A Phase 2 Efficacy and Safety Study of TAK-063 in Participants With an Acute Exacerbation of Schizophrenia

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy, safety and tolerability of TAK-063 compared with placebo in treatment of acutely exacerbated schizophrenia.

Detailed Description
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The drug being tested in this study is called TAK-063. TAK-063 is being tested to treat people who have schizophrenia. This study will look at the different symptoms associated with schizophrenia including cognitive symptoms, personal and social functioning and functional capacity (ability to perform tasks associated with real, everyday life such as household chores, communication, finance, transportation, and planning recreational activities) in people who take TAK-063. The study enrolled 164 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need): TAK-063 20 mg Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient. All participants will be asked to take the tablets once daily at nighttime. All participants will initially receive TAK-063, 20 mg/day. The dose may be titrated down to 10 mg/day, if intolerable. The multi-center trial will be conducted in the United States. The overall time to participate in this study is 6 weeks. Participants will be hospitalized until the Week 3 visit. Participants will make 11 visits to the clinic during the treatment and 1 visit during the follow-up.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-group, 6-Week Study to Evaluate the Efficacy and Safety of TAK-063 in Subjects With an Acute Exacerbation of Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: TAK-063 20 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is capable of understanding and complying with protocol requirements. The participants or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures. Has a primary diagnosis of schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition [DSM-5], 295.90) confirmed by clinical interview (Structured Clinical Interview for DSM-5 Clinical Trial Version [SCID-5-CT]). The participant's initial diagnosis must be greater than or equal to (>=) 1 year from screening. Is a man or woman age 18 to 65, inclusive, at Screening. Male participant who is nonsterilized and sexually active with a female partner of child bearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose. Female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose. The participant's psychotic symptoms were exacerbated within 2 months (60 days) prior to Screening (example, aggravated delusion). Has a score of 5 (moderate severe) or higher in 3 or more items of the following Positive and Negative Symptom Scale (PANSS) items at Screening and Day 1: delusions (P1), conceptual disorganization (P2), hallucinations (P3), suspiciousness (P6), and unusual thought content (G9). Has a PANSS total score of 80 or higher at Screening and Day 1. Has a Clinical Global Impression Scale- Severity of Illness Scale (CGI-S) of 4 or greater at Screening and Day 1. Is able and agrees to remain off prior antipsychotic medication and all excluded medications as outlined in the protocol for the duration of the study. Has an identified, reliable caregiver. A caregiver is defined as a family member, informant or friend who is able and willing to assist and support the administration of study drug, adherence to protocol requirements and to the study schedule. Has a body mass index (BMI) score between 18.0 and 35.0 kilogram per square meter (kg/m^2), inclusive, at Screening. Exclusion Criteria: Has received any investigational compound within 30 days prior to Screening, or within 5 half-lives prior to screening, whichever is longer. Has received TAK-063 in a previous clinical study or as a therapeutic agent or has previously or is currently participating in this study or have participated in 2 or more clinical studies within 12 months prior to Screening. Has a decrease in the PANSS Total Score by 20 percent (%) or more at Baseline (Day 1) compared with that at Screening [(PANSS Total Score at Screening- PANSS total score at Baseline)/(PANSS Total Score at Screening- 30)]*100 >=20%]. Is an immediate family member, study site employee, or in a dependent relationship with a study site employee who is involved in the conduct of this study (example, spouse, parent, child, and sibling) or may consent under duress. Has uncontrolled, clinically significant neurologic, cardiovascular, pulmonary, hepatic, renal, metabolic, gastrointestinal, or endocrine disease or other abnormality (other than the disease being studied), which may impact the ability of the participant to participate or potentially confound the study results. Has a history of severe head injury/traumatic brain injury, myocardial infarction or stroke. Has a known hypersensitivity to any component of the formulation of TAK-063 or the practice pills (i.e., small colored candies) during the AiCure device training. Has a positive urine drug result (illicit, illegal or without valid prescription or medical need) at Screening. Has a moderate or severe substance use disorder (meeting more than 5 diagnostic criteria of DSM-5 either currently or within the last 6 months) for alcohol or other substances of abuse except nicotine or caffeine. Has taken any excluded medication, supplements, or food products or has had insufficient washout of medications, supplements, or food products as listed in the Excluded /Allowed Medications, Procedures, and Treatments table or is unable or unwilling to discontinue medications as required by the protocol. If female, the participant is pregnant or lactating or intending to become pregnant (a positive pregnancy test at Screening or Day 1), or intending to donate ova, before or during the course of the study or within 12 weeks after last dose. If male, the participant intends to donate sperm during the course of this study or for 12 weeks after last dose. Has