission of the protocol for a special of special interest. protocol assessment (SPA). Data from 9 Phase 2 or 3 studies and SPECTRUM provide full characterization of safety. AEs, AEs of Special Interest, and discussions of Common AEs, SAEs, Discontinuations due to AEs and Deaths are included in Sections 8.5, 8.6, 8.7. Safety of SPECTRUM is included in Section 8.8. 4) Provide a detailed assessment of the risks of The limitations and risks of ECV are discussed in Section electrical cardioversion (ECV) 3.4.2 and Sections 8.6.1.4, 8.6.2.5, 8.6.3.5, and Risk Summary Section 9.2 5) FDA noted that “the one patient who died had a) Risks of available alternatives are outlined in Sections significant aortic stenosis and received repeat 3.4.1, 3.4.2, and 3.4.3. treatment after a significant hypotensive response b) Safety experience with use of vernakalant in the outside to the first infusion” and requested that the trial environment is described in SPECTRUM (Sections Sponsor: 6.3 and 8.8) and the Post Marketing environment a) Discuss risks and provide reasons to (Section 8.9). accept the risks of vernakalant given c) AEs are discussed in Sections 8.5 through 8.7 and put available alternatives into context by analyses in Target Patient Population b) Address the concerns of potential (Table 14) to reflect the intended population as well as consequences of vernakalant use in the the proposed labelling with respect to contraindicated outside trial environment populations (Section 2.1) and risk mitigation strategies c) Discuss adverse effects and provide (Sections 8.6.1.7, 8.6.2.8, 8.6.3.8, 8.8, 8.10 and 9.2) appropriate context d) Watchful waiting is discussed in Sections 3.3, 3.4, d) Provide an analysis of why vernakalant 3.4.3, and 3.5 represents an alternative to waiting plus cardioversion 6) Provide preclinical or clinical data to establish The preclinical data that establish the mechanism of the mechanism of vernakalant-induced vernakalant induced hypotension are found in Section hypotension. 4.2.1.2. 7) Include a Safety Update as described in There were no new nonclinical safety data since the original 21CFR314.50 (d)(5)(vi)(b) that includes data NDA. A summary of nonclinical safety is in Section 4.3. from all nonclinical and clinical studies of the Tables containing integrated analysis of clinical safety data drug under consideration regardless of indication, (original NDA vs new vs cumulative) are found in Sections dosing form or dose level. 8.5-8.9. Although safety data were summarized for the oral formulation in the NDA resubmission, they are not discussed within this Briefing Book. Correvio International Sàrl 04 November 2019 Page 73 of 166
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8.2 NDA Resubmission As described in Section 6, data from five Phase 2/3 safety and efficacy studies (ACT I, ACT III, ACT II, Scene 2, and CRAFT) were included in the original NDA. In this resubmission, data from an additional four Phase 2/3 efficacy and safety clinical studies (ACT IV, ACT V, AVRO, and Asia-Pacific Study) have been included as well as five additional pharmacokinetic studies. The clinical study program is supported by data from a PASS characterizing the risks of vernakalant in clinical practice as well as spontaneous reporting from post-marketing sources.
These data taken together address the following key points from the Approvable Letter:
• Vernakalant risks are well characterized on the basis of nine clinical safety and efficacy studies and supported by data in the post-marketing setting including a 2009-treatments post-approval safety study. • Summaries of the adverse events (AEs) of interest in 8 patients identified by the Agency are discussed below and details are included in Appendix 3. o Assessment of ECV risks within the program are presented in Section 8.6 and a literature review on ECV was submitted to the NDA. o Data from the ACT V study conducted in response to the Approvable Letter are included along with data from three additional studies. • The approved EU SmPC (which mirrors the proposed US labeling) has been used in the “the outside-trial environment” for 9 years with an estimated 58,298 treatment courses. • Vernakalant represents a reasonable alternative for pharmacological cardioversion as outlined in Section 9. A Target Patient Population has been identified, consistent with the European SmPC and the proposed US PI, that is at low risk for serious adverse events with a demonstrable benefit to these patients. The positive risk/benefit assessment and appropriate use in the target population has been supported by the post marketing study in which there were only 2 cases of serious hypotension associated with bradycardia at the time of conversion; both resolved with a saline infusion and atropine. • Preclinical and clinical data explain the mechanism of action for vernakalant-induced hypotension and show that it occurs in the setting of decreased myocardial reserve or is associated with transient bradyarrhythmias that occur at the time of cardioversion.
8.3 Eight Cases of Interest As noted above, the Approvable Letter (08 August 2008) from the Division identified eight AEs of potential significant concern related to hypotension, arrhythmias, and/or sinus pause which are summarized in Table 23. Detailed narratives of the eight patients are presented in Appendix 3 followed by comments from Correvio with the Sponsor’s opinion. Of the 8 cases identified by the FDA, 4 patients would be identified as having contraindications for vernakalant use based on a history of severe heart failure (NYHA Class III or IV or known moderate or severe left ventricular dysfunction) or evidence of clinically significant aortic stenosis prior to study drug infusion based on the current approved European SmPC and the proposed US PI. Three patients, one of which would also have been contraindicated prior to treatment due to systolic blood pressure <100 mmHg, experienced bradyarrhythmias at the time of cardioversion (2 with sinus pauses and one with complete heart Correvio International Sàrl 04 November 2019 Page 74 of 166
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block after ECV). Bradyarrhythmias can occur irrespective of conversion modality used1,2,3 and with rare exception are typically transient and self-limiting requiring no treatment, or, on occasion may be symptomatic, requiring atropine or isoproterenol and rarely, external pacing. The eighth patient, with undiagnosed idiopathic cardiomyopathy, experienced cardiogenic shock 12 hours after receiving vernakalant injection, 10 hours after ECV and proximate to multiple doses of sedatives and a respiratory depressing and sedating anti-psychotic, which resulted in respiratory depression and hypotension. The sponsor considers this event unrelated to vernakalant. Table 23 summarizes the 8 cases and how the labeling under the current approved European SmPC and proposed US PI would address these patients such that they are not included in the Target Patient Population.
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Table 23. Summary of Eight Patient Cases of Interest Identified by FDA Study Demographics & Time from Start Duration of Labeling Section to Address Patient Baseline Event of First Infusion Treatment Outcome Event(s) Patient Number Characteristics to Event Ventricular Arrhythmias 64 yo male • Contraindicated in aortic EF 36-49% stenosis CHF (NYHA class • Contraindicated in SBP SAE of VF at 14 min II) <100 mmHg (or fluid ACT III 47 min (defibrillated Defibrillation, Aortic stenosis resuscitation or inotropes to (b) SAE of VF (12 min after the to pulseless atropine, Death (6) Dyspnea maintain SBP) end of second electrical CPR Hypertension infusion) activity) • Contraindicated in ACS within 30 days • Warning if sudden drop in BP to DC vernakalant 74 yo male • Contraindicated in severe Warfarin DC’d ACT III EF 26-35% SAE of tachycardia heart failure (NYHA class 5 min 6 units plasma (b) IHD (overlapping SAE of GI 28 min Resolved III/IV) or left ventricular (6) (dose discontinued) + 4 units RBC AF hemorrhage) dysfunction administered Hypertension Hypotension 48 yo male SAE of hypotension 10 min • Contraindicated in severe EF <25% (70/55 mmHg with sweating, (drug discontinued heart failure (NYHA class ACT III CHF (NYHA class pallor, nausea, LOC, and at end of first Saline, III/IV) or left ventricular (b) 2 hr 16 min Resolved (6) II) seizure) infusion) Trendelenburg dysfunction
Asymptomatic monomorphic 25 mins VT on Holter 49 yo male SAE of hypotension 10 min • Warning if sudden drop in EF 25% (82/68 mmHg with sweating, (drug discontinued BP to DC vernakalant ACT I Saline, Cardiomyopathy pallor, diarrhea, feeling hot at end of first 15 min Resolved (b) (6) Trendelenburg HF and cold) infusion) SAE of cardiogenic shock 12 hr 35 min
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Study Demographics & Time from Start Duration of Labeling Section to Address Patient Baseline Event of First Infusion Treatment Outcome Event(s) Patient Number Characteristics to Event 54 yo male • Contraindicated in severe Hypertension heart failure (NYHA class Hypotension (88/60 mmHg), III/IV) or left ventricular ACT I (b) (6) diaphoresis, nervousness, 40 min 5 min None Resolved dysfunction
nausea, nose twitching • Warning to use with caution in NYHA class I/II CHF Bradycardia 90 yo female 3 hr 4 min • instructions SAE of complete heart block Administration ACT I EF 45% (following Atropine ×2, to give in a monitored (b) (6) (pulse 40 bpm, BP 47/23 <1 min Resolved Angina, attempted electrical isoprenaline clinical setting with all mmHg) Pulmonary edema cardioversion) necessary items for 58 yo male SAE of sinus bradycardia and resuscitation and to observe ACT I Acute MI sinus arrest (and AE of 13 min (at time of Atropine×3, for at least 2 hours after (b) (6) 9 min Resolved CABG hypotension; pulse 30 bpm, conversion to SR Trendelenburg cessation of vernakalant BP 79/44 mmHg) treatment or until clinical 51 yo female status and ECG are stable Baseline • Warning that bradycardia ACT I Extreme bradycardia and 77 min (at time of (b) (6) hypotension <1 min Not reported Resolved has been reported during or sinus pause (pulse <40 bpm) conversion to SR) shortly after use of vernakalant Abbreviations: AF, atrial fibrillation; BP; blood pressure; CABG, coronary artery bypass graft; CHF, congestive heart failure; CPR; cardiopulmonary resuscitation; DC, discontinue; EF, ejection fraction; GI, gastrointestinal; IHD, ischemic heart disease; MI, myocardial infraction; NYHA, New York Heart Association; SAE, serious adverse event; SR, sinus rhythm; VF, ventricular fibrillation; VT, ventricular tachycardia; yo, year old
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8.4 Death Resulting in Clinical Hold In 2010, during the course of the ACT V trial, a patient experienced a serious adverse event of cardiogenic shock immediately following infusion of vernakalant injection. This subject subsequently died (Day 29) and as a result of this significant event the vernakalant injection program was placed on clinical hold in the US. The following is a description of the patient and the course of events. Detailed narrative of this patient is presented in Appendix 3 followed by comments from Correvio with the Sponsor’s opinion. (b) (6) Patient (ACT V): This 77-year-old white male had a history of hypertension since 2006 and chronic alcohol abuse, along with recent dyspnea and palpitations. He presented with symptoms of dyspnea of one week duration and palpitations and was found to be in AF. He was given IV fluids and his baseline blood pressure was 139/70 mmHg. His respiratory rate was 22-28 throughout the screening and baseline exams. He had a transthoracic echocardiogram which per the medical records showed diffuse global hypokinesis, a moderate decrease in systolic function and the ejection fraction was estimated to be 44%. His blood pressure at the initiation of 60 mL (270 mg) of vernakalant given over 10 minutes was 140/82 mmHg, and his heart rate was 135 bpm. At 5 minutes into the infusion, his blood pressure was 126/95 mmHg and then his pressure dropped to 72/60 mmHg at 10 minutes. He was given saline beginning at 10 minutes at the end of the infusion. He then became pulseless and received cardiopulmonary resuscitation, intubation, epinephrine, norepinephrine, dopamine, bicarbonate, and calcium, and an echocardiogram done during the resuscitation showed ventricular standstill while the ECG still showed a cardiac rhythm. After 40 minutes of resuscitation, he regained a pulse, his blood pressure was reported to be 130/80 mmHg, and he was in AF. He was admitted to the critical care unit, cardioverted to sinus rhythm 4 hours later and was started on amiodarone. A bedside echocardiogram on Day 3 was reported to show his ejection fraction to be 25% with severe mitral regurgitation, a left atrial size of 50 mm, left ventricular hypertrophy, and mitral annular calcification. During the next 4 days, he developed evidence of renal failure requiring dialysis, aspiration pneumonia, rhabdomyolysis, a coagulopathy and severe liver failure. He had multiple cardiac arrests and resuscitation attempts. On Day 11, he developed gastrointestinal bleeding which was determined to be from a necrotizing enterocolitis. On Day 23, coronary angiography showed no evidence of coronary disease, and no ventriculogram was done. The patient continued to bleed requiring multiple transfusions. He never regained consciousness and died from bleeding on Day 29. The initial echocardiogram described as showing moderate global hypokinesis and an estimated ejection fraction likely underestimated his cardiac function as estimates of ejection fraction are particularly difficult and often inaccurate during rapid AF. The follow-up echocardiogram showing left ventricular hypertrophy, a left atrial size of 50 mm and mitral regurgitation suggests long standing mitral regurgitation secondary to left ventricular dysfunction (the valve itself was not reported as abnormal) and an ejection fraction of 25%. With normal coronary anatomy, the most likely etiology is alcohol cardiomyopathy and long-standing hypertension. It is very unusual to develop either renal failure, liver failure, or rhabdomyolysis or coagulopathy after cardiac resuscitation suggesting that he had a very prolonged state of inadequate circulation. He ultimately died from complications of prolonged organ ischemia secondary to cardiac arrest.
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8.5 Overview of Adverse Events In this summary of safety, treatment-emergent AEs were defined as any non-serious AEs starting or worsening after the start of the first dose of study drug through Day 10, and SAEs and AEs of AF and AFL starting or worsening after the first dose of study drug through Day 30. An SAE was defined as any AE that resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or congenital anomaly/birth defect or was considered an important medical event (e.g., jeopardized the health of the patient) (according to the ICH E2A). The investigator made the determination of whether an AE met the criteria for an SAE. As described in Section 6.2.3.2, the safety analyses in this document focus on the All Patients Population (CRAFT, Scene 2, ACT I, ACT II, ACT III, ACT IV, ACT V, AVRO and AP studies) and the Target Patient Population (patients with AF ≤ 7 days and no contraindications in the Phase 3 studies). The analysis of TEAEs was performed for 4 time periods: all post dose, 0-2 hours post dose, 2-24 hours post dose, and 0-24 hours post dose. The study design restricted treatment with IV Class I or III antiarrhythmic medications or ECV within the 2 hours following study drug administration, unless the investigator determined it was necessary to restore SR quickly, such as in cases of electrical or hemodynamic instability. Subsequent to the 2-hour post-dose time point, patients who had not converted from AF to sinus rhythm could receive additional antiarrhythmic medications and/or undergo ECV at the discretion of the investigator. Due to its rapid redistribution after administration, drug concentration is approximately 20% of Cmax at 90 minutes after discontinuation and its short half-life (about 3 hours in extensive metabolizers), levels of vernakalant would be negligible by 24 hours post dose. Thus, the time frames for AE analysis were chosen in an effort to distinguish AEs associated with vernakalant injection from those associated with follow-up treatments and to focus on the time period when vernakalant’s pharmacodynamic effects would most likely be observed. A discussion of common and related TEAEs and SAEs can be found in Section 8.7. 8.6 Adverse Events of Special Interest Events of interest associated with antiarrhythmic drugs, including ventricular arrhythmia, bradycardia and hypotension, were prospectively identified for close scrutiny at the beginning of the clinical development program. A thorough and systematic assessment of the safety database was conducted to evaluate the incidence of these events. The data sources include the AE database (with multiple preferred terms within each of the events of interest), cardiologist over-read of ECGs, Holter device cardiologist assessments, CEC over-read of ECGs, and vital sign data, as appropriate for the event of interest. These analyses were performed on the All Patients Population excluding patients from the CRAFT study. CRAFT patients were excluded from these analyses because ECG and Holter data were not collected at the same time points for this study and therefore these patients could not be pooled for these analyses. Further, dosing was different for CRAFT patients. These analyses have also been performed on the Target Patient Population. In pre-NDA discussions (October 2018), the FDA requested a separate analysis of AEs of special interest (“FDA AEs of Special Interest”). The FDA provided groupings of preferred terms. These analyses are presented for the All Patients Population.
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The following sections provide a detailed review of both the Sponsor’s and FDA’s approach to analysis of AEs of special interest. Table 24 provides a comparison of the FDA Requested and Sponsor assessments of these events of interest. The comparison shows that the Sponsor’s assessment process was more inclusive, as noted by the higher event rates, however, relative rates for both assessments were directionally similar across the reported events. Table 24. Incidence of Subjects Reporting FDA Requested and Sponsor Assessments of Events of Interest (All Patients Population) Adverse Event Post Incidence of AEs, % Dose Timepoint Assessments per FDA Request Sponsor Assessment Events of Interest* Placebo Vernakalant Placebo Vernakalant (N=459) (N=1073) (N=437) (N=1037) Ventricular arrhythmia 0-2 hr 0.7 1.5 2.5 3.8 2-24 hr 2.2 1.2 9.8 6.9 Bradycardia 0-2 hr 0.4 3.3 2.7 5.1 2-24 hr 2.8 1.9 12.8 7.5 Hypotension 0-2 hr 2.8 6.4 4.8 5.7 2-24 hr 3.9 2.5 5.9 3.4 *events identified via analyses across multiple data sources, as described in Section 6.2.3.2.
8.6.1 Ventricular Arrhythmia 8.6.1.1 Sponsor’s Events of Interest Analysis The data sources for analysis of all events of ventricular arrhythmias included the following: • AE preferred terms of TdP, tachycardia, syncope, ventricular fibrillation, ventricular tachycardia (VT), ventricular extrasystoles and ventricular arrhythmia. • Cardiologist over-read of 12-lead ECGs for TdP, VT, junctional tachycardia, idioventricular rhythm, unsustained monomorphic VT, nonsustained VT, ventricular fibrillation, ventricular flutter and other rhythms, as prespecified in the ISS statistical analysis plan. • Holter device cardiologist over-read (including runs ≥3 beats with heart rate ≥100 bpm, classified as VT by the cardiologist): ventricular fibrillation, unsustained monomorphic VT, unsustained polymorphic VT, TdP, sustained monomorphic VT, sustained polymorphic VT, and ventricular flutter • CEC Assessment of 12-lead ECG: VT. The incidence of ventricular arrhythmia events using all of these data sources combined for the All Patients Population excluding CRAFT is presented for 0-2 hours, 2-24 hours, and 0-24 hours post- dose in Table 25. The incidence of the above defined ventricular arrhythmia events from all sources combined was 3.8% in vernakalant patients and 2.5% in placebo patients from 0-2 hours post-dose and 6.9% in vernakalant patients and 9.8% in placebo patients from 2-24 hours post-dose.
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The most common ventricular arrhythmia AE in the 0-2 hr time period was ventricular tachycardia; 0.7% in the vernakalant patients and 0.2% in placebo patients. In the 2-24 hr period, these rates were 0.8% in the vernakalant patients and 1.6% in placebo patients. The most common ventricular arrhythmia identified in the 0-2 hour period by Holter was unsustained monomorphic ventricular tachycardia; vernakalant 1.7% and placebo 1.1%. In the 2-24 hr period, these rates were 4.9% in the vernakalant patients and 6.6% in placebo patients. There was one case of sustained ventricular tachycardia seen on Holter which was read by the blinded events committee as AF with aberrancy. There were 2 instances of ventricular fibrillation in the vernakalant group: the patient with severe aortic stenosis and the patient with known moderate decrease in left ventricular function. Both instances occurred in the setting of hypotension. Of note, there was a third instance of VF in the CRAFT study (not included here) that occurred in a 24 year old woman at the time of unsynchronized cardioversion of AF. The event was considered by the investigator to be related to a loose ECG electrode. Table 25. Incidence of Ventricular Arrhythmia Events from 0-2, 2-24, and 0-24 Hours Post- Dose (Safety Set, All Patients Population Excluding CRAFT) 0-2 hours 2-24 hours 0-24 hours Pbo Vkt Pbo Vkt Pbo Vkt (N=439) (N=1037) (N=439) (N=1037) (N=439) (N=1037) Source Event n (%) n (%) n (%) n (%) n (%) n (%) All Groups Any ventricular arrhythmia event 11 (2.5%) 39 (3.8%) 43 (9.8%) 72 (6.9%) 48 (10.9%) 98 (9.5%) AE Any ventricular arrhythmia event 2 (0.5%) 15 (1.4%) 9 (2.1%) 14 (1.4%) 11 (2.5%) 29 (2.8%) a Database Syncope 0 1 (0.1%) 0 2 (0.2%) 0 3 (0.3%) Tachycardia 0 1 (0.1%) 0 0 0 1 (0.1%) Ventricular extrasystoles 1 (0.2%) 5 (0.5%) 2 (0.5%) 4 (0.4%) 3 (0.7%) 9 (0.9%) Ventricular fibrillation 0 2 (0.2%) 0 0 0 2 (0.2%) Ventricular tachycardia 1 (0.2%) 7 (0.7%) 7 (1.6%) 8 (0.8%) 8 (1.8%) 15 (1.4%) CEC Any ventricular arrhythmia event 1 (0.2%) 2 (0.2%) 0 0 1 (0.2%) 2 (0.2%) assessment of 12-lead Ventricular tachycardia 1 (0.2%) 2 (0.2%) 0 0 1 (0.2%) 2 (0.2%) ECG 12-lead Any ventricular arrhythmia event 1 (0.2%) 7 (0.7%) 0 3 (0.3%) 1 (0.2%) 10 (1.0%) ECG Idioventricular rhythm 0 1 (0.1%) 0 0 0 1 (0.1%) cardiologist Junctional tachycardia 0 0 0 1 (0.1%) 0 1 (0.1%) over-read Other rhythm 1 (0.2%) 3 (0.3%) 0 1 (0.1%) 1 (0.2%) 4 (0.4%) Unsustained monomorphic 0 0 0 1 (0.1%) 0 1 (0.1%) ventricular tachycardia Ventricular flutter 0 1 (0.1%) 0 0 0 1 (0.1%) Ventricular tachycardia 0 2 (0.2%) 0 0 0 2 (0.2%) Holter Any ventricular arrhythmia event 8 (1.8%) 22 (2.1%) 38 (8.7%) 61 (5.9%) 40 (9.1%) 71 (6.8%) device Sustained monomorphic 0 1 (0.1%) 0 0 0 1 (0.1%) cardiologist ventricular tachycardia over-read Torsade de Pointes 0 0 0 1 (0.1%) 0 1 (0.1%) Unsustainedb monomorphic 5 (1.1%) 18 (1.7%) 29 (6.6%) 51 (4.9%) 30 (6.8%) 59 (5.7%) ventricular tachycardia Unsustainedb polymorphic 4 (0.9%) 5 (0.5%) 13 (3.0%) 23 (2.2%) 14 (3.2%) 24 (2.3%) ventricular tachycardia Ventricular fibrillation 0 1 (0.1%) 0 0 0 1 (0.1%) Abbreviations: AE, adverse event; AV, atrioventricular; CEC, Clinical Events Committee; ECG, electrocardiogram; NDA, New Drug Application; Pbo, placebo; Vkt, vernakalant
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a AEs are defined as any non-serious event starting or worsening after the start of the first dose through 10 days after the last dose in addition to all serious events starting or worsening after the start of the first dose through 30 days after the last dose. b ≤30 seconds Notes: The ALL Patients Excluding CRAFT Population includes the following studies: Scene 2, AVRO (vernakalant patients only), ACT I, ACT II, ACT III, ACT IV, ACT V, and AP. The 12-lead ECG data includes data from start of first dose through Day 10. Multiple occurrence of the same event in one individual are counted only once. Within a data source, patients may have experienced more than one type of event. The sum of terms by source may exceed 100%.
The effects of vernakalant injection on QTcF interval were evaluated in the All Patients Population, excluding the CRAFT study. The differences in change in QTcF interval from baseline for the placebo/comparator group and vernakalant group are presented in Table 26. Significant differences are observed during the first 4 hours post dose. Table 26. Differences in Change from Baseline in QTcF Interval Through Follow-up (All Patients, excluding CRAFT) Time Point Placebo /Comparator Vernakalant Inferential Analysis N Mean (SD) N Mean (SD) P-value Difference (95% CI) 5 min 257 0.1 (19.90) 482 14.2 (23.43) <0.001 12.9 (9.6, 16.1) 10 min 387 1.5 (17.52) 834 25.7 (24.47) <0.001 23.3 (20.6, 25.9) 15 min 249 0.5 (18.81) 466 22.1 (25.90) <0.001 20.4 (16.9, 24.0) 20 min 255 0.2 (16.78) 514 19.0 (26.24) <0.001 16.9 (13.5, 20.4) 25 min 388 1.5 (17.52) 801 15.3 (24.44) <0.001 12.8 (10.2, 15.5) 30 min 251 2.3 (18.43) 439 16.8 (26.43) <0.001 13.3 (9.7, 16.9) 35 min 384 0.9 (17.18) 791 20.4 (24.14) <0.001 18.5 (15.9, 21.1) 40 min 245 1.8 (19.32) 416 19.0 (25.87) <0.001 16.3 (12.7, 19.9) 45 min 291 0.1 (20.27) 619 17.6 (25.97) <0.001 15.8 (12.5, 19.1) 50 min 394 1.9 (19.19) 834 14.7 (23.92) <0.001 11.5 (8.8, 14.1) 90 min 399 1.5 (20.04) 916 10.9 (22.59) <0.001 7.9 (5.4, 10.4) 2 houra 402 2.2 (18.84) 638 11.3 (22.97) <0.001 8.4 (5.9, 11.0) 4 hour 394 4.5 (21.69) 729 11.6 (23.29) <0.001 5.5 (2.9, 8.2) 8 hour 254 6.4 (23.03) 618 12.7 (25.86) 0.023 4.0 (0.5, 7.4) 24 hour 396 11.4 (26.11) 855 14.8 (25.99) 0.294 1.6 (-1.4, 4.5) Follow-up 386 12.6 (26.72) 877 12.2 (28.97) 0.092 -2.7 (-5.9, 0.4) Abbreviations: CI, confidence interval; min, minute; Pbo, placebo; SD, standard deviation; Vkt, vernakalant a Two hours after administration of study drug, interventions which could have included electrical cardioversion and/or administration of antiarrhythmic drugs for conversion and/or maintenance of sinus rhythm were permitted.
The number of patients experiencing shifts in QTcF intervals from baseline to ≥500 msec and ≥550 msec by timepoint is presented in Table 27. In the vernakalant group, peaks in the incidence of shifts in QTcF to ≥500 msec coincided with the end of the infusions. By minute 40 the incidence of QTcF shifts to ≥500 msec were similar in both groups. The vernakalant group had no increased risk of QTcF shifts to ≥550 msec compared to the placebo group.
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Table 27. Number (%) of Patients with Shifts in QTcF Interval from Baseline to Outliers of ≥500, ≥550 msec (Safety Set, All Patients Population Excluding CRAFT) ≥500 mseca ≥550 msecb Time Pbo Vkt Pbo Vkt (N=439) (N=1037) (N=439) (N=1037) Any timepoint 0-24 hours 25 (5.7) 67 (6.5) 4 (0.9) 7 (0.7) 5 min 6 (1.4) 11 (1.1) 0 0 10 min 4 (0.9) 20 (1.9) 0 0 15 min 7 (1.6) 13 (1.3) 0 1 (0.1) 20 min 4 (0.9) 13 (1.3) 0 1 (0.1) 25 min 6 (1.4) 12 (1.2) 0 1 (0.1) 30 min 5 (1.1) 11 (1.1) 0 1 (0.1) 35 min 3 (0.7) 15 (1.4) 0 1 (0.1) 40 min 4 (0.9) 9 (0.9) 0 0 45 min 8 (1.8) 11 (1.1) 1 (0.2) 0 50 min 5 (1.1) 12 (1.2) 1 (0.2) 1 (0.1) 90 min 6 (1.4) 8 (0.8) 0 0 2 hourc 8 (1.8) 9 (0.9) 1 (0.2) 0 4 hour 6 (1.4) 8 (0.8) 0 1 (0.1) 8 hour 7 (1.6) 6 (0.6) 0 1 (0.1) 24 hour 10 (2.3) 17 (1.6) 2 (0.5) 3 (0.3) Abbreviations: min, minute; Pbo, placebo; Vkt, vernakalant Note: Patients who had pacemakers, patients with bundle branch block at any time point, and ACT II patients with paced rhythm at any time point are excluded. a Patients shifted from ≤500 msec at baseline to >500 msec at the specified time point. b Patients shifted from ≤550 msec at baseline to >550 msec at the specified time point. c Two hours after administration of study drug, interventions which could have included electrical cardioversion and/or administration of antiarrhythmic drugs for conversion and/or maintenance of sinus rhythm were permitted.
8.6.1.2 FDA Adverse Events of Special Interest Ventricular arrhythmia-related events were more common in the vernakalant group than placebo (1.5% versus 0.7%) in the 0-2 hour time period and more common in the placebo group than vernakalant (1.2% for vernakalant versus 2.2% for placebo) in the 2-24 hour period. These rates are lower, but consistent in direction of effect, than the incidence of ventricular arrhythmia based on the analysis performed by Correvio and described in Section 8.6.1.1 above. The most common ventricular arrhythmia event in the FDA AE of Special Interest analysis in the 0-24 hour time period was ventricular tachycardia in both groups (1.4% vernakalant, 1.7% placebo).
