A Study to Evaluate Efficacy, Safety, Tolerability, and Pharmacokinetics of 3 Dose Levels of TAK-831 in Adjunctive Treatment of Adult Participants With Negative Symptoms of Schizophrenia

Study Overview
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Brief Summary
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The purpose of this study is to determine whether add-on TAK-831 is superior to placebo on the Positive and Negative Syndrome Scale Negative Symptom Factor Score (PANSS NSFS).

Detailed Description
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The drug being tested in this study is called TAK-831. TAK-831 is being tested to treat negative symptoms in participants who have schizophrenia. The study will enroll approximately 234 participants. Participants will then be randomly assigned (by chance, like flipping a coin) to one of the four treatment groups in the double-blind period-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need): TAK-831 50 mg once daily TAK-831 125 mg once daily TAK-831 500 mg once daily Placebo once daily This multi-center trial will be conducted in the United States, Spain, Italy, Czech Republic, Poland, Bulgaria and Ukraine. The overall time to participate in this study is approximately 20 weeks. Participants will make 11 visits to the clinic, and will be followed up for safety assessment 10 to 14 days after the last dose of study drug (Day 98).

Official Title
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A Phase 2, 12-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel Study to Evaluate Efficacy, Safety, Tolerability, and Pharmacokinetics of 3 Dose Levels of TAK-831 in Adjunctive Treatment of Adult Subjects With Negative Symptoms of Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Luvadaxistat
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a current diagnosis of schizophrenia as defined by the Mini International Neuropsychiatric Interview (MINI) 7.0.2 for Psychotic Disorders for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) and the general psychiatric evaluation. Initial diagnosis must be greater than or equal to (>=1) year from screening. Is receiving primary background antipsychotic therapy (other than clozapine) at a total daily dose between 2 and 6 mg of risperidone equivalents. Concomitant treatment with a sub-therapeutic dose of a second antipsychotic may be permitted with sponsor or designee approval if used to treat specific symptoms, such as insomnia or anxiety (for example, quetiapine 25-50 mg or its equivalent as needed for anxiety), but not if it is used for refractory positive psychosis symptoms. Is treated with a stable regimen of psychotropic medications with no clinically meaningful change (no increase in dose, less than or equal to [<=] 25 percent [%] decrease in dose for tolerability) in the prescribed dose for 2 months before the screening visit and no dose adjustment is anticipated throughout study participation up to the Day 84/early termination visit. Has a BNSS total score (12-item, excluding number 4) >=28; stable Single-blind Placebo Run-in and baseline BNSS total (12-item, excluding number 4) scores (<= 20% change from the screening score). Has no more than moderate-severe (<=5) rating on PANSS positive symptom items P1, P3, P4, P5, P6, or unusual thought content (G9), with a maximum of 2 of these items rated '5'; no more than moderate (<=4) rating on conceptual disorganization (P2). There is evidence that the participant has stable symptomatology >=3 months prior to the screening visit (example, no hospitalizations for schizophrenia, no emergency room admission due to symptoms of schizophrenia, no increase in level of psychiatric care due to worsening of symptoms of schizophrenia). Have an adult informant who will be able to provide input for completing study rating scales, including the PANSS and SCoRS (for example, a family member, social worker, caseworker, residential facility staff, or nurse who spends >=4 hours/week with the participant) and is considered reliable by the investigator. The informant must be able and willing to provide written informed consent and to participate in at least 1 in-person interview, then be able to provide continuing input by attending each clinical assessment visit or via participating in a telephone interview for other study visits that include the PANSS or SCoRS endpoints. Exclusion Criteria: Has a lifetime diagnosis of schizoaffective disorder; a lifetime diagnosis of bipolar disorder; or a lifetime diagnosis of obsessive compulsive disorder based on the MINI combined with the general psychiatric evaluation. Has a recent (within the last 6 months) occurrence of panic disorder, depressive episode, or other comorbid psychiatric conditions currently requiring clinical attention based on the MINI for DSM-5 and the general psychiatric evaluation. Has a diagnosis of substance use disorder (with the exception of nicotine dependence) within the preceding 6 months based on the MINI for DSM-5 and the general psychiatric evaluation. Is participating in a formal structured nonpharmacological psychosocial therapeutic treatment program (cognitive remediation, cognitive-behavioral therapy, intensive symptom/vocational rehabilitation) for a duration of less than (<) 3 months before randomization. In addition, initiation of such nonpharmacological treatment programs is not permitted during study participation through the Day 84 visit. The participant exhibits more than a minimal