a psychiatric disorder other than schizophrenia as their primary diagnosis. Has a history of or known personality disorder or other psychiatric disorder that, in the opinion of the investigator, would interfere with participation in the study. Has a history of neuroleptic malignant syndrome, water intoxication, or paralytic ileus or other conditions that may interfere with absorption of study medication. Is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property or participants who within the past year prior to Screening have attempted suicide or have positive answers on item 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) at Screening or Day 1. Has Parkinson disease, tardive dyskinesia, or other chronic movement disorder that may interfere with the interpretation of study results. Has any existing or previous history of cancer that has been in remission for less than 5 years prior to Screening. (This criterion does not include those participants with basal cell, stage I squamous cell skin cancer or in situ cervical cancer). Has newly diagnosed diabetes or requiring insulin for their treatment; diabetic participants that have had changes to their diabetic treatment regimen within 30 days prior to screening or diabetic participants that have had hospitalizations for their diabetes and/or diabetes related conditions in the past year prior to screening. Has long QT syndrome or under the treatment with Class 1A (example, quinidine, procainamide) or Class 3 (example, amiodarone, sotalol) anti-arrhythmic drugs. Is known to be currently infected or have been infected with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Has received any depot preparation (sustained-release formulation) of antipsychotic drugs within 1 month (30 days) of Screening. Has received clozapine for the treatment of schizophrenia (lifetime) before screening (this does not include the use of low-dose clozapine for sleep). Has received monoamine oxidase (MAO) inhibitors or fluoxetine within 1 month (30 days) before Screening. Is considered to be treatment resistant. Treatment resistance is defined as prior nonresponse to 2 courses of treatment with antipsychotics of different chemical classes for at least 4 weeks each at doses considered to be effective. Has received electroconvulsive therapy within 6 months (180 days) before Screening. Has a history of hypersensitivity to more than one distinct chemical class of drug (including anaphylaxis, rash, or urticaria caused by drugs). Is considered otherwise inappropriate for the study by the investigator or Sponsor's medical monitor and/or designee. Has 1 or more laboratory values outside the normal range that are considered by the investigator to be clinically significant at the Screening Visit; or has any of the following at the Screening Visit: a serum creatinine value >1.5 times the upper limit of normal (ULN). A total serum total bilirubin value >1.5*ULN. A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value >2*ULN, or prolactin >= 100 nanogram/milliliter (ng/mL).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAK-063 20 mg<br>TAK-063 20 mg, tablets, orally, once daily for up to 6 weeks. Dose may be titrated down to 10 mg/day, if intolerable. | Drug: TAK-063 20 mg<br>* TAK-063 tablet.<br>|
| Placebo Comparator: Placebo<br>TAK-063 matching-placebo tablets, orally, once daily for up to 6 weeks. | Drug: Placebo<br>* TAK-063 matching-placebo tablet.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Positive and Negative Symptom Scale (PANSS) Total Score at Week 6 | PANSS assesses the positive symptoms, negative symptoms, and general psychopathology specifically associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). The sum of the 30 items is defined as the PANSS total score and ranges from 30 to 210; higher score indicates greater severity. Least square mean and standard error values were determined using a mixed model for repeated measures (MMRM). A negative change from Baseline indicates improvement. | Baseline and Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in PANSS Total Score at Weeks 1, 2, 3, 4 and 5 | PANSS assesses the positive symptoms, negative symptoms, and general psychopathology specifically associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). The sum of the 30 items is defined as the PANSS total score and ranges from 30 to 210; higher score indicates greater severity. Least square mean and standard error values were determined using a MMRM. A negative change from Baseline indicates improvement. | Baseline and Weeks 1, 2, 3, 4 and 5 | 
| Change From Baseline in PANSS Subscales Using the Marder 5-factor Model at Weeks 1, 2, 3, 4, 5, and 6 | PANSS subscales using the Marder 5-factor model include positive symptoms (8-items, total score = total score = 8 to 56, with a higher score indicating greater severity of symptoms), negative symptoms (7-items, total score = 7 to 49, with a higher score indicating greater severity of symptoms), disorganized thoughts (7-items, total score = 7 to 49, with a higher score indicating greater severity of symptoms), impulsivity/hostility (4-items, total score = 4 to 28, with a higher score indicating greater severity of symptoms), anxiety/depression (4-items, total score = 4 to 28, with a higher score indicating greater severity of symptoms). Responses to each item range from 1 = absence of symptom, to 7 = most extreme symptoms. An improvement in symptoms is represented by change from baseline values that are negative. | Baseline and Weeks 1, 2, 3, 4, 5 and 6 | 
