A Study to Assess the Effects of RO6889450 (Ralmitaront) in Participants With Schizophrenia or Schizoaffective Disorder and Negative Symptoms

Study Overview
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Brief Summary
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This study investigates the effects of RO6889450 on the negative symptoms associated with schizophrenia and schizoaffective disorder.

Official Title
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Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Effects of RO6889450 (Ralmitaront) in Patients With Schizophrenia or Schizoaffective Disorder and Negative Symptoms

Conditions
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Schizophrenia, Schizoaffective Disorder

Intervention / Treatment
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* Drug: RO6889450
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnosis of schizophrenia or schizoaffective disorder as confirmed by the Mini International Neuropsychiatric Interview (MINI) Part B only: Stable treatment with a dopamine/serotonin (D2/5HT2A) antagonist or pure D2 antagonist(s), or a D2 partial agonist for a minimum of 6 months and receiving no more than two antipsychotics Medically stable during the 3 months prior to study entry Participant is an outpatient with no psychiatric hospitalizations within the prior 6 months PANSS negative symptom factor score of 18 or higher The following rating on items of the PANSS: (a) less than 5 on G8 (uncooperativeness), P1 (delusions), P3 (hallucinations), P4 (excitement/hyperactivity), and P6 (suspiciousness/persecution); (b) less than 4 on P7 (hostility), and G14 (poor impulse control) Has an informant who is considered reliable by the Investigator Body mass index (BMI) between 18-40 kg/m2 inclusive Female participants are eligible to participate if not pregnant, not breastfeeding and agree to remain abstinent or use acceptable contraceptive methods during the treatment period and for at least 28 days after the last dose of study drug Exclusion Criteria: Moderate to severe substance use disorder within six months of study entry (excluding nicotine or caffeine) as defined by DSM-5 Extrapyramidal symptom rating scale (ESRS-A CGI) subscore greater than or equal to 3 Other current DSM-5 diagnosis (e.g., bipolar disorder, major depressive disorder) PANSS item G6 (depression) greater than or equal to 5 Significant risk of suicide or harming him- or herself or others according to the Investigator's judgment A prior or current general medical condition that might be impairing cognition or other psychiatric functioning Positive result at screening for hepatitis B surface antigen (HBsAg), hepatitis C (HCV), or HIV-1 and HIV-2. HCV antibody positive participants are eligible if HCV RNA is negative Tardive dyskinesia that is moderate to severe or requires treatment History of neuroleptic malignant syndrome Average triplicate Fridericia's Correction Formula (QTcF) interval greater than 450 milliseconds (msec) for males and 470 msec for females or other clinically significant abnormality on screening electrocardiogram (ECG) based on centralized reading Clinically significant abnormalities in laboratory safety test results Significant or unstable physical condition that in the investigator's judgment might require a change in medication or hospitalization during the course of the study On more than one antidepressant, or if on one antidepressant, a change in dose within 28 days prior to screening History of clozapine treatment History of treatment with electroconvulsive therapy (ECT) Concomitant use of prohibited medications Positive urine drug screen for amphetamines, methamphetamines, opiates, buprenomorphine, methadone, cannabinoids, cocaine, and barbiturates Receipt of an investigational drug within 28 days or five times the half-life of the investigational drug (whichever is longer) before the first study drug administration Donation of blood over 400 mL within 3 months prior to screening Diagnosis of COVID-19 infection (confirmed or presumptive) 4 weeks prior to screening or during screening. Participants can be re-screened after 4 weeks of full recovery in addition to Investigator and/or institutional approval to enroll

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Part A: Monotherapy<br>Participants will receive RO6889450 or a dose-matched placebo. NOTE: Part A has completed enrollment. | Drug: RO6889450<br>* Participants will receive a once-daily, oral dose of RO6889450 for 12 weeks.<br>Drug: Placebo<br>* Participants will receive a once-daily, oral dose of placebo matched to RO6889450 for 12 weeks.<br>|
| Experimental: Part B: Add-On Therapy<br>Participants will receive a low or high dose of RO6889450 or a dose-matched placebo in addition to their usual anti-psychotic treatment(s). | Drug: RO6889450<br>* Participants will receive a once-daily, oral dose of RO6889450 for 12 weeks.<br>Drug: Placebo<br>* Participants will receive a once-daily, oral dose of placebo matched to RO6889450 for 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline at Week 12 in Brief Negative Symptoms Scale (BNSS) Avolition/Apathy Subscore |  | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Clinical Global Impression Severity (CGI-S) Overall Scores |  | Baseline to week 12 | 
| Change from Baseline in CGI-S Negative Symptoms Scores |  | Baseline to week 12 | 
| Clinical Global Impression - Improvement (CGI-I) Overall Scores |  | Week 12 | 
| CGI-I Negative Symptoms Scores |  | Week 12 | 
| Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Total Scores |  | Baseline to week 12 | 
| Change from Baseline in Positive and Negative Syndrome Scale (PANSS) Symptom Factor Scores |  | Baseline to week 12 | 
| Change from Baseline in Brief Negative Symptom Scale (BNSS) Total Scores |  | Baseline to week 12 | 
| Change from Baseline in Brief Negative Symptom Scale (BNSS) Symptom Factor Scores |  | Baseline to week 12 | 
| Change from Baseline in Defeatist Performance Attitude Scale (DPAS) Scores |  | Baseline to week 12 | 
| Percentage of Participants with Adverse Events (AE) |  | Baseline through the end of the follow-up period (approximately 16 weeks) | 
| Change from Baseline in Columbia Suicide Severity Rating Scale (C-SSRS) Scores |  | Baseline through the end of the follow-up period (approximately 16 weeks) | 
| Change from Baseline in Extrapyramidal Symptom Rating Scale, Abbreviated (ESRS-A) |  | Baseline through the end of the follow-up period (approximately 16 weeks) | 
| Area Under the Curve at Steady State (AUCss) of RO6889450 |  | At pre-defined intervals from Day 7 through the end of the follow-up period (approximately 16 weeks) | 
| Maximum Serum Concentration (Cmax) of RO6889450 |  | At pre-defined intervals from Day 7 through the end of the follow-up period (approximately 16 weeks) |