level of antipsychotic-induced parkinsonism symptoms, as documented by a score on the modified Simpson Angus Scale (SAS) (excluding item number 10, Akathisia) greater than (>) 6. Has evidence of depression as measured by a Calgary Depression Scale Score (CDSS) > 9. Is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or the participant has attempted suicide within the past year prior to screening. Participants who have positive answers on item number 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) (based on the past year) prior to randomization are excluded. Has a history of brain trauma associated with loss of consciousness for >15 minutes. Diagnosis of schizophrenia occurred prior to 12 years of age. Has received electroconvulsive therapy within 6 months (180 days) before Screening. Has a history of developmental intellectual disability or mental retardation. Antipsychotic plasma levels for the participant's primary background antipsychotic are below the minimum acceptable concentration criteria per the Antipsychotic Reference document at the screening or placebo run-in visits. This criterion is not applicable to participants on a primary background antipsychotic for which a clinical assay is unavailable. Is treatment resistant. Treatment resistance is defined as prior nonresponse of positive symptoms of schizophrenia to 2 courses of treatment with antipsychotics of different chemical classes for at least 4 weeks, each at doses considered to be effective. Does not have a stable residence or is homeless.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Double-blind: Luvadaxistat 50 mg<br>Luvadaxistat 50 milligram (mg), tablets, orally, once daily up to 14 weeks. | Drug: Luvadaxistat<br>* TAK-831 tablets.<br>* Other names: TAK-831;|
| Experimental: Double-blind: Luvadaxistat 125 mg<br>Luvadaxistat 125 mg, tablets, orally, once daily up to 14 weeks. | Drug: Luvadaxistat<br>* TAK-831 tablets.<br>* Other names: TAK-831;|
| Experimental: Double-blind: Luvadaxistat 500 mg<br>Luvadaxistat 500 mg, tablets, orally, once daily up to 14 weeks. | Drug: Luvadaxistat<br>* TAK-831 tablets.<br>* Other names: TAK-831;|
| Placebo Comparator: Double-blind: Placebo<br>Luvadaxistat placebo-matching tablets, orally, once daily up to 14 weeks. | Drug: Placebo<br>* Luvadaxistat placebo-matching tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline on the PANSS NSFS at Day 84 | PANSS assesses the positive symptoms, negative symptoms, and general psychopathology 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). Negative subscale consists of 7 items which assess the negative symptoms with sub scale score ranging from 7 to 49, where higher score indicates greater severity. | Baseline and Day 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline on the PANSS NSFS at Days 28 and 56 | PANSS assesses the negative symptoms 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). 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. | Baseline, Days 28 and 56 | 
| Change from Baseline on the Brief Negative Symptom Scale (BNSS) at Day 84 | The BNSS is a 13-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. | Baseline and Day 84 | 
| Change from Baseline on the Brief Assessment of Cognition in Schizophrenia (BACS) Composite Score at Day 84 | The BACS is specifically designed to measure treatment-related improvements in cognition and includes alternate forms. BACS is a reliable and sensitive measure of cognitive function in schizophrenia. The BACS is a cognition assessment battery that assesses 6 domains of cognitive function found to be consistently impaired in schizophrenia: verbal memory, working memory, motor speed, attention, executive functions, and verbal fluency. 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. | Baseline and Day 84 | 
| Change from Baseline on the Clinical Global Impression-Schizophrenia-Severity (CGI-SCH-S) Score at Day 84 | The CGI-SCH scale is an adapted version of the CGI scale that is designed to assess global illness status in participant's with schizophrenia. CGI-SCH-S is a 7-point scale that requires the investigator 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. | Baseline and Day 84 | 
| Clinical Global Impression Schizophrenia Improvement (CGI-SCH-I) Score at Day 84 | The CGI-SCH-I assesses the participant's improvement (or worsening). The investigator is required to assess the participant's condition relative to baseline on a 7-point scale where 1. very much improved; 2. much improved; 3. minimally improved; 4. no change; 5. minimally worse; 6. much worse; or 7. very much worse. | At Day 84 | 
| Change from Baseline on the Schizophrenia Cognition Rating Scale (SCoRS) at Day 84 | The SCoRS is an interview-based measure of cognitive functioning that is developed to specifically assess aspects of cognitive functioning in participants with schizophrenia. The items assess the 7 cognitive domains of attention, memory, reasoning and problem solving, working memory, processing speed, language functions, and social cognition. The SCoRS global total scores is the sum of the 20 items and it varies from 20 to 80 with 20 being the best outcome and 80 being the worst. | Baseline and Day 84 | 
| Change from Baseline on the PANSS Total Score and Additional Subscales and Factors at Day 84 |  | Baseline and Day 84 | 
| Plasma Concentrations of TAK-831 |  | Day 1 pre-dose and at multiple time points (up to Day 84) post-dose | 

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