| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Behavioral Disciplines and Activities [F04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10039626 |
| E.1.2 | Term | Schizophrenia |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine whether add-on TAK-831 is superior to placebo
on the Positive and Negative Syndrome Scale Negative Symptom Factor Score (PANSS NSFS). |
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| E.2.2 | Secondary objectives of the trial |
To determine whether add-on TAK-831 is superior to placebo on the Brief Negative Symptom Scale (BNSS) total score, on the Brief Assessment of Cognition in Schizophrenia (BACS) composite cognition score, on global severity as measured by the Clinical Global Impression-Schizophrenia-Severity (CGI-SCH-S) score, on global improvement as measured by the Clinical Global Impression-Schizophrenia-Improvement (CGI-SCH-I) score, on the Schizophrenia Cognition Rating Scale (SCoRS) assessment of cognitive functional outcome.To determine whether add-on TAK-831 is superior to placebo on the Positive and Negative Syndrome Scale (PANSS) total score and additional subscales and factors.
To assess the safety and tolerability of TAK-831. To assess the PK of TAK-831. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacogenomic study
Objectives :
- To identify potential deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) biomarkers that predict response to TAK-831.
-To evaluate the effects of TAK-831 on D-serine pathway gene expression by pharmacogenomics (PGx) analysis.
-To identify potential biomarkers of disease activity and drug response in the plasma, such as inflammatory mediators. |
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| E.3 | Principal inclusion criteria |
• The subject has a current diagnosis of schizophrenia as defined by the 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.
The subject’s initial diagnosis must be ≥1 year from Screening.
• The subject is male or female and aged 18 to 60 years, inclusive.
• The subject is receiving primary background antipsychotic therapy (other than clozapine) at a total daily dose between 2mg and 6 mg of risperidone equivalents (as outlined in an Antipsychotic Dose Equivalency reference supplied to the sites). Concomitant treatment with a subtherapeutic dose of a second antipsychotic may be permitted with sponsor or designee approval if used as to treat specific symptoms, such as insomnia, but not if it is used for refractory positive psychosis symptoms.
• The subject is treated with a stable regimen of psychotropic medications with no clinically meaningful change (no increase in dose, <25 % decrease in dose for tolerability) in the prescribed dose for 2 months before to the Screening Visit and no dose adjustment is anticipated throughout study participation up to the Day 84/Early Termination Visit. As an exception, prohibited medications that are used as hypnotics or anxiolytics may be replaced with permitted medications as medically appropriate with approval from the sponsor or designee
• The subject 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).
• The subject 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 subject has stable symptomatology ≥3 months prior to the Screening Visit (eg, 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).
• The subject must have an adult informant who will be able to provide input for completing study rating scales, including PANSS and SCoRS (eg, family member, social worker, caseworker, residential facility staff, or nurse who spends ≥4 hours/week with the subject) and is considered reliable by the investigator .
Please see the protocol for additional inclusion criteria |
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| E.4 | Principal exclusion criteria |
• The subject 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. As an exception, subjects with a historical prior lifetime diagnosis of schizoaffective disorder may be enrolled in the study with sponsor or designee approval provided that the principal investigator can attest that the subject’s overall history and current clinical presentation and history is most consistent with schizophrenia, not schizoaffective disorder.
• The subject has a recent (within the last 6 months) occurance of panic disorder, depressive episode, or other comorbid psychiatric conditions requiring clinical attention based on the MINI for DSM-5 and the general psychiatric evaluation.
• The subject 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.
• The subject is participating in a formal structured nonpharmacological therapeutic treatment program (cognitive remediation, cognitive-behavioral therapy, intensive symptom/vocational rehabilitation) for <3 months prior to randomization. In addition, initiation of such nonpharmacological treatment programs is not permitted during study participation through the Day 84 Visit.
• The subject 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) >6.
• The subject has evidence of depression as measured by a Calgary Depression Scale Score (CDSS) >9.
• The subject's diagnosis of schizophrenia occurred prior to 12 years of age.
• The subject has a history of developmental intellectual disability or mental retardation.
• Antipsychotic plasma levels for the subject’s primary background antipsychotic are below the minimum acceptable concentration criteria per the Antipsychotic Drug Level Reference Document at the Screening or Placebo Run-in Visits. This criterion is not applicable to subjects on a primary background antipsychotic for which a clinical assay is unavailable (ie, not listed in the Antipsychotic Reference Document).
• The subject is treatment resistant. Treatment resistance is defined as prior nonresponse or positive symptoms od schizophrenia to 2 courses of treatment with antipsychotics of different chemical classes for at least 4 weeks, each at doses considered to be effective.
• The subject is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or the subject has attempted suicide within the past year prior to Screening. Subjects who have positive answers on item number 4 or 5 on the C-SSRS (based on the past year) prior to randomization are excluded.
• The subject has a history of brain trauma associated with loss of consciousness for >15 minutes.
• The subject has received electroconvulsive therapy within 6 months (180 days) before Screening.
• The subject does not have a stable residence or is homeless.
See protocol for further exclusion criteria |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Change from Baseline on the PANSS NSFS. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Change from Baseline on the PANSS NSFS at Days 28 and 56.
Change from Baseline on the BNSS at Day 84.
Change from Baseline on the BACS composite score at Day 84.
Change from Baseline on the CGI-SCH-S score at Day 84.
CGI-SCH-I score at Day 84.
Change from Baseline on the SCoRS at Day 84.
Change from Baseline on the PANSS total score and additional subscales and factors at Day 84.
TAK-831 plasma concentrations. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Czech Republic |
| Germany |
| Italy |
| Poland |
| Spain |
| Ukraine |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the date the last subject completes the Safety Follow-up Visit (Visit 11).
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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