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SAEs of TdP were reported in 2 (0.2%) vernakalant patients and 1 (0.2%) placebo patient; none of the TdP SAEs occurred within 24 hours post dose of vernakalant injection. In the first of the 2 vernakalant-treated patients with TdP, the event started approximately 30 hours after treatment with vernakalant, and after she underwent ECV which resulted in third degree heart block and had a spontaneous run of ventricular tachycardia. Her TdP was treated with amiodarone and reverted to AF. In the second case, the event occurred approximately 17 days after treatment with vernakalant and approximately 3 days after mitral and tricuspid surgeries. An additional case of TdP (not classified as an SAE or AE and initially classified as VT) occurred in a patient with AFL who did not convert to sinus rhythm after receiving vernakalant. The patient received ibutilide 1 hours and 45 minutes after completion of the second vernakalant infusion and then experienced a nine-beat run captured by Holter monitoring, which was classified as TdP by the CEC. In the placebo patient, the TdP event occurred 2 days after administration of study treatment and 3 days of sotalol dosing. The event occurred approximately 1 hour after ECV; the patient initially converted to SR then developed TdP, which resolved spontaneously.
8.6.1.4 Ventricular Arrhythmia Events within 0-2 and 2-24 Hours Following Vernakalant, Placebo, and ECV The incidence of ventricular arrhythmia in the All Patients Population (excluding CRAFT) in 0-2 and 2-24 hours from the start of the infusion, and 0-2 and 2-24 hours following ECV attempt, is presented in Table 30 below. In the first 2 hours following the first infusion, 2.5% of patients receiving placebo developed ventricular arrhythmia, compared to 3.8% of vernakalant-treated patients. In the first 2 hours following ECV, 2.3% of patients receiving placebo developed ventricular arrhythmia compared to 1.5% of vernakalant-treated patient. From 2-24 hours, the ventricular arrhythmia rates were higher in the placebo group after the first infusion and after first ECV attempt. Table 30. Incidence of Ventricular Arrhythmia From 0-2 and 2-24 Hours from Start of Study Drug Infusion for Vernakalant-Treated Patients and 0-2 and 2-24 Hours Following ECV for Placebo-Treated Patients (All Patients, Excluding CRAFT) Time Period Treatment Placebo Vernakalant 0-2 hrs following first infusion 11/439 (2.5) 39/1037 (3.8) 0-2 hrs following first ECV attempt 6/261 (2.3) 6/404 (1.5) 2-24 hrs following first infusion 43/439 (9.8) 72/1037 (6.9) 2-24 hrs following first ECV attempt 18/261 (6.9) 17/404 (4.2) Abbreviations: hrs: hours; ECV, electrical cardioversion
8.6.1.5 1 vs 2 doses The incidence of SAEs of ventricular arrhythmia in the All Patients Population in 0-2 and 2-24 hours based on the number of doses received is presented in Table 31. Overall there is no trend regarding the number of doses on the incidence of SAEs of ventricular arrhythmia reported for vernakalant.
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Table 31. Incidence of SAEs of Ventricular Arrythmias from 0-2 and 2-24 hours by Number of Doses Administered (Safety Set, All Patients Population) 0-2 hours 2-24 hours 1 dose 2 doses 1 dose 2 doses Placebo VKT Placebo VKT Placebo VKT Placebo VKT (N=9) (N=379) (N=450) (N=694) (N=9) (N=379) (N=450) (N=694) Event n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Tachycardia 0 1 (0.3%) 0 0 0 0 0 0 Ventricular 0 1 (0.3%) 0 0 0 0 1 (0.2%) 0 extrasystoles Ventricular 0 0 0 2 (0.3%) 0 0 0 0 fibrillation Ventricular 0 1 (0.3%) 0 0 0 0 1 (0.2%) 0 tachycardia Abbreviations: VKT,vernakalant
8.6.1.6 Subpopulation Analysis The risk of ventricular arrhythmia was not impacted in a clinically meaningful manner by duration of the current episode, age, sex, history of hypertension, history of ischemic heart disease, or history of myocardial infarction. It was also not impacted in a clinically meaningful way by the following extrinsic factors: use of rate control medications, calcium channel blockers, digoxin, rhythm control medications, CYP2D6 inhibitors, CYP2D6 substrates, and use of QT prolonging medications. In patients with a history of CHF, a greater risk of ventricular arrhythmia was observed with vernakalant than placebo from 0-2 hours (% risk difference for vernakalant - placebo [95% CI]: 6.5 [0.4, 12.7]); however, from 2-24 hours the risk was greater with placebo than vernakalant (% risk difference [95% CI]: -9.7 [-22.3, 2.9]). In patients with a history of valvular heart disease, from 0-2 hours, there was a greater risk of ventricular arrhythmia observed with vernakalant than placebo (% risk difference for vernakalant - placebo [95% CI]: 7.1 [1.5, 12.7]). Most ventricular arrhythmias were detected through continuous ECG monitoring, and the number of patients with a history of valvular heart disease was small making the clinical interpretation of this finding uncertain. 8.6.1.7 Analysis of AEs Using Risk Mitigation Strategies From 0-2 hours post-dose the incidence of ventricular arrhythmia was 3.8% in vernakalant patients and 2.5% in placebo patients and from 2-24 hours post-dose, the incidence was 6.9% in vernakalant patients and 9.8% in placebo patients. SAEs or discontinuations for a ventricular arrhythmia event were reported in 0.7% (8/1073) of the vernakalant group and 0.4% (2/459) of the placebo group in the first 24 hours. Three cases of ventricular fibrillation were reported with vernakalant. One occurred in a patient with known severe aortic stenosis and findings suggestive of acute coronary syndrome (chest pain and ST segment elevation on the ECG) who developed severe hypotension and then the arrhythmia. Another occurred during an attempted ECV and was attributed to a non-synchronized cardioversion. The third occurred in a patient with cardiogenic shock who experienced ventricular fibrillation during attempted resuscitation.
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SAEs of TdP were reported in 0.2% (2/1073) of vernakalant patients and 0.2% (1/459) of placebo patients; none of the TdP occurred within 24 hours post-dose. An instance of asymptomatic TdP (which was not recorded as an SAE or AE) was captured on the Holter recordings of a patient with atrial flutter shortly after the patient had received ibutilide. In patients with a history of CHF, a greater risk of ventricular arrhythmia was observed with vernakalant than placebo from 0-2 hours; however, from 2-24 hours the risk was greater with placebo than vernakalant. In patients with a history of valvular heart disease, from 0-2 hours, there was a greater risk of ventricular arrhythmia observed with vernakalant than placebo. Most ventricular arrhythmias were simple ventricular ectopy and there were few cases of non-sustained monomorphic ventricular tachycardia detected through continuous ECG monitoring in which to calculate risk. This combined with the relatively small number of patients with valvular heart disease make the clinical implications uncertain. As discussed in other sections, the presence of clinically significant aortic stenosis and evidence of an acute coronary syndrome and evidence of Class III/IV heart failure of known moderate or severe left ventricular function will be contraindicated. The risk of ventricular arrhythmia in patients with a history of valvular heart disease is proposed to be included in the Warnings and Precautions section of the prescribing information. Patients with a family history of Long QT syndrome or Brugada syndrome may be at increased risk for developing TdP. Vernakalant use is not recommended in these patients unless a diagnosis of Long QT syndrome has been definitively ruled out by specialized testing in the patient to be treated. Further, due to the risk of developing clinically-relevant arrhythmias, vernakalant use in patients with significant prolonged QT at baseline, e.g., uncorrected QT >440 msec, is contraindicated. Though limited by the size of the clinical database in the assessment of relatively rare events, vernakalant has been administered to patients with an uncorrected QT <440 msec without an increased risk of TdP. A contraindication regarding the administration of vernakalant within 4 hours prior to, or following, intravenous Class I and III antiarrhythmics is also included. As noted above, there is also a contraindication to the administration of vernakalant in case of prolonged QT (uncorrected >440 msec). This contraindication is considered sufficient to guard against excessive prolongation of QT interval which is the main risk when antiarrhythmic drugs are co-administered. In the Target Patient Population, the incidence of ventricular arrhythmias detected from both reported events and 12-lead ECG and Holter sources was 3.0% in vernakalant patients and 2.3% in placebo patients from 0-2 hours post-dose and 5.1% in vernakalant patients and 6.9% in placebo patients in the 2-24 hour period. Of these, 1.3% and 0.4% were adverse events of ventricular arrhythmia in the vernakalant and placebo groups respectively in the 0-2 hour period and 1.2% of patients were adverse events in the 2-24 hour period in both treatment groups. There were 4 SAEs or discontinuations of study drug for ventricular arrhythmia in the vernakalant group (0.6%) and 0 in the placebo group from 0-2 hours post-dose in the Target Patient Population. The two SAEs were ventricular tachycardia and ventricular extrasystole (0.3%, 2/668) and the drug discontinuation was due to ventricular tachycardia, none of these (b) (6) three events required treatment. However, the AE of ventricular fibrillation in patient (the patient with known moderate LV dysfunction who had VF during the resuscitation attempt) required defibrillation. Table 32 summarizes these events in the Target Patient Population.
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Table 32. SAEs and Discontinuations and Treatment for Ventricular Arrhythmia in the Target Patient Population 0-2 Hours 2-24 Hours Placebo Vernakalant Placebo Vernakalant SAEs and discontinuations N=259 N=668 N=259 N=668 Ventricular arrhythmia, n (%) 0 4 (0.6) 0 0 Use of defibrillation, n 0 1 0 0 No treatment, n 0 3 0 0
8.6.2 Bradycardia 8.6.2.1 Pharmacology of conversion Bradycardia is commonly associated with conversion of AF to sinus rhythm irrespective of modality. Sinus bradycardia and sinus pauses have been observed after spontaneous conversion of AF to sinus rhythm.85 Bradyarrhythmias after cardioversion for AF1 may be a manifestation of sino-atrial dysfunction. In a study of 140 patients with persistent AF, sinus bradycardia (sinus rate < 40 bpm for ≥2 consecutive cycles) and/or sinus pauses (≥2 seconds) were present in the first minute of sinus rhythm after electrical cardioversion in 22% of patients.85 Similarly, in a large retrospective study of electrical cardioversions of acute AF (< 48 hours) 0.9% (63/6906) of ECVs resulted in bradyarrhythmia; asystole of > 5 secs in 51 cardioversions with 7 cases requiring short resuscitations and extrinsic pacing required in 2 patients.86 Similar post-conversion bradycardia with pauses of up to 5 secs have been observed with pharmacological converting agents including flecainide (2.0%, 2/101) and ibutilide (2.8%, 3/106).87 8.6.2.2 Correvio Events of Interest Analysis The data sources for all events of bradycardia included the following: • AE preferred terms of atrioventricular block complete, bradycardia, cardiac pacemaker insertion, cardio-respiratory arrest, nodal rhythm, sick sinus syndrome, sinus arrest, sinus node dysfunction, sinus bradycardia, and heart rate decreased. • Cardiologist over-read of 12-lead ECGs: 2nd degree atrioventricular block, 3rd degree atrioventricular block, complete heart block, junctional rhythm, sinus bradycardia, and other rhythms as prespecified in the statistical analysis plan. • CEC assessment of 12-lead ECG: 2nd degree atrioventricular block, heart rate <40 bpm, junctional rhythm. • 12-lead ECG – alerts and interval data: heart rate <40 bpm. • Holter device cardiologist over-read: complete heart block, sinus pause. • Holter alerts: complete heart block, heart rate <40 bpm. • Holter interval data: heart rate <40 bpm. The incidence of above defined bradycardia events using these data sources for the All Patients Population excluding CRAFT is presented for 0-2 hours, 2-24 hours, and 0-24 hours post-dose in Table 33. The incidence of bradycardia events was 5.1% in vernakalant patients and 2.7% in placebo patients from 0-2 hours post-dose and 7.5% in vernakalant patients and 12.8% in placebo patients from 2-24 hours post-dose.
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The increased occurrence of bradycardia with vernakalant in the 0-2 hour time period is associated with cardioversion. Similarly, it seems likely that the higher incidence of bradycardia in the placebo group following 2-24 hours is also likely associated with cardioversion given the higher incidence of ECV in this time period following the initial 2 hour observation period. Thirty-nine percent (404/1037) of patients in the vernakalant group had an ECV attempt and 59.5% (261/439) of patients in the placebo group had an ECV attempt. Vernakalant did not affect response to subsequent cardioversion. Electrical cardioversion was successful in 92.3% (241/261) of patients in the placebo group and 89.4% (361/404) of patients in the vernakalant group. Table 33. Incidence of Bradycardia Events from 0-2, 2-24, and 0-24 Hours Post-Dose (Safety Set, All Patients Population Excluding CRAFT)
0-2 hours 2-24 hours 0-24 hours Placebo Vernakalant Placebo Vernakalant Placebo Vernakalant (N=439) (N=1037) (N=439) (N=1037) (N=439) (N=1037) Source Event n (%) n (%) n (%) n (%) n (%) n (%) All Groups Any bradycardia event 12 (2.7%) 53 (5.1%) 56 (12.8%) 78 (7.5%) 64 (14.6%) 117 (11.3%) AE Any bradycardia event 3 (0.7%) 41 (4.0%) 11 (2.5%) 24 (2.3%) 14 (3.2%) 63 (6.1%) Databasea Atrioventricular block 0 1 (0.1%) 0 1 (0.1%) 0 2 (0.2%) complete Bradycardia 1 (0.2%) 26 (2.5%) 6 (1.4%) 9 (0.9%) 7 (1.6%) 35 (3.4%) Heart rate decreased 1 (0.2%) 0 0 1 (0.1%) 1 (0.2%) 1 (0.1%) Nodal rhythm 0 2 (0.2%) 0 4 (0.4%) 0 5 (0.5%) Sick sinus syndrome 0 1 (0.1%) 0 0 0 1 (0.1%) Sinus arrest 1 (0.2%) 6 (0.6%) 0 2 (0.2%) 1 (0.2%) 8 (0.8%) Sinus bradycardia 0 8 (0.8%) 5 (1.1%) 9 (0.9%) 5 (1.1%) 17 (1.6%) CEC Any bradycardia event 0 3 (0.3%) 2 (0.5%) 4 (0.4%) 2 (0.5%) 6 (0.6%) assessment 2nd degree AV block 0 1 (0.1%) 0 1 (0.1%) 0 2 (0.2%) of 12-lead ECG Heart rate <40 bpm 0 1 (0.1%) 0 0 0 1 (0.1%) Junctional rhythm 0 1 (0.1%) 2 (0.5%) 3 (0.3%) 2 (0.5%) 3 (0.3%) 12-lead ECG Any bradycardia event 1 (0.2%) 9 (0.9%) 6 (1.4%) 13 (1.3%) 6 (1.4%) 21 (2.0%) cardiologist 2nd degree AV block 0 1 (0.1%) 0 0 1 (0.1%) over-read 3rd degree AV block 0 1 (0.1%) 1 (0.2%) 0 1 (0.2%) 1 (0.1%) Complete heart block 0 0 1 (0.2%) 0 1 (0.2%) 0 Junctional rhythm 0 3 (0.3%) 1 (0.2%) 4 (0.4%) 1 (0.2%) 6 (0.6%) Other rhythm 1 (0.2%) 4 (0.4%) 2 (0.5%) 2 (0.2%) 2 (0.5%) 6 (0.6%) Sinus bradycardia 0 0 3 (0.7%) 7 (0.7%) 3 (0.7%) 7 (0.7%) Holter Any bradycardia event 0 2 (0.2%) 2 (0.5%) 1 (0.1%) 2 (0.5%) 3 (0.3%) device Complete heart block 0 0 1 (0.2%) 0 1 (0.2%) 0 cardiologist over-read Sinus pause 0 2 (0.2%) 1 (0.2%) 1 (0.1%) 1 (0.2%) 3 (0.3%) 12-lead ECG Any bradycardia event 3 (0.7%) 3 (0.3%) 12 (2.7%) 6 (0.6%) 12 (2.7%) 8 (0.8%) alerts Heart rate <40 bpm 3 (0.7%) 3 (0.3%) 12 (2.7%) 6 (0.6%) 12 (2.7%) 8 (0.8%)
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0-2 hours 2-24 hours 0-24 hours Placebo Vernakalant Placebo Vernakalant Placebo Vernakalant (N=439) (N=1037) (N=439) (N=1037) (N=439) (N=1037) Source Event n (%) n (%) n (%) n (%) n (%) n (%) Holter alerts Any bradycardia event 5 (1.1%) 11 (1.1%) 30 (6.8%) 25 (2.4%) 35 (8.0%) 34 (3.3%) Complete heart block 0 2 (0.2%) 5 (1.1%) 6 (0.6%) 5 (1.1%) 8 (0.8%) Heart rate <40 bpm 5 (1.1%) 9 (0.9%) 28 (6.4%) 20 (1.9%) 33 (7.5%) 28 (2.7%) 12-lead ECG Any bradycardia event 1 (0.2%) 9 (0.9%) 3 (0.7%) 3 (0.3%) 4 (0.9%) 12 (1.2%) interval data Heart rate <40 bpm 1 (0.2%) 9 (0.9%) 3 (0.7%) 3 (0.3%) 4 (0.9%) 12 (1.2%) Holter Any bradycardia event 1 (0.2%) 6 (0.6%) 6 (1.4%) 18 (1.7%) 7 (1.6%) 21 (2.0%) interval data Heart rate <40 bpm 1 (0.2%) 6 (0.6%) 6 (1.4%) 18 (1.7%) 7 (1.6%) 21 (2.0%) Abbreviations: AE, adverse event; AV, atrioventricular; CEC, Clinical Events Committee; ECG, electrocardiogram; NDA, New Drug Application a AEs are defined as any non-serious event starting or worsening after the start of the first dose through 10 days after the last dose in addition to all serious events starting or worsening after the start of the first dose through 30 days after the last dose. Notes: The ALL Patients Excluding CRAFT Population includes the following studies: Scene 2, AVRO (vernakalant patients only), ACT I, ACT II, ACT III, ACT IV, ACT V, and AP. The 12-lead ECG data includes data from start of first dose through Day 10. Multiple occurrence of the same event in one individual are counted only once. Within a data source, patients may have experienced more than one type of event. The sum of terms by source may exceed 100%.
The bradycardia observed in the 0-24 hour period appears to be directly related to the higher rate of cardioversion (see Table 34). In patients who converted to sinus rhythm in the first 90 minutes in the vernakalant group the rate of bradycardia was higher in the first 2 hours than in the 2-24 hour period, 7.2% and 5.0% respectively. In patients who did not convert to sinus rhythm in the first 90 minutes, the rate of bradycardia was higher in the 2-24 hour period than the 0-2 hour period, 9.2% and 13.0% in the vernakalant and placebo groups respectively.
Table 34. Bradycardia and Conversion to Sinus Rhythm from 0-2 Hours and 2-24 Hours Post- Dose (All Patients Population Excluding CRAFT) Placebo Vernakalant (N=439) (N=1037) All Patients Bradycardia eventsa from 0-2 hours post-dose 12 (2.7%) 53 (5.1%) Bradycardia eventsa from 2-24 hours post-dose 56 (12.8%) 78 (7.5%) Patients who converted to sinus rhythm within 90 minutes N 23 416 Bradycardia eventsa from 0-2 hours post-dose 0 30 (7.2%) Bradycardia eventsa from 2-24 hours post-dose 2 (8.7%) 21 (5.0%) Patients who did not convert to sinus rhythm within 90 minutesb N 416 621 Bradycardia eventsa from 0-2 hours post-dose 12 (2.9%) 23 (3.7%) Bradycardia eventsa from 2-24 hours post-dose 54 (13.0%) 57 (9.2%) a Events determined from cardiologist over-read of 12-lead electrocardiograms (ECGs), Clinical Events Committee assessment of 12-lead ECGs and calculated interval data from 12-lead ECGs are included in this total. b These patients would have been eligible for electrocardioversion at 2 hours.
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8.6.2.3 FDA Adverse Events of Special Interest Bradycardia-related events were more common in the vernakalant group than placebo (3.3% versus 0.4%) in the 0-2 hour time period and more common in the placebo group than vernakalant (2.8% versus 1.9%) in the 2-24 hour period. These event rates are lower, but consistent in direction of effect, than the incidence of bradycardia based on the analysis performed by the Sponsor (which also included ECG/ Holter assessments) and described in Section 8.6.2.2 above. Bradycardia was likely related to cardioversion. The most common bradycardia event in the FDA AE of Special Interest analysis in vernakalant patients in the 0-24 hour time period was the preferred term bradycardia (3.3% vernakalant, 1.7% placebo), which was driven by the findings in the 0-2 hour time period. Table 35. Incidence of FDA Adverse Events of Special Interest of Bradycardia by Time Period (Safety Set, All Patients Population) Special MedDRA Preferred Term 0-2 hours Postdose 2-24 hours Postdose 0-24 hours Postdose Grouping Pbo Vkt Pbo Vkt Pbo Vkt (N=459) (N=1073) (N=459) (N=1073) (N=459) (N=1073) n (%) n (%) n (%) n (%) n (%) n (%) Bradycardia Any Bradycardia 2 (0.4%) 35 (3.3%) 13 (2.8%) 20 (1.9%) 15 (3.3%) 55 (5.1%) Atrioventricular block complete 0 1 (0.1%) 0 1 (0.1%) 0 2 (0.2%) Bradycardia 1 (0.2%) 26 (2.4%) 7 (1.5%) 9 (0.8%) 8 (1.7%) 35 (3.3%) Heart rate decreased 1 (0.2%) 0 0 1 (0.1%) 1 (0.2%) 1 (0.1%) Sinus bradycardia 0 8 (0.7%) 6 (1.3%) 9 (0.8%) 6 (1.3%) 17 (1.6%) Abbreviations: Pbo, placebo; vernakalant Notes: All Patients Population includes the following studies: CRAFT, Scene 2, AVRO (vernakalant subjects only), ACT I, ACT II, ACT III, ACT IV, ACT V, and AP. Multiple occurrences of the same event in one individual are counted only once. Within a special grouping, subjects may have experienced more than one type of event. The sum of the events by special grouping may exceed 100%.
8.6.2.4 SAEs and Study Drug Discontinuations due to Bradycardia Table 36 shows all SAEs and discontinuations due to bradycardia events that occurred within 24 hours of study drug administration. There was a total of 15 SAEs or discontinuations due to bradycardia events in the vernakalant group (1.4%, 15/1073) and 2 in the placebo group (0.4%, 2/459). Of the total 15 SAEs or discontinuations of bradycardia in the vernakalant group, 12 occurred within the first 2 hours of infusion. Six of the 9 SAEs in the vernakalant group in the first 2 hours following infusion were associated with conversion to sinus rhythm. The 3 that occurred in the 2-24 hour period are described briefly here. (b) (6) • Subject received two doses of vernakalant and converted to sinus rhythm. After conversion the subject had episodes of asymptomatic sinus bradycardia (HR 42-93). Amiodarone was started 98 minutes after the completion of vernakalant for maintenance of sinus rhythm and the subject experienced the SAE of bradycardia 3 hours after the amiodarone dose. (b) (6) • Subject was treated with two doses of vernakalant and did not convert. She was given an oral dose of metoprolol between the two infusions. Two hours and 38 minutes after initiation of vernakalant, she had an ECV which resulted in sinus rhythm with complete heart block and a pulse of 40 bpm and a blood pressure of 47/23 mmHg. She was given 2 boluses of atropine and then placed on intravenous isoprenaline and the pulse and sinus rhythm returned at 120 bpm. Correvio International Sàrl 04 November 2019 Page 92 of 166
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Study Demographics Time from start of Duration Minimum Treatment Target Outcome Patient & Baseline first infusion to of event Heart Rate Patient number Characteristics bradycardia Symptoms Population Amiodarone 48 yo male SAE of cardiac arrest 2 mins BP zero, loss of CPR, atropine, Yes Resolved AF, EF 65% starting at 37 minutes consciousness IV saline into the infusion of AVRO amiodarone, asystole (b) (6) and absent BP, recovered with treatment Abbreviations: AF, atrial fibrillation; AFL, atrial flutter; AV, atrioventricular; BP, blood pressure; bpm, beats per minute; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF, congestive heart failure; CPR, cardiopulmonary resuscitation; d, days; DC, discontinuation; EF, ejection fraction; h/hr, hours; HR, heart rate; HTN, hypertension; IHD, ischemic heart disease; IV, intravenous; LAH, left anterior hemiblock; MI, myocardial infarction; NA, not available; NYHA, New York Heart Association; RBBB, right bundle branch block; SAE, serious adverse event; SBP, systolic blood pressure; yo, year-old Patient Population: CRAFT, ACT I, ACT II, ACT III, ACT IV, ACT V, AVRO, Asia-Pacific
8.6.2.5 Sinus Pause Events within 0-2 and 2-24 Hours Following Vernakalant, Placebo, and ECV The incidence of sinus pause in the All Patients Population excluding CRAFT in 0-2 and 2-24 hours from the start of the infusion, and 0-2 and 2-24 hours following ECV attempt, is presented in Table 37 below. In the first 2 hours following the first infusion, 0.5% of patients receiving placebo developed sinus pause; compared to 1.1% of vernakalant-treated patients. In the first 2 hours following ECV, 4.2% of patients receiving placebo developed sinus pause compared to 1.7% of vernakalant-treated patients. From 2-24 hrs, the sinus pause rates were higher in the placebo group after the first infusion and after first ECV attempt.
Table 37. Incidence (%) of Sinus Pause From 0-2 and 2-24 Hours From Start of Study Drug Infusion for Vernakalant-Treated Patients and 0-2 and 2-24 Hours Following ECV for Placebo-Treated Patients (All Patients, Excluding CRAFT) Time Period Treatment Placebo Vernakalant 0-2 hrs following first infusion 2/439 (0.5%) 11/1037 (1.1%) 0-2 hrs following first ECV attempt 11/261 (4.2%) 7/404 (1.7%) 2-24 hrs following first infusion 3/439 (0.7%) 6/1037 (0.6%) 2-24 hrs following first ECV attempt 1/261 (0.4%) 0/404 (0) Abbreviations: hrs: hours; ECV, electrical cardioversion
8.6.2.6 1 vs 2 doses The incidence of SAEs of bradycardia in the All Patients Population in 0-2 and 2-24 hours based on the number of doses received is presented in Table 38. There was a trend for increased incidence of SAEs of bradycardia after the first dose compared to patients receiving 2 doses. However, all of these patients had an SAE associated with conversion to sinus rhythm.
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Table 38. Incidence (%) of SAEs of Bradycardia from 0-2 and 2-24 hours by Number of Doses Administered (Safety Set, All Patients Population) 0-2 hours 2-24 hours 1 dose 2 doses 1 dose 2 doses Placebo VKT Placebo VKT Placebo VKT Placebo VKT (N=9) (N=379) (N=450) (N=694) (N=9) (N=379) (N=450) (N=694) Event n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Atrioventricular 0 1 (0.3%) 0 0 0 0 0 1 (0.1%) block complete Bradycardia 0 3 (0.8%) 0 1 (0.1%) 0 0 2 (0.4%) 1 (0.1%) Sick sinus 0 1 (0.3%) 0 0 0 0 0 0 syndrome Sinus arrest 0 2 (0.5%) 0 0 0 1 (0.3%) 0 0 Sinus bradycardia 0 2 (0.5%) 0 0 0 0 0 0 Abbreviations: VKT, vernakalant
8.6.2.7 Subpopulation Analysis The risk of bradycardia was not impacted in a clinically meaningful manner by duration of the current AF episode, age, sex, history of hypertension, history of ischemic heart disease, or history of myocardial infarction. It was also not impacted in a clinically meaningful way by the following extrinsic factors: use of rate control medications, calcium channel blockers, digoxin, rhythm control medications, CYP2D6 inhibitors, CYP2D6 substrates, and use of QT prolonging medications. In patients with a history of CHF, a greater risk of bradycardia was observed with placebo than vernakalant from 2-24 hours (% risk difference for vernakalant - placebo [95% CI]: -12.1 [-22.6, - 1.6]). However, from 0-2 hours there was no increased risk with vernakalant compared to placebo (% risk difference [95% CI]: -1.6 [-9.2, 5.9]). In patients with a history of valvular heart disease, from 0-2 hours, there was a greater risk of bradycardia observed with vernakalant than placebo (% risk difference [95% CI]: 8.7 [1.5, 15.9]). Also, in AFL patients, a greater risk of bradycardia was observed with vernakalant than placebo from 0-24 hours (% risk difference for vernakalant - placebo [95% CI]: 8.1 [-7.8, 24.0]). However, AFL is not being pursued as an indication for vernakalant injection as vernakalant was not found effective at the doses evaluated. In patients with background use of Class I antiarrhythmics, a greater risk of bradycardia was observed with vernakalant than placebo at 2-24 hours (% risk difference for vernakalant – placebo [95% CI]: 17.2 [3.5, 30.9]) and 0-24 hours (% risk difference for vernakalant - placebo [95% CI]: 11.0 [-8.3, 30.3]). There were no meaningful increases in the incidence of bradycardia from 0-2 hours following vernakalant treatment. A small number of patients had background use of Class I antiarrhythmics (n=74) compared to those who did not (n=1402) so no inference can be drawn from these data. 8.6.2.8 Analysis of AEs Using Risk Mitigation Strategies As with all forms of cardioversion, bradycardia, heart block, and a prolonged time to sinus node recovery may occur at the time of conversion. Vernakalant should be administered by physicians qualified to provide resuscitative treatment in a location where full resuscitative measures are
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readily available. Bradycardia may also be anticipated as a consequence of prior treatment with rate control agents and in patients with known sick sinus syndrome or atrioventricular nodal disease. In the analysis of bradycardia from the AE database, an increased incidence of bradycardia in the first 2 hours post-dose is apparent (4.0% in vernakalant patients and 0.7% in placebo patients). However, there were no differences in incidence of bradycardia identified from 12-lead ECGs as assessed by the CEC and 24-hour Holter monitoring data (cardiologist over-read) between groups in the first 2 hours post-dose. From 2-24 hours post-dose, the incidence of bradycardia events (all sources combined) was greater for placebo than vernakalant (12.8% in placebo patients and 7.5% for vernakalant patients). The increased rate of bradycardia with vernakalant from 0-2 hours was suspected to be related to conversion to SR. Similarly, the increasing rate of bradycardia in the placebo group from 2-24 hours post-dose is likely indicative of the risks of ongoing AF and the use of other measures for conversion in the 2-24 hour time period and helps put the assessment of the risks of vernakalant into context. The incidence of SAEs of bradycardia events or AEs leading to discontinuation was generally low in the clinical program: 1.4% (15/1073) in vernakalant-treated patients versus 0.4% (2/459) in placebo-treated patients for 0-24 hours. In patients with a history of CHF, from 0-2 hours there was no increased risk with vernakalant compared to placebo but a greater risk of bradycardia was observed with placebo than vernakalant from 2-24 hours. In patients with a history of valvular heart disease, from 0-2 hours, there was a greater risk of bradycardia observed with vernakalant than placebo. In patients with background use of Class I antiarrhythmics, there was no meaningful increase in the incidence of bradycardia from 0-2 hours following vernakalant treatment, however, a greater risk of bradycardia was observed with vernakalant than placebo at 2-24 hours (% risk difference for vernakalant – placebo [95% CI]: 17.2 [3.5, 30.9]). The risk of bradycardia is proposed to be included in the Warnings and Precautions section of the prescribing information. Vernakalant should be used with caution in patients with valvular heart disease due to increased risk of bradycardia. Due to the risk of developing cardiac conduction defects, use of vernakalant in patients with known severe bradycardia, sinus node dysfunction, or second degree or third degree atrioventricular heart block, in the absence of an in situ properly functioning pacemaker, is proposed to be included as a Contraindication in the prescribing information. Since there is limited experience with the use of vernakalant in patients with previously documented left ventricular ejection fraction ≤35%, use in these patients is not recommended. In the Target Patient Population, the incidence of bradycardia from any source was 4.2% in vernakalant patients and 1.5% in placebo patients from 0-2 hours post-dose and 6.7% of vernakalant patients and 7.7% of placebo patients in the 2-24 hour period. Of these patients, 3.4% and 0.8% experienced adverse events of bradycardia in the vernakalant and placebo groups respectively in the 0-2 hour period and 2.4% and 1.9% of patients experienced adverse events in the 2-24 hour period in the vernakalant and placebo groups respectively.
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bradycardia, 1 sick sinus syndrome and 3 bradycardia. Of these patients, 3 received atropine and 3 received no treatment (see Table 39). The 2 patients who had an SAE or discontinuation in the 2- 24 hour time period, did not receive treatment for the event.
Table 39. SAEs and Discontinuations and Treatment for Bradycardia in the Target Patient Population 0-2 Hours 2-24 Hours Placebo Vernakalant Placebo Vernakalant SAEs and discontinuations N=259 N=668 N=259 N=668 Bradycardia, n (%) 0 6 (0.9) 0 2 (0.3) Use of atropine, n 0 3 0 0 No treatment, n 0 3 0 2
8.6.3 Hypotension 8.6.3.1 Mechanism of vernakalant-induced hypotension Based on the preclinical and clinical data collected in this program, hypotension may occur in the setting of decreased myocardial reserve or at the time of cardioversion, associated with transient bradyarrhythmias. The nonclinical data are further described in Section 4.2.1.2 and the clinical details are provided in the following section. 8.6.3.2 Correvio Events of Interest Analysis The data sources for events of hypotension included the following: • AE preferred terms of blood pressure decreased, blood pressure systolic decreased, cardiogenic shock, dizziness postural, hypotension, hypovolemia, hypovolemic shock, orthostatic hypotension, pulseless electrical activity, syncope, and syncope vasovagal. • Vital signs assessments of systolic blood pressure <90 mmHg on the case report forms (CRFs) The incidence of above defined hypotension events using these data sources for the All Patients Population excluding CRAFT is presented for 0-2 hours, 2-24 hours, and 0-24 hours post-dose in Table 40. The incidence all combined hypotension events was 5.7% in vernakalant patients and 4.8% in placebo patients from 0-2 hours post-dose and 3.4% in vernakalant patients and 5.9% in placebo patients from 2-24 hours post-dose. An AE of hypotension occurred in 3.7% of vernakalant patients and 1.4% of placebo patients. The vital sign data for the same period indicated no difference in the frequency of systolic blood pressure <90 mmHg across treatment groups; 4.5% in vernakalant patients and 4.8% in placebo patients.
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Table 40. Incidence of Hypotension Events from 0-2, 2-24, and 0-24 Hours Post-Dose (Safety Set, All Patients Population Excluding CRAFT) 0-2 hours 2-24 hours 0-24 hours Placebo Vernakalant Placebo Vernakalant Placebo Vernakalant (N=439) (N=1037) (N=439) (N=1037) (N=439) (N=1037) Source Event n (%) n (%) n (%) n (%) n (%) n (%) All Groups Any hypotension event 21 (4.8%) 59 (5.7%) 26 (5.9%) 35 (3.4%) 41 (9.3%) 84 (8.1%) AE Any hypotension event 6 (1.4%) 44 (4.2%) 13 (3.0%) 18 (1.7%) 19 (4.3%) 60 (5.8%) Databasea Blood pressure 0 1 (0.1%) 0 0 0 1 (0.1%) decreased Blood pressure systolic 0 1 (0.1%) 0 0 0 1 (0.1%) decreased Cardiogenic shock 0 1 (0.1%) 0 1 (0.1%) 0 2 (0.2%) Hypotension 6 (1.4%) 38 (3.7%) 13 (3.0%) 16 (1.5%) 19 (4.3%) 53 (5.1%) Pulseless electrical 0 1 (0.1%) 0 0 0 1 (0.1%) activity Syncope 0 1 (0.1%) 0 2 (0.2%) 0 3 (0.3%) Syncope vasovagal 0 2 (0.2%) 0 0 0 2 (0.2%) Vital signs Any hypotension event 21 (4.8%) 47 (4.5%) 19 (4.3%) 26 (2.5%) 34 (7.7%) 64 (6.2%) Systolic blood pressure 21 (4.8%) 47 (4.5%) 19 (4.3%) 26 (2.5%) 34 (7.7%) 64 (6.2%) <90 mmHg Abbreviations: AE, adverse event; NDA, New Drug Application a AEs are defined as any non-serious event starting or worsening after the start of the first dose through 10 days after the last dose in addition to all serious events starting or worsening after the start of the first dose through 30 days after the last dose. Notes: The ALL Patients Excluding CRAFT Population includes the following studies: Scene 2, AVRO (vernakalant patients only), ACT I, ACT II, ACT III, ACT IV, ACT V, and AP. Multiple occurrence of the same event in one individual are counted only once. Within a data source, patients may have experienced more than one type of event. The sum of terms by source may exceed 100%.
8.6.3.3 FDA Adverse Events of Special Interest Hypotension-related events (includes additional terms potentially associated with hypotension) were more common in the vernakalant group than placebo (6.4% versus 2.8%) in the 0-2 hour time period and more common in the placebo group than vernakalant (3.9% versus 2.5%) in the 2-24 hour time period. These data are similar to the incidence of hypotension based on the analysis performed by Correvio and described in Section 8.6.3.2 above. The most common hypotension- related event in the FDA AE of Special Interest analysis in vernakalant patients in the 0-24 hour time period was the preferred term hypotension which was present in a similar proportion of both treatment groups (5.0% vernakalant, 4.4% placebo).
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Table 41. Incidence of FDA Adverse Events of Special Interest of Hypotension by Time Period (Safety Set, All Patients Population) Special MedDRA Preferred Term 0-2 hours Postdose 2-24 hours Postdose 0-24 hours Postdose Grouping Pbo Vkt Pbo Vkt Pbo Vkt (N=459) (N=1073) (N=459) (N=1073) (N=459) (N=1073) n (%) n (%) n (%) n (%) n (%) n (%) Hypotension- Any Hypotension-related event 13 (2.8%) 69 (6.4%) 18 (3.9%) 27 (2.5%) 30 (6.5%) 93 (8.7%) related event Blood pressure decreased 0 1 (0.1%) 0 0 0 1 (0.1%) Blood pressure systolic 0 1 (0.1%) 0 0 0 1 (0.1%) decreased Cardiogenic shock 0 1 (0.1%) 0 1 (0.1%) 0 2 (0.2%) Dizziness 7 (1.5%) 29 (2.7%) 3 (0.7%) 8 (0.7%) 10 (2.2%) 37 (3.4%) Dizziness postural 0 0 0 1 (0.1%) 0 1 (0.1%) Hypotension 6 (1.3%) 39 (3.6%) 14 (3.1%) 16 (1.5%) 20 (4.4%) 54 (5.0%) Hypovolemic shock 0 0 0 0 0 0 Orthostatic hypotension 0 0 0 0 0 0 Presyncope 0 1 (0.1%) 1 (0.2%) 0 1 (0.2%) 1 (0.1%) Pulseless electrical activity 0 1 (0.1%) 0 0 0 1 (0.1%) Syncope 0 3 (0.3%) 0 3 (0.3%) 0 6 (0.6%)
8.6.3.4 SAEs and Study Drug Discontinuations due to Hypotension Table 42 shows all SAEs and discontinuations due to hypotension events that occurred within 24 hours of study drug administration. There was a total of 11 SAEs or discontinuations for hypotension in the vernakalant group (1.0%, 11/1073) and 3 in the placebo group (0.7%, 3/459). Of the total 11 SAEs or discontinuations of hypotension in the vernakalant group, 10 occurred within the first 2 hours of infusion. In 7 of the cases, saline, positioning or no treatment were adequate to resolve the hypotension. (b) (6) The 1 SAE that occurred in the 2-24 hour period was a patient ) who received one dose of vernakalant and converted to sinus rhythm at the end of the first dose then reverted to AF and received a second dose of vernakalant again converting to sinus rhythm. Approximately 5 hours later the patient was given oral verapamil and an hour following this the patient experienced hypotension, vomiting, and abdominal discomfort. An abdominal scan indicated possible cholecystitis.
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8.6.3.5 Hypotension Events within 0-2 and 2-24 Hours Following Vernakalant, Placebo, and ECV In the All Patients Population in the first 2 hours from the start of study drug infusion, the incidence of hypotension was similar between treatment groups (risk difference 0.9%, 95% CI: -1.7 to 3.5%) although higher in the vernakalant group when considering AEs alone (risk difference 2.9% [95% CI: 1.1, 4.7%]). The incidence of hypotension in the All Patients Population (excluding CRAFT) in 0-2 and 2-24 hours from the start of the infusion, and 0-2 and 2-24 hours following ECV attempt, is presented in Table 43 below. In the first 2 hours following ECV, 4.8% of patients receiving placebo developed hypotension; whereas in the first 2 hours following vernakalant, 5.7% (of vernakalant- treated patients) developed hypotension. The data show similar incidences of hypotension in the 2 hours following vernakalant infusion and placebo infusion and in the 2 hours after ECV. Table 43. Incidence of Hypotension Events 0-2 and 2-24 Hours from the Start of Study Drug Infusion and 0-2 and 2-24 Hours Following Electrical Cardioversion (All Patients, Excluding CRAFT) Time Period Treatment Placebo Vernakalant 0-2 hrs following first infusion 21/439 (4.8) 59/1037 (5.7) 0-2 hrs following first ECV attempt 16/261 (6.1) 12/404 (3.0) 2-24 hrs following first infusion 26/439 (5.9) 35/1037 (3.4) 2-24 hrs following first ECV attempt 3/261 (1.1) 4/404 (1.0) Abbreviations: hrs: hours; ECV, electrical cardioversion
8.6.3.6 1 vs 2 doses The incidence of SAEs of hypotension in the All Patients Population in 0-2 and 2-24 hours based on the number of doses received is presented in Table 44. Overall there is no trend regarding the number of doses on the incidence of SAEs of hypotension reported for vernakalant. Table 44. Incidence of SAEs of Hypotension from 0-2 and 2-24 hours by Number of Doses Administered (Safety Set, All Patients Population) 0-2 hours 2-24 hours 1 dose 2 doses 1 dose 2 doses Placebo VKT Placebo VKT Placebo VKT Placebo VKT (N=9) (N=379) (N=450) (N=694) (N=9) (N=379) (N=450) (N=694) Event n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Cardiogenic shock 0 1 (0.3%) 0 0 0 1 (0.3%) 0 0 Hypotension 0 5 (1.3%) 0 3 (0.4%) 0 0 1 (0.2%) 1 (0.1%) Syncope 0 0 0 0 0 1 (0.3%) 0 0 Abbreviations: VKT, vernakalant
8.6.3.7 Subpopulation Analysis The risk of hypotension was not impacted in a clinically meaningful manner by duration of the current episode, age, sex, history of hypertension, history of ischemic heart disease, or history of myocardial infarction. It was also not impacted in a clinically meaningful way the following extrinsic factors: use of rate control medications, calcium channel blockers, digoxin, rhythm Correvio International Sàrl 04 November 2019 Page 103 of 166
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control medications, CYP2D6 inhibitors, CYP2D6 substrates, and use of QT prolonging medications. In patients with a history of CHF, a greater risk of hypotension was observed with vernakalant than placebo from 0-2 hours (% risk difference for vernakalant - placebo [95% CI]: 9.1 [0.8, 17.4]). In patients with AFL, a greater risk of hypotension was observed with vernakalant than placebo from 0-2 hours (% risk difference for vernakalant - placebo [95% CI]: 16.9 [4.7, 29.2]) and from 0-24 hours (% risk difference for vernakalant - placebo [95% CI]: 18.5. [3.2, 33.7]). However, AFL is not being pursued as an indication for vernakalant injection as vernakalant was not found effective at the doses evaluated. In patients with a background use of beta blockers, there was a greater risk of hypotension observed with vernakalant than placebo from 0-2 hours (% risk difference for vernakalant -placebo [95% CI]: 4.4 [0.8, 8.0]). 8.6.3.8 Analysis of AEs Using Risk Mitigation Strategies Hypotension was characterized as an identified risk from the integrated analysis of events of interest using multiple data sources (AEs and vital sign assessments). Hypotension events generally occurred within 15 minutes of the end of vernakalant injection and resolved without sequelae. Overall, the incidence of the hypotension events from all sources combined was greater for vernakalant patients during the first 2 hours post-dose than placebo patients (5.7% in vernakalant patients and 4.8% in placebo patients). After that time period, the incidence of hypotension events in the All Patients Population was greater for placebo than vernakalant (5.9% in placebo patients and 3.4% for vernakalant patients from 2-24 hours postdose). Of the total 11 SAEs or discontinuations of hypotension in the vernakalant group, 10 occurred within the first 2 hours of infusion (0.9%, 10/1073). Of the 3 SAEs or discontinuations of hypotension in the placebo group, one occurred in the first 2 hours. Generally, the hypotension resolved quickly (within <1 hour in the majority of these cases). As hypotension is considered to be the most clinically significant adverse effect across the program, the label will specify the conditions and contraindications for use. Vernakalant should be administered by intravenous infusion in a monitored clinical setting appropriate for cardioversion which includes all the necessary items used for resuscitation. Only a qualified healthcare professional should administer vernakalant and the patient should be carefully observed for signs and symptoms of a sudden decrease in blood pressure or heart rate, during infusion and for at least 2 hours after cessation of treatment, and until clinical status and ECG parameters are stable. A recognized drop in systolic blood pressure is an indication to stop the infusion. The risk of hypotension events is increased in the first 2 hours in patients with CHF and in patients with background use of beta blockers. The proposed label indicates that severe heart failure (including New York Heart Association [NYHA] class III and IV or known moderate or severe left ventricular dysfunction) is a contraindication. Also, systolic blood pressure <100 mmHg (or having received fluid resuscitation or inotropes to maintain BP >100mmHg) is proposed as a contraindication. In the proposed Warnings section, it is stated: “In the clinical development program, loading oral doses or intravenous use of beta-blockers were withheld from 2 hours before and until 2 hours after completion of the study drug infusion. Therefore, use of intravenous beta- blockers is not recommended within 2 hours prior to, or 2 hours after, vernakalant administration.”
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In the Target Patient Population, the incidence of hypotension from any source was 3.3% in vernakalant patients and 3.9% in placebo patients from 0-2 hours post-dose and 2.7% in vernakalant patients and 6.2% in placebo patients in the 2-24 hour period. Of these patients, 2.8% and 1.5% experienced adverse events of hypotension in the vernakalant and placebo groups respectively in the 0-2 hour period and 2.1% and 3.5% of patients experienced adverse events in the 2-24 hour period in the vernakalant and placebo groups respectively. There were 6 SAEs or discontinuations of study drug for hypotension-related events in the vernakalant group (0.9%) of which 5 were SAEs (0.7%, 5/668) and 0 in the placebo group from 0- 2 hours post-dose. Two of the hypotension events were treated with saline and/or pentastarch and Trendelenburg positioning and one hypotension SAE resolved without intervention and for one patient the treatment was unknown. Two patients received pressors for treating the hypotension; a post-surgical patient who concurrently experienced a non-sustained wide complex tachycardia, and (b) (6) patient (the patient with known moderate LV dysfunction who had VF during the resuscitation attempt) who was treated with multiple interventions including dopamine and norepinephrine. There was one SAE of hypotension in the placebo group in the 2-24 hour period who was treated with saline and Trendelenburg positioning, and 0 in the vernakalant group in the same period.
Table 45. SAEs and Discontinuations and Treatment for Hypotension in the Target Patient Population 0-2 Hours 2-24 Hours Placebo Vernakalant Placebo Vernakalant SAEs and discontinuations N=259 N=668 N=259 N=668 Hypotension, n (%) 0 6 (0.9) 1 (0.4) 0 Use of pressors, n 0 2 0 0 Use of saline/Trendelenburg, n 0 2 1 0 No treatment, n 0 1 0 0 Unknown, n 0 1 0 0
8.6.4 Other Adverse Events of Interest 8.6.4.1 Atrial Flutter In the All Patient Population 2.5% of vernakalant-treated patients and 0.4% of placebo-treated patients experienced an AE of atrial flutter (Table 46). Of these, three of the vernakalant events were considered serious and one event led to drug discontinuation in the vernakalant group. There were no cases of atrial flutter with 1:1 atrioventricular conduction in the clinical development program. Table 46. Incidence of Atrial Flutter Events from 0-2, 2-24, and 0-24 Hours Post-Dose (Safety Set, All Patients Population) 0-2 hours 2-24 hours 0-24 hours Placebo Vernakalant Placebo Vernakalant Placebo Vernakalant (N=459) (N=1073) (N=459) (N=1073) (N=459) (N=1073) Event n (%) n (%) n (%) n (%) n (%) n (%) Atrial flutter AEs 1 (0.2) 22 (2.1) 1 (0.2) 5 (0.5) 2 (0.4) 27 (2.5) SAEs 0 3 (0.3) 0 0 0 3 (0.3)
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8.6.4.1.1 SAEs and Study Drug Discontinuations due to Atrial Flutter Table 47 shows all SAEs and discontinuations due to atrial flutter that occurred within 24 hours of study drug administration. There were a total of 3 SAEs or discontinuations for atrial flutter in the vernakalant group and none in the placebo group. Of the 3 total SAEs or discontinuations of atrial flutter in the vernakalant group, 1 occurred within the first 2 hours of infusion.
Table 47. Atrial Flutter Events Reported as a Serious Adverse Event and/or Adverse Event Leading to Discontinuation of Study Drug Within 24 Hours of Study Drug Administration Study Demographics & Time from start of Duration Symptoms Treatment Target Outcome Patient Baseline first infusion to of AFL Patient Number Characteristics AFL event Population Vernakalant Injection ACT IV 76 yo female SAE and D/C for 21 hrs Nausea, hot, Amiodarone No Resolved (b) (6) AF, HTN, stroke AFL 3 mins into 1st AFL with fast IV furosemide x AF>7 days EF ≥50% infusion. SAE of ventricular 3 pulmonary edema at response rate 39 mins after 1st of 178 bpm infusion ACT V 67 yo male SAE of AFL at 25 1 hr 5 None IV metoprolol at Yes Resolved (b) (6) AF mins then min 1 hr 10 and 2 hr administered 2nd 44 min after start dose. of VKT. 1st degree AV block followed by SR at 4 hrs post dose ACT V 80 yo female Received VKT 3 days None Bisoprolol, Yes Resolved (b) (6) HTN infusion (per Holter reported propranolol, subject in SR at amiodarone at baseline). SAE of discharge AFL next day (onset time unknown) Abbreviations: AE, adverse event; AF, atrial fibrillation; AFL, atrial flutter; AV, atrioventricular; bpm, beats per minute; DC, discontinuation; EF, ejection fraction; HTN, hypertension; IV, intravenous; SAE, serious adverse event; SR, sinus rhythm; VKT, vernakalant; yo, years old. Patient Population: CRAFT, ACT I, ACT II, ACT III, ACT IV, ACT V, AVRO, Asia-Pacific
The outcome of patients who developed atrial flutter on vernakalant per CEC adjudication of 12- lead ECGs was studied in the subgroup of vernakalant-treated patients in the pooled ACT I/III population with AF at baseline (n=339). In this population, 33 patients with only AF on pre- treatment ECGs developed atrial flutter within 90 minutes after receiving vernakalant (33/339, 9.7%). None of these AFL episodes was considered a serious adverse event. Of the 33 patients who developed atrial flutter, 10 converted to sinus rhythm within 90 minutes of initiating vernakalant.
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8.7 Other Adverse Events 8.7.1 Overview of AEs An overview of TEAEs in the 0-2, 2-24 hour and all post-dose periods is presented in Table 48. The majority of adverse events in the vernakalant group occurred in the 0-2 hour period following start of infusion. Table 48. Overview of Treatment-Emergent AEs (Safety Set, All Patients Population) 0-2 hours 2-24 hours All Post-Dose Placebo Vernakalant Placebo Vernakalant Placebo Vernakalant (N=459) (N=1073) (N=459) (N=1073) (N=459) (N=1073) n (%) n (%) n (%) n (%) n (%) n (%) Any TEAE 75 (16.3%) 521 (48.6%) 112 (24.4%) 257 (24.0%) 259 (56.4%) 750 (69.9%) Any related TEAE 31 (6.8%) 458 (42.7%) 16 (3.5%) 53 (4.9%) 50 (10.9%) 496 (46.2%) Any severe TEAE 7 (1.5%) 52 (4.8%) 13 (2.8%) 29 (2.7%) 42 (9.2%) 124 (11.6%) Any treatment-emergent SAE 3 (0.7%) 32 (3.0%) 15 (3.3%) 21 (2.0%) 75 (16.3%) 142 (13.2%) Any related treatment- 0 21 (2.0%) 1 (0.2%) 3 (0.3%) 1 (0.2%) 23 (2.1%) emergent SAE Drug discontinuations due to - - - - 3 (0.7%) 34 (3.2%) TEAE Deaths 0 1 0 0 1 (0.2%) 8 (0.7%)
8.7.2 Common TEAEs Common TEAEs are defined as AEs that occurred in ≥1% of patients (cumulatively) in either treatment group for purposes of presentation in the in-text tabular summaries. Appendix 5 presents the common TEAEs (cumulative events) in the All Patients Population by each time period as well as the common TEAEs (cumulative events) by each time period for the Primary AF Population. The most frequent TEAEs in vernakalant patients over the first 2 hours were dysgeusia (17.1%), sneezing (12.6%) and paresthesia (6.8%). These TEAEs were also the most frequent in vernakalant patients from 0-24 hours. The most frequent TEAEs in placebo patients over the first 2 hours post-dose were dysgeusia (2.2%), headache (2.2%) and dizziness (1.5%) and over the first 24 hours were AF (4.4%), hypotension (4.4%; compared with 5.0% in vernakalant-treated patients), headache (3.1%), dysgeusia (2.2%), and dizziness (2.2%). 8.7.3 SAEs 8.7.3.1 Serious Adverse Events over Time From 0 to 24 hours post dose, SAEs occurring in more than 1 vernakalant patient included: hypotension, AF, bradycardia, AFL, sinus arrest, angina pectoris, atrioventricular block complete, cardiogenic shock, sinus bradycardia, and ventricular fibrillation. Within the first 2 hours, the incidence of SAEs was greater in the vernakalant group (3.0% in the vernakalant group versus 0.7% in placebo). The most frequent SAE in vernakalant patients in the first 2 hours was hypotension (0.7%). In the 2-24 hours post-dose, the incidence of SAEs was greater in the placebo group (3.3% in the placebo group versus 2.0 % in vernakalant). The most frequent SAE from 2-24 hours post-dose was AF (1.1% for placebo and 0.6% for vernakalant). In the 0-24 hours post-dose analysis, the incidence of SAEs was greater in the vernakalant group (4.8%) than placebo (3.9%). Correvio International Sàrl 04 November 2019 Page 107 of 166
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Table 49. All Serious Treatment-Emergent AEs from 0-2 hours, 2-24 hours, and 0-24 hours (Safety Set, All Patients Population) MedDRA System Organ 0-2 hours 2-24 hours 0-24 hours Class Placebo Vernakalant Placebo Vernakalant Placebo Vernakalant Preferred Term (N=459) (N=1073) (N=459) (N=1073) (N=459) (N=1073) n (%) n (%) n (%) n (%) n (%) n (%) All Systems 3 (0.7%) 32 (3.0%) 15 (3.3%) 21 (2.0%) 18 (3.9%) 51 (4.8%) Blood and lymphatic 0 0 1 (0.2%) 1 (0.1%) 1 (0.2%) 1 (0.1%) system disorders Coagulopathy 0 0 0 1 (0.1%) 1 (0.2%) 1 (0.1%) Iron deficiency anemia 0 0 1 (0.2%) 0 1 (0.2%) 0 Cardiac disorders 2 (0.4%) 19 (1.8%) 10 (2.2%) 13 (1.2%) 12 (2.6%) 32 (3.0%) Angina pectoris 0 1 (0.1%) 1 (0.2%) 1 (0.1%) 1 (0.2%) 2 (0.2%) Atrial fibrillation 0 2 (0.2%) 5 (1.1%) 6 (0.6%) 5 (1.1%) 8 (0.7%) Atrial flutter 0 3 (0.3%) 0 0 0 3 (0.3%) Atrial thrombosis 0 0 0 1 (0.1%) 0 1 (0.1%) Atrioventricular block 0 1 (0.1%) 0 1 (0.1%) 0 2 (0.2%) complete Atrioventricular block 0 0 0 1 (0.1%) 0 1 (0.1%) first degree Bradycardia 0 4 (0.4%) 2 (0.4%) 1 (0.1%) 2 (0.4%) 5 (0.5%) Cardiac failure 0 0 1 (0.2%) 0 1 (0.2%) 0 congestive Cardiogenic shock 0 1 (0.1%) 0 1 (0.1%) 0 2 (0.2%) Mitral valve 1 (0.2%) 0 0 0 1 (0.2%) 0 incompetence Pericardial effusion 1 (0.2%) 0 0 0 1 (0.2%) 0 Sick sinus syndrome 0 1 (0.1%) 0 0 0 1 (0.1%) Sinus arrest 0 2 (0.2%) 0 1 (0.1%) 0 3 (0.3%) Sinus bradycardia 0 2 (0.2%) 0 0 0 2 (0.2%) Tachycardia 0 1 (0.1%) 0 0 0 1 (0.1%) Ventricular extrasystoles 0 1 (0.1%) 1 (0.2%) 0 1 (0.2%) 1 (0.1%) Ventricular fibrillation 0 2 (0.2%) 0 0 0 2 (0.2%) Ventricular tachycardia 0 1 (0.1%) 1 (0.2%) 0 1 (0.2%) 1 (0.1%) Gastrointestinal disorders 1 (0.2%) 3 (0.3%) 0 0 1 (0.2%) 3 (0.3%) Diarrhea 1 (0.2%) 0 0 0 1 (0.2%) 0 Gastrointestinal 0 1 (0.1%) 0 0 0 1 (0.1%) hemorrhage Hematochezia 0 1 (0.1%) 0 0 0 1 (0.1%) Nausea 0 1 (0.1%) 0 0 0 1 (0.1%) General disorders and ad- 1 (0.2%) 0 1 (0.2%) 0 2 (0.4%) 0 ministration site conditions Hyperthermia 1 (0.2%) 0 0 0 1 (0.2%) 0 Non-cardiac chest pain 0 0 1 (0.2%) 0 1 (0.2%) 0 Hepatobiliary disorders 0 0 0 2 (0.2%) 0 2 (0.2%) Cholecystitis 0 0 0 1 (0.1%) 0 1 (0.1%) Hepatic failure 0 0 0 1 (0.1%) 0 1 (0.1%) Immune system disorders 0 1 (0.1%) 0 0 0 1 (0.1%) Hypersensitivity 0 1 (0.1%) 0 0 0 1 (0.1%)
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MedDRA System Organ 0-2 hours 2-24 hours 0-24 hours Class Placebo Vernakalant Placebo Vernakalant Placebo Vernakalant Preferred Term (N=459) (N=1073) (N=459) (N=1073) (N=459) (N=1073) n (%) n (%) n (%) n (%) n (%) n (%) Injury, poisoning and 0 1 (0.1%) 0 0 0 1 (0.1%) procedural complications Accidental overdose 0 1 (0.1%) 0 0 0 1 (0.1%) Infections and infestations 0 0 0 2 (0.2%) 0 2 (0.2%) Device related infection 0 0 0 1 (0.1%) 0 1 (0.1%) Sepsis 0 0 0 1 (0.1%) 0 1 (0.1%) Investigations 0 0 0 2 (0.2%) 0 2 (0.2%) Electrocardiogram QT 0 0 0 1 (0.1%) 0 1 (0.1%) prolonged Troponin T increased 0 0 0 1 (0.1%) 0 1 (0.1%) Metabolism and nutrition 0 0 0 1 (0.1%) 0 1 (0.1%) disorders Hypoglycemia 0 0 0 1 (0.1%) 0 1 (0.1%) Musculoskeletal and 0 0 0 1 (0.1%) 0 1 (0.1%) connective tissue disorders Rhabdomyolysis 0 0 0 1 (0.1%) 0 1 (0.1%) Nervous system disorders 0 1 (0.1%) 1 (0.2%) 1 (0.1%) 1 (0.2%) 2 (0.2%) Cerebrovascular accident 0 0 1 (0.2%) 0 1 (0.2%) 0 Headache 0 1 (0.1%) 0 0 0 1 (0.1%) Syncope 0 0 0 1 (0.1%) 0 1 (0.1%) Psychiatric disorders 0 1 (0.1%) 0 0 0 1 (0.1%) Confusional state 0 1 (0.1%) 0 0 0 1 (0.1%) Renal and urinary 0 0 0 2 (0.2%) 0 2 (0.2%) disorders Renal failure acute 0 0 0 1 (0.1%) 0 1 (0.1%) Urinary retention 0 0 0 1 (0.1%) 0 1 (0.1%) Respiratory, thoracic 0 3 (0.3%) 0 1 (0.1%) 0 4 (0.4%) and mediastinal disorders Dyspnea 0 1 (0.1%) 0 0 0 1 (0.1%) Pulmonary edema 0 1 (0.1%) 0 0 0 1 (0.1%) Pneumonia aspiration 0 0 0 1 (0.1%) 0 1 (0.1%) Suffocation feeling 0 1 (0.1%) 0 0 0 1 (0.1%) Skin and subcutaneous tis 0 1 (0.1%) 0 0 0 1 (0.1%) sue disorders Cold sweat 0 1 (0.1%) 0 0 0 1 (0.1%) Vascular disorders 0 10 (0.9%) 2 (0.4%) 1 (0.1%) 2 (0.4%) 11 (1.0%) Aortic stenosis 0 1 (0.1%) 0 0 0 1 (0.1%) Deep vein thrombosis 0 0 1 (0.2%) 0 1 (0.2%) 0 Hypertension 0 1 (0.1%) 0 0 0 1 (0.1%) Hypotension 0 8 (0.7%) 1 (0.2%) 1 (0.1%) 1 (0.2%) 9 (0.8%) Abbreviations: MedDRA, Medical Dictionary of Regulatory Activities; NDA, New Drug Application Notes: Multiple occurrence of the same adverse event in 1 individual subject are counted only once. Within a system organ class, subjects may have experienced more than one adverse event. The sum of terms by system organ class may exceed 100%. Data includes: CRAFT, Scene 2, ACT I, ACT II, ACT III, ACT IV, ACT V, AVRO, and AP.
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8.7.3.2 Serious Adverse Events by Dose The incidence of SAEs in the All Patients Population from 0-2 and 2-24 hours based on the number of doses received is presented in Table 50. It is difficult to draw any conclusions from these data since the two populations, patients who receive only one dose and those who receive second dose, are different. Overall the highest incidence of SAEs is in 0-2 hours post dose for patients who received a single dose of vernakalant, suggesting that the second dose does not increase the risk of serious adverse events. Table 50. Incidence of Overall SAEs from 0-2 and 2-24 hours by Number of Doses Administered (Safety Set, All Patients Population) 0-2 hours 2-24 hours 1 dose 2 doses 1 dose 2 doses Placebo VKT Placebo VKT Placebo VKT Placebo VKT (N=9) (N=379) (N=450) (N=694) (N=9) (N=379) (N=450) (N=694) Event n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) All Systems 0 23 (6.1%) 3 (0.7%) 9 (1.3%) 0 6 (1.6%) 15 (3.3%) 15 (2.2%) Blood and lymphatic system 0 0 0 0 0 1 (0.3%) 1 (0.2%) 0 disorders Coagulopathy 0 0 0 0 0 1 (0.3%) 0 0 Iron deficiency anemia 0 0 0 0 0 0 1 (0.2%) 0 Cardiac disorders 0 14 (3.7%) 2 (0.4%) 5 (0.7%) 0 3 (0.8%) 10 (2.2%) 10 (1.4%) Angina pectoris 0 0 0 1 (0.1%) 0 0 1 (0.2%) 1 (0.1%) Atrial fibrillation 0 1 (0.3%) 0 1 (0.1%) 0 0 5 (1.1%) 6 (0.9%) Atrial flutter 0 2 (0.5%) 0 1 (0.1%) 0 0 0 0 Atrial thrombosis 0 0 0 0 0 0 0 1 (0.1%) Atrioventricular block 0 0 0 0 1 (0.3%) 0 0 1 (0.1%) complete Atrioventricular block first 0 0 0 0 0 1 (0.3%) 0 0 degree Bradycardia 0 3 (0.8%) 0 1 (0.1%) 0 0 2 (0.4%) 1 (0.1%) Cardiac failure congestive 0 0 0 0 0 0 1 (0.2%) 0 Cardiogenic shock 0 1 (0.3%) 0 0 0 1 (0.3%) 0 0 Mitral valve incompetence 0 0 1 (0.2%) 0 0 0 0 0 Pericardial effusion 0 0 1 (0.2%) 0 0 0 0 0 Sick sinus syndrome 0 1 (0.3%) 0 0 0 0 0 0 Sinus arrest 0 2 (0.5%) 0 0 0 1 (0.3%) 0 0 Sinus bradycardia 0 2 (0.5%) 0 0 0 0 0 0 Tachycardia 0 1 (0.3%) 0 0 0 0 0 0 Ventricular extrasystoles 0 1 (0.3%) 0 0 0 0 1 (0.2%) 0 Ventricular fibrillation 0 0 0 2 (0.3%) 0 0 0 0 Ventricular tachycardia 0 1 (0.3%) 0 0 0 0 1 (0.2%) 0 Gastrointestinal disorders 0 2 (0.5%) 1 (0.2%) 1 (0.1%) 0 0 0 0 Diarrhea 0 0 1 (0.2%) 0 0 0 0 0 Gastrointestinal 0 0 0 0 1 (0.3%) 0 0 0 hemorrhage Hematochezia 0 0 0 1 (0.1%) 0 0 0 0 Nausea 0 1 (0.3%) 0 0 0 0 0 0 General disorders and ad- 0 0 0 0 1 (0.2%) 0 1 (0.2%) 0 ministration site conditions Hyperthermia 0 0 1 (0.2%) 0 0 0 0 0
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0-2 hours 2-24 hours 1 dose 2 doses 1 dose 2 doses Placebo VKT Placebo VKT Placebo VKT Placebo VKT (N=9) (N=379) (N=450) (N=694) (N=9) (N=379) (N=450) (N=694) Event n (%) n (%) n (%) n (%) n (%) n (%) n (%) n (%) Non-cardiac chest pain 0 0 0 0 0 0 1 (0.2%) 0 Hepatobiliary disorders 0 0 0 0 0 1 (0.3%) 0 1 (0.1%) Cholecystitis 0 0 0 0 0 0 0 1 (0.1%) Hepatic failure 0 0 0 0 0 1 (0.3%) 0 0 Immune system disorders 0 1 (0.3%) 0 0 0 0 0 0 Hypersensitivity 0 1 (0.3%) 0 0 0 0 0 0 Injury, poisoning and 0 0 0 0 1 (0.1%) 0 0 0 procedural complications Accidental overdose 0 0 0 1 (0.1%) 0 0 0 0 Infections and infestations 0 0 0 0 0 1 (0.3%) 0 1 (0.1%) Device related infection 0 0 0 0 0 0 0 1 (0.1%) Sepsis 0 0 0 0 0 1 (0.3%) 0 0 Investigations 0 0 0 0 0 0 0 2 (0.3%) Electrocardiogram QT 0 0 0 0 0 0 0 1 (0.1%) prolonged Troponin T increased 0 0 0 0 0 0 0 1 (0.1%) Metabolism and nutrition 0 0 0 0 0 0 0 1 (0.1%) disorders Hypoglycemia 0 0 0 0 0 0 0 1 (0.1%) Musculoskeletal and 0 0 0 0 0 1 (0.3%) 0 0 connective tissue disorders Rhabdomyolysis 0 0 0 0 0 1 (0.3%) 0 0 Nervous system disorders 0 1 (0.3%) 0 0 0 1 (0.3%) 1 (0.2%) 0 Cerebrovascular accident 0 0 0 0 0 0 1 (0.2%) 0 Headache 0 1 (0.3%) 0 0 0 0 0 0 Syncope 0 0 0 0 0 1 (0.3%) 0 0 Psychiatric disorders 0 1 (0.3%) 0 0 0 0 0 0 Confusional state 0 1 (0.3%) 0 0 0 0 0 0 Renal and urinary disorders 0 0 0 0 0 2 (0.5%) 0 0 Renal failure acute 0 0 0 0 0 1 (0.3%) 0 0 Urinary retention 0 0 0 0 0 1 (0.3%) 0 0 Respiratory, thoracic 0 0 0 0 3 (0.8%) 1 (0.3%) 0 0 and mediastinal disorders Dyspnea 0 1 (0.3%) 0 0 0 0 0 0 Pulmonary edema 0 1 (0.3%) 0 0 0 0 0 0 Pneumonia aspiration 0 0 0 0 0 1 (0.3%) 0 0 Suffocation feeling 0 1 (0.3%) 0 0 0 0 0 0 Skin and subcutaneous 0 0 0 0 1 (0.3%) 0 0 0 tissue disorders Cold sweat 0 1 (0.3%) 0 0 0 0 0 0 Vascular disorders 0 6 (1.6%) 0 4 (0.6%) 0 0 2 (0.4%) 1 (0.1%) Aortic stenosis 0 0 0 1 (0.1%) 0 0 0 0 Deep vein thrombosis 0 0 0 0 0 0 1 (0.2%) 0 Hypertension 0 1 (0.3%) 0 0 0 0 0 0 Hypotension 0 5 (1.3.%) 0 3 (0.4%) 0 0 1 (0.2%) 1 (0.1%) Abbreviations: VKT,vernakalant
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8.7.4 Discontinuations due to Adverse Events A summary of TEAEs resulting in discontinuation from study drug is presented for the All Patients Population in Table 51. The most common TEAEs resulting in discontinuation in vernakalant patients were hypotension (0.8%) and bradycardia (0.5%). Table 51. Treatment-Emergent Adverse Events Resulting in Discontinuation of Study Drug (Safety Set, All Patients Population) MedDRA System Organ Class Overall Preferred Term Placebo (N=459) Vernakalant (N=1073) n (%) n (%) All Systems 3 (0.7%) 34 (3.2%) Cardiac disorders 0 17 (1.6%) Angina pectoris 0 1 (0.1%) Atrial flutter 0 1 (0.1%) Atrioventricular block complete 0 1 (0.1%) Bradycardia 0 5 (0.5%) Bundle branch block left 0 2 (0.2%) Bundle branch block right 0 2 (0.2%) Cardiogenic shock 0 1 (0.1%) Nodal rhythm 0 1 (0.1%) Supraventricular extrasystoles 0 1 (0.1%) Tachycardia 0 1 (0.1%) Ventricular extrasystoles 0 2 (0.2%) Ventricular tachycardia 0 3 (0.3%) Gastrointestinal disorders 0 3 (0.3%) Nausea 0 3 (0.3%) General disorders and administration site conditions 0 2 (0.2%) Feeling hot 0 1 (0.1%) Infusion site pain 0 1 (0.1%) Injection site pain 0 1 (0.1%) Immune system disorders 0 1 (0.1%) Hypersensitivity 0 1 (0.1%) Investigations 2 (0.4%) 4 (0.4%) Electrocardiogram QRS complex prolonged 0 3 (0.3%) Electrocardiogram QT prolonged 2 (0.4%) 1 (0.1%) Nervous system disorders 0 4 (0.4%) Burning sensation 0 1 (0.1%) Dizziness 0 1 (0.1%) Dysgeusia 0 1 (0.1%) Headache 0 2 (0.2%) Psychiatric disorders 0 1 (0.1%) Confusional state 0 1 (0.1%) Respiratory, thoracic and mediastinal disorders 0 4 (0.4%) Dyspnea 0 1 (0.1%) Nasal discomfort 0 1 (0.1%) Pulmonary edema 0 1 (0.1%) Suffocation feeling 0 1 (0.1%)
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MedDRA System Organ Class Overall Preferred Term Placebo (N=459) Vernakalant (N=1073) n (%) n (%) Skin and subcutaneous tissue disorders 0 3 (0.3%) Cold sweat 0 2 (0.2%) Urticaria pressure 0 1 (0.1%) Vascular disorders 1 (0.2%) 10 (0.9%) Hypotension 1 (0.2%) 9 (0.8%) Pallor 0 1 (0.1%)
8.7.5 Deaths 8.7.5.1 Overview of Deaths Across all the clinical studies for follow-up periods to 30 days, 8 patients who received vernakalant injection and 1 patient who received placebo died. With the exception of 2 deaths in the vernakalant groups, the cause of the death was unique in each of the six patients with no common pathophysiological mechanism. Most deaths occurred long after vernakalant infusion (> 24 hours) and were associated with their underlying comorbid conditions. One of the 8 deaths was considered related to administration of vernakalant injection by the investigator. This patient was a 64-year-old man with known severe aortic stenosis (gradient 120mmHg), as well as evidence of acute coronary ischemia, who was treated for new onset AF. Prior to receiving vernakalant the patient was treated with beta-blockers and became hypotensive; which required fluid resuscitation. During the first infusion of vernakalant the patient again became hypotensive requiring more treatment and the drug was not discontinued; he was then given a second dose and became profoundly hypotensive and then developed VF and could not be resuscitated. A second death was considered by the sponsor as related to vernakalant administration but not by the investigator. This patient is discussed in detail in Section 8.4. This event resulted in the IND clinical hold. The 6 additional deaths were as follows: • A 68-year-old man with known COPD. He failed to convert with vernakalant and was electrically cardioverted and sent home. He was readmitted 17 days later for respiratory arrest and died on day 24 with a diagnosis of pulmonary embolism; • A 68-year-old woman admitted with chest pain, nausea, and vomiting, failed vernakalant, and received electrical cardioversion. During gastroscopy on Day 2, she died of a ruptured aortic aneurysm; • 90-year-old woman with a history of angina and pulmonary edema failed vernakalant and then after electrical cardioversion developed complete heart block and severe hypotension, which was treated with atropine and isoprenaline. The patient then developed runs of ventricular tachycardia, required a temporary pacemaker, and was discharged on Day 17. The patient was readmitted 8 days later with pulmonary congestion and hypoxemia and died on Day 26;
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• A 67-year-old man with metastatic lung cancer cardioverted after 1 dose of vernakalant. The patient developed pneumonia with a respiratory arrest on Day 7, and life support was withdrawn on Day 8; • A 70-year-old woman with a history of breast cancer and leukopenia was cardioverted with vernakalant and discharged on Day 11. She was readmitted with internal bleeding on Day 16, which led to her death on Day 27; • An 82-year-old man with a history of an abdominal aneurysm, heart failure, and pulmonary fibrosis was converted with vernakalant and treated with flecainide and anticoagulants. He was discharged against advice and was found dead in bed 5 days later. The placebo-treated patient was an 84-year-old woman with a history of prior coronary bypass and several comorbid conditions, including a past brain arteriovenous fistula and prior stroke. The patient did not convert but developed a new stroke 9 days later, along with other serious complications, and died on Day 9. Full narratives are included in Appendix 3.
8.8 SPECTRUM 8.8.1 Events of Interest One of the primary objectives of the post authorization study, SPECTRUM, was to estimate the incidence of prespecified medically significant health outcomes of interest (HOIs) including “significant” hypotension, ventricular arrhythmia, bradycardia, and atrial flutter (see Section 6.3.1 for definitions). As described in Section 6.3.1, patients were followed up for 24 hours after the last vernakalant IV infusion or until end of medical encounter, whichever occurred first, in order to obtain information on medically significant HOIs and SAEs. For patients with hospital stays exceeding 24 hours following last infusion of vernakalant injection, data on concomitant medications and therapies for restoration and/or maintenance of SR were recorded up to 7 days post-dose. Patient demographics and baseline characteristics are discussed in Section 6.3.2. Data are presented for the total number of treatment episodes as well as for the prospective only treatment episodes. This allows for assessment of any potential reporting bias in the retrospective cohort of subjects. A total of 19 HOIs (defined by the investigator, study-defined criteria, and/or the safety review committee (SRC) were reported in 17 patients (of which 18 HOIs were reported in 16 prospective patients; one was reported in a retrospective patient). One event which was identified by the investigator as having sustained ventricular tachycardia was adjudicated as being Atrial Flutter with 1: 1 conduction by the SRC. Per the analysis plan both events are included in the tables. The incidence of events classified as HOIs in the analysis set of 2009 patient episodes is included in Table 52 The cumulative incidence of patients with HOIs was 0.8% (17/2009) (95% CI: 0.5% to 1.4%; for prospective patients only: 16 HOIs in 1580 treatment episodes, 1.0%, 95% CI: 0.6%- 1.6%).
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Table 52. Incidence of Health Outcomes of Interest All Patients Prospective patients (N=2009) (N=1580) Cumulative HOI Investigator/Study definition 16 0.8 (0.5-1.3) 15 0.9 (0.5-1.6) incidence, N (%, SRC classificationb 12 0.6 (0.3-1.0) 11 0.7 (0.3-1.2) 95% CI)a Investigator, Study, and/or SRCc 17 0.8 (0.5-1.4) 16 1.0 (0.6-1.6) Significant Investigator/Study definition 1 <0.1 (<0.1-0.3) 1 <0.1 (<0.1-0.4) ventricular SRC classificationb 0 0 0 0 arrhythmia, N (%, Investigator, Study, and/or SRCc 1 <0.1 (<0.1-0.3) 1 0.1(<0.1-0.4) 95% CI)a Significant Investigator/Study definition 14 0.7 (0.4-1.2) 13 0.8 (0.4-1.4) bradycardia, N (%, SRC classificationb 10 0.5 (0.2-0.9) 9 0.6 (0.3-1.1) 95% CI)a Investigator, Study, and/or SRCc 15 0.7 (0.4-1.2) 14 0.9 (0.5-1.5) Significant Investigator/Study definition 2 0.1 (<0.1-0.4) 2 0.1 (<0.1-0.5) hypotension, N (%, SRC classificationb 2 0.1 (<0.1-0.4) 2 0.1 (<0.1-0.5) 95% CI)a Investigator, Study, and/or SRCc 2 0.1 (<0.1-0.4) 2 0.1 (<0.1-0.5) Significant atrial Investigator/Study definition 1 <0.1 (<0.1-0.3) 1 <0.1 (<0.1-0.4) flutter, N (%, 95% SRC classificationb 2 0.1 (<0.1-0.4) 2 0.1 (<0.1-0.5) CI)a Study and/or SRCc 2 0.1 (<0.1-0.4) 2 0.1 (<0.1-0.5) Abbreviations: HOI, Health Outcome of Interest and includes (hypotension, ventricular arrhythmia, atrial flutter and bradycardia); SRC, Safety Review Committee; CI, confidence interval; SAE, serious adverse event a Incidence calculated as the number of patients who have a specific pre-specified event starting during the study period, divided by the total number of patients enrolled, multiplied by 100. b Incidence of HOIs when considered as such by the external SRC. c Incidence of HOIs whether they were considered as such either by study definition or by the SRC (most conservative approach).
Eighteen of the 19 HOIs occurred in the 2 hours following vernakalant infusion, with significant bradycardia being the most common HOI, occurring in 15 of the 2009 patient episodes (0.7%; 95% CI: 0.4% to 1.2%: prospective patients only: 14 events in 1580 treatment episodes; 0.9%, 95% CI: 0.5% to 1.5%). Two of these events were associated with significant hypotension. These 2 patients with bradycardia-associated significant hypotension were the only HOIs of hypotension in the study. In both cases, the patients were managed with IV fluids for the hypotension and atropine for the bradycardia. Therefore, the cumulative incidence of significant bradycardia with significant hypotension within the first 2 hours from the start of vernakalant infusion was 0.1% (2/2009) (95% CI: <0.1% to 0.4%; prospective patients only: 2/1580; 0.1%, 95% CI: <0.1% to 0.5%). All of the bradycardia events were either transient or responded to resuscitative measures. Of the 15 episodes with significant bradycardia, 8 resolved spontaneously, 5 patients required atropine, 1 received cardiac massage and 2 post-cardiac surgery patients received a temporary external pacing. All patients recovered without sequalae. There were no cases of sustained ventricular tachycardia, torsade de pointes, or ventricular fibrillation. There were 2 cases of atrial flutter with 1:1 conduction (as classified by the SRC); the first occurring in the 0-2 hour period (initially classified as VT by the investigator) and the second occurring 3.1 hours after initiation of the infusion. Both were treated with urgent ECV. A total of 28 (1.3%; 95% CI: 0.8% - 1.9%) SAEs were reported in 26 patients as shown in Table 53. Nineteen of these also met the protocol-specified definition of HOIs. Twenty-one of the 28 SAEs were cardiac related; the overall incidence of cardiac SAEs was 0.6%, (95% CI: 0.6% - 1.6%). The incidence of SAEs of hypotension, including presyncope, was 0.3% in prospective Correvio International Sàrl 04 November 2019 Page 115 of 166
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patients (5/1580); there were no hypotension SAEs in retrospective patients. The incidence of SAEs of bradycardia was 0.9% in prospective patients (14/1580); and 0.7% in the all patients (15/2009). The incidence of SAEs of ventricular arrhythmia was 0.2% in prospective patients (3/1580); there were no ventricular arrhythmia SAEs in retrospective patients. There were 9 SAEs that did not meet an HOI definition: 2 cases of hypotension and 1 case of each of the following: non-sustained ventricular tachycardia, non-sustained wide QRS complex tachycardia, supraventricular tachycardia, angina pectoris, pericardial effusion, visual disturbance, and 1 vernakalant injection overdose. In five cases, the SAE resolved without further treatment and of the remaining four: one patient was treated with position and IV fluids, one was treated with ECV, one was treated with amiodarone and for one patient, treatment was not stated. All but 5 of the 28 SAEs (angina pectoris, visual impairment, pericardial effusion, cardiac arrest, and 1 hypotension event) were considered by the investigator to be possibly related to the administration of vernakalant injection. Table 53. SPECTRUM – HOIs and SAEs Investigator SRC- Site- Pat Verbatim MedDRA SRC event Contra- /Study defined Treatment Outcome ID Type Event Term PT term term Indication defined HOI HOI (b) (6) P VT VT Yes: Sig AFL with 1:1 Yes: Sig No ECV Resolved ventricular conduction AFL arrhythmia/NA P Nonsustained VT No/No Wide QRS No No None Resolved VT complex tachycardia, nonsustained P Nonsustained VT No/No Nonsustained No No No Resolved VT VT P Hypotension Hypotension No/No Hypotension No No Shock Resolved positioning, parenteral volume IV fluid P Hypotension Hypotension No/No Hypotension No No No details Resolved provided P Bradycardia Bradycardia/ No/Yes Bradycardia Yes: Sig No Atropine Resolved with Hypotensiond with bradycardia IV fluid Hypotension hypotension significant hypotension P Hypotension Bradycardia/ No/Yes Hypotension Yes: Sig No Atropine Resolved with Hypotensiond with bradycardia IV fluid bradycardia bradycardia / sig hypotension P Vaso-vagal Presyncope No/No Sinus Yes: Sig No Atropine Resolved reaction bradycardia bradycardia with hypotension P Asystole for 6 Sinus arrest No/Yes Transient No No None Resolved seconds asystole of 6 secs P Symptomatic Bradycardia No/Yes Symptomatic Yes: Sig No ECV Resolved bradycardia bradycardia bradycardia P Prolongs Sinus No/Yes Sinus Yes: Sig No None Resolved hospitalization bradycardia bradycardia bradycardia sinus bradycardia Correvio International Sàrl 04 November 2019 Page 116 of 166
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a Use of Class III intravenous antiarrhythmics (amiodarone) within 4 hours prior to the start of vernakalant injection administration. b History of myocardial infarction within the previous 30 days. c A query to the site revealed that electrical pacing was not needed. The investigator selected the option due to a technical issue. This event should be considered an SAE involving bradycardia which met the criteria of significant bradycardia HOI by study definition. e Did not require resuscitation
All patients with either an HOI or an SAE recovered with the exception of a case of pericardial effusion which was considered recovered with sequelae as the patient was diagnosed as having tachycardia-induced cardiomyopathy after discovery of the pericardial effusion (the event was not considered related to vernakalant). There were no fatal events. The SPECTRUM study population represents the indicated population for the proposed US prescribing information and therefore more accurately reflects the anticipated risk profile of vernakalant injection. Serious adverse event rates in SPECTRUM are thus consistent with those in the Target Population of the clinical trials, in which incidence of SAEs for ventricular arrhythmia, bradycardia and hypotension in the 2 hours following start of infusion were 0.4%, 0.9% and 0.7% respectively in the vernakalant group compared to 0.2%, 0.9% and 0.3% in prospective patients in the SPECTRUM study. 8.8.2 FDA Events of Interest The FDA AEs of Special Interest in SPECTRUM are summarized in Table 54. This tabular summary includes 2009 patient episodes treated with vernakalant in 1778 unique patients. FDA AEs of Special Interest were reported in 4.3% of patient episodes. Ventricular arrhythmia-related events occurred in 0.4% of patient episodes, bradycardia-related events occurred in 1.0% of patient episodes, and hypotension-related events occurred in 1.2% of patient episodes. Generally, the rates of ventricular arrhythmia, bradycardia, and hypotension related AEs were lower in the SPECTRUM study compared to those reported in the equivalent monitoring period (0-24 hours) in the All Patients Population (2.8%, 6.1%, and 5.8% for any ventricular arrhythmia, bradycardia, and hypotension AEs, respectively). However, the All Patients Population enrolled patients with longer duration AF and there were differences in baseline characteristics between the populations including; history of CHF 3.1% and 15.7% in SPECTRUM and All Patients Population, respectively.
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Table 54. Incidence of FDA AEs of Special Interest (Safety Set, SPECTRUM Population) Special Grouping MedDRA Preferred Term Vernakalant (N=2009) n (%) Ventricular arrhythmia Any Ventricular arrhythmia 8 (0.4%) Ventricular extrasystoles 2 (0.1%) Ventricular tachycardia 7 (0.3%) Bradycardia Any Bradycardia 21 (1.0%) Bradycardia 17 (0.8%) Electrocardiogram RR interval prolonged 1 (0.0%) Sinus bradycardia 3 (0.1%) Hypotension Any Hypotension-related event 25 (1.2%) -related event Blood pressure systolic decreased 1 (0.0%) Dizziness 5 (0.2%) Hypotension 16 (0.8%) Loss of consciousness 1 (0.0%) Presyncope 4 (0.2%) Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities Notes: Includes all patient episodes from the SPECTRUM study. Patients may have been treated more than once for separate episodes. There were 1778 unique patients for 2009 episodes. Multiple occurrences of the same event in one individual are counted only once. Within a special grouping, subjects may have experienced more than one type of event. The sum of terms by special grouping may exceed 100%. AEs are defined to be any non-serious event starting or worsening after the start of the first dose through 10 days after the last dose in addition to all serious AEs starting or worsening after the start of the first dose through 30 days after the last dose.
8.8.3 Overdose Another objective of the post-authorization safety study (SPECTRUM) was to investigate the potential risk of overdose and medication error by describing vernakalant injection administration/dosing by body weight, total dose with intravenous infusion, and length of time for each intravenous infusion. Information on body weight and exact posology was known in > 90% of cases: • 1805 patients with known body weight <113 kg • 1801 patients with known body weight <113 kg and known given posology for the first infusion • 714 patients with known body weight <113 kg and known given posology for the second infusion Of the 1805 patients with body weight <113 kg, 2.0% of the first infusions (36/1801) and 3.8% of second infusions (27/714; 3.8%) corresponded to a dose higher than 105% of the weight-based dosing recommendation. There is a weight cap applicable for vernakalant dosing: any patient with body weight ≥113 kg (250 lbs) will have a posology of a patient of 113 kg (due to non-linear relation of blood volume and body weight specifically in obese patients). For some patients, HCPs administered a posology of 3mg/kg for the first dose and 2 mg/kg for the second dose, despite a body weight of >113 kg, thus they did not apply the weight cap. Of the 97 patients with body weight ≥113 kg: 9.3% of the first infusions (9/97) and 15.9% of second infusions (7/44) administered >105% of the weight-based recommended dose. Most of these were within 115% of the weight-based dose and few were associated with an AE; as discussed below.
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One patient had a non-serious AE of dysgeusia after receiving a 500 mg dose (6.0 mg/kg) for the first infusion. The patient did not receive a second infusion. One SAE of overdose was manifested as nausea and vomiting, after administration of 151% of the weight-based recommended vernakalant injection dose. The patient was observed for 2 hours and discharged home. There were 25 cases in the SPECTRUM study in which vernakalant (at 100% of the planned dose) was infused for less than 9 minutes; none of these cases were associated with SAEs. 8.9 Post-Marketing Safety Experience The first regulatory approval for vernakalant injection was received in September 2010 via the centralized approval process in the EU. Vernakalant injection is currently registered in 41 countries and marketed in 25 countries. 8.9.1 Risk Management Activities in the Post-Marketing Setting In Europe, Risk Management activities are in place to minimize risk of vernakalant associated safety concerns in clinical practice. In order to evaluate the effectiveness of the risk management activities, information from ongoing and planned pharmacovigilance activities are regularly evaluated to assess the frequency and severity of post-marketing adverse drug reactions (ADRs) relating to identified and potential risks (assessed in signal detection, periodic safety reports and periodic benefit/risk evaluation reports). The risk management activities in Europe include: Routine Risk minimization and PV activities: • Product labeling: Communication with Health Care Providers (HCPs) via the Summary of Product Characteristics (SmPC) and the patient information leaflet (PIL) • Legal status of the product: Medicinal product subject to restricted medical prescription • Specific ADR follow-up questionnaires (for identified safety concerns) • Signal detection activities. • Review and assessment by the marketing authorization holder (MAH) and the European Health Authority of new case reports received for vernakalant on a weekly basis to identify new spontaneous cases of serious hypotension. Additional Risk Minimization activities: • HCP education materials: HCP Education Card and Pre-Infusion checklist. The objectives of these additional risk minimization activities are to increase awareness by educating prescribers in the risks and means of minimizing the risk. The HCP Education Card and Pre-Infusion checklist are also sent, in addition to the SmPC, with all Medical Information responses for vernakalant injection.
o HCP Education Card (“Appropriate Use of Brinavess”): All HCPs potentially involved in the prescription or administration of vernakalant IV have received education materials, including an information card that reinforces key safety information from the product label, to help support appropriate prescribing behavior. These materials identify the risk of hypotension with vernakalant use, and Correvio International Sàrl 04 November 2019 Page 120 of 166
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provide appropriate advice to minimize this risk. It has been distributed through national mailouts on a periodic basis and is available at the MAH’s conference booths and during symposia.
o Pre-Infusion Checklist: The MAH has developed the Pre-Infusion Checklist as an additional educational tool to provide further support for appropriate patient selection and monitoring. The Pre-Infusion Checklist (1) highlights the contraindications for vernakalant use, in an accessible check-list format, and (2) provides instructions for patient monitoring and management of medically significant ADRs when administering vernakalant. This tool is included in the vernakalant injection package, and delivered directly to the point of care, thus increasing the exposure of HCPs to the education materials. The Pre-Infusion Checklist also reinforces the importance of careful review of the SmPC and the HCP Card prior to use of the product. 8.9.2 Spontaneous Adverse Reports The estimated cumulative exposure to vernakalant injection in the marketed setting from 01 Sep 2010 until 31 Aug 2019 is 58,298 treatment courses. This included the 2,009 treatments from the SPECTRUM study at the time of the data cut-off for the Periodic Benefit-Risk Evaluation Report (PBRER) on 31 Aug 2019. Post-marketing exposure was estimated using marketed product distribution data of the 500 mg vial, with the assumption that one vial corresponded to one course of treatment. There was a cumulative total of 463 spontaneous adverse reports (199 were classified as serious, including 6 deaths) from post-marketing sources, which include competent authorities (worldwide), HCPs, consumers and literature. Characterization of safety from post-marketing data reflect use in the outside trial environment and to date have been consistent with the identified safety profile. AFL with 1:1 atrioventricular conduction was observed in this setting and is now considered an important identified risk of treatment with vernakalant. The most common spontaneously reported serious ADRs were AFL (21 events), hypotension (12 events), and ventricular tachycardia (15 events) cumulatively.
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Table 55. Numbers of Serious Adverse Drug Reactions in >1 Patient from Post-Marketing Data Sources System Organ Class Spontaneous, including competent authorities Preferred term (worldwide) and literature Cardiac disorders 84 Atrial fibrillation 3 Atrial flutter 21 Atrioventricular block 2 Atrioventricular block complete 2 Bradycardia 7 Cardiac arrest 6 Cardiogenic shock 2 Sinus arrest 4 Sinus node dysfunction 2 Supraventricular tachycardia 2 Tachycardia 3 Ventricular fibrillation 2 Ventricular tachycardia 15 Gastrointestinal disorders 9 Nausea 3 Vomiting 3 General disorders and administration site conditions 18 Drug ineffective 9 Fatigue 3 Hepatobiliary disorders 2 Immune system disorders 2 Anaphylactic reaction 2 Injury, poisoning and procedural complications 5 Off label 2 Overdose 2 Investigations 11 Blood pressure decreased 5 Nervous system disorders 19 Dizziness 3 Dysgeusia 3 Paresthesia 3 Taste disorder 2 Respiratory, thoracic and mediastinal disorders 18 Cough 2 Dyspnea 2 Skin and subcutaneous tissue disorders 5 Pruritus 2 Surgical and medical procedures 2 Cardioversion 2 Vascular disorders 21 Circulatory collapse 2 Hemodynamic instability 3 Hypotension 12 Total 199
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8.9.2.1 Overdose A review of the post-marketing safety database indicates 3 cases of overdose have been reported. One patient received 321 mg and experienced nausea and vomiting. The patient converted to SR, did not require additional cardioversion, and recovered from the nausea and vomiting. Another patient received a dose of 1750 mg, 516% of the maximum allowable first dose and developed cardiogenic shock and atrioventricular block, with bradycardia and wide QRS complex after which therapy was discontinued and the event resolved. The third patient received 48 mL of undiluted vernakalant (868.8 mg of vernakalant, 256% of the maximum allowable first dose) due to a misunderstanding by the nurse. The patient had complete atrioventricular block, with bradycardia with wide QRS complex. This condition was treated with an epicardial pacemaker; and the associated hypotension was treated with intravenous liquids and noradrenaline. After the patient's stabilization, the pacemaker was retired. 8.9.2.2 Post-Marketing Reports of Death In total, the following six deaths have been reported in the post marketing database (01 Sep 2010 until 31 Aug 2019). These deaths occurred in complicated patients. The cause of the death was unique in each patient with no common pathophysiological mechanism that may have contributed to the deaths. Most were late, occurring hours or days later, and due to comorbid conditions. From the data available and the setting in which the drug was used, it is unclear if vernakalant contributed to many of these events. (b) (6) An 80-year-old male, described as having a reduced general condition and (b) (6) urinary tract sepsis (urine culture on : multi-drug resistant Escherichia coli) with fever, (b) (6) sepsis (blood culture on : Enterococcus faecium). He was also described as having lung obstruction and a history of partial cystectomy due to bladder diverticula, prostate carcinoma and transurethral prostate resection. He developed AF on the urology ward and was transferred to the (b) (6) intensive care unit. On , at 09:00 am, he was unsuccessfully treated with flecainide acetate, 50 mg for AF. That same day, at 11:20 am, the patient received one dose of vernakalant for treatment of AF. There are conflicting reports as to whether he converted. Concomitant medications included meropenem (MERONEM), ampicillin sodium (+) sulbactam sodium, an (b) (6) unspecified beta blocker, digitalis, prednisolone, albuterol and ipratropium bromide. On (one day later), the patient spontaneously converted to sinus rhythm and his infection parameters “had diminished” (values not reported), such that he was transferred from the intensive care unit to a normal ward. Later that day, the patient was transferred back to intensive care unit because of signs of multi-organ failure and cardiovascular instability, an increase of retention parameters and transaminases (values not reported). That same day, at 10:20 pm (35 hours after treatment with vernakalant), the patient required resuscitation due to asystole. After almost 40 minutes resuscitation with repeated doses of catecholamines, resuscitation measures were stopped and, at 11:00 pm, the patient died. The cause of death was listed as multi-organ failure in the context of sepsis with Enterococcus faecium and subsequent asystole. The reporting physician felt that worsening of sepsis and multi-organ failure and subsequent asystole and death were not related to the use of vernakalant, but to the patient's severe underlying illness. He considered therapy with vernakalant as ineffective. Asystole was considered to be immediately life-threatening. Additional information is not expected. The patient did not convert with vernakalant and did not experience AEs during treatment and was transferred to a lesser acute ward in an improved condition. The patient presumably died from
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septic shock a day and a half later when the drug would not be detectable and thus is unlikely to be associated with the treatment. The rhythm of asystole would suggest a respiratory arrest or pulmonary embolization precipitated the event. Although likely not relevant in this case, in the Warnings section of the proposed US label, the following is stated: Use of intravenous antiarrhythmic drugs (Class I or III) within 4 hours prior to, or 4 hours after, Brinavess administration is contraindicated [see Contraindications]. Brinavess is not recommended in patients who have received intravenous Class I or Class III antiarrhythmic drugs 4 to 24 hours prior to Brinavess administration due to lack of data. (b) (6) (b) (6) . In of 2011, an elderly female patient was hospitalized for bowel obstruction and was to undergo urgent surgery. AF (at a rate of 200 bpm) and hypotension were noted. The patient was given intravenous fluids and the blood pressure improved. The patient was then treated with vernakalant and the patient’s condition was stated as “stabilized”. Anesthesia was then administered in preparation for surgery, and the patient became hypotensive and the “heart stopped.” The patient was then “reanimated” and proceeded with surgery. The patient died on the following day with the cause noted as septic shock. The cause of hypotension and cardiac arrest was listed as possibly related to treatment. From the information provided, this patient was severely ill from acute bowel obstruction and was stated to have died because of sepsis. The cardiac arrest seems likely due to hypotension following anesthesia and vernakalant treatment. The proposed label indicates that systolic blood pressure <100 mmHg (or having received fluid resuscitation or inotropes to maintain BP >100 mmHg) is a contraindication. (b) (6) . An 80-year-old female patient with a history of esophageal carcinoma, gastric carcinoma, and severe aortic stenosis was in the midst of treatment for an open and septic abdominal wall following a Whipple's procedure. She developed arrhythmia at an undocumented time after surgery with an abnormal PR in the ECG, type not exactly known (even possibly "slow VT [ventricular tachycardia]" but presumably was AF). Concomitant therapy included catecholamines presumably to maintain blood pressure. The treating intensive care unit physicians consulted with a cardiologist (reported as the treating physician) about the possibility of using vernakalant for cardioversion. The administration of vernakalant had already been started by the intensive care unit physicians at the time of consultation. The treating cardiologist consulted with the reporting cardiologist who advised against using the drug because of the underlying severe aortic stenosis. Follow-up information received from the reporting cardiologist on 25-Apr-2012 revealed that, while on therapy with vernakalant, the patient developed ventricular fibrillation/flutter (previously reported as "atrial flutter"). Therapy with vernakalant was discontinued after 5-7 minutes. The patient recovered from ventricular fibrillation/flutter. After an unspecified period, the patient developed “septic cardiopulmonary failure.” The patient died, presumably in the context of her underlying disease (not further specified). The actual cause of death was reported as septic cardiopulmonary failure. In follow-up received on 09-May-2012, the reporting cardiologist stated that the patient developed ventricular fibrillation/flutter during the infusion of vernakalant. However, he did not see the ECG and was not present. The patient's death occurred approximately 2-3 hours after discontinuation of the infusion. The death was associated with septic shock (presumably from widespread bowel contamination. The cardiologist rated the case as "possibly related" because of the severe aortic stenosis which may also have contributed to septic shock which was being managed using catecholamines. The reporting cardiologist “urgently requested” closure of the case. He had no
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further additions and his colleague from the hospital wanted to remain anonymous. Furthermore, the reporting cardiologist had not seen the patient and all of his information was hearsay. In all of the controlled studies, there has not been an excess of serious ventricular arrhythmias following treatment with vernakalant compared to placebo-treated patients. The cases of cardiac arrest and ventricular fibrillation have all been initiated by severe hypotension and then subsequent myocardial ischemia resulting in ventricular fibrillation. In the proposed contraindications section of the label, two contraindications are aimed to mitigate use in similar patients: • Systolic blood pressure <100 mmHg (or having received fluid resuscitation or inotropes to maintain BP >100mmHg) • Clinically significant aortic stenosis (b) (6) . A 73-year-old male with type 2 diabetes mellitus, hypertension, polymyalgia, prior cerebellar infarction (no sequelae), coronary artery bypass graft surgery, percutaneous coronary intervention, and prior echocardiogram showing a left ventricular diameter 5.8, systolic diameter 4.2 and ejection fraction of 47%, was initially evaluated by a general practitioner for chest pain and found to be in AF with a ventricular rate 148 bpm and blood pressure of 100/63 mmHg. (b) (6) He was sent to an emergency room and admitted on at 20:29 with chest pain for 2 hours. Rhythm on admission was AF. Blood pressure on admission was 117/79 mmHg and the heart rate was 124 bpm in AF. Laboratory values on admission showed a troponin 26 ng/mL (upper limit of normal of 19) WBC of 18,000, creatine of 194 mmol, urea of 30.1, sodium level of 139, potassium level of 4.1, and the chest x-ray reported as “normal." He was admitted to hospital with suspected Non-ST Segment Elevation Myocardial Infarction. There was no record regarding any symptoms in the emergency department notes. There was no sign of cardiac insufficiency. The subject received oral metoprolol 25 mg in the emergency department. Hospital Course (Day 0, overnight): admitted to coronary care unit and monitored. Pulse recorded as 122-130 bpm; sequential blood pressures of 88/66, 106/66, 107/77, and 91/61 mmHg. No additional medications were given. No further episodes of chest pain or any other problems reported overnight. (b) (6) Hospital Course (Day 1): in the morning of , ECG showed AF and troponin reported to (b) (6) be elevated to 400 ng/ml. The patient was seen by the treating physician on the at approximately 9:00 am. He found the patient to be comfortable, well perfused, free from chest pain, and in AF. Vernakalant was given at approximately 9:30 am. Pre-vernakalant heart rate was 128 bpm in AF, and blood pressure was 105/79 mmHg. Vernakalant 3mg/kg in 100 ml over 10 minutes was administered. Towards the end of infusion, the heart rate was 95 bpm (AF), and blood pressure at that time reported to be 85/64 mmHg. He was reported to have converted to sinus rhythm immediately after infusion. The patient was described as being "sweaty" and nauseated by the nurse. Post-infusion vital signs were: blood pressure of 79/70 mmHg, heart rate of 83 bpm (sinus rhythm); blood pressure of 73/60 mmHg, heart rate of 80 bpm (sinus rhythm); blood pressure of 91/54 mmHg, heart rate of 66 bpm (sinus rhythm). The lowest rate 66 bpm. No interventions were administered. At 11 am, 'medical on-call' was called to see the patient for hypotension. No interventions were administered. After 2 pm (4.5 hours after initiation of the drug), blood pressure was 60/38 mmHg. The on-call physician saw the patient and it is stated the patient was a "bit bubbly," no chest x-ray done but intravenous furosemide 40 mg and intravenous Cyclimorph
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2.5 mg were administered suggesting new onset of pulmonary edema. The blood pressure continued to decrease, and the patient became 'profoundly hypotensive.’' At approximately 3 pm (5.5 hours after treatment) the patient became hypoxic and developed ventricular tachycardia and then ventricular fibrillation with cardiac arrest. He received atropine and adrenaline (dose and time not given). He was intubated and ventilated. Time of death 23:25 (approximately 14 hours after vernakalant). The cause of death was listed as hypotension. The physician thought vernakalant hydrochloride “probably contributed to hypotension” which led to cardiogenic shock.' Follow up information was received on 02-May-2012. The physician felt the elevated troponin was not due to acute coronary syndrome “and that this was a leak of troponin.” The chest pains the patient presented with (and raised troponin) was attributed to AF. The ECG showed no signs of ischemia (no ST elevation/depression or t-wave inversion). No echo was done. The patient received one vernakalant hydrochloride infusion.” Concurrent medications included gliclazide (DIAMICRON), bisoprolol fumarate (CARDICOR), isosorbide mononitrate (IMDUR), spironolactone, aspirin, clopidogrel bisulfate (PLAVIX), nitroglycerin (SUSCARD), nicorandil, perindopril arginine-suggesting both a history of ischemic heart disease and reduced left ventricular function. The 2 hours of chest pain and troponin elevation 20 times higher than normal in a patient with known coronary disease are diagnostic of acute myocardial infarction. Rapid AF by itself causes either no or minor elevations at best. There would be negligible levels of vernakalant at 14 hours post treatment. The occurrence of a ruptured papillary muscle should also have been in the differential diagnosis and been investigated. The proposed contraindications in the label would suggest that similar patients should not be treated, as the contraindications include acute coronary syndrome (including myocardial infarction) within the last 30 days. (b) (6) (b) (6) . On , a 50-year-old patient was hospitalized for non-specific chest pain with a working diagnosis of acute coronary syndrome. Initial hospital studies showed normal left ventricular function and a dilated aortic root and ascending aorta of 49 mm, a thickened aortic wall, and signs of acute inflammation with dense non-calcified echoes in the wall which is consistent with possible aortic dissection. A coronary angiogram showed normal coronary arteries. The patient was treated in the intensive care unit due to chest pain and unspecified ECG changes. Thirty-six hours later, the patient developed rapid AF of 160-170 bpm with blood pressure of 90- (b) (6) 100 mmHg. On at 08:00, the patient was initially treated with intravenous amiodarone which was not effective at restoring sinus rhythm. At 12:00, the patient was treated with vernakalant 3mg/kg for 10 minutes after which the patient converted to sinus rhythm at 80-85 bpm. There was a temporary drop of blood pressure to 80-85 mmHg which lasted for one minute. Trendelenburg position and short saline infusion restored blood pressure to 110 mmHg. There were no signs of ST-T changes, atrioventricular block, bradycardia or detectable conduction abnormality. Following treatment, the patient felt well and ate. Nine and a half hours later, the patient deteriorated very suddenly, became pulseless with a broad QRS complex bradycardia. The patient died shortly following onset of these symptoms as “circulation could not be maintained.” An autopsy was not performed. The suspected diagnosis was acute aortic rupture unrelated to vernakalant. The case was also reported to a mortality/morbidity committee of the department of cardiology as well as to the hospital committee who both agreed that the death was unrelated to vernakalant administration.
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Given the 9+ hour delay from treatment and descriptions, it is highly unlikely this is related to vernakalant and the mode of death and aortic findings, most likely are consistent with acute aortic rupture. (b) (6) . A 59-year-old male patient with an unspecified medical history and concomitant medications was treated with vernakalant injection 5 mg/kg (total dose unknown) on 15 January 2019 for recent onset AF. The patient successfully cardioverted after the first dose of iv vernakalant. On 7 February 2019 the patient presented again with AF. He received treatment with two doses of vernakalant injection (total of 5 mg/kg/dose) but was not successfully cardioverted to sinus rhythm after two doses. It is not reported if this patient received additional medications or interventions to induce cardioversion. The patient died due to cerebral stroke on an unknown date. The causality of cerebral stroke was reported as not related to vernakalant injection. 8.9.3 Literature Reviews 8.9.3.1 Vernakalant Safety A systematic review of the literature was performed to identify studies on the clinical effectiveness and safety of vernakalant injection in adults with recent-onset AF in the post-marketing setting, including where possible, comparisons with other pharmacological cardioversion therapies, ECV, or watchful waiting. Overall, the literature review (involving 34 studies reporting on 2,028 vernakalant patients) found that although vernakalant treatment is associated with occurrences of AFL, transient ventricular arrhythmias, and other AEs; these generally appear self-limiting and do not require further medical intervention. There were no reports of serious events, such as death, ventricular fibrillation, or TdP in patients treated with vernakalant. Three investigator-initiated studies, including two randomized trials, compared vernakalant to ibutilide. The most common adverse events with vernakalant were sneezing, paresthesia, dysgeusia, atrial flutter, bradycardia and hypotension, consistent with the safety profile in clinical studies. In contrast, there was as a trend for more drug discontinuations with ibutilide and ventricular arrhythmia events, including TdP were only observed in patients treated with ibutilide. This is consistent with more pronounced QT interval prolongation observed with ibutilide in these studies. published studies.75,83,81 8.10 Safety Summary and Conclusions Vernakalant was generally well-tolerated across all clinical trials and in an AF population representative of that seen in clinical practice. Ventricular arrhythmia, bradycardia and hypotension, events of interest for antiarrhythmic agents, have been carefully characterized across the clinical development program, and further investigated in the post-approval setting in SPECTRUM and by specific ADR follow-up questionnaires (for identified safety concerns) in the Sponsor’s pharmacovigilance activities. In the clinical program, the incidence of ventricular arrhythmia was higher in patients treated with vernakalant compared to placebo (3.8% vs. 2.5%, respectively) in the first two hours post-dose, however, this was reversed in the 2-24 hour period (placebo 9.8% vs. vernakalant 6.9%). In the first 2 hours post-dose, a greater incidence of bradycardia was observed with vernakalant than placebo patients (5.1% in vernakalant patients and 2.7% in placebo patients). This is postulated to be related to the greater proportion of patients treated with vernakalant who Correvio International Sàrl 04 November 2019 Page 127 of 166
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experienced cardioversion relative to placebo patients. However, after that time period, the incidence was greater for placebo than vernakalant (12.8% in placebo patients and 7.5% for vernakalant patients from 2-24 hours post dose). The incidence of hypotension events from all sources combined (AEs and vital sign assessments) was similar in both groups: 5.7% in vernakalant patients and 4.8% in placebo patients from 0-2 hours post-dose however, adverse events alone, were higher in the vernakalant group over this period (4.2% and 1.4% in vernakalant and placebo patients respectively). In the 2-24 hour period the incidence of hypotension was higher in the placebo group; 3.4% in vernakalant patients and 5.9% in placebo patients. Adverse events of hypotension tended to occur during or immediately following the infusion and resolve quickly (median duration of 20.5 minutes) with management using the Trendelenburg position or IV fluids in most cases. The proposed label indicates that the patient should be carefully observed for signs and symptoms of a sudden decrease in blood pressure or heart rate during infusion and for at least 2 hours after cessation of treatment, and until clinical status and ECG parameters are stable, to mitigate the risk of significant hypotension. The label also includes a contraindication for patients with systolic blood pressure <100 mm Hg (or having received fluid resuscitation or inotropes to maintain BP >100 mm Hg). The drug is also contraindicated in those patients who by history are likely to have a decreased cardiac reserve; e.g. Functional class III, IV heart failure or known moderate or systolic dysfunction, clinically significant aortic stenosis. Serious events of hypotension tended to occur in the first 2 hours post dose. The incidence of treatment-emergent SAEs from 0-2 hours post dose was numerically greater in the vernakalant group (3.0%) than in the placebo group (0.7%). However, from 2-24 hours post dose, the incidence of SAEs was higher in the placebo group than the vernakalant group (2.0% in vernakalant group and 3.3% in the placebo group). The incidence of SAEs or discontinuation’s for ventricular arrhythmia, bradycardia and hypotension in the 2 hours following start of infusion were 0.7%, 1.1% and 0.9% respectively in the vernakalant group and 0%, 0% and 0.2% respectively in the placebo group. In the 2-24 hour period the incidence of SAEs or discontinuation’s for ventricular arrhythmia, bradycardia and hypotension in the vernakalant group was 0%, 0.2% and 0.1% respectively and 0.4% for each event in the placebo group in the same time period. A post-hoc analysis of the clinical database was conducted to assess the risks in the Target Patient Population; patients with no contraindications per the current approved European Summary of Product Characteristics (SmPC) and proposed US package insert (PI) in placebo-controlled Phase 3 studies in patients with AF ≤ 7 days duration. The incidence of SAEs or discontinuation’s for ventricular arrhythmia, bradycardia and hypotension in the 2 hours following start of infusion were 0.6%, 0.9% and 0.9% respectively in the vernakalant group in this population. Importantly, of the 4 patients experiencing a ventricular arrhythmia only one patient required intervention (b) (6) (defibrillation of patient , the patient with echocardiogram evidence of reduced systolic function), of the 6 patients with reported bradycardia 3 required atropine and of the 6 patients with (b) (6) reported hypotension, 2 required pressors – the patient noted above, , and a second coronary bypass surgery patient who developed transient hypotension. Patients with CHF had an increased incidence of ventricular arrhythmia and hypotension events with vernakalant from 0-2 hours post dose. Use of vernakalant in patients with severe heart failure (including NYHA Class III or IV or with known moderate or severe left ventricular dysfunction)
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will be contraindicated. Patients with valvular heart disease had an increased incidence of ventricular arrhythmia and bradycardia with vernakalant injection from 0-2 hours post dose. All but one of the bradycardia events from 0-2 hours was associated with acute cardioversion. Use in patients with clinically significant aortic stenosis or with evidence of Class III, IV heart failure or known moderate or severe left ventricular dysfunction will be contraindicated. Patients with background use of beta blockers had an increased incidence of hypotension from 0-2 hours post dose; however, there was no increased risk at 0-24 hours and there was no risk in patients with background use of rate controlling medications making interpretation of this finding uncertain. The label will indicate that use of intravenous beta blockers within the first 2 hours prior or 2 hours after vernakalant administration is not recommended. Patients with background use of Class I antiarrhythmics had an increased incidence of bradycardia with vernakalant injection from 2-24 hours (and also across 0-24 hours post dose). However, background use of these agents was reported in a small number of patients, also making interpretation difficult. Use of intravenous Class I and Class III antiarrhythmics will be contraindicated within 4 hours prior to or 4 hours after vernakalant injection. In general, there was a higher incidence of TEAEs, SAEs, and severe AEs associated with vernakalant treatment occurring from 0-2 hours. However, from 2-24 hours, the number of TEAEs, SAEs, and severe AEs was similar to the placebo group or higher in the placebo group. Given the short half of vernakalant, its PK characteristics and the study designs that allowed other therapies to be administered after 2 hours, the increased rate of AEs in the 2-24 hour time period in the placebo group (relative to the rate in the placebo group in the 0-2 hour time period) is likely related to the risks associated with ongoing AF, and other treatments including electrocardioversion and anesthesia, administered for the treatment of ongoing AF. The proposed Dosage and Administration section will instruct prescribing physicians to carefully observe patients for the entire duration of the infusion and for at least 2 hours after completion of the infusion with assessment of vital signs and continuous cardiac rhythm monitoring until the patient is stable. The proposed label also states that vernakalant should be dosed in a monitored clinical setting appropriate for cardioversion which includes all the necessary items used for resuscitation. The post-approval safety study SPECTRUM demonstrated that in a real-world use setting, physicians used vernakalant in compliance with labelling thus minimizing the risk. Potentially serious clinical events were uncommon, all patients with a clinically significant event of interest or SAE recovered, and no TdP, ventricular fibrillation, or fatal events occurred. Only one event of interest SAE in 2009 treatment episodes occurred after 2 hours-a single instance of asymptomatic atrial flutter with 1:1 conduction occurred at 2 hours and 56 minutes that reverted to 2:1 conduction following carotid massage and eventually was electrocardioverted.
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9 BENEFIT-RISK EVALUATION
Summary • Vernakalant has consistently demonstrated its effectiveness in the rapid conversion of recent onset AF to sinus rhythm with attendant symptomatic relief. • The safety profile of vernakalant has been well characterized based on 7 Phase 3 trials and is corroborated by post-marketing experience, including a post- authorization safety study. • The appropriate target patient population has been identified based on understanding of the safety data from the clinical program and has been further supported by the findings from the PASS. • The potential risks of ventricular arrhythmias, bradycardia and hypotension are low in the target patient population and manageable in the intended setting for vernakalant use. • The proposed labeling and the Pre-Infusion check list provide guidance for appropriate patient selection and patient management. • Pharmacological cardioversion of recent onset AF is a reasonable strategy for selected patients and supported by guidelines14. The efficacy and safety profile of vernakalant is favorable relative to existing pharmacologic agents used for acute conversion of AF.
Recent onset AF commonly causes discomfort and is associated with a number of symptoms which for some patients may be severe.6,11 Conversion to sinus rhythm provides symptom relief, normalizes ventricular rate and improves cardiac function and exercise capacity.10 In certain new onset patients who present early and who are at low risk for thromboembolism, cardioversion at the time of presentation can obviate the need for weeks of anticoagulation before cardioversion is done. Moreover, early conversion of AF mitigates the development of atrial electrical and structural remodeling associated with untreated AF and may reduce the progression of AF to a permanent condition. 6,11 Alleviation of symptoms, patient’s age, patient preference, co-morbidities, including history of AF, all influence the decision on whether to seek rhythm control.14 When cardioversion is chosen, the AHA/ACC/HRS guideline14 recommends both pharmacological and electrical cardioversion. In the US, two drugs, dofetilide and ibutilide, are FDA-approved for the conversion of AF to sinus rhythm. Both are Class III agents that affect the IKs and IK1 currents, with resultant effects on ventricular repolarization leading to significant QT prolongation and risk of TdP. The most commonly used agent for pharmacological conversion in the US, amiodarone, is not approved for AF conversion, has a slow onset of action along with reported risks of bradycardia, hypotension and ventricular arrhythmia (see Table 10). Other agents recommended by US guidelines are
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approved for indications other than AF conversion and have either limited efficacy and/or significant side effects.
Vernakalant has been thoroughly evaluated in a total of 9 Phase 2/3 efficacy/safety studies, including 4 new Phase 3 studies conducted since the original 2006 NDA. A total of 1073 patients have received vernakalant in these clinical trials. Across these studies, vernakalant has consistently demonstrated effectiveness at rapid conversion of recent onset AF to sinus rhythm in non-surgery and in post-cardiac surgery patients and in a broad range of AF subjects with co- morbidities typical of this population. Importantly, vernakalant also provides symptomatic relief to patients and the results of conversion to sinus rhythm are durable. The safety profile of vernakalant has been thoroughly characterized and the risks of ventricular arrhythmia, bradycardia and hypotension have been assessed, indicating events are infrequent in the target patient population and are manageable in the setting for which vernakalant is intended. Data from SPECTRUM, which represents the target patient population in the post-marketing setting, is supportive of the risk characterization and the appropriateness of the approved European SmPC and proposed US label. Further, the spontaneous reporting from 58,298 treatment courses over 9 years of marketed use, suggests that the risk management activities, including label and pre-infusion checklist, are adequate and appropriate. There exists a need for a rapidly acting drug for pharmacologic conversion from AF to SR in appropriately selected symptomatic recent onset AF patients to afford the possibility of rapidly improving symptoms and restoring sinus rhythm as well as in some, reducing the need for weeks of anticoagulation with its associated risk of bleeding. Early pharmacologic cardioversion with vernakalant also reduces the need for ECV and avoids the risk of potentially serious effects of anesthesia, the need for hospitalization associated with other antiarrhythmic drugs, and the burden of additional hospital admissions/ procedures to be cardioverted. Vernakalant injection provides a viable alternative to the currently available treatments for the rapid conversion of recent onset AF to SR.
The clinical data generated, and the practical experience obtained since 2010, provide robust support for the addition of vernakalant injection to the current US antiarrhythmic drugs available for rapid conversion of AF to SR in adults: non-cardiac surgery patients AF ≤7 days duration and post-cardiac surgery patients: AF ≤3 days duration.
9.1 Benefits Summary Five randomized double-blind placebo-controlled Phase 3 trials, 1 active comparator controlled Phase 3 trial, and a single arm Phase 3 trial have consistently demonstrated the efficacy of vernakalant injection for rapid conversion of recent onset AF (≤ 7 days) to SR within 90 minutes in 45.7 to 52.9% of both non-surgery and post-cardiac surgery patients. Conversion rates of recent onset AF to SR within 90 minutes were significantly lower in placebo-treated patients in these same studies (1.5 to 14%). Conversion after vernakalant injection occurred rapidly; the median time to conversion ranged from 8 to 14 minutes for all patients receiving vernakalant injection. In the post-marketing setting, vernakalant was associated with conversion of AF to sinus rhythm in 70.2% of patients. This higher efficacy rate was associated with a shorter duration of the index AF episode in SPECTRUM (11.1 hours) compared to the earlier Phase 2 and 3 trials (median Correvio International Sàrl 04 November 2019 Page 131 of 166
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duration of 17.7 to 28.2 hours and is also consistent with other post-marketing reports (see Figure 6). The median time to conversion of ~11 minutes, and the 51% conversion within 90 minutes is shorter than has been reported for the other current FDA approved treatments. Most patients with recent-onset AF (in the ACT I/III pivotal studies) who converted to SR after receiving vernakalant injection remained in SR during the study observation period (97% maintenance at 24 hours; 93% at 7 days). Further, vernakalant provided rapid relief of the AF symptoms that had prompted the hospital visit/assessment (vernakalant; 48.9% with no AF related symptoms at 90 minutes, 18.2% at baseline, placebo; 26.4% no AF related symptoms at 90 minutes, 17.0% at baseline). Thus, vernakalant injection provides a rapidly acting, effective and durable option for pharmacological conversion of AF to SR. Of note, the Agency has previously indicated (August 2008) that vernakalant is “clearly effective in promptly converting patients with recent atrial fibrillation (AF) to normal sinus rhythm (NSR).” The efficacy of vernakalant was also acknowledged during the discussion at the December 2007 CRDAC Meeting held to discuss the vernakalant original NDA application. 9.2 Risks Summary The safety of vernakalant has been more extensively and thoroughly characterized since 2006. The clinical development program has demonstrated that vernakalant is generally well tolerated. Adverse events reported in trials were generally transient, rarely treatment limiting, and manageable in the clinical setting for which vernakalant injection is intended. Clinically important potential risks of ventricular arrhythmias, bradycardia, and hypotension have been identified and systematically assessed. The new studies, conducted since 2006, have allowed confirmation of the appropriate patient population for treatment with vernakalant and the findings in the PASS support use in the proposed target patient population as evidenced by a very low rate of hypotension requiring drug management. Over the course of the vernakalant clinical development, the target patient population has become more clearly defined. The warnings and precautions section, and contraindications in the proposed labelling, guide physicians to identify the appropriate patients. Risks are mitigated by identification of the clinical characteristics of patients who should not be treated (contraindications) and also by defining the appropriate monitoring time and setting, during and following vernakalant infusion. Thus, the additional safety information and clinical experience presented within this resubmission provides a full characterization of the safety profile and risks of vernakalant injection in the intended patient population and supports a positive benefit risk profile for this drug. The potential risks of ventricular arrhythmias, bradycardia, and hypotension have been thoroughly evaluated in the clinical program and post-marketing setting. The incidence of any ventricular arrhythmia event in the clinical trial database 0-2 hours postdose was slightly greater for vernakalant (3.8%) than placebo (2.5%). However, in 2-24 hours postdose the incidence of was greater for placebo compared to vernakalant (9.8% vs. 6.9%, respectively). SAEs or discontinuations for a ventricular arrhythmia event were <1% in both the vernakalant group and placebo group in the first 24 hours (0.7% [8/1073] and 0.4% [2/459], respectively). All of these events in the vernakalant group occurred in the first 2 hours after infusion. In the PASS, there were 2 cases of atrial flutter with 1:1 conduction (as classified by the SRC, one of which was initially classified as VT by the investigator) and no cases of sustained ventricular tachycardia, torsade de pointes, or ventricular fibrillation. Generally, these events resolved without treatment or with ECV.
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Overall, in the analysis of bradycardia from the clinical trial AE database, an increased incidence of bradycardia in the first 2 hours post-dose is apparent (4.0% in vernakalant patients and 0.7% in placebo patients). From 2 to 24 hours post-dose, the incidence of bradycardia events (all sources combined) was greater for placebo than vernakalant (12.8% in placebo patients and 7.5% for vernakalant patients). SAEs or discontinuations for a bradycardia event were 1.4% (15/1073) in the vernakalant group and 0.4% (2/459) in the placebo group in the first 24 hours. Twelve of the total 15 SAEs or discontinuations in the vernakalant group occurred within the first 2 hours of infusion. Two of the SAEs or discontinuations in the vernakalant group from 2 to 24 hours post- dose occurred in the Target Patient Population; however, both of these events resolved without treatment. In the PASS, the cumulative incidence of significant bradycardia HOIs in the first 2 hours post-dose was 0.7% (15/2009; 95% CI: 0.4% to 1.2%) including two instances of significant bradycardia with significant hypotension. Events of bradycardia generally resolved spontaneously or following treatment with atropine, positioning, external pacing, and/or other antiarrhythmics. The most clinically significant adverse effect across the program was hypotension. The mechanism of action for vernakalant-induced hypotension has been elucidated and is understood (Section 4.2.1.2). This was the most commonly reported SAE in vernakalant patients in the early trials. Severe hypotension was associated with severe aortic stenosis and in patients with moderate to severe reductions in baseline left ventricular function, i.e., conditions associated with reduced cardiac reserve to compensate for any reduction in myocardial contractility and cardiac output. By including contraindications in patients with clinically significant aortic stenosis and in patients with NYHA Class III, IV heart failure or with known moderate or severe left ventricular dysfunction, the risk of serious hypotension events should be mitigated, leaving primarily those hypotension events that may be associated with any form of cardioversion and that are manageable. The proposed labeling includes warnings regarding hypotension. In the clinical trial AE database, the incidence all combined hypotension events was slightly higher for 5.7% in vernakalant patients and 4.8% in placebo patients from 0-2 hours post-dose. However, the in 2-24 hours post dose the incidence was higher for placebo than vernakalant (5.9% compared to 3.4%, respectively). There was a total of 11 SAEs or discontinuations for hypotension from 0- 24 hours postdose in the vernakalant group (1.0%, 11/1073) and 3 in the placebo group (0.7%, 3/459). Of the total 11 SAEs or discontinuations of hypotension in the vernakalant group, 10 occurred within the first 2 hours of infusion. In 7 of the cases, saline, positioning or no treatment were adequate to resolve the hypotension. The PASS is supportive of the above; hypotension SAEs occurred in 5 (0.3%) of 1580 prospective uses. Only 2 HOIs of significant hypotension occurred, both transient and associated with bradycardia at the time of cardioversion and treated with atropine and saline alone, and 3 SAEs of hypotension occurred and were treated with shock, positioning and IV fluids, atropine, and in 1 case, treatment was unknown. In a post hoc analysis of serious hypotension events in the target population identified from the clinical studies, of the 6 SAEs of hypotension, only 2 required intervention other than saline and positioning; the patient with echo identified reduced systolic function and a post-surgical patient with transient hypotension who required a pressor. The proposed labeling indicates that patients should be carefully observed for signs and symptoms of a sudden decrease in blood pressure or heart rate, during infusion and for at least 2 hours after cessation of treatment, and until clinical status and ECG parameters are stable. The proposed
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labeling also states that vernakalant should be administered by intravenous infusion in a monitored clinical setting appropriate for cardioversion which includes all the necessary items used for resuscitation. In the post-marketing setting, atrial flutter with 1:1 atrio-ventricular conduction has been identified as a rare risk. There were no cases of AFL with1:1 conduction in the clinical development program, however, two occurred in the PASS. Both were treated with urgent ECV; nonclinical and clinical data have demonstrated that vernakalant does not affect response to ECV. Both ECV and pharmacologic cardioversion have risks. ECV is not suitable for all patients requiring cardioversion of AF to sinus rhythm, such as the non-fasting patient, those with significant pulmonary disease or with significant respiratory depression, and those post chest surgery. There is much greater emphasis on early anticoagulation (as soon as possible after onset in higher risk patients) due to the associated risk of thromboembolism, as well as emphasis on early cardioversion if it can be carried out in less than 48 hours in low risk patients and avoid the need for longer term anticoagulation and to avoid remodeling in the hopes of reducing the progression of AF. The use of ECV in these patients is not practical in many US centers because of its complexity and the need for anesthesia support in order to be done safely. Given the limitations related to efficacy, time to onset of action, and safety of current pharmacological agents used to acutely convert AF, there is a need for additional effective pharmacological treatment alternatives in appropriately selected patients where ECV is not feasible, not recommended, or not preferred. The data from vernakalant injection trials and the post-marketing setting indicate that in appropriate patients with recent onset AF for whom rapid cardioversion is indicated, the benefits of vernakalant infusion outweigh its risks when used in appropriate patients. 9.2.1 Risk Mitigation 9.2.1.1 Product Labeling The proposed prescribing information provides specific information to the prescriber on how to use vernakalant injection and when it should not be used, together with appropriate warnings and precautions, such as a potential risk for ventricular arrhythmias, bradycardia, and hypotension, which may occur with any form of cardioversion. Labeling is therefore the cornerstone of risk minimization and management for this product to be administered in a closely monitored clinical setting appropriate for cardioversion which includes all the necessary items used for resuscitation. Further, the Sponsor is proposing providing a Pre-Infusion Checklist with each vial of vernakalant, as described below, to ensure that the healthcare provider is aware of all contraindications and potential important risks. Only qualified healthcare professionals should administer vernakalant and the setting will be in a hospital setting, appropriate for cardioversion and resuscitation, hence a controlled, well-equipped medical location. It is recommended per the proposed labelling that the patient be carefully observed for signs and symptoms of a sudden decrease in blood pressure or heart rate, during infusion and for at least 2 hours after cessation of treatment, and until clinical status and ECG parameters are stable. Prior to attempting pharmacological cardioversion, proposed labeling indicates that patients should be adequately hydrated and hemodynamically stable with a minimum systolic blood pressure of >100 mmHg patients should not require blood pressure support before treatment. Anticoagulants Correvio International Sàrl 04 November 2019 Page 134 of 166
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should be used in accordance with treatment guidelines. In patients with uncorrected hypokalemia (serum potassium of less than 3.5 mmol/L), potassium levels should be corrected prior to use of vernakalant. The risk of ventricular arrhythmia in patients with a history of valvular heart disease and the risk of bradycardia is included in the Warnings and Precautions section of the prescribing information. This risk of hypotension is communicated via the Warnings and Precautions section of the prescribing information and may be anticipated and managed in the clinical setting in which vernakalant will be administered. Due to the risk of developing clinically-relevant hypotension (or ventricular arrhythmias), use of vernakalant in patients with clinically significant aortic stenosis, systolic blood pressure <100 mmHg (or having received either fluid resuscitation or inotropes to maintain blood pressure above 100 mmHg), or NYHA Class III or IV heart failure or known moderate or severe left ventricular dysfunction, are proposed to be included in the prescribing information as Contraindications. Further, the prescribing information indicates that vernakalant should be discontinued and appropriate medical management provided if: (1) a sudden drop in blood pressure or heart rate, with or without symptomatic hypotension or bradycardia is observed; or (2) ECG changes, such as a clinically meaningful sinus pause, complete heart block, new bundle branch block, significant prolongation of the QRS or QT interval, changes consistent with ischemia or infarction and ventricular arrhythmia, are observed. 9.2.1.2 Pre-Infusion Checklist An additional risk minimization measure includes a Pre-Infusion Checklist. A copy of the proposed Pre-Infusion checklist is included in Appendix 6. The Sponsor has developed this checklist to provide further support to the healthcare provider for appropriate patient selection, patient monitoring, and dosing instructions. The Pre-Infusion Checklist: (1) highlights the contraindications for vernakalant use, in an accessible checklist format; and (2) provides instructions for patient monitoring and management of medically significant adverse drug reactions when administering vernakalant. The checklist also offers a list of dose-stopping criteria to exclude patients from receiving the second injection of vernakalant if applicable. This tool will be included in the vernakalant package and delivered directly to the point of care. The Pre-Infusion Checklist also reinforces the importance of careful review of the prescribing information prior to use of the product. The healthcare provider uses the Pre-Infusion Checklist prior to the first infusion, as well as the second infusion (if applicable). In addition, the Pre-Infusion Checklist will be made available on the company website. A Pre-infusion checklist is currently used in the EU and in Canada and one is proposed in the US. The Pre-Infusion Checklist was implemented during the conduct of the PASS (SPECTRUM). In SPECTRUM, data collected on appropriateness of prescribing behavior in the context of the prescribing information showed that the Pre-Infusion Checklist was used for more than two-thirds of the patients. The majority of the patients in SPECTRUM were treated with vernakalant injection according to the prescribing information (>99% for the approved indication and 95% of patients without contraindications).
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9.3 Conclusions Vernakalant injection has been demonstrated to be efficacious for the rapid conversion of recent onset AF to SR and offers a valuable therapeutic alternative to current pharmacological agents and electrical cardioversion, both of which have limitations related to availability, efficacy, onset of action, and safety. In general, pharmacological conversion of AF to SR has the potential to occur sooner after admission, alleviate patient symptoms, reduce the need for anticoagulation (and increased risk of bleeding) prior to delayed cardioversion, and reduce the risk of early recurrence of AF compared with electrical cardioversion or waiting.13,34 The risks of ventricular arrhythmias, bradycardia, and hypotension with vernakalant injection in the clinical program have been systematically assessed. Similar risks have been identified with other agents used in cardioversion. Risks of these events are mitigated by treating appropriate patients, and by the guidance of the proposed labeling that identifies those patients who should not be treated with vernakalant injection, as well as appropriate monitoring during and after the infusion. Though ECV is used for the conversion of AF to sinus rhythm in many cases, pharmacologic cardioversion is appropriate and may be preferred in some instances. There are potentially serious risks associated with the FDA approved pharmacological treatments for AF. • The ibutilide product label contains a boxed warning for life threatening arrhythmias and appropriate treatment environment to manage the potentially fatal arrhythmias that may occur with ibutilide treatment. • The dofetilide product label contains a boxed warning that patients should be placed for a minimum of 3 days in a facility that can adequately monitor creatinine clearance, provide continuous electrocardiographic monitoring and cardiac resuscitation. The most commonly used drug for the treatment of AF, amiodarone, which is not FDA- approved for the treatment of AF, is slow acting and requires hospitalization for infusion and monitoring. The safety and efficacy of vernakalant have been thoroughly characterized based on a thorough clinical development program, a post-authorization safety study (SPECTRUM) that focused on the key events of clinical interest (hypotension, ventricular arrhythmias bradycardia and atrial flutter), and via analysis of post-marketing safety experience encompassing over 9 years of experience and >58,000 treatment episodes. Together, the totality of data supports the approval of vernakalant as an AF conversion agent which offers the target patient population a better pharmacological alternative than the approved and unapproved agents which are currently used for the treatment of recent onset AF.
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51. Morani G, Bergamini C, Angheben C, et al. General anaesthesia for external electrical cardioversion of atrial fibrillation: experience of an exclusively cardiological procedural management. Europace. 2010;12(11):1558-1563. 52. Steinberg BA, Schulte PJ, Hofmann P, Ersbøll M, Alexander JH, Broderick-Forsgren K, Anstrom KJ, Granger CB, Piccini JP, Velazquez EJ, Shah BR. Outcomes after nonemergent electrical cardioversion for atrial arrhythmias. Am J Cardiol. 2015;115(10):1407-1414. 53. Scheuermeyer FX, Grafstein E, Stenstrom R, et al. Thirty-day Outcomes of Emergency Department Patients Undergoing Electrical Cardioversion for Atrial Fibrillation or Flutter. Acad Emer Med. 2010;17(4):408–415. 54. Burton JH, Vinson DR, Drummond K et al. Electrical cardioversion of emergency department patients with atrial fibrillation. Ann Emerg Med. 2004;44(1):20-30. 55. Decker WW, Smars PA, Vaidyanathan L et al. A prospective, randomized trial of an emergency department observation unit for acute onset atrial fibrillation. Ann Emerg Med. 2008;52(4):322-328. 56. Vinson DR, Hoehn T, Graber DJ, Williams TM. Managing Emergency Department Patients with Recent-onset Atrial Fibrillation. J Emerg Med. 2012 Feb;42(2):139-48. 57. Gowda RM, Misra D, Khan IA, Schweitzer P 2003b, Acute pulmonary edema after successful electrical cardioversion of atrial fibrillation. Am J Ther. 2003;10(1):73-74. 58. Goli AK, Koduri M, Byrd RP, Mackall J. Acute pulmonary edema associated with direct current cardioversion in a structurally normal heart. Rev Cardiovasc Med. 2008;9(2):137- 141. 59. Eggleton S, Mathur G, Lambros J. An unusual precipitant of tako-tsubo cardiomyopathy. Heart Lung Circ. 2008;17(6):512-514. 60. Davarashvili I., Acha M.R., Glikson M., Farkash R., Mazouz B., Butnaru A., Hasin T. Pulmonary Congestion Complicating Atrial Fibrillation Cardioversion. Am J Cardiol 2018 122(10):1701-1706. 61. Fatkin D, et al. Transesophageal echocardiography before and during direct current cardioversion of atrial fibrillation: evidence for “atrial stunning” as a mechanism of thromboembolic complications. J Am Coll Cardiol. 1994;23(2):307-316. 62. Harjai KJ, et al. Clinical variables affecting recovery of left atrial mechanical function after cardioversion from atrial fibrillation. J Am Coll Cardiol. 1997;30(2):481-486. 63. Manning WJ, et al. Pulsed Doppler evaluation of atrial mechanical function after electrical cardioversion of atrial fibrillation. J Am Coll Cardiol. 1989;13(3):617-623. 64. Mattioli AV, et al. Clinical and echocardiographic features influencing recovery of atrial function after cardioversion of atrial fibrillation. Am J Cardiol. 1998;82(11):1368-1371. 65. Waller C, Callies F, Langenfeld H. Adverse effects of direct current cardioversion on cardiac pacemakers and electrodes Is external cardioversion contraindicated in patients with permanent pacing systems? Europace. 2004;6(2):165-168. 66. Nishida T, Nakajima T, Goryo Y, et al. Pacemaker system malfunction resulting from external electrical cardioversion: a case report. J Arrhythmia. 2009;25(4):209-213. 67. Pluymaekers NA, Dundink EA, Luermans JG, et al. Early or delayed cardioversion in recent-onset atrial fibrillation. N Engl J Med 2019;380:1499-1508.
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68. Fedida D, Orth PMR, Chen JYC, et al. The mechanism of atrial antiarrhythmic action of RSD1235. J Cardiovasc Electrophysiol. 2005;16:1227-1238. 69. Dorian P, Pinter A, Mangat I, et al. The effect of vernakalant (RSD1235), an investigational antiarrhythmic agent, on atrial electrophysiology in humans. J Cardiovasc Pharmacol 2007;50:35-40. 70. Varkevisser R, van der Heyden M, Tieland R, et al. Vernakalant is devoid of proarrhythmic effects in the complete AV block dog model. Eur J Pharmacol. 2013 Nov 5;720:49-54. 71. van Middendorp LB, Strik M, Houthuizen P, Kuiper M, Maessen JG, Auricchio A, Prinzen FW. Electrophysiological and hemodynamic effects of vernakalant and flecainide in dyssynchronous canine hearts. Europace. 2014 Aug;16(8):1249-56. 72. TAMBOCOR (flecainide acetate) [package insert]. Bridgewater, NJ; Amneal Pharmaceuticals LLC; Revised May 2017. 73. Costabel JP, Lambardi F, Aragon M, Campos R, Urdapilleta M, Ariznavarreta P, et al. Predictors of conversion of recent-onset atrial fibrillation treated with vernakalant. Pacing Clin Electrophysiol 2015;38(2):196-200. 74. Juul-Moller S. Vernakalant in recently developed atrial fibrillation: how to translate pharmacological trials into clinical practice. Eur J Cardiovasc Med 2013;2(4):226-233. 75. Simon A, Niederdoeckl J, Skyllouriotis E, et al. Vernakalant is superior to ibutilide for achieving sinus rhythm in patients with recent-onset atrial fibrillation: a randomized controlled trial at the emergency department. Europace (2017) 19, 233–240 76. Simon A, Niederdoeckl J, Janata K, Spiel AO, Schuetz N, Schnaubelt S, Herkner H, Cacioppo F, Laggner AN, Domanovits H. Vernakalant and electrical cardioversion for AF - Safe and effective. Int J Cardiol Heart Vasc. 2019 Jul 11;24:100398. 77. Pohjantähti-Maaroos H., Hyppölä H., Lekkala M., et al. Intravenous vernakalant in comparison with intravenous flecainide in the cardioversion of recent-onset atrial fibrillation. European heart journal. Acute cardiovascular care 2019;8(2):114-120. 78. Stoneman P, Gilligan P, Mahon P, Sheahan R. Chemical cardioversion of recent-onset atrial fibrillation in the emergency department using vernakalant hydrochloride achieves safe and rapid restoration of sinus rhythm and facilitates same day discharge. Ir J Med Sci 2017;186(4):903-908. 79. Cosin-Sales J, Loscos A, Peiro A, Sorando MR, Buendia F, Ruescas L. Real-world data on the efficacy of vernakalant for pharmacological cardioversion in patients with recent-onset atrial fibrillation. Rev Esp Cardiol 2016;69(6):619-20. 80. Carbajosa Dalmau J, Cosin-Sales J, Perez-Dura MJ, Noceda J, Urtubia-Palacios A, Hernandez-Sori N, et al. [Vernakalant in hospital emergency practice: safety and effectiveness]. Emergencias 2017;29(6):397-402. 81. Kriz R, Freynhofer MK, Weiss TW, Egger F, Gruber SC, Eisenburger P, et al. Safety and efficacy of pharmacological cardioversion of recent-onset atrial fibrillation: a single-center experience. Am J Emerg Med 2016;34(8):1486-90. 82. Manolis AS, Bethanis S, Metaxa S, Polytarchou K, Sakellaris N, Pyrros I. Use of intravenous vernakalant for atrial fibrillation conversion in the regular ward under only bedside monitoring. Hellenic J Cardiol 2018 Feb 15. pii: S1109-9666(17)30506-7. doi: 10.1016/j.hjc.2018.02.003. [Epub ahead of print]
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83. Vogiatzis I, Papavasiliou E, Dapcevitch I, Pittas S, Koulouris E. Vernakalant versus ibutilide for immediate conversion of recent-onset atrial fibrillation. Hippokratia 2017;21(2):67-73. 84. Sigmund E, Martinek M, Derndorfer M, et al. Vernakalant: Medicinal cardioversion in atrial fibrillation. J Kardiol 2014; 21 (Suppl A): 16–8. 85. Poçi D, Abrahamssom B-M, Edvardsson N, Bergfeldt L. Sinus Bradycardia and Sinus Pauses Immediately after Electrical Cardioversion of Persistent Atrial Fibrillation – What do they mean? Ann Noninvasive Electrocardiol 2013;18(3):281–287. 86. Grönberg T, Nuotio I, Nikkinen M, Ylitalo A, Vasankari T, Hartikainen JEK, and Airaksinen KEJ. Arrhythmic complications after electrical cardioversion of acute atrial fibrillation: The FinCV study. Europace (2013) 15, 1432–1435 doi:10.1093/europace/eut106 87. Reisinger J, Gatterer E, Lang W, Vanicek T, Eisserer G, Bachleitner T, Niemeth C, Aicher F, Grander W, Heinze G, Kühn P, Siostrzonek P. Flecainide versus ibutilide for immediate cardioversion of atrial fibrillation of recent onset. European Heart Journal (2004) 25, 1318– 1324.
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APPENDIX 1 Table of Clinical Efficacy Endpoints by Study Study Primary, Secondary and Exploratory Efficacy Endpoints Primary: Proportion of subjects with short-duration AF (>3 hours and ≤ 7 days) who had a treatment-induced conversion of AF to sinus rhythm within 90 minutes of first exposure to study medication and for a minimum duration of one minute. Secondary: • Time to conversion of AF to sinus rhythm (for a minimum duration of one minute) in subjects with short-duration AF. 1235-0703 • Time to termination of AF (defined as the absence of AF or atrial flutter for a minimum (ACT I) duration of one minute) in the overall population (AF duration >3hours and ≤45 days). PIVOTAL • The proportion of subjects in the overall population who had a treatment-induced termination Phase 3 of AF (minimum duration of one minute) within 90 minutes after first exposure to study medication. • Time to termination of AF (defined as the absence of AF or atrial flutter for a minimum duration of 1 minute) in subjects with long-duration AF. • The proportion of subjects with long-duration AF who had a treatment-induced termination of AF (minimum duration of 1 minute) within 90 minutes after first exposure to study medication. Primary: Proportion of subjects with short-duration AF (>3 hours and ≤ 7 days) who had a treatment-induced conversion of AF to sinus rhythm for a minimum duration of one minute within 90 minutes of first exposure to study drug. Secondary: • Time from first study drug exposure to first conversion of AF to sinus rhythm (minimum duration of one minute) within 24 hours of first study drug exposure for subjects with short- duration AF. • The proportion of subjects with AF (>3 hours and ≤ 45 days) who had treatment-induced AF termination (minimum duration of one minute) within 90 minutes of first exposure to study drug. • The proportion of subjects with short-duration AF or AFL who had treatment-induced AF or 04-07-010 AFL termination (minimum duration of one minute) within 90 minutes of first exposure to (ACT III) study drug. PIVOTAL • The proportion of subjects with AF or AFL (>3 hours and ≤ 45 days) who had treatment- Phase 3 induced AF or AFL termination (minimum duration of one minute) within 90 minutes of first exposure to study drug. • The proportion of subjects with long-duration AF (>7 days and ≤ 45 days) who had treatment- induced AF termination (minimum duration of one minute) within 90 minutes of first exposure to study drug. • The proportion of subjects with long-duration AF or AFL who had treatment-induced AF or AFL termination (minimum duration of one minute) within 90 minutes of first exposure to study drug. • The proportion of subjects with AFL (>3 hours and ≤ 45 days) who had treatment induced AFL termination (minimum duration of one minute) within 90 minutes of first exposure to study drug. Primary: Proportion of subjects with AF or AFL who had treatment-induced conversion to sinus rhythm for a minimum duration of 1 minute within 1.5 hours of first exposure to study drug. Secondary: 1235-0104 • Time to conversion of AF/AFL to SR within 1.5 hours of first exposure to study drug for a (ACT II) minimum duration of one minute. PIVOTAL • The proportion of subjects with AF who had treatment-induced conversion of AF to SR within Phase 3 1.5 hours of first exposure to study drug for a minimum duration of one minute. • Time to conversion of AF to SR within 1.5 hours of first exposure to study drug for a minimum duration of one minute.
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Study Primary, Secondary and Exploratory Efficacy Endpoints • The proportion of subjects with AFL who had treatment-induced conversion of AFL to SR within 1.5 hours of first exposure to study drug for a minimum duration of one minute. • Time to conversion of AFL to SR within 1.5 hours of first exposure to study drug for a minimum duration of one minute. Exploratory: • The proportion of subjects who met the primary endpoint and who remained in SR at hour 2, hour 4, hour 6, hour 24 and day 7/follow-up visit. • The time to conversion from AF/AFL to SR in subjects who converted within 90 minutes. • The proportion of AF/AFL subjects, AF subjects, and AFL subjects with treatment-induced conversion to SR within 90 minutes with a single dose of study drug. • The proportion of AF/AFL subjects, AF subjects, and AFL subjects with at least one arrhythmia symptom at each time point and the proportion of subjects who reported each symptom at each time point. Primary: The termination of AF during infusion or during the 30-minute post-infusion period. 1235-1001 Secondary: (CRAFT) • Number (percentage) of patients in NSR at 0.5, 1.0, and 24 hours post end of last infusion. SUPPORTIVE • Time to conversion, calculated as the time (in minutes) from the start of first infusion to the Phase 2a time when AF was converted to NSR. Primary: Proportion of subjects who had treatment-induced conversion of AFL to sinus rhythm for a minimum duration of 1 minute within 90 minutes after first exposure to study medication Secondary: 1235-0703B • Time-to-conversion of AFL to sinus rhythm. (Scene 2) • The proportion of subjects who had treatment-induced termination of AFL within 90 minutes SUPPORTIVE of first exposure to study medication (defined as the absence of AF or AFL for a minimum Phase 2/3 duration of 1 minute). • Time-to-termination of AFL. • Absolute reduction (change from baseline) of the ventricular response rate at 50 minutes after first exposure to treatment. 6517-CL-0020 Primary: Successful conversion to sinus rhythm for at least 1 minute documented by the Holter (ACT V) monitor or by two consecutive 12-lead ECGs recorded > 1 minute apart within 90 minutes of first SUPPORTIVE exposure to study treatment. Phase 3b Secondary: • Time from first exposure to study treatment to conversion of AF to SR, within 90 minutes • Proportion of subjects reporting no symptoms at 90 minutes after first exposure to study treatment. Exploratory: • Proportion of subjects reporting no symptoms at 90 minutes for specific symptoms; • Proportion of subjects who convert to SR within 90 minutes after first exposure to study treatment and maintained SR to 24 + 4 hours documented by Holter or two consecutive 12-lead ECGS recorded > 1 minute apart at 24 +4 hours. A subject is considered success for this exploratory efficacy endpoint if the subject converted to SR as defined in the primary efficacy variable and maintained SR documented by Holter or by two consecutive 12-lead ECGs recorded > 1 minute apart at 24 + 4 hours. • Severity of symptoms at 90 minutes after first exposure to study treatment, as measured on a 5 point scale (0=Asymptomatic with respect to AF through 5=AF Symptoms have severe impact on quality of life). VERI-305- Primary: Proportion of subjects with conversion of AF to SR within 90+3 minutes of AMIO first exposure to study medication and for a minimum duration of one minute (AVRO) Secondary: SUPPORTIVE • Time to conversion of SR within the first 90+3 minutes after the start of infusion. Phase 3 • Proportion of subjects exhibiting none of the following AF symptoms at 90 minutes: shortness of breath, palpitations, chest tightness/pain, dizziness, edema, fatigue, rapid heart beat, Correvio International Sàrl 04 November 2019 Page 144 of 166
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Study Primary, Secondary and Exploratory Efficacy Endpoints diaphoresis, orthopnea, paroxysmal nocturnal dyspnea, syncope, irregular pulse, nausea, vomiting, cough, and headache. • Change in EQ-5D quality of life assessment Visual Analogue Scale (VAS) from screening to hour 2. Exploratory: • Time to conversion of SR within the first 240 minutes after the start of infusion. Subjects who did not convert within 240 minutes were censored at minute 240 (note, subjects who were electrically cardioverted were censored at the time of electrical conversion). • Subjects exhibiting no AF symptoms at Day 7. • Subjects exhibiting each AF symptom at minute 90 and Day 7. • Reduction in the number of symptoms at minute 90. • Reduction in the number of symptoms at Day 7. • Proportion of subjects who met the primary endpoint and maintained SR with no AF relapse at hour 4. A relapse was defined as AF occurring after conversion to SR had been documented, lasting at least 30 seconds on Holter, or AF on two consecutive 12-lead ECGs taken at least 30 seconds apart. • Proportion of subjects who met the primary endpoint and maintained SR with no AF relapse through Day 7. A relapse was defined as above; however, if the Day 7 ECG showed AF, the subject was considered to have relapsed (the reason for this was that there was only a single 12-lead ECG collected at Day 7 and so documentation of AF for 30 seconds was not possible). • Proportion of subjects who met the primary endpoint and maintained SR with no AF relapse through Day 30. A relapse was defined based on adverse event (AE) data; any AE of AF or AFL occurring after a subject was successfully converted to SR within 90 minutes was counted as a relapse if the start date/time was prior to Day 30. • The descriptive system of the EQ-5D health-related quality of life tool consisted of 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each of which had one of three responses. The responses recorded 3 levels of severity (no problems; some or moderate problems; extreme problems) within a particular EQ-5D dimension. Each dimension was assessed individually. • Proportion of subjects ready for discharge at two hours. • For subjects who converted to sinus rhythm within 90 minutes, a descriptive summary of the time to conversion was presented by treatment group; no comparison between groups was made. 6621-010-04 Primary: Proportion of patients with treatment-induced conversion of AF to sinus rhythm (for a (Asia-Pacific) minimum duration of 1 minute) within the 90-minute period after first exposure to study drug. SUPPORTIVE Secondary: Phase 3 • Time to conversion of AF to sinus rhythm (for a minimum duration of 1 minute) within the 24-hour period after first infusion • Number of symptoms associated with AF at 90 minutes after first infusion • Proportion of converted patients maintained in sinus rhythm at 24 hours • Proportion of converted patients maintained in sinus rhythm at 7 days Tertiary: • Time to conversion of AF to sinus rhythm (for a minimum duration of 1 minute) within the 90-minute period after first infusion • Time to conversion of AF to sinus rhythm (for a minimum duration of 1 minute) within the 4- hour period after the first infusion. 05-7-012 Primary: proportion of subjects with short duration of AF who have treatment-induced (ACT IV) conversion of AF to SR within 1.5 hours of first exposure to study medication for a minimum SUPPORTIVE duration of one minute Phase 3 Exploratory: • Time taken from first exposure to study medication to conversion of AF to SR for a minimum duration of one minute within 1.5 hours of first exposure to study medication in subjects with short and short-plus-long duration of AF
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APPENDIX 2 Summary of Excluded Populations in the Pivotal Phase 3 Studies ACT I ACT III ACT II Bradycardia Bradycardia Sick sinus syndrome Sick sinus syndrome VR <50 bpm VR <50 bpm VR <45 bpm QRS > 0.14 sec (no pacemaker) QRS > 0.14 sec (no pacemaker) QRS > 0.14 sec (no pacemaker) Reversible/secondary AF Reversible/secondary AF Reversible/secondary AF Unstable Class IV CHF Unstable Class IV CHF HF requiring IV inotrope HF requiring IV inotrope ACS within 30 days ACS within 30 days Cardiac surgery within 30 days Cardiac surgery within 30 days SBP 90-160 mmHg SBP 90-160 mmHg SBP 90-160 mmHg DBP ≤95 mmHg DBP ≤95 mmHg DBP ≤95 mmHg QT > 440 msec QT > 440 msec QT > 500 msec, QTcB >460a Familial long QT syndrome Familial long QT syndrome Familial long QT syndrome Brugada syndrome Brugada syndrome Brugada syndrome History of TdP History of TdP History of TdP Other medical conditions that may Other medical conditions that may Other medical conditions that may interfere with the conduct/validity of interfere with the conduct/validity of interfere with the conduct/validity of the study or compromise subject the study or compromise subject the study or compromise subject safetyb safetyb safetyb Digoxin toxicity Digoxin toxicity Digoxin toxicity IV Class I or Class III antiarrhythmic IV Class I or Class III antiarrhythmic IV Class I or Class III antiarrhythmic within 24 hours within 24 hours post-surgery Prior ECV failure Prior ECV failure
Oral amiodarone within 3 months “typical”AFL (ACT I only) Significant valvular stenosis 2nd or 3rd degree AV block (no Hypertrophic obstructive pacemaker) cardiomyopathy QTcB >460 msec pre-surgery Restrictive cardiomyopathy Constrictive pericarditis Abbreviations: ACS=acute coronary syndrome; AF=atrial fibrillation; AV=atrioventricular; CHF=congestive heart failure; DBP=diastolic blood pressure; ECV=electrical cardioversion; SBP=systolic blood pressure; TdP=Torsades de Pointes; VR=ventricular rate a Pre-surgery b As judged by the investigator (eg, serious pulmonary, hepatic, metabolic, renal, gastrointestinal, central nervous system, psychiatric disease, end stage disease states, hemodynamic instability, etc.)
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APPENDIX 3 Narratives: Eight Adverse Events of Significant Concern Identified by FDA and Deaths Eight Adverse Events of Significant Concern Identified by FDA (b) (6) Patient (ACT III) FDA Description in Approvable Letter (additional clarification added by Correvio is in bold font): (b) (6) Patient in Act III was a 64-year-old male with aortic stenosis and a history of hypertension who died shortly after the second infusion. The presentation at the Advisory Committee meeting suspected that he was ineligible for the trial, but he was in fact eligible at the time of his randomization. Eligibility criteria were changed after his death to exclude patients with aortic stenosis. Prior to the vernakalant infusion he was treated with intravenous metoprolol, became mildly hypotensive (90/70 mmHg), and was given a saline infusion with restoration of blood pressure to 115/75 mmHg. He was also given an oral dose of metoprolol. Immediately prior to vernakalant infusion his blood pressure was about 102-110/60-90 mmHg and heart rate about 152 bpm. Within minutes of the first infusion he became nauseated and diaphoretic with hypotension to 62/42 mmHg. QTc prolongations of about 100 msec (max 507) for Fridericia’s corrected QT interval (QTcF), and 90 msec (max 567) for QTcB were recorded as were ECG changes suggestive of ischemia. He was given metoclopramide, saline, and hydroxyethyl starch. By about 25 minutes after infusion start he was reported to be better symptomatically (was sitting up, awake, lucid, good color), with blood pressure 104/74 mmHg and heart rate 109 bpm. He was then given the second infusion. He again became nauseated and hypotensive (65/41 mmHg) but with recovery to 103/60 mmHg at 21 minutes after the start of the second infusion. However, at 22 minutes he developed a polymorphic ventricular tachycardia and lost consciousness. The precise nature of the arrhythmia was unclear (TdP vs. others), but he did pass through bradycardic “sinus” rhythm (20-30 bpm), possibly ventricular flutter, ventricular fibrillation, and electromechanical dissociation before being declared dead at about 14 minutes after the arrest started. An autopsy confirmed the presence of aortic stenosis and ventricular hypertrophy. No sign of acute myocardial infarction was found.
Sponsor’s Comment on the Case: This 64-year-old man had a history of hypertension, CHF NYHA Class II, and dyspnea and had a recent echocardiogram, the same month, showing severe aortic stenosis with a gradient of 120 mmHg and an ejection fraction of 40%. He presented to hospital with 4 hours of chest tightness, fatigue, and an irregular pulse (along with rapid heart rate and nausea) and was found to be in AFL/AF with ST segment elevation and had a clear chest and an audible aortic murmur.He was given two IV doses of 2.5 mg of metoprolol at 7:38 am and 8:10 am. His blood pressure was 90/70 mmHg and he was given saline which increased his blood pressure to 105/85 mmHg and then to 115/75 mmHg. He was given 50 mg of oral metoprolol at 8:15 am. His pre-infusion blood pressures were 104/53, 102/66, 110/95 mmHg and heart rate was 152 bpm. He began the infusion at 09:41 am and 2 minutes later had nausea and a blood pressure of 103/60; at 6 minutes into the infusion, blood pressure was 89/72 mmHg, and at 10 minutes (end of the infusion) was 75/42 mmHg, with heart rate of 113 bpm. At 15 minutes, he felt faint with a blood pressure of 62/42 mmHg and was given hydroxyethyl starch at 17 minutes. At 25 minutes after the beginning of the Correvio International Sàrl 04 November 2019 Page 147 of 166
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infusion and with a blood pressure of 88/67 mmHg, he was started on the second infusion of vernakalant. He became more nauseated and hypotensive and at the end of that infusion developed ventricular tachycardia, was cardioverted to a pulseless rhythm, received resuscitative maneuvers and died 16 minutes later. The patient presented with known severe aortic stenosis and AF (a very poor prognostic sign) and had findings suggestive of acute coronary syndrome (chest pain and ST segment elevation on the ECG). Pharmacologic cardioversion is never clinically indicated in symptomatic aortic stenosis and vernakalant is contraindicated in patients with a possible acute coronary syndrome. In addition, the drug should have been discontinued at the first onset of hypotension, 5 minutes into the first infusion. We propose to mitigate this situation by making (a) clinically significant aortic stenosis, (b) systolic blood pressure <100 mmHg (or having received fluid resuscitation or inotropes to maintain blood pressure >100 mmHg), and (c) evidence of a possible acute coronary syndrome within the last 30 days as three contraindications in the label and in the Pre-Infusion Checklist. In addition, in the proposed Warnings section of the US label for vernakalant injection, it is stated that a sudden drop in blood pressure mandates stopping the drug and in Section 5.5 of the label, it is stated that the use of intravenous beta-blockers within 2 hours of treatment is not recommended.
(b) (6) Patient (ACT III) FDA Description in Approvable Letter: (b) (6) Patient in Act III was a 48-year-old male with “Class II” heart failure (although historical ejection fraction was “ ≤25%” ) and a biventricular pacemaker who was receiving carvedilol, spironolactone, and furosemide (i.e., vigorous CHF treatment) who developed severe hypotension, ventricular tachycardia, and seizures after the first infusion. Baseline blood pressure was about 100/76 mmHg. Five minutes into the infusion it fell to 70/55 mmHg and at the end 81/64 mmHg with one reported symptom of taste disturbance. At about the time of the infusion end or immediately thereafter, he developed what the investigator called AFL and severe hypotension with unmeasurable blood pressure for about 30 minutes. The AFL on Holter was described as “ATRIAL FLUTTER WITH AV [atrioventricular] BLOCKS VARYING II TO I AND III TO I AND FUNCTIONAL RBBB ALTERNATING WITH LBB [left bundle branch block].” This could have been a polymorphic ventricular tachycardia and one tracing was read by the chair of the DSMB as sustained monomorphic ventricular tachycardia. During this time he lost onsciousness and had generalized seizures. He was treated with a saline infusion, feet elevation, and oxygen with gradual recovery. After about five hours he was successfully electrically cardioverted. Blood pressures on that day stayed around 90/60 mmHg with blood pressure 110/70 mmHg six days later. It seems possible that this patient’s poor ventricular function was at the root of this episode.
Sponsor’s Comment on the Case: The patient’s severe CHF and known severe left ventricular dysfunction, as shown by the decreased left ventricular ejection fraction, in conjunction with the infusion of vernakalant was the most likely cause of the episode. Per the proposed labeling, the use of vernakalant in patients with severe heart failure (NYHA Class III or IV or with known moderate or severe left ventricular dysfunction) is contraindicated. In addition, the Warnings section of the proposed US vernakalant injection label indicates that a sudden drop in blood pressure mandates stopping the drug.
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(b) (6) Patient (ACT I) FDA Description in Approvable Letter (additional clarification added by Correvio is in bold font): (b) (6) Patient in Act I was a 49-year-old male without prior recognized cardiovascular disease, although he had recent symptoms of fatigue, orthopnea, cough and pedal edema on admission. He developed severe hypotension after the first infusion and subsequently was diagnosed as having a cardiomyopathy. The patient received intravenous and oral metoprolol, as well as intravenous furosemide. Baseline blood pressure was 112/80 mmHg and pulse 96 bpm. About 8 minutes into the first infusion the patient complained of back pain behind the right shoulder, then hot and cold sensations, and he then became diaphoretic and pale. He was noted to be hypotensive (<75 mmHg) and was placed in Trendelenburg position and given intravenous saline. At 10 minutes his systolic blood pressure was recorded as 82 mmHg and his pulse was 157 bpm. We have no Holter overreads and the high rate, so far as we know, was still AF. With the position change, saline, and discontinuation of drug the hypotension resolved by about 27 minutes, although heart rates remained elevated through ECV at about 3 hours. At about 11 hours after the infusion, he went into cardiogenic shock and was ultimately diagnosed as having an idiopathic cardiomyopathy by myocardial biopsy. The patient experienced cardiogenic shock approximately 12 hours after the initiation of study drug infusion and approximately 10 hours after ECV. Plasma levels of vernakalant had decreased from a peak of approximately 5600 ng/mL at 10 minutes to 1010 ng/mL at 90 minutes (0 ng/mL at 24 hours). At the time of ECV, the patient was on both sotalol and metoprolol. He was ultimately diagnosed as having an idiopathic cardiomyopathy by myocardial biopsy. This case again raises the question of whether poor ventricular function predicts a bad outcome and how this can best be detected so that treatment with vernakalant can be avoided.
Sponsor’s Comment on the Case: This 49-year-old man presented with cough, fatigue, peripheral edema, and rapid heart rate and was in rapid AF. Blood pressure prior to vernakalant was 112/80 mmHg; he developed back and chest pain during the infusion and systolic BP dropped to 75 mmHg at 8 min and then to 50 mmHg. The infusion was continued to completion and he was given saline and placed in Trendelenburg. The systolic blood pressure increased to 111 mmHg by 17 minutes after the end of infusion. No conversion occurred. His blood pressure remained stable and the AF was converted to sinus rhythm by ECV 2.5 hours later. At 21:00 that night, he was given sotalol. At 22:32 intravenous lorazepam was given and at 22:54 his blood pressure was reported to be 96 systolic. At 23:15 he was agitated and at midnight his speech was incoherent (now 8 hours 30 minutes after initiating vernakalant). At 01:05 and at 02:05 intravenous doses of haloperidol were given. Cheyne Stokes respirations were reported at 03:00 and intravenous dopamine was initiated at 03:04. He appeared cyanotic, was intubated, and between 03:10 and 03:33 received intravenous fentanyl, anectine, morphine and midazolam. His blood pressure for the remainder of the times was stable. He had recurrent episodes of AF and received intravenous and oral amiodarone. A cardiac catheterization was done later that day and showed normal coronaries and an ejection fraction of 25% and a biopsy with non-specific changes consistent with cardiomyopathy. He was treated for heart failure and discharged 20 days later.
The patient had an undiagnosed cardiomyopathy on presentation; the only possible indicators of which were the history of dyspnea and the finding of peripheral edema. His vital signs and other findings made him a candidate for vernakalant. His physician stopped the drug shortly after Correvio International Sàrl 04 November 2019 Page 149 of 166
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hypotension was noted and no second dose was given. His event of respiratory compromise, hypotension and “shock” were most likely related to over sedation with multiple doses of sedatives and haloperidol. Blood concentrations obtained at 90 min were 1010 ng/ml and modeling would predict they would be minimal at the time of his respiratory arrest. At the time of the attempted first cardioversion with vernakalant, the sudden drop in blood pressure should have been an indication to discontinue the infusion earlier. The Warnings section of the proposed vernakalant US label indicates that a sudden drop in blood pressure mandates stopping the drug.
(b) (6) Patient (ACT I) FDA Description in Approvable Letter: (b) (6) Patient in Act I was a 58-year-old male with a history of myocardial infarction and coronary artery bypass graft and taking bisoprolol who converted after the first infusion but experienced severe bradycardia, hypotension, and sinus arrests. BP at baseline was 125/64 mmHg and pulse was 79 bpm. A few minutes after the start of the study drug infusion he experienced dizziness, nausea and the taste of metal. At 14 minutes after the start of infusion he converted to sinus bradycardia and sinus arrest with a nodal escape rhythm of 30 bpm. His BP fell to 79/44 mmHg and he was placed in Trendelenburg position. He was clammy and sweaty but remained awake during these events. Holter monitoring revealed an episode of asystole of 8.6 seconds duration and he was given three doses of atropine. By about 22 minutes sinus rhythm was restored and his BP was adequate (111/75 mmHg).
Sponsor’s Comment on the Case: Data suggest that sinus pauses, high degree atrioventricular block, and bradycardia (which at times can be associated with hypotension) may occur with any form of cardioversion1,2,3,51. The hypotension that occurred in this patient was likely associated with the observed sinus pause.
The proposed Dosage and Administration section of the label indicates that vernakalant should be administered by intravenous infusion in a monitored clinical setting appropriate for cardioversion which includes all the necessary items used for resuscitation. Only a qualified healthcare professional should administer vernakalant, and the patient should be carefully observed for signs and symptoms of a sudden decrease in blood pressure or heart rate, during infusion and for at least 2 hours after cessation of vernakalant treatment, and until clinical status and ECG parameters are stable. The Warning section of the label indicates that SAEs of bradycardia have been reported during or following treatment with vernakalant infusion. In general, bradycardia responded well to discontinuation of vernakalant and/or administration of atropine or isoprenaline, however, some events of bradycardia requiring electrical pacing have been reported. On occasion, these events were associated with clinically-relevant hypotension.
(b) (6) Patient (ACT III) FDA Description in Approvable Letter (additional clarification added by Correvio is in bold font): (b) (6) Patien in Act III was a 74 year-old male with a history of hypertension (on lisinopril and metoprolol, but neither taken on the day of event) and ischemic heart disease started on coumadin (international normalized ratio 3.6) three days earlier who developed a wide complex tachycardia after receiving the first infusion in one-half the prescribed time (5’ rather than 10’). The patient had a history of moderate to severe left ventricular dysfunction with an ejection Correvio International Sàrl 04 November 2019 Page 150 of 166
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fraction of 26% to 35% but no recorded history of CHF on the case report form (CRF). The tachycardia began when he had received most (“58.4” ml of 60 ml) of the first infusion. Study medication was discontinued. His blood pressure dropped but remained adequate (from about 140/80 to 110/70 mmHg) and he was apparently asymptomatic. Ten minutes after the start of study drug infusion, the subject had a bloody stool. The wide complex tachycardia resolved without treatment. While the rhythm was described as a wide complex tachycardia, it was also read as a monomorphic ventricular tachycardia and the tracings in the CRFs show some polymorphic features. The gastrointestinal hemorrhage (which was not considered related to study drug) resolved 3 days later.
Sponsor’s Comment on the Case: A 74-year-old man who had known hypertension, diverticulosis, and AF in the past and on warfarin, had evidence of ischemic heart disease. His ejection fraction was 26-35%. He received almost all of the initial infusion of vernakalant over the first 5 minutes. His pre-dose systolic blood pressure was 113-143 mmHg, and his heart rate was 140-179 bpm, essentially unchanged from baseline. He had multiple episodes of nonsustained ventricular tachycardia shortly after the start of the infusion and for the following 28 minutes. No treatment was given and then the patient began having a gastrointestinal bleed felt to be secondary to anticoagulation and diverticula which is the likely cause of hypotension. The Holter also showed multiple episodes of both monomorphic and polymorphic nonsustained runs of ventricular tachycardia in the hour before vernakalant. The drug level at the end of infusion was 2610 ng/ml-half the typical maximum concentration expected. There is no clear evidence that the ventricular arrhythmia seen after the excessive infusion rate had any relationship to administration of the drug as the same arrhythmias were seen prior to treatment and are not uncommon in patients with moderate to severe left ventricular dysfunction.
In the proposed label for vernakalant, severe heart failure (including NYHA Class III and IV or with known moderate or severe left ventricular dysfunction) will be listed as a Contraindication and would preclude use in future similar patients.
(b) (6) Patient (ACT I) FDA Description in Approvable Letter: (b) (6) Patient in Act I was a 51-year-old female started on metoprolol the previous day who experienced extreme bradycardia and a sinus pause at the time of conversion. Her baseline BP was 87-113/63-79 mmHg and pulse was about 90 bpm. At 77 minutes she was reported to convert and experienced AEs of extreme bradycardia and sinus arrest at this time; panic alerts reported complete heart block and heart rate <40 bpm at this time. Holter documents a sinus pause of 10.7 seconds.
Sponsor’s Comment on the Case: This patient had baseline hypotension. Low systolic blood pressure at baseline has been found to increase the probability of patients becoming hypotensive (defined as SBP ≤90 mmHg) in the first 0-120 minutes after start of infusion. The proposed label for vernakalant indicates that patients are contraindicated if systolic blood pressure <100 mmHg (or having received fluid resuscitation or inotropes to maintain BP [blood pressure] >100mmHg.
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Data suggest that sinus pause is a risk associated with conversion to sinus rhythm, irrespective of modality, and sinus pauses >10 seconds occur following ECV. Sinus pauses, high-degree atrioventricular block, and bradycardia (which at times can be associated with hypotension) may occur following any form of cardioversion1,2,3,51. The hypotension that occurred in this patient was likely associated with the observed sinus pause.
The Administration section of the proposed label will specify that vernakalant should be administered by intravenous infusion in a monitored clinical setting appropriate for cardioversion which includes all the necessary items used for resuscitation. Only a qualified healthcare professional should administer vernakalant and the patient should be carefully observed for signs and symptoms of a sudden decrease in blood pressure or heart rate, during infusion and for at least 2 hours after cessation of vernakalant treatment, and until clinical status and ECG parameters are stable. The Warning section indicates that SAEs of bradycardia have been reported during or following treatment with vernakalant infusion. Most cases occurred soon after conversion to sinus rhythm. In general, bradycardia responded well to discontinuation of vernakalant and/or administration of atropine or isoprenaline, however, some events of bradycardia requiring electrical pacing have been reported. On occasion, these events were associated with clinically-relevant hypotension.
(b) (6) Patient (ACT I) FDA Description in Approvable Letter (additional clarification added by Correvio is in bold font): (b) (6) Patient in Act I was a 54 year-old male with a history of hypertension, “cardiac insufficiency,” and asthma on fosinopril and hydrochlorothiazide and also given intravenous digoxin, metoprolol, and furosemide who experienced hypotension, diaphoresis, and nausea after the second infusion. Baseline blood pressure was about 140/90 mmHg and pulse was 100 bpm. He experienced hot flushes, upper limb itching, and hand and leg numbness after the first infusion and blood pressure decreased to 115/85 mmHg. Immediately after the second infusion at 35 minutes he experienced diaphoresis, nervousness, and nausea followed by hypotension and nose itching. At 40 minutes blood pressure was 88/60 mmHg with pulse remaining about 100 bpm. The hypotension lasted 5 minutes and resolved. He converted to sinus rhythm at 90 minutes from the start of the first infusion.
Sponsor’s Comment on the Case: This 54-year-old man had a history of hypertension and heart failure (“cardiac insufficiency”) and presented with shortness of breath and AF. On the day prior to vernakalant treatment, he was given intravenous furosemide (presumably for signs of pulmonary congestion and dyspnea), intravenous diltiazem, intravenous metoprolol, and oral metoprolol. He was treated with two doses of vernakalant on the following day and converted to sinus rhythm. His blood pressure was 138/86 mmHg before treatment and 10 minutes after the second dose was transiently 88/60 mmHg. No treatment was given in the following 5 minutes and then blood pressure was 100/76 mmHg and 5 minutes after that it was 118/80 mmHg. He had chest pain on Day 2 and subsequently showed normal coronaries and a dilated cardiomyopathy.
The Sponsor proposes to mitigate such uses by listing severe heart failure (NYHA Class III and IV or with known moderate or severe left ventricular dysfunction) as a contraindication in the label. Further, the proposed Warnings section of vernakalant US label indicates the following: Correvio International Sàrl 04 November 2019 Page 152 of 166
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Due to the higher incidence of hypotension and ventricular arrhythmias in patients with CHF, vernakalant should be used with caution in patients with hemodynamically stable CHF functional classes NYHA I to II. There is limited experience with the use of vernakalant in patients with previously documented left ventricular ejection fraction ≤35% and use in these patients is not recommended. The use of vernakalant in CHF patients NYHA Class III or IV or with moderate or severe left ventricular dysfunction is contraindicated.
(b) (6) Patient (ACT I) FDA Description in Approvable Letter (additional clarification added by Correvio is in bold font): (b) (6) Patient in Act I was a 90 year-old female with a history of angina and pulmonary “stasis.” Results of a transesophageal echocardiogram conducted 3 days prior to study drug infusion demonstrated hypokinesis. She did not convert on the two infusions but was given oral metoprolol between infusions, a protocol violation. ECV was successful at just under 3 hours after the first infusion was started, but her BP fell to 47/23 mmHg with bradycardia of approximately 40 bpm. The rhythm was later described as complete heart block. Two 0.5 mg doses of atropine were administered intravenous with no change in heart rhythm. Intravenous isoprenalin was then administered and immediately the subject’s heart rate increased to 120 bpm and she converted to sinus rhythm. Her subsequent course was deteriorating with TdP reported the next day, a pacemaker insertion, worsening heart failure, and death within a month.
Sponsor’s Comment on the Case: This 90-year-old woman was admitted with shortness of breath, chest pain, a rapid heart rate. She had a history of pulmonary edema, angina, and hyponatremia. She was in AF. Three days before receiving treatment in the study, a transesophageal echo was done which showed lateral wall ischemia and an estimated ejection fraction of 45%. She was treated with two doses of vernakalant and did not convert. She was given an oral dose of metoprolol between the two infusions. Two hours and 38 minutes after initiation of vernakalant, she had an ECV which resulted in complete heart block with a pulse of 40 bpm and a blood pressure of 47/23 mmHg. She was given 2 boluses of atropine and then placed on intravenous isoprenaline and the pulse and sinus rhythm returned at 120 bpm. One hour and 23 minutes later, runs of ventricular beats were described, the longest of which was 18 seconds and she received amiodarone and magnesium (it was unclear whether she was maintained on isoprenaline during this time). On the next day a temporary pacemaker was placed which was kept in place for 3 days. She was discharged 17 days after treatment with vernakalant. Eight days later she was readmitted with dyspnea and cough and found to be in AF. A chest x-ray showed bilateral pleural effusions for which she received a diuretic. On the following day she had a bloody cough, became progressively hypoxemic and died with the cause “pulmonary edema.”
The episode of complete heart block is common to all forms of cardioversion and can be attended with bradycardia and hypotension. It is unlikely that the heart block after electrocardioversion and her subsequent death after first being discharged home was caused by vernakalant treatment.
The Dosage and Administration section of the proposed label indicates that vernakalant should be administered by intravenous infusion in a monitored clinical setting appropriate for cardioversion which includes all the necessary items used for resuscitation. Only a qualified healthcare professional should administer vernakalant and the patient should be carefully observed for signs Correvio International Sàrl 04 November 2019 Page 153 of 166
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and symptoms of a sudden decrease in blood pressure or heart rate, during infusion and for at least 2 hours after cessation of vernakalant treatment, and until clinical status and ECG parameters are stable. The Warning section of the label indicates that SAEs of bradycardia have been reported during or following treatment with vernakalant infusion. Most cases occurred soon after conversion to sinus rhythm. In general, bradycardia responded well to discontinuation of vernakalant and/or administration of atropine or isoprenaline, however, some events of bradycardia requiring electrical pacing have been reported. On occasion, these events were associated with clinically-relevant hypotension.
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Narratives of Deaths (b) (6) Patient (AVRO): The patient was a 68-year-old white male enrolled in the AVRO study. The patient had a long history of chronic obstructive pulmonary disease (COPD) and a history of tuberculosis, in addition to coronary heart disease, ischemic heart disease, hypertension, and AF since 1991, acute myocardial infarction in 1991, NYHA Class II heart failure (duration of >12 months), and a recent diagnosis of hyponatremia. The patient received both infusion doses of vernakalant and was electrically cardioverted to sinus rhythm on Day 1. An SAE of COPD began on Day 17, for which the patient was hospitalized. The patient’s respiratory condition worsened and artificial lung ventilation was initiated. On Day 24 an SAE of pulmonary embolism began, which resulted in the patient’s death approximately 2.5 hours later. The investigator assessed both SAEs to be severe and not related to study drug. Sponsor’s comment on the case: This 68-year-old man had a history of ischemic heart disease, hypertension and severe chronic obstructive heart disease. He was admitted with a one-day history of AF and had an echocardiogram showing a left atrial dimension of 44 mm and the ejection fraction was estimated to be 65%. He was treated with two doses of vernakalant and remained in AF and then was electrically cardioverted. He was readmitted on Day 17 with respiratory failure and hyponatremia. The next day he was intubated. On Day 24, he became hypotensive and died with the cause being pulmonary embolus. The cause of death and timing do not suggest any relationship with the use of vernakalant. (b) (6) Patient (ACT I): The patient was a 68-year-old white female who was enrolled in the ACT I study. She received two doses of vernakalant injection, did not convert to sinus rhythm, and was subsequently electrically cardioverted to sinus rhythm. An SAE of hemopericardium due to rupture of dissecting aortic aneurysm occurred on Day 2 during a gastroscopy procedure (a scheduled biopsy procedure) and resulted in death. The investigator assessed the severity of this event to be life-threatening and not related to study drug. Sponsor’s comment on the case: This 68-year-old woman was admitted to hospital with “oppressive” chest pain radiating to neck and left side of the head. She was in sinus rhythm with no acute changes of ischemia and no enzyme evidence of myocardial infarction. No comment was made about any admission chest x-ray findings. She continued to have chest pain and nausea and vomiting. On Day 3 of hospitalization, she developed AF. She was treated with 2 doses of vernakalant on Day 4 and did not convert and then underwent ECV to sinus rhythm. She had fluctuating T wave changes on the ECG. On Day 5 of the hospitalization, she underwent gastroscopy to evaluate her gastrointestinal complaints and during the procedure became cyanotic and was pulseless in sinus rhythm. An autopsy showed a thoracic aortic dissection with rupture into the pericardium. The death was not related to treatment with vernakalant. It seems likely that the dissection occurred on the day of admission 4 days prior to treatment for AF. (b) (6) Patient (ACT I): The patient was a 90-year-old white female who was enrolled in the ACT I study. She received two doses of vernakalant injection, did not convert to sinus rhythm and ECV was attempted. An SAE of complete heart block (possibly related) occurred immediately
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following the ECV attempt. TdP (not related) occurred 32 hours post-dose. An SAE of deterioration of dyspnea (pulmonary edema) resulting in death occurred 24 days after vernakalant administration. The investigator assessed the severity of this event to be fatal and not related to study drug. Sponsor’s Comment on the Case: This 90-year-old woman was admitted with shortness of breath, chest pain, a rapid heart rate. She had a history of pulmonary edema, angina, and hyponatremia. She was in AF. Three days prior to study drug treatment, a transesophageal echo was done which showed lateral wall ischemia and an estimated ejection fraction of 45%. She was treated with two doses of vernakalant and did not convert. She was given an oral dose of metoprolol between the two infusions. Two hours and 38 minutes after initiation of vernakalant, she had an ECV which resulted in complete heart block with a pulse of 40 bpm and a blood pressure of 47/23 mmHg. She was given 2 boluses of atropine and then placed on intravenous isoprenaline and the pulse and sinus rhythm returned at 120 bpm. One hour and 23 minutes later, runs of ventricular beats were described, the longest of which was 18 seconds and she received amiodarone and magnesium (it was unclear whether she was maintained on isoprenaline during this time). On the next day a temporary pacemaker was placed which was kept in place for 3 days. She was discharged 17 days after treatment with vernakalant. Eight days later she was readmitted with dyspnea and cough and found to be in AF. A chest x-ray showed bilateral pleural effusions for which she received a diuretic. On the following day she had a bloody cough, became progressively hypoxemic and died with the cause “pulmonary edema.” The episode of complete heart block is common to all forms of cardioversion and can be attended with bradycardia and hypotension. It is unlikely that the heart block and her subsequent death after first being discharged home is caused by vernakalant treatment. Although the Sponsor does not believe there was sufficient evidence that the episode of block following ECV was influenced by vernakalant, the administration section of the proposed label indicates: vernakalant should be administered by intravenous infusion in a monitored clinical setting appropriate for cardioversion which includes all the necessary items used for resuscitation. Only a qualified healthcare professional should administer vernakalant and the patient should be carefully observed for signs and symptoms of a sudden decrease in blood pressure or heart rate, during infusion and for at least 2 hours after cessation of vernakalant treatment, and until clinical status and ECG parameters are stable. The Warning section of the proposed US label indicates: SAEs of bradycardia have been reported during or following treatment with vernakalant infusion. Most cases occurred soon after conversion to sinus rhythm. In general, bradycardia responded well to discontinuation of vernakalant and/or administration of atropine or isoprenaline, however, some events of bradycardia requiring electrical pacing have been reported. On occasion, these events were associated with clinically-relevant hypotension. (b) (6) Patient (ACT I): The patient was a 67-year-old white male with stage IV non-small cell lung cancer with bone metastases. He was enrolled in the ACT I trial, received one dose of vernakalant injection and converted to sinus rhythm. An SAE of pneumonia (not related) began 4 days after receiving study drug, and a second SAE of respiratory arrest began 2 days later. The family withdrew life support the following day (7 days post-dose) and the patient died. The investigator assessed the severity of the SAE of respiratory arrest to be life threatening and the relationship to the study drug unlikely.
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Sponsor’s Comment on the Case: This 67-year-old man with metastatic non-small cell lung cancer was admitted with shortness of breath and an irregular pulse. One day later he was treated with one dose of vernakalant and reverted to sinus rhythm. One day post-dose he developed a productive cough; on three days post-dose he had one 5-beat run of ventricular tachycardia. On five days post-dose, he was diagnosed with pneumonia. On seven days post-dose, his overall condition deteriorated and during a coughing spell became unresponsive without a pulse associated with a respiratory arrest. He was intubated and given intravenous epinephrine and the pulse and blood pressure returned but required norepinephrine for maintenance of blood pressure. Following a family discussion, he was extubated and died. The timing of both the 5-beat run of ventricular tachycardia and his respiratory arrest were not likely related to treatment with vernakalant. (b) (6) Patient (ACT III): The patient was a 64-year-old white male with a history of critical aortic stenosis who was enrolled in the ACT III trial. He was admitted with chest pain, AF with a rapid ventricular rate of 158 bpm, ST segment elevation, and troponin elevation. He was treated with intravenous and oral metoprolol and his blood pressure fell to 90/70 mm Hg, requiring fluid resuscitation to improve blood pressure. He became hypotensive (75/42 mmHg) following a first infusion dose of vernakalant injection and received further fluid resuscitation. A second vernakalant dose was administered again resulting in hypotension (65/41 mmHg). An SAE of ventricular fibrillation developed 13 minutes after completion of the second dose of vernakalant injection, and resuscitation was unsuccessful. The patient’s aortic stenosis was also recorded as an SAE. The investigator assessed the severity of both events to be severe and possibly related to study drug. The patient’s clinical presentation of acute coronary syndrome should have excluded him from the study based on the protocol exclusion criteria. In addition, the patient’s repeated episodes of hypotension should have led to cessation of dosing, based on the dose-stopping criteria for blood pressure <85 mmHg and intolerable side effects. Sponsor’s Comment on the Case: This 64-year-old man had a history of hypertension, CHF NYHA Class II, and dyspnea and had a recent echocardiogram the same month showing severe aortic stenosis with a gradient of 120 mmHg and an ejection fraction of 40%. He presented to hospital with 4 hours of chest tightness, fatigue, and an irregular pulse and was found to be in AFL/AF with ST segment elevation and had a clear chest and an audible aortic murmur. He was given two IV doses of 2.5 mg of metoprolol at 7:38 am and 8:10 am. His blood pressure was 90/70 mmHg and he was given saline which increased his blood pressure to 105/85 mmHg and then to 115/75 mmHg, was given 50 mg of oral metoprolol at 8:15 am. His pre-infusion blood pressures were 104/53, 102/66, 110/95 mmHg and heart rate was 152 bpm. He began the infusion at 09:41 am and 2 minutes later had nausea and a blood pressure of 103/60 (a 50 mmHg drop); at 6 minutes into the infusion, blood pressure was 89/72 mmHg, and at 10 minutes (end of the infusion) was 75/42 mmHg, with heart rate of 113 bpm. At 15 minutes, he felt faint with a blood pressure of 62/42 mmHg, was given hydroxyethyl starch at 17 minutes. At 25 minutes after the beginning of the infusion and with a blood pressure of 88/67 mmHg, he was started on the second infusion of vernakalant. He became more nauseated and hypotensive and at the end of that infusion developed ventricular tachycardia, was cardioverted to a pulseless rhythm, received resuscitative maneuvers and died 15 minutes later.
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The patient presented with known severe aortic stenosis and AF (a very poor prognostic sign) and had findings suggestive of acute coronary syndrome (chest pain and ST segment elevation on the ECG). Pharmacologic cardioversion is never clinically indicated in symptomatic aortic stenosis and vernakalant is contraindicated in someone with a possible acute coronary syndrome. In addition, the drug should have been discontinued at the first onset of hypotension, 5 minutes into the first infusion. The Sponsor proposes to mitigate this situation by making (a) clinically significant aortic stenosis and (b) systolic blood pressure <100 mmHg (or having received fluid resuscitation or inotropes to maintain blood pressure >100 mmHg), and (c) evidence of a possible acute coronary syndrome three contraindications in the label and in the Pre-Infusion Checklist. In addition, in the Warnings section of the proposed US label, it is proposed that a sudden drop in blood pressure mandates stopping the drug and in Section 5.5 of the label, it is stated that the use of intravenous beta-blockers within 2 hours of treatment is not recommended. (b) (6) Patient (ACT IV): The patient, a 70-year-old white female with a history of breast cancer, was enrolled in the ACT IV open label study and received 2 doses of vernakalant and converted to sinus rhythm. An SAE of internal bleeding began 16 days after receiving vernakalant and resulted in death 9 days later. A death certificate was not provided and additional details were unavailable. The investigator assessed the severity of this event to be severe and not related to study drug. Sponsor’s Comment on the Case: This 70-year-old woman had a prior history of AF and breast cancer. She was admitted with leukopenia and a one-day history of AF. She was treated with vernakalant on Day 2 of hospitalization and reverted to sinus rhythm. She was discharged on Day 11 on antibiotics and then readmitted 5 days later with gastrointestinal bleeding and died from bleeding on Day 27 (25 days post-dose). The cause of death and timing do not suggest a relationship with the use of vernakalant. (b) (6) Patient (ACT V): This patient, a 77-year-old white male enrolled in the ACT V study, had a history of hypertension since 2006 and chronic alcohol abuse, along with recent dyspnea and palpitations. He had an SAE of cardiogenic shock, with symptoms of sweating and nausea along with decreased blood pressure and HR, beginning 10 minutes after the start of vernakalant infusion. The cardiogenic shock was assessed by the investigator as being life-threatening, severe, and possibly related to study drug. The patient lost consciousness and had several bradycardic events, as well as episodes of ventricular fibrillation which were terminated with defibrillation. He did not receive the second dose of vernakalant and was electrically cardioverted to sinus rhythm approximately 4 hours later. The SAE of cardiogenic shock resolved 18 days later. From Day 2 to 10, the patient also had an SAE of rhabdomyolysis, two SAEs of electromechanical dissociation, and AEs of gastritis and encephalopathy. Multiple additional SAEs were reported and resulted in a fatal outcome, including coagulopathy, aspiration pneumonia, hepatic failure, acute renal failure, and sepsis (all beginning on Day 2); anemia (starting on Day 4); gastrointestinal hemorrhage (starting on Day 12); ischemic colitis (starting on Day 17); and hypovolemic shock (starting on Day 29). All of these AEs and SAEs were assessed by the investigator as not related to study drug. Sponsor’s Comment on the Case: This 77-year-old man was first evaluated in the emergency department for symptoms of dyspnea and palpitations and found to be in AF. He had a history of chronic alcohol abuse and hypertension. Correvio International Sàrl 04 November 2019 Page 158 of 166
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He was given IV fluids and his baseline blood pressure was 139/70 mmHg. He had a transthoracic echocardiogram which showed moderate global hypokinesis and the ejection fraction was estimated to be 44%. His blood pressure at the initiation of 60 mL (270 mg) of vernakalant given over 10 minutes was 140/82 mmHg, and his heart rate was 135 bpm. At 5 minutes into the infusion, his blood pressure was 126/95 mmHg and then his pressure dropped to 72/60 mmHg. He was given saline beginning at 10 minutes at the end of the infusion. He then became pulseless and received cardiopulmonary resuscitation, intubation, epinephrine, norepinephrine, dopamine, bicarbonate, and calcium, and an echocardiogram done during the resuscitation showed ventricular standstill while the ECG still showed a cardiac rhythm. After 40 minutes of resuscitation, he regained a pulse, his blood pressure was reported to be 130/80 mmHg, and he was in AF. He was admitted to the critical care unit, cardioverted to sinus rhythm 4 hours later and was started on amiodarone. A bedside echocardiogram on Day 3 was reported to show his ejection fraction to be 25% with severe mitral regurgitation, a left atrial size of 50 mm, left ventricular hypertrophy, and mitral annular calcification. During the next 4 days, he developed evidence of renal failure requiring dialysis, aspiration pneumonia, rhabdomyolysis, a coagulopathy and severe liver failure. He had multiple cardiac arrests and resuscitation attempts. On Day 11, he developed gastrointestinal bleeding which was determined to be from a necrotizing enterocolitis. On Day 23, coronary angiography showed no evidence of coronary disease, and no ventriculogram was done. The patient continued to bleed requiring multiple transfusions. He never regained consciousness and died from bleeding on Day 29. The initial echocardiogram described as showing moderate global hypokinesis and an estimated ejection fraction likely underestimated his cardiac function as estimates of ejection fraction are particularly difficult and often inaccurate during rapid AF. The follow-up echocardiogram showing left ventricular hypertrophy, a left atrial size of 50 mm and mitral regurgitation suggests long standing mitral regurgitation secondary to left ventricular dysfunction (the valve itself was not reported as abnormal) and an ejection fraction of 25%. With normal coronary anatomy, the most likely etiology is alcohol cardiomyopathy and long-standing hypertension. It is very unusual to develop either renal failure, liver failure, or rhabdomyolysis or coagulopathy after cardiac resuscitation suggesting that he had a very prolonged state of inadequate circulation. He ultimately died from complications of prolonged organ ischemia secondary to cardiac arrest. Similar such occurrences could be mitigated by the contraindications in the proposed label. Serious CHF (NYHA Class III or IV CHF or evidence of moderate or severe left ventricular dysfunction) will be contraindicated. Evidence of moderate global hypokineses was described on the pre- treatment echocardiogram. The proposed Contraindications in the label include severe heart failure (including NYHA class III and IV or known moderate or severe left ventricular dysfunction). (b) (6) Patient (AP study): An 82-year-old male with a history of abdominal aortic aneurysm, heart failure, idiopathic pulmonary fibrosis, rectal cancer, and pulmonary tuberculosis was in AF for 7 days prior to randomization. Concomitant therapy included aspirin, carvedilol, furosemide, hydrochlorothiazide (+) spironolactone, flecainide acetate, enoxaparin sodium, warfarin, potassium chloride and heparin. The site wanted to hospitalize the patient because of the risk of anticoagulation bleeding, but he refused and was discharged. On Day 5, the patient died while sleeping. An autopsy was not performed. The investigator assessed the cause of death as unknown and not related to study drug.
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Sponsor’s Comment on the Case: This 82-year-old was seen for a 7-day history of AF. He was treated with 2 doses of vernakalant and converted to sinus rhythm. In addition to the drugs listed above, he was also treated with enoxaparin and warfarin and started on flecainide. He was discharged home 2 days after treatment and was seen one day later for a check as an outpatient and found dead in bed two days later. The likely cause of sudden death was cardiac and could be associated with treatment with flecainide. Following an uncomplicated cardioversion and then death 5 days later, it seems unlikely that it was related to vernakalant which would be non-detectable at that time.
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APPENDIX 4 FDA AEs of Special Interest Groupings Special Grouping MedDRA Preferred Term
All groupings Any Adverse Event of Special Interest Hypotension-related event Any Hypotension-related event Blood pressure decreased Blood pressure systolic decreased Cardiogenic shock Dizziness Dizziness postural Hypotension Hypovolemic shock Orthostatic hypotension Presyncope Pulseless electrical activity Syncope Palpitations Any Palpitations Palpitations Conduction disturbance Any Conduction disturbance Atrioventricular blocka Atrioventricular block complete Atrioventricular block first degree Bundle branch block Bundle branch block left Bundle branch block right ECG QRS complex prolonged Sinus arrest SA node arrest, pause, block, Any SA node arrest, pause, block, dysfunction dysfunction Sick sinus syndrome Sinus arrest Sinus node dysfunction QRS prolonged, bundle branch block Any QRS prolonged, BBB Bundle branch block Bundle branch block left Bundle branch block right ECG QRS complex prolonged High degree AV block Any High degree AV block Atrioventricular block complete AV block Any AV block Atrioventricular blocka Atrioventricular block complete Atrioventricular block first degree
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Special Grouping MedDRA Preferred Term
Arrhythmia Any Arrhythmia Arrhythmia Atrial fibrillation Atrial flutter Atrial tachycardia Bradycardia Extrasystoles Heart rate decreased Heart rate increased Heart rate irregular Nodal rhythm Sick sinus syndrome Sinus arrest Sinus arrhythmia Sinus bradycardia Sinus pause Sinus tachycardia Supraventricular VT Supraventricular extrasystoles Supraventricular tachycardia Tachycardia Torsade de Pointes Ventricular arrhythmia Ventricular extrasystoles Ventricular fibrillation Ventricular tachycardia Supra-ventricular arrhythmia Any Supra-ventricular arrhythmia Atrial fibrillation Atrial flutter Atrial tachycardia Heart rate increased Sick sinus syndrome Sinus arrest Sinus arrhythmia Sinus bradycardia Sinus node dysfunction Sinus pause Sinus tachycardia Supraventricular extrasystoles Supraventricular tachycardia PACs Any PACs Supraventricular extrasystoles Atrial fibrillation Any AF Atrial fibrillation Atrial flutter Any AFL Atrial flutter Atrial fibrillation or atrial flutter Any AF or AFL Atrial fibrillation Atrial flutter Atrial tachycardia Any Atrial Tach Atrial tachycardia Heart rate increased Supraventricular tachycardia Ventricular arrhythmia Any Ventricular arrhythmia Torsade de Pointes Ventricular arrhythmia Ventricular extrasystoles
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Special Grouping MedDRA Preferred Term
Ventricular fibrillation Ventricular tachycardia Ventricular tachycardia Any VT Ventricular tachycardia Ventricular fibrillation Any Ventricular fibrillation Ventricular fibrillation Torsade de Pointes Any Torsade de Pointes Torsade de Pointes PVCs Any PVCs Extrasystoles Ventricular extrasystoles Tachycardia Any Tachycardia Atrial flutter Atrial tachycardia Heart rate increased Sinus tachycardia Supraventricular tachycardia Tachycardia Torsade de Pointes Ventricular tachycardia Bradycardia Any Bradycardia Atrioventricular block complete Bradycardia Heart rate decreased Sinus bradycardia QT prolonged Any QT prolonged Electrocardiogram QT prolonged Long QT syndrome Sick sinus syndrome Any SSS Sick sinus syndrome Presyncope or syncope Any Presyncope or syncope Cardio-respiratory arrest Presyncope Syncope Presyncope Any Presyncope Presyncope Syncope Any Syncope Cardio-respiratory arrest Syncope Abbreviations: AF, atrial fibrillation; AFL, atrial flutter; AV, atrioventricular; BBB, bundle branch block; ECG, electrocardiogram; MedDRA, Medical Dictionary for Regulatory Activities; PAC, premature atrial contraction; Pbo, placebo; PVC, premature ventricular contraction; SA, sinoatrial; SSS, sick sinus syndrome; Vkt, vernakalant; VT, ventricular tachycardia. a unspecified degree of block assigned by the investigator
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APPENDIX 5 Tables of Most Common Treatment Emergent Adverse Events Common Treatment-Emergent Adverse Events (≥1% of Patients in Either Treatment Group) by Time Period (Safety Set, All Patients Population) 0-2 Hours 2-24 Hours 0-24 Hours MedDRA System Organ Placebo Vernakalant Placebo Vernakalant Placebo Vernakalant Class (N=459) (N=1073) (N=459) (N=1073) (N=459) (N=1073) Preferred Term n (%) n (%) n (%) n (%) n (%) n (%) All Systems Any adverse event 75 (16.3%) 521 (48.6 %) 112 (24.4%) 257 (24.0%) 163 (35.5%) 629 (58.6%) Cardiac disorders Atrial fibrillation 5 (1.1%) 16 (1.5%) 15 (3.3%) 29 (2.7%) 20 (4.4%) 45 (4.2%) Atrial flutter 1 (0.2%) 22 (2.1%) 1 (0.2%) 5 (0.5%) 2 (0.4%) 27 (2.5%) Atrioventricular block 1 (0.2%) 8 (0.7%) 4 (0.9%) 9 (0.8%) 5 (1.1%) 17 (1.6%) first degree Bradycardia 1 (0.2%) 26 (2.4%) 7 (1.5%) 9 (0.8%) 8 (1.7%) 35 (3.3%) Sinus bradycardia 0 8 (0.7%) 6 (1.3%) 9 (0.8%) 6 (1.3%) 17 (1.6%) Supraventricular 0 6 (0.6%) 6 (1.3%) 7 (0.7%) 6 (1.3%) 13 (1.2%) extrasystoles Ventricular 1 (0.2%) 7 (0.7%) 3 (0.7%) 5 (0.5%) 4 (0.9%) 12 (1.1%) extrasystoles Ventricular tachycardia 1 (0.2%) 7 (0.7%) 8 (0.7%) 9 (0.8%) 8 (1.7%) 15 (1.4%) Gastrointestinal disorders Diarrhea 1 (0.2%) 8 (0.7%) 3 (0.7%) 5 (0.5%) 4 (0.9%) 13 (1.2%) Nausea 1 (0.2%) 48 (4.5%) 4 (0.9%) 12 (1.1%) 5 (1.1%) 60 (5.6%) Paresthesia oral 1 (0.2%) 19 (1.8%) 0 0 1 (0.2%) 19 (1.8%) Vomiting 0 11 (1.0%) 2 (0.4%) 2 (0.2%) 2 (0.4%) 13 (1.2%) General disorders and administration site conditions Chest discomfort 3 (0.7%) 4 (0.4%) 2 (0.4%) 3 (0.3%) 5 (1.1%) 7 (0.7%) Fatigue 2 (0.4%) 11 (1.0%) 4 (0.9%) 18 (1.7%) 6 (1.3%) 29 (2.7%) Feeling hot 2 (0.4%) 25 (2.3%) 0 0 2 (0.4%) 25 (2.3%) Infusion site pain 1 (0.2%) 20 (1.9%) 0 0 1 (0.2%) 20 (1.9%) Injury, poisoning and procedural complications Cardiac procedure 0 1 (0.1%) 8 (1.7%) 10 (0.9%) 8 (1.7%) 11 (1.0%) complications Metabolism and nutrition disorders Hypokalemia 0 2 (0.2%) 5 (1.1%) 4 (0.4%) 5 (1.1%) 6 (0.6%) Nervous system disorders Dizziness 7 (1.5%) 29 (2.7%) 3 (0.7%) 8 (0.7%) 10 (2.2%) 37 (3.4%) Dysgeusia 10 (2.2%) 184 (17.1%) 0 3 (0.3%) 10 (2.2%) 186 (17.3%) Headache 10 (2.2%) 16 (1.5%) 4 (0.9%) 25 (2.3%) 14 (3.1%) 38 (3.5%) Paresthesia 3 (0.7%) 73 (6.8%) 2 (0.4%) 2 (0.2%) 5 (1.1%) 75 (7.0%) Respiratory, thoracic and mediastinal disorders Cough 2 (0.4%) 41 (3.8%) 2 (0.4%) 1 (0.1%) 4 (0.9%) 42 (3.9%) Dyspnea 0 9 (0.8%) 2 (0.4%) 7 (0.7%) 2 (0.4%) 16 (1.5%) Nasal discomfort 0 20 (1.9%) 0 0 0 20 (1.9%) Sneezing 0 135 (12.6%) 0 0 0 135 (12.6%) Skin and subcutaneous tissue disorders Hyperhidrosis 1 (0.2%) 27 (2.5%) 2 (0.4%) 4 (0.4%) 3 (0.7%) 30 (2.8%) Pruritus 0 30 (2.8%) 0 1 (0.1%) 0 31 (2.9%) Vascular disorders Hypertension 2 (0.4%) 14 (1.3%) 2 (0.4%) 4 (0.4%) 4 (0.9%) 16 (1.5%) Hypotension 6 (1.3%) 39 (3.6%) 14 (3.1%) 16 (1.5%) 20 (4.4%) 54 (5.0%) Abbreviations: MedDRA, Medical Dictionary of Regulatory Activities; NDA, New Drug Application Notes: Events occurring in 1 or more vernakalant subjects cumulatively and more frequent than placebo. Multiple occurrence of the same adverse event in 1 individual subject are counted only once. Data includes: CRAFT, Scene 2, ACT I, ACT II, ACT III, ACT IV, ACT V, AVRO, and AP studies, cumulative TEAEs for each time period.
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CRDAC Briefing Document – Vernakalant injection
APPENDIX 6 Preinfusion Checklist
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