NCT03697252
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A Phase 2, Randomized, Double-blinded Study to Assess the Safety, Tolerability, and Efficacy of KarXT in Hospitalized Adults with DSM-5 Schizophrenia
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3SYNOPSIS
Protocol Number: KAR-004 Title: A Phase 2, Randomized, Double-blinded Study to Assess the Safety, Tolerability, and Efficacy of KarXT in Hospitalized Adults with DSM-5 Schizophrenia Investigational Product: KarXT Study Centers: Approximately 12 study centers in the United States Phase: Phase 2 Objectives: Primary objective: The primary objective of the study is to assess the efficacy of KarXT (a fixed combination of xanomeline and trospium chloride) (xanomeline 125 mg/trospium 30 mg twice daily [BID]) versus placebo in reducing Positive and Negative Syndrome Scale (PANSS) total scores in adult inpatients with a Diagnostic and Statistical Manual‒Fifth Edition (DSM-5) diagnosis of schizophrenia. Secondary objectives: The secondary objectives of the study are to assess overall safety and tolerability of KarXT in adult inpatients with a DSM-5 diagnosis of schizophrenia:
x To assess spontaneously reported adverse events (AEs) in subjects treated with KarXT versus placebo
x To assess spontaneously reported cholinergic symptoms in subjects treated with KarXT versus placebo
x To assess orthostatic vital signs in subjects treated with KarXT versus placebo
x To assess electrocardiogram (ECG) parameters in subjects treated with KarXT versus placebo
x To assess reduction of PANSS positive score in subjects treated with KarXT versus placebo
x To assess reduction of PANSS Marder Factor score in subjects treated with KarXT versus placebo
x To assess the pharmacokinetics (PK) of xanomeline and trospium following administration of KarXT in adult subjects with a DSM-5 diagnosis of schizophrenia
x To assess Clinical Global Impression-Severity (CGI-S) results in subjects with KarXT versus placebo
Study Design: The study will be an inpatient study in adult subjects with DSM-5 schizophrenia. Subjects will be randomized to receive either placebo or KarXT (xanomeline 125 mg/trospium 30 mg BID) for a treatment Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 5 of 127
period of 5 weeks. Subjects will start on a lead-in dose of xanomeline 50 mg/trospium 20 mg 2 times per day (BID) for the first 2 days followed by xanomeline 100 mg/trospium 20 mg BID for the remainder of Week 1 (Days 3 to 7). On Day 8, dosing will be titrated upwards to xanomeline 125 mg/trospium 30 mg BID unless the subject is continuing to experience AEs from the previous dose increase of xanomeline 100 mg/trospium 20 mg BID. All subjects who were increased to xanomeline 125 mg/trospium 30 mg BID, depending on clinical response and tolerability, will have the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period. Dosing must not change after Visit 7 of the study and may be decreased for tolerability reasons no more than once during the study. Number of Subjects: A total of approximately 180 subjects planned to be randomized in a 1:1 ratio to either KarXT or placebo. Treatment: x Fixed dose Xanomeline 50 mg/Trospium 20 mg BID, oral x Fixed dose Xanomeline 100 mg/Trospium 20 mg BID oral x Fixed dose Xanomeline 125 mg/Trospium 30 mg BID oral x Matching placebo BID oral Study Duration: Total study duration is up to 7 weeks, including a 7-day screening phase (up to a 7-day extension of the screening phase is allowed, if necessary) and a 5-week treatment period. Inclusion Criteria: 1. Subject is aged 18-60 years, inclusive, at screening. 2. Subject has a primary diagnosis of schizophrenia established by a comprehensive psychiatric evaluation based on the DSM-5 (American Psychiatric Association 2013) criteria and confirmed by Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2. 3. Subject is experiencing an acute exacerbation or relapse of symptoms, with onset less than 2 months before screening. a. The subject requires hospitalization for this acute exacerbation or relapse of symptoms. b. If already an inpatient at screening, has been hospitalized for less than 2 weeks for the current exacerbation at the time of screening. 4. Positive and Negative Syndrome Scale total score between 80 and 120, inclusive. a. Score of ≥ 4 (moderate or greater) for ≥ 2 of the following Positive Scale (P) items: i. Item 1 (P1; delusions) ii. Item 2 (P2; conceptual disorganization) iii. Item 3 (P3; hallucinatory behavior) iv. Item 6 (P6; suspiciousness/persecution) 5. There should not be a change (improvement) in PANSS total score between screening and baseline of more than 20%. 6. Subject will have been off lithium therapy for at least 2 weeks before baseline and free of all oral antipsychotic medications for at least 2 weeks before baseline. 7. Subjects taking a depot antipsychotic could not have received a dose of medication for at least 1 and a half injection cycles before baseline (eg, 3 or more weeks off for a 2-week cycle). 8. Subject is capable of providing informed consent. a. A signed informed consent form must be provided before any study assessments are performed. b. Subject must be fluent (oral and written) in English to consent 9. Subject is willing and able to be confined to an inpatient setting for the study duration, follow instructions, and comply with the protocol requirements. 10. Subject has a CGI-S score of ≥ 4 at screening and baseline visits. 11. Body mass index (BMI) must be ≥ 18 and ≤ 40 kg/m2. 12. Subject resides in a stable living situation and is anticipated to return to that same stable living situation after discharge, in the opinion of the investigator. Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 6 of 127
13. Both females of child-bearing potential and males with partners of child-bearing potential must be willing to use a double-barrier method of birth control (ie, any double combination of male or female condom with spermicidal gel, diaphragm, sponge, or cervical cap with spermicidal gel) during the study and for 7 days after the last dose of study drug. 14. Subject has an identified reliable informant. An informant is needed at the screening and baseline visits as well as at the end of the study for relevant assessments. (Site staff may act as informant while the subject is an inpatient.) An informant may not be necessary if the subject has been the patient of the investigator for ≥ 1 year. Exclusion Criteria 1. Any primary DSM-5 disorder other than schizophrenia within 12 months before screening (confirmed using MINI version 7.0.2 at screening). 2. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or oncologic disease or any other condition that, in the opinion of the investigator, would jeopardize the safety of the subject or the validity of the study results, to exclude patients with human immunodeficiency virus (HIV), cirrhosis, biliary duct abnormalities, hepatobiliary carcinoma, and/or active hepatic viral infections based on the liver function test results. 3. History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma. 4. History of irritable bowel syndrome (with or without constipation) or serious constipation requiring treatment within the last 6 months 5. Has a DSM-5 diagnosis of moderate to severe substance abuse disorder (except tobacco use disorder) within the 12 months before screening (confirmed using MINI version 7.0.2 at screening), or current abuse as determined by urine toxicology screen or alcohol test. A screening subject with mild substance abuse disorder within the 12 months before screening must be discussed and agreed upon with the medical monitor before he/she can be allowed into the study. Use of cannabis at screening will result in screen failure with the allowance to rescreen at a later date if no moderate to severe substance use disorder is determined. 6. Risk for suicidal behavior during the study as determined by the investigator’s clinical assessment and Columbia Suicide Severity Rating Scale (C-SSRS) as confirmed by the following: a. Answers “Yes” on items 4 or 5 (C-SSRS – ideation) with the most recent episode occurring within the 2 months before screening, or answers “Yes” to any of the 5 items (C-SSRS-behavior) with an episode occurring within the 12 months before screening. Nonsuicidal self-injurious behavior is not exclusionary. 7. Clinically significant abnormal finding on the physical examination, medical history, ECG, or clinical laboratory results at screening. 8. Subjects cannot currently (within 2 weeks of baseline) be receiving oral antipsychotic medications, MAO inhibitors, anticonvulsants (eg, lamotrigine, Depakote), tricyclic antidepressants (eg, imipramine, desipramine), selective serotonin reuptake inhibitors, or any other psychoactive medications except for as needed anxiolytics (eg, lorazepam, chloral hydrate). 9. Pregnant, lactating, or less than 3 months postpartum. Sperm donation is not allowed for 90 days after the final dose of study drug. 10. If, in the opinion of the investigator (and/or Sponsor), subject is unsuitable for enrollment in the study or subject has any finding that, in the view of the investigator (and/or Sponsor), may compromise the safety of the subject or affect their ability to adhere to the protocol visit schedule or fulfill visit requirements. 11. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) during the 90 days before screening. 12. Subject has a history of treatment resistance to schizophrenia medications defined as failure to respond to 2 adequate courses of pharmacotherapy (a minimum of 4 weeks at an adequate dose per the label) or required clozapine within the last 12 months. 13. Risk of violent or destructive behavior. 14. Current involuntary hospitalization or incarceration. 15. Participation in another clinical study in which the subject received an experimental or investigational drug agent within 3 months of screening. Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 7 of 127