| Change From Baseline in PANSS Subscales at Weeks 1, 2, 3, 4, 5 and 6 | PANSS assesses the positive symptoms, negative symptoms, and general psychopathology specifically associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). Positive subscale consists of 7 items which assesses the positive symptoms with subscale score ranging from 7 to 49, where higher score indicates greater severity. Negative subscale consists of 7 items which assesses the negative symptoms with subscale score ranging from 7 to 49, where higher score indicates greater severity. General psychopathology subscale consists of 16 items which assesses the general symptoms of schizophrenia with subscale score ranging from 16 to 96, where higher score indicates greater severity. Least square mean and standard error values were determined using a MMRM. A negative change from Baseline indicates improvement. | Baseline and Weeks 1, 2, 3, 4, 5 and 6 | 
| Percentage of Clinical Responders Based on the PANSS Total Score | Clinical responders based on the PANSS total score is defined as at least 30% improvement from baseline in the total score. PANSS assesses the positive symptoms, negative symptoms, and general psychopathology specifically associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). The sum of the 30 items is defined as the PANSS total score and ranges from 30 to 210; higher score indicates greater severity. | Weeks 1, 2, 3, 4, 5 and 6 | 
| Change From Baseline in Clinical Global Impression - Severity (CGI-S) Score at Weeks 1, 2, 3, 4, 5,and 6 | The CGI-S is a clinician rated scale designed to assess global severity of illness. CGI-S is a 7-point scale that requires the clinician to rate the severity of the participant's illness at the time of assessment. A participant is assessed on severity of mental illness on the following scale: 1, normal, not at all ill; 2, borderline ill; 3, mildly ill; 4, moderately ill; 5, markedly ill; 6, severely ill; or 7, extremely ill. Least square mean and standard error values were determined using a MMRM. A negative change from Baseline indicates improvement. | Baseline, Weeks 1, 2, 3, 4, 5 and 6 | 
| Clinical Global Impression Scale - Improvement (CGI-I) Score at Weeks 1, 2, 3, 4, 5 and 6 | The CGI-I assesses the participant's improvement (or worsening). The clinician is required to assess the participant's condition relative to baseline on a 7-point scale. CGI-I scale assesses the participant's improvement (or worsening) on a 7-point scale: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. Least square mean and standard error values were calculated using a MMRM. | Weeks 1, 2, 3, 4, 5 and 6 | 
| Percentage of Responders Based on CGI-I Ratings Score | Responder based on CGI-I is defined as a rating of much improved or very much improved. The CGI-I assesses the participant's improvement (or worsening). The clinician is required to assess the participant's condition relative to baseline on a 7-point scale: 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. | Weeks 1, 2, 3, 4, 5 and 6 | 
| Change From Baseline in Brief Assessment of Cognition in Schizophrenia (BACS) Score at Weeks 3 and 6 | BACS is specifically designed to measure treatment- related improvements in cognition and includes alternate forms. The battery of tests in the BACS includes brief assessments of reasoning and problem solving, verbal fluency, attention, verbal memory, working memory, and motor speed. The primary measure from each test of the BACS is standardized by creating z-scores whereby the mean of the test session of a healthy participant is set to 0 and the standard deviation set to 1. A composite score was calculated by averaging all of the 6 standardized primary measures from the BACS, and then calculating a z-score of the composite. The composite z-score indicates how much higher or lower the participant's cognition is compared to a healthy person. Least square mean and standard error values were determined using a MMRM. | Baseline, Weeks 3 and 6 | 
| Change From Baseline in Brief Negative Symptom Scale (BNSS) Score at Weeks 3 and 6 | The BNSS is a13-item instrument designed for use in clinical trials and other studies that measures 5 domains of negative symptoms: blunted affect, alogia, asociality, anhedonia, and avolition. All the items in the BNSS are rated on a 7-point (0-6) scale, with anchor points generally ranging from the symptom's being absent (0) to severe (6). A scale total score is calculated by summing the 13 individual items; total score range of 0 to 78, where higher score indicates higher severity of negative symptoms. Least square mean and standard error values were determined using a MMRM. A negative change from Baseline indicates improvement. | Baseline, Weeks 3 and 6 | 
| Change From Baseline in the Personal and Social Performance (PSP) Scale Score at Weeks 3 and 6 | The PSP scale is a clinician-reported outcome instrument that was developed to evaluate social and personal functioning. It measures 4 domains of social functioning: socially useful activities including work and study, personal and social relationships, self-care and disturbing and aggressive behaviors. The clinician assigns an initial 6-degree of severity to each area (absent, mild, manifest, marked, severe or very severe). The final result is a single assessment of social functioning ranging from 0 (no autonomy) to 100 (excellent functioning). Least square mean and standard error values were determined using a MMRM. A positive change from Baseline indicates improvement. | Baseline, Weeks 3 and 6 | 
| Change From Baseline in the University of California San Diego Performance-based Skills Assessment - Brief Version (UPSA-B) at Week 3 and 6 | The UPSA-B evaluates the abilities of individuals to perform everyday tasks that are considered necessary for independent functioning in the community. The UPSA-B uses role playing situations to evaluate skills in 5 areas: household chores, communication, finance, transportation, and planning recreational activities. Subscale scores range from 0 to 20 points, and total scores range from 0 to 100 points; higher scores reflect better performance. Least square mean and standard error values were determined using a MMRM. A positive change from Baseline indicates improvement. | Baseline, Weeks 3 and 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy