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Clinical Study Report E5501-G000-311 16.1.1 Protocol and Protocol Amendments The final study protocol is provided on the following pages. Eisai Confidential Page 1 of 101 Clinical Study Protocol E5501-G000-311 (Protocol Amendment 04) Revisions to V6.0: 31 May 2016 (Amendment 03) Date: V7.0: 02 Dec 2016 (Amendment 04) Change Rationale Affected Protocol Sections Sample size reduced from After consultation with the FDA, it Synopsis – approximately 300 subjects to was decided that the current study Number of Subjects approximately 200 subjects has reached adequate enrollment Sample Size to demonstrate the safety and Rationale benefit of avatrombopag in Section 9.3 reducing the need for platelet Section 9.4.3 transfusion in subjects with Section 9.7.2 thrombocytopenia and liver disease undergoing an elective procedure. The secondary endpoint, Given the rare occurrence of Synopsis – proportion of subjects with a bleeding events (less than Secondary World Health Organization expected), this endpoint is better Objectives (WHO) bleeding score ≥2 suited as an exploratory endpoint. Exploratory after randomization and up to Objectives 7 days following an elective Secondary Endpoints procedure, will be an Exploratory exploratory endpoint Endpoints Secondary Efficacy Variable Analyses Exploratory Efficacy Variables Section 8.2 Section 8.3 Section 9.7.1.1 Section 9.7.1.6 FINAL (v7.0): 02 Dec 2016 Page i of viii CONFIDENTIAL Eisai Confidential Page 2 of 101 Clinical Study Protocol E5501-G000-311 (Protocol Amendment 04) Revisions to V5.0: 22 June 2015 (Amendment 02) Date: V6.0: 31 May 2016 (Amendment 03) Change Rationale Affected Protocol Sections Clarification to Inclusion Per FDA request Synopsis – Criteria #3: replace the word Inclusion Criteria "change" with the word Section 9.3.1 "increase FINAL (v7.0): 02 Dec 2016 Page ii of viii CONFIDENTIAL Eisai Confidential Page 3 of 101 Clinical Study Protocol E5501-G000-311 (Protocol Amendment 04) REVISION HISTORY Revisions to V4.0: 12 Nov 2013 (Amendment 01) Date: V5.0: 22 June 2015 (Amendment 02) Change Rationale Affected Protocol Sections Revised the risk of bleeding Additional procedures included in Synopsis – associated with procedures the source article (Malloy et al., Study Design 2009) that originated the initial Statistical Methods classification were added. Efficacy Analyses Ongoing study observations, supported by key opinion leader Section 9.1.2.3 (KOL) review and current Table 1 literature review resulted in Section 9.7.1.6 additional updates in the bleeding risk categories classification Clarification of Inclusion #3 Clarification Synopsis – that subjects scheduled to Inclusion Criteria undergo a permitted elective Section 9.3.1 procedure who will require a platelet transfusion unless there is a clinically significant change to platelet count from baseline Revised the exclusion around Based upon feedback received Synopsis – hemoglobin changing the from the KOL that these criteria Exclusion Criteria upper limit from 16 to 17 g/dL are in contradiction with the Section 9.1.1.1 and removed the white blood requirement for platelet count Section 9.3.2 9 cell count and serum sodium <50 x 10 /L (ie, subjects meeting levels exclusion criteria. such lab criteria would be Subjects who screen failed relatively too healthy to present previously will be permitted with such a low platelet count). to rescreen due to removal of Other existing criteria (eg, MELD this criteria. score and BCLC) will ensure subjects are not too compromised. This also provides for a more diverse population by dropping these restrictions. Addition of eltrombopag and As eltrombopag and romiplostim Synopsis – romiplostim as prohibited are used off-label for this Prohibited Concomitant indication, both approved Therapy FINAL (v7.0): 02 Dec 2016 Page iii of viii CONFIDENTIAL Eisai Confidential Page 4 of 101 Clinical Study Protocol E5501-G000-311 (Protocol Amendment 04) Revisions to V4.0: 12 Nov 2013 (Amendment 01) Date: V5.0: 22 June 2015 (Amendment 02) Change Rationale Affected Protocol Sections medication thrombopoietin receptor agonists Section 9.4.7.3 were added Added an evaluation for Japan’s Pharmaceuticals and Synopsis – platelet aggregation to be Medical Devices Agency (PMDA) Safety Assessments measured at selected sites requires exploratory assessment of Section 9.5.1.5, platelet aggregation as part of the Table 4, Table 5 platelet function study. Section 11.3 Updated study director and Change in Eisai staffing Protocol Signature Page medical monitor information Clarified in the appendix the Clarification Appendix 2 fasting glucose laboratory result should only be considered a treatment-emergent significant abnormality if the result is within normal limits at baseline and has increased in severity to meet the sponsor’s grading criteria for laboratory values of Grade 3 or above when fasting. FINAL (v7.0): 02 Dec 2016 Page iv of viii CONFIDENTIAL Eisai Confidential Page 5 of 101 Clinical Study Protocol E5501-G000-311 (Protocol Amendment 04) Revisions to previous V3.0, 29 Sep 2013 Date: V4.0 (Amendment 01): 12 Nov 2013 Change Rationale Affected Protocol Sections Addition of tranexanic acid as a Changes were made upon ● Synopsis, Study Design regulatory agency request rescue procedure when used ● Section 9.1.2.3 specifically for bleeding during a Voluntary Harmonisation Procedure ● Section 9.5.1.3 submitted to the following EU Member States: Austria, Belgium, France, Germany, Hungary, Italy, Spain, and United Kingdom. Inclusion of specific For clarity ● Synopsis, Exclusion examples of genetic Criteria prothrombotic syndromes ● Section 9.3.2 (eg, Factor V Leiden; prothrombin G20210A; ATIII deficiency etc.) FINAL (v7.0): 02 Dec 2016 Page v of viii CONFIDENTIAL Eisai Confidential Page 6 of 101 Clinical Study Protocol E5501-G000-311 (Protocol Amendment 04) Revisions to previous Version 2.0, 24 Jul 2013 Date: V3.0, 29 Sep 2013 Change Rationale Affected Protocol Sections Removal of language indicating Administrative change – ● Appendix 3 a training program will be incorrect language used to implemented for the sonography describe sonography operator operation Medical monitor updated Change in Eisai staffing ● Protocol Signature Page FINAL (v7.0): 02 Dec 2016 Page vi of viii CONFIDENTIAL Eisai Confidential Page 7 of 101 Clinical Study Protocol E5501-G000-311 (Protocol Amendment 04) Revisions to previous Version 1.0, 21 Mar 2013 Date: V2.0, 24 Jul 2013 Change Rationale Affected Protocol Sections Sponsor information updated to Japanese address required ● Title page title page as 310 & 311 are global studies The higher baseline platelet Required due to the ● Synopsis – Objectives inclusion criterion and count cohort was changed from ● Synopsis – Study Design 40 to ≤50 × 109/L to 40 to baseline platelet count <50 × 109/L which resulted in cohort change from ● Synopsis – Exploratory ≤50 × 109/L to <50 Endpoints endpoints changing accordingly. 9 × 10 /L. ● Section 7 ● Section 8 ● Section 9 Added exploratory objective Eisai agrees with CHMP ● Synopsis – Exploratory and endpoint to characterize that the BARC bleeding Objectives platelet count changes from scale could be used in baseline, the extent of platelet addition to the WHO ● Synopsis – Exploratory transfusion use, and assess the bleeding score and Endpoints severity of any bleeding events therefore proposes it be included as an exploratory ● Section 8.3 endpoint. Inclusion criteria age changed to Brings protocol into line ● Synopsis – Inclusion include those subjects ≥18 years with current pediatric Criteria of age for both US and rest of strategy world ● Section 9.3.1 Occurrence of bleeding as EMA requested that the ● Synopsis – Efficacy measured by World Health BARC bleeding scale be Assessments Organization (WHO) bleeding used in addition to the score and Bleeding Academic WHO bleeding score. ● Section 9.2 Research Consortium (BARC) EMA agreed to Eisai ● Section 9.5 bleeding scale proposal for BARC scale to be included as an exploratory endpoint. ● Section 9.7.1 FINAL (v7.0): 02 Dec 2016 Page vii of viii CONFIDENTIAL Eisai Confidential Page 8 of 101 Clinical Study Protocol E5501-G000-311 (Protocol Amendment 04) Revisions to previous Version 1.0, 21 Mar 2013 Date: V2.0, 24 Jul 2013 Change Rationale Affected Protocol Sections The hypothesis testing for the Agreed with both FDA ● Synopsis – Primary combined group (regardless of and EMA Efficacy Variable baseline platelet count cohort) Analysis was removed from the primary efficacy analysis and the first ● Section 9.7.1.6 2 secondary efficacy variable analyses. The primary efficacy variable analysis to clarify the null hypothesis will be tested separately within each baseline cohort. This study will be considered as Statistical analysis ● Synopsis – Primary positive if statistical changes requested by the Efficacy Variable significance is achieved for the FDA Analysis primary efficacy endpoint for both baseline platelet count ● Section 9.7.1.6 cohorts. Clarification that the safety Requested as clarification ● Synopsis, Interim parameters the DSMB will during PRC review Analysis review will include variables that are also being assessed in ● Section 9.7.3 this study for efficacy Sample size /power calculation Requested as clarification ● Synopsis, Sample Size was removed for the test on the by the FDA Rationale combined group ● Section 9.7.2 FINAL (v7.0): 02 Dec 2016 Page viii of viii CONFIDENTIAL Eisai Confidential Page 9 of 101 Clinical Study Protocol E5501-G000-311 (Protocol Amendment 04)
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  • 202155Orig1s000

    202155Orig1s000

    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 202155Orig1s000 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) Clinical Pharmacology/Biopharmaceutics Review (Addendum to Previous Review – DARRTS date: 02/15/2012) PRODUCT (Generic Name): Apixaban NDA: 202-155 PRODUCT (Brand Name): ELIQUIS® DOSAGE FORM: Tablets DOSAGE STRENGTHS: 2.5 mg and 5 mg INDICATION: Prevention of stroke, systemic embolism, (b) (4) in patients with non-valvular atrial fibrillation SUBMISSION DATE: Study report submission on 8/14/2012 SPONSOR: Bristol-Myers Squibb and Pfizer REVIEWERS: Ju-Ping Lai, Ph.D. TEAM LEADER: Rajanikanth Madabushi, Ph.D. OCP DIVISION: DCP 1 OND DIVISION: HFD 120 TABLE OF CONTENTS 1.0 EXECUTIVE SUMMARY 2 1.1 RECOMMENDATION 2 2.0 DETAILED LABELING RECOMMENDATIONS 3 3.0 INDIVIDUAL STUDY REVIEW 6 Reference ID: 3232801 1.0 EXECUTIVE SUMMARY The sponsor submitted a study report on August 14, 2012: Effect of Activated Charcoal on the Pharmacokinetics of Apixaban in Healthy Subjects, to support NDA 202155 (NME) for apixaban while the original NDA was submitted on September 30, 2011 as a final submission of a series of rolling submissions. Since there is no antidote for apixaban while high systemic exposure increases bleeding. This study evaluated whether activated charcoal could be used to reduce apixaban exposure following oral administration of apixaban. The key findings are as follows: Administration of activated charcoal 2 and 6 hours after ingestion of apixaban reduced apixaban exposure (AUC) by approximately 50% and 27%, respectively. Peak exposure (Cmax) of apixaban was not affected by the administration of activated charcoal at 2 hours or 6 hours after apixaban administration.