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5 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation Definition AE adverse event AESI adverse event of special interest AIMS Abnormal Involuntary Movement Scale ALT alanine aminotransferase AST aspartate aminotransferase AUC area under the plasma concentration-time curve BID twice daily BMI body mass index CFR Code of Federal Regulations CGI-S Clinical Global Impression‒Severity C-SSRS Columbia-Suicide Severity Rating Scale DILI drug-induced liver injury DSM-5 Diagnostic and Statistical Manual‒Fifth Edition EDC electronic data capture ECG electrocardiogram eCRF electronic case report form ET early termination FDA US Food and Drug Administration GCP Good Clinical Practice IB Investigator’s Brochure ICF informed consent form ICH International Council on Harmonisation IEC Independent Ethics Committee IRB Institutional Review Board IWRS interactive web response system MCC microcrystalline cellulose MINI Mini International Neuropsychiatric Interview MMRM mixed model for repeated measures PANSS Positive and Negative Syndrome Scale PK pharmacokinetic SAE serious adverse event SAP statistical analysis plan SUSAR suspected unexpected serious adverse reaction ULN upper limit of the normal range Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 13 of 127
INTRODUCTION
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7 STUDY OBJECTIVES AND ENDPOINTS
7.1 Objectives
7.1.1 Primary Objective
The primary objective of the study is to assess the efficacy of KarXT (a fixed combination of xanomeline and trospium chloride; xanomeline 125 mg/trospium 30 mg) versus placebo in reducing PANSS total score in adult inpatients with a Diagnostic and Statistical Manual‒Fifth Edition (DSM-5) diagnosis of schizophrenia. 7.1.2 Secondary Objectives
The secondary objectives of the study are to assess overall safety and tolerability of KarXT in adult inpatients with a DSM-5 diagnosis of schizophrenia:
x To assess spontaneously reported AEs in subjects treated with KarXT versus placebo
x To assess spontaneously reported cholinergic symptoms in subjects treated with KarXT versus placebo
x To assess orthostatic vital signs in subjects treated with KarXT versus placebo
x To assess ECG parameters in subjects treated with KarXT versus placebo
x To assess reduction of PANSS positive score in subjects treated with KarXT versus placebo
x To assess reduction of PANSS Marder Factor score in subjects treated with KarXT versus placebo
x To assess the pharmacokinetics (PK) of xanomeline and trospium following administration of KarXT in adult subjects with a DSM-5 diagnosis of schizophrenia
x To assess Clinical Global Impression‒Severity (CGI-S) scale results in subjects with KarXT versus placebo
7.2 Endpoints
7.2.1 Primary Endpoint
x Change in PANSS total score at Week 5
7.2.2 Secondary Endpoints
x Efficacy Endpoints: Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 22 of 127
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An Independent Safety Monitoring Committee (ISMC) will be responsible for reviewing on a periodic basis the safety data from this study and confirming that the study may continue. Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 25 of 127
8.1.1 Study Design
Phase: Screening Inpatient Treatment End of Treatment
Day: Day -7 to -1 Day 1 Day 3 ± 1 Day 7 ± 2 Day 8 ± 2 Day 14 ± 2 Day 21 ± 2 Day 28 ± 2 Day 35 − 2 day days days days days days days
Visit: Visit 1 Visit 2 Visit 3 Visit 4 Visit 5 Visit 6 Visit 7 Visit 8 Visit 9
Xanomeline/ N/A 50 mg/20 100 mg/20 100 mg/20 125 mg/30 125 mg/30 125 mg/30 125 mg/30 N/A trospium mg BID mg BID mg BID mg BID mg BID mg BID mg BID (KarXT): (Option: 100 (Option: 100 (Option: 100 (Option: 100 mg/20 mg mg/20 mg mg/20 mg mg/20 mg BID)a BID)a BID)a BID)b
Comment: Up to a 7-day 2-day lead- Upward Upward Downward dose adjustment No dose adjustment allowed extension to in dose titration of titration of allowed according to clinical (after Day 21) the screening dose dose response/tolerability phase is allowed.
BID = twice daily. a All subjects who were increased to xanomeline 125 mg/trospium 30 mg, depending on clinical response and tolerability, will have the option to return to xanomeline 100 mg/trospium 20 mg BID for the remainder of the treatment period. b No dose adjustment will be allowed after Visit 7. All subjects will continue taking the doses chosen for xanomeline and trospium at Visit 7. Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 26 of 127
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2. The investigator will be provided with a Study Site Binder for storing study related regulatory and study site documentation; eg, study logs and forms. 3. The investigator must review all eCRF entries for completeness and accuracy. 4. Periodic monitoring visits will be conducted on a regular basis by the Sponsor or designee in order to verify the accuracy of data entered on each eCRF against the raw data from source documents at the site. Items needing correction/clarification will be identified and brought to the attention of the study site personnel and principal investigator, and corrections will be made as appropriate. 5. The Sponsor or designee will perform a final review and data management of the eCRF. The study database will be validated using appropriate validation processes. 6. The Sponsor or designee may perform a regulatory audit of the study site, and may include a complete review of the overall study conduct, regulatory documentation, and selected subject eCRFs and source documents. 8.3 Selection of Study Population
8.3.1 Number of Planned Subjects
A total of approximately 180 study subjects and approximately 12 sites in the United States are planned. Subjects who are randomized into the double-blind treatment phase but discontinue or withdraw will not be replaced.
8.3.2 Inclusion Criteria
To be eligible for enrollment, subjects must satisfy all of the following criteria:
1. Subject is aged 18-60 years, inclusive, at screening. 2. Subject has a primary diagnosis of schizophrenia established by a comprehensive psychiatric evaluation based on the DSM-5 (American Psychiatric Association 2013) criteria and confirmed by Mini International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorder Studies (MINI) version 7.0.2. 3. Subject is experiencing an acute exacerbation or relapse of symptoms, with onset less than 2 months before screening. a. The subject requires hospitalization for this acute exacerbation or relapse of symptoms. b. If already an inpatient at screening, has been hospitalized for less than 2 weeks for the current exacerbation at the time of screening. 4. Positive and Negative Syndrome Scale total score between 80 and 120, inclusive, at screening. a. Score of ≥ 4 (moderate or greater) for ≥ 2 of the following Positive Scale (P) items at screening: i. Item 1 (P1; delusions) ii. Item 2 (P2; conceptual disorganization) iii. Item 3 (P3; hallucinatory behavior) iv. Item 6 (P6; suspiciousness/persecution) Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 33 of 127
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5. Has a DSM-5 diagnosis of moderate to severe substance abuse disorder (except tobacco use disorder) within the 12 months before screening (confirmed using MINI version 7.0.2 at screening), or current abuse as determined by urine toxicology screen or alcohol test. A screening subject with mild substance abuse disorder within the 12 months before screening must be discussed and agreed upon with the medical monitor before he/she can be allowed into the study. Use of cannabis at screening will result in screen failure with the allowance to rescreen at a later date if no moderate to severe substance use disorder is determined. 6. Risk for suicidal behavior during the study as determined by the investigator’s clinical assessment and the C-SSRS as confirmed by the following: a. Answers “Yes” on items 4 or 5 (C-SSRS – ideation) with the most recent episode occurring within the 2 months before screening, or answers “Yes” to any of the 5 items (C-SSRS-behavior) with an episode occurring within the 12 months before screening. Nonsuicidal self-injurious behavior is not exclusionary. 7. Clinically significant abnormal finding on the physical examination, medical history, ECG, or clinical laboratory results at screening. 8. Subjects cannot currently (within 2 weeks of baseline) be receiving oral antipsychotic medications, MAO inhibitors, anticonvulsants (eg, lamotrigine, Depakote), tricyclic antidepressants (eg, imipramine, desipramine), selective serotonin reuptake inhibitors, or any other psychoactive medications except for anxiolytics (eg, lorazepam, chloral hydrate) taken as needed. 9. Pregnant, lactating, or less than 3 months postpartum. Sperm donation is not allowed for 90 days after the final dose of study drug. 10. If, in the opinion of the investigator (and/or Sponsor), subject is unsuitable for enrollment in the study or subject has any finding that, in the view of the investigator (and/or Sponsor), may compromise the safety of the subject or affect their ability to adhere to the protocol visit schedule or fulfill visit requirements. 11. Subject has had psychiatric hospitalization(s) for more than 30 days (cumulative) during the 90 days before screening. 12. Subject has a history of treatment resistance to schizophrenia medications defined as failure to respond to 2 adequate courses of pharmacotherapy (a minimum of 4 weeks at an adequate dose per the label) or required clozapine within the last 12 months. 13. Risk of violent or destructive behavior. 14. Current involuntary hospitalization or incarceration. 15. Participation in another clinical study in which the subject received an experimental or investigational drug agent within 3 months of screening. 8.3.4 Removal of Subjects from Therapy or Assessments
The availability of any new adverse safety information related to KarXT may result in stopping the study. An investigator, Sponsor, or Institutional Review Board (IRB) may take such actions. If the study is terminated for safety reasons, subjects will be notified immediately and assured that appropriate treatment and follow-up will be available. If an investigator terminates the study, the Sponsor, subjects, and IRB will be informed Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 35 of 127
about the reason for such action. Similarly, if the Sponsor terminates the study, it will inform the investigators, the IRB, and the subjects of the reason for such an action. Similar notifications will be sent by the IRB if it takes such an action.
8.3.5 Subject Withdrawal
Subjects who are randomized into the double-blind treatment phase but then discontinue or withdraw will not be replaced.
Subjects may withdraw from the study at any time as stated in the ICF (given to the subject at the time of enrollment) and without prejudice to further treatment. Subjects may be withdrawn or be discontinued from the study by the study investigator or the Sponsor for the following reasons:
1. Violation of entry criteria; ie, subjects who are enrolled but are later discovered not to meet entry criteria 2. Adverse event(s) 3. Protocol noncompliance (eg, if a study subject is off study drug for >5 days in a row). 4. Pregnancy (females of childbearing potential). Any study subject who becomes pregnant while participating in the study will be unblinded to study treatment randomization. If she is found to be on active treatment assignment, she will be followed until her pregnancy reaches term. 5. Development of suicidal or assaultive behavior 6. Alcohol or illegal drug use 7. Development of an intercurrent systemic illness requiring significant medical intervention or a clinically significant change in laboratory testing as per the investigator. 8. Sponsor’s decision to discontinue study 9. Subject withdraws consent 10. Subject has need for a medication prohibited by the protocol. Subjects withdrawing from the study will be encouraged to complete the same final evaluations as subjects completing the study according to this protocol, particularly safety evaluations. The aim is to record data in the same way as for subjects who completed the study.
Reasonable efforts will be made to contact subjects who leave the unit or are lost to follow-up. These efforts must be documented in the subject’s file. Subjects with AEs ongoing at end of study will be followed until the AE is resolved or the subject is considered to be in stable condition.
The Sponsor has the right to terminate the study at any time in case of SAEs or if special circumstances concerning the study drug become known, making further Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 36 of 127
treatment of subjects impossible. In this event, the investigator(s) will be informed of the reason for study termination.
The reason for withdrawal or discontinuation must be recorded on the subject’s eCRFs. If a subject discontinues the study prematurely, for any reason, all procedures that would have been completed at the study discharge should be performed before subject study discontinuation, and the termination eCRF is to be completed.
All subjects withdrawn from the study because of an emergent adverse experience will continue to be followed until the AE(s) resolve or stabilize.
Pregnancy
No evidence of mutagenicity, or treatment effects on reproduction, fertility, or fetal parameters have been demonstrated in animals following administration of xanomeline, but there are no adequate and well-controlled studies in pregnant women (FDA Pregnancy Category B). Animal reproduction studies of trospium chloride have shown an adverse effect on the fetus, but potential benefits may warrant the use of the drug in pregnant women despite the risk (FDA Pregnancy Category C).
Therefore, participation of women of childbearing potential in this study must be willing to use a double-barrier method of birth control (ie, any double combination of male or female condom with spermicidal gel, diaphragm, sponge, or cervical cap with spermicidal gel) during the study and for 7 days after the last dose of study drug. Females of childbearing potential will have a serum pregnancy test at screening and a urine pregnancy test on Day 1 (before receiving xanomeline and/or trospium) and Day 35. Should a woman become pregnant or suspects she is pregnant while participating in this study, she should inform study staff and her primary care physician immediately.
Definition of women of childbearing potential: For the purpose of this study, a woman is considered of childbearing potential following menarche and until confirmed post- menopausal state, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
Pregnant women are excluded from this study because the effects of xanomeline and trospium on the developing human fetus are unknown with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with xanomeline or trospium, women who are breastfeeding must not be enrolled in the study.
The effects of study drug on sperm are unknown. Men who agree to enroll in the study must agree to use a double-barrier method of birth control (ie, any double combination Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 37 of 127
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6WXG\VXEMHFWVLQIRUPDQWVLQYHVWLJDWRUVVLWHSHUVRQQHOLQYROYHGLQVXEMHFWHYDOXDWLRQ and the Sponsor’s medical monitor will be blinded to the subject treatment assignment. %RWKDFWLYHVWXG\GUXJDQGSODFHERZLOOEHVXSSOLHGDVLGHQWLFDOPDWFKLQJFDSVXOHV7KLV SUHYHQWVELDVRQWKHSDUWRIWKHVWXG\VWDIIDQGWKHVXEMHFWWRLQIOXHQFHWKHUHVXOWVRIWKH VWXG\
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7KHPHPEHUVRIWKH,60&ZLOOEHXQEOLQGHGDVWKH\UHYLHZWKHVDIHW\GDWDIURPWKH VWXG\7KHUHZLOOEHDQXQEOLQGHGSKDUPDFLVWWRPDQDJHVWXG\GUXJLQYHQWRU\IRUHDFK VLWHDQGDQXQEOLQGHGVWXG\PRQLWRUIRUGUXJDFFRXQWDELOLW\DQGUHYLHZRI GRFXPHQWDWLRQRIGUXJLQYHQWRU\ Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 42 of 127
If unblinding is necessary for the welfare of a subject who has experienced an AE, unblinding of study drug may occur for just that subject. If an AE is thought to be related to the study drug and poses a safety risk, the investigator must decide whether to stop investigational treatment and/or treat the subject. Subject withdrawal should be avoided, if possible. If discontinuation of treatment occurs, every attempt should be made to restart study drug if medically appropriate, whatever the duration of discontinuation. When a subject has an AE that requires that the investigator be unblinded, the investigator can obtain the treatment assignment from the IWRS system. The site is expected to notify the study medical monitor before breaking the study blind, unless it is in the subject’s best interest if the blind is broken immediately. Note: in most circumstances it is not necessary to unblind a subject, even if an SAE has occurred. For many drugs there is no specific therapy for AEs. The appropriate course of action is to stop the investigational drug, and treat the signs and symptoms resulting from the AE.
8.4.10 Prior and Concomitant Therapy
8.4.10.1 Prior Medications
Subjects will be asked for all prior medications he/she were taking up to 6 months before the study, up to the time of the first dose of study medication on Day 1. All prior medications will be recorded on the eCRF.
8.4.10.2 Prohibited Medication/Therapy
During the study (ie, from the time of enrollment at the screening visit until study completion), subjects will refrain from the use of any new concomitant medications without the specific prior approval of the principal investigator. The administration of any other concomitant medications during the study period is prohibited without the prior approval of the principal investigator unless its use is deemed necessary in a medical emergency. Any medication taken by a subject during the course of the study and the reason for its use will be documented in the source documents and eCRF.
Within 2 weeks of baseline, subjects could not have taken oral antipsychotic medications, MAO inhibitors, mood stabilizers (ie, lithium), anticonvulsants (eg, lamotrigine, Depakote), tricyclic antidepressants (eg, imipramine, desipramine), selective serotonin reuptake inhibitors, or any other psychoactive medications except for anxiolytics that were taken on an as needed basis (eg, lorazepam, chloral hydrate). Intramuscular antipsychotic medications taken before baseline should not have been taken within 1 and a half cycles from baseline (eg, 3 or more weeks off for a 2-week cycle). Please direct questions relating to prohibited medications to the assigned Medical Monitor.
Subjects are not to have alcohol or illegal drug abuse within the prior 12 months of screening (unless medical monitor provided approval at screening), or at any time during the study. Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 43 of 127
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with the use of a medicinal (investigational) product, whether or not it is related to the medicinal (investigational) product. This includes an exacerbation of pre-existing conditions or events, intercurrent illnesses, drug interaction or the significant worsening of the indication under investigation that is not recorded elsewhere in the eCRF under specific efficacy assessments. Anticipated fluctuations of pre-existing conditions, including the disease under study that does not represent a clinically significant exacerbation or worsening need not be considered AEs.
In accordance with the protocol, the investigator and/or clinic staff will elicit AEs and inter-current illness during and at the end of the study period and these will be recorded on the appropriate page of the eCRF. Adverse events will be elicited by asking the subject a nonleading question, for example, “Have you experienced any new or changed symptoms since we last asked?” The eCRF will be completed at the end of the study as soon as the results of the final lab tests are available.
The reporting period for AEs is the period immediately following the administration of study product on Visit 2/Day 1 and up to the time of discharge (Visit 9/Day 35) of the subject from the study.
Adverse events will be reported on the AE eCRF using a recognized medical term or diagnosis that accurately reflects the event. Adverse events will be assessed by the investigator for severity, relationship to the study product, possible etiologies and whether the event meets criteria as a SAE and therefore requires immediate notification of the Sponsor, the IRB, and the FDA. If the event has not resolved at the end of the study reporting period it will be documented as still present on the eCRF. If an AE evolves into a condition that becomes “serious” it will also be reported as an SAE.
Assessment of Severity
Each AE will be assigned a category by the investigator as follows:
Mild: An AE that is easily tolerated by the subject, causes minimal discomfort, and does not interfere with everyday activities. Moderate: An AE that is sufficiently discomforting to interfere with normal everyday activities; intervention may be needed. Severe: An AE that prevents normal everyday activities; treatment or other intervention usually needed. If there is a change in severity of an AE, it must be recorded as a separate event.
Assessment of Causality
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the study drug. Causality should be assessed using the categories presented in the following table: Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 52 of 127
Unrelated: Clinical event with an incompatible time relationship to study drug administration, and that could be explained by underlying disease or other drugs or chemicals or is incontrovertibly not related to the study drug. Unlikely: Clinical event whose time relationship to study drug administration makes a causal connection improbable, but that could plausibly be explained by underlying disease or other drugs or chemicals. Possible: Clinical event with a reasonable time relationship to study drug administration, but that could also be explained by concurrent disease or other drugs or chemicals. Probable: Clinical event with a reasonable time relationship to study drug administration, and is unlikely to be attributed to concurrent disease or other drugs or chemicals. Very Clinical event with plausible time relationship to study drug Likely/Certain: administration, and that cannot be explained by concurrent disease or other drugs or chemicals.
Action Taken
The investigator will describe the action taken in the appropriate section of the eCRF, as follows:
x None x Study drug stopped x Study drug temporarily interrupted x Concomitant medication x Other, specify
Follow-up of Adverse Events
Subjects with AEs/SAEs will be treated if necessary and followed by the investigator until the event resolves or until, in the opinion of the investigator, the event is stabilized or determined to be chronic. The investigator will provide or arrange for appropriate follow-up (if required) for subjects, and document the course of the subject’s condition. Additional medical evaluation and treatment will be arranged as appropriate. Details of AE resolution must be documented in the eCRF.
Documentation and Reporting of Adverse Events
AEs should be reported and documented in accordance with the procedures outlined below. All AEs occurring during the study must be documented on the relevant eCRF pages. The following data should be documented for each AE: Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 53 of 127
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11.2 Analysis Populations
11.2.1 Intent-To-Treat Population
Intent-to-treat (ITT) population is defined as subjects who are randomized to the study.
11.2.2 Modified Intent-To-Treat Population
Modified Intent-to-treat (mITT) population is defined as randomized subjects who receive at least 1 dose of study drug and have a baseline assessment. The mITT population will be used for efficacy analyses.
11.2.3 Safety Population
Safety population is defined as subjects who receive at least 1 dose of study drug. The safety population will be used for safety analyses.
11.2.4 Pharmacokinetic Population
Pharmacokinetic population is defined as randomized subjects who receive at least 1 dose of study drug and have at least 1 measurable serum concentration of study medication. PK population will be used for PK analyses.
11.3 Statistical Analyses
11.3.1 Subject Disposition
The number of subjects in each analysis population and the reasons for discontinuation will be summarized. In addition, subjects’ status with regard to study treatment and follow-up will also be summarized.
11.3.2 Demographic and Other Baseline Characteristics
Subject disease and baseline characteristics will be summarized using frequency distribution or descriptive statistics as appropriate.
11.3.3 Efficacy Analyses
The primary endpoint of the study is the change from baseline in PANSS total score at Week 5. The difference between KarXT and placebo at Week 5 will be estimated using a mixed model for repeated measures (MMRM). The model will include the observed change from baseline PANSS total score at Week 2, Week 4, and Week 5 as the response. The treatment difference at Week 5 will be estimated using contrasts. The MMRM will include the treatment group (KarXT or placebo), visit, and the interaction between the treatment group and visit as fixed factors. Site, age, gender, and baseline Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 63 of 127
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x For the primary efficacy analysis, likelihood-based modeling approach will be used to handle incomplete data. For this purpose, an MMRM will be applied. x Sensitivity analysis for the primary efficacy endpoint will be conducted using the last observation carried forward approach. In this analysis, the missing values will be replaced by the previous visit PANSS total score carried forward. x Sensitivity analysis for the primary efficacy endpoint will be conducted using the Multiple Imputation approach; ie, by replacing each missing value with a set of plausible values that represent the uncertainty about the right value to impute.
11.4 Determination of Sample Size
Assuming a PANSS total score difference of 9 between drug and placebo and standard deviation of 18, a sample size of approximately 180 (90 evaluable subjects per arm) will result in a power of 91% for a 2-sided alpha of 0.05.
11.5 Protocol Deviations
All protocol deviations will be tracked in the eCRF/electronic data capture (EDC) system. Deviations considered major will be identified as such before study unblinding during medical monitor periodic review.
Major protocol deviations will be tabulated including the frequency and percentage of subjects with each type of deviation by treatment group.
12 QUALITY ASSURANCE AND QUALITY CONTROL
12.1 Audit and Inspection
Study centers and study documentation may be subject to a Quality Assurance audit during the course of the study by the Sponsor or its nominated representative. In addition, inspections may be conducted by regulatory authorities at their discretion.
The study site personnel and principal investigator must make all study records (including source data and documentation) available to US and International regulatory agency personnel, the IRB and the study Sponsor or designee, for the purposes of monitoring, auditing, inspection, and copying. In addition, disclosure of study information to third parties may be required by law.
12.2 Monitoring
The study will be monitored by the Sponsor or its designee on a regular basis throughout the study period. Data for each subject will be recorded on an eCRF. Data collection must be completed for each subject who signs an ICF and is administered study drug. Some data such as scale assessments and laboratory results will be maintained in the vendor systems. Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 66 of 127
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13 RECORDS AND SUPPLIES
13.1 Drug Accountability
The accountability for the study drug at the study site rests with unblinded study monitors. These persons will maintain records of all the investigational products (drug and placebo), including their delivery and receipt, inventory at the site, use by each subject, and the destruction of unused study drug according to the directions of the Sponsor or designee. The investigators will assure that drug and placebo are used according to the protocol. The investigators will assure that the study drug and the records described in this paragraph will be stored in a locked area suitable for storage of pharmaceutical products, and in accordance with the conditions specified on the study drug label. Further, the investigators assure that the study drug and the records will be available for examination by the unblinded study monitor on periodic visits.
All unused study drug supplies and equipment will be destroyed according to directions of the Sponsor or designee at the end of the study.
On receipt of the study drug, an unblinded pharmacist at the study site will conduct an inventory of the supplies and verify that study drug supplies are received intact and in the correct amounts before completing a supplies receipt. The unblinded pharmacist will retain a copy of this receipt at the study center and it will be reviewed by the unblinded study monitor. The unblinded study monitor may check the study supplies at each study center at any time during the study.
It is the responsibility of the unblinded study monitor to ensure that the unblinded pharmacist has correctly documented the amount of the study drug received, dispensed, and returned on the dispensing log that will be provided. A full drug accountability log will be maintained at the study center at all times. The unblinded study monitor will also perform an inventory of study drug at the close-out visit to the study center. All discrepancies must be accounted for and documented. Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 68 of 127
14 ETHICS
14.1 Independent Ethics Committee or Institutional Review Board
The protocol, informed consent, and other written material given to the subjects, and any other relevant study documentation will be reviewed and approved by the governing IRB of the participating center before study initiation and/or before the study drug is released to the investigator, and the investigator will keep the IRB informed as to the progress of the study.
Modifications or changes to the protocol, the informed consent, or other study documentation may not be initiated without prior written IRB approval except when necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or administrative aspects of the study. Such modifications will be submitted to the IRB and written verification that the modification was submitted should be obtained.
The IRB must be informed by the principal investigator of informed consent changes or revisions of other documents originally submitted for review; serious and/or unexpected adverse experiences occurring during the study; new information that may affect adversely the safety of the subjects or the conduct of the study; an annual update and/or request for re-approval; and when the study has been completed.
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records will be identified by a coded number and initials only; on some specimen collection records, the subject’s birth date may also appear. All study records will be kept in a locked file cabinet and code sheets linking a subject’s name to a subject identification number will be stored separately in another locked file cabinet. Clinical information will not be released without written permission of the subject, except as necessary for monitoring by the FDA or the Sponsor of the clinical study.
14.2 Regulatory Authorities
Relevant study documentation will be submitted to the US regulatory authorities, according to local/national requirements, for review and approval before the beginning of the study. On completion of the study, the regulatory authorities will be notified that the study has ended.
14.3 Ethical Conduct of the Study
The study will be conducted in accordance with the ethical principles set forth in the Declaration of Helsinki, the Guideline for GCP (ICH E6), the United States CFR governing the protection of human subjects (21CFR§50), IRBs (21CFR§56), the requirements for conducting clinical investigations (21CFR§312), and all applicable local, state and federal government regulations and laws. Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 69 of 127
14.4 Informed Consent
Written informed consent must be obtained before any protocol-specified procedures or interventions are carried out. Subjects will be counseled about the study before giving their written informed consent. The investigator or designated personnel will inform the subject of the objectives, methods, anticipated benefits, potential risks, and inconveniences of the study. The subject should be given every opportunity to ask for clarification of any points s/he does not understand and, if necessary, ask for more information. Subjects must be given ample opportunity to inquire about details of the study. The process of obtaining informed consent must be in accordance with applicable regulatory requirement(s) and must adhere to GCP.
The investigator will explain the nature of the study and will inform the subject that participation is voluntary and that they can withdraw at any time. Written informed consent will be obtained from each subject before entry into the study. A copy of the signed consent form will be given to every participant and the original will be maintained with the subject’s records. The Informed Consent should be translated and certified into the local language of the respondent, as deemed necessary.
It should be emphasized that the subject may refuse to enter the study or to withdraw from the study at any time, without consequences for their further care or penalty or loss of benefits to which the subject is otherwise entitled. Subjects who refuse to give or who withdraw written informed consent should not be included or continue in the study.
The consent form must be approved by the IRB and be acceptable to the Sponsor. Consent forms must be written so as to be understood by the prospective subject. Informed consent will be documented by the use of a written consent form approved by the IRB and signed and dated by the subject and by the person who conducted the informed consent discussion. The signature confirms the consent is based on information that has been understood. Each signed ICF must be kept on file by the investigator for possible inspection by Regulatory Authorities and/or the Sponsor or its designee. The subject should receive a copy of the signed and dated written ICF and any other written information provided to the subjects, and should receive copies of any signed and dated consent form updates and any amendments to the written information provided to subjects.
If new information becomes available that may be relevant to the subject’s willingness to continue participation in the study, a new ICF will be approved by the IEC(s)/IRB(s) (and regulatory authorities, if required). The study subjects will be informed about this new information, and reconsent will be obtained.
14.5 Conflict of Interest
The investigators will be partially paid by the Sponsor of this study for the study related expenses, but they will not profit from results, either positive or negative, with regard to Karuna Pharmaceuticals 13 Dec 2018 KAR-004 Amendment 3 Version 4.0 Page 70 of 127
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