A Trial of the Efficacy and the Safety of RO6889450 (Ralmitaront) vs Placebo in Patients With an Acute Exacerbation of Schizophrenia or Schizoaffective Disorder

Study Overview
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Brief Summary
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This study will investigate the efficacy and safety of RO6889450 as monotherapy in participants experiencing an acute exacerbation of symptoms of schizophrenia or schizoaffective disorder.

Official Title
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A Phase II, Multi-Center, Randomized, Double-Blind, Parallel Group, Placebo-Controlled Trial of the Efficacy and the Safety of RO6889450 (Ralmitaront) vs Placebo in Patients With an Acute Exacerbation of Schizophrenia or Schizoaffective Disorder

Conditions
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Schizophrenia, Schizoaffective Disorder

Intervention / Treatment
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* Drug: RO6889450
* Drug: Placebo
* Drug: Risperidone


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Participant must be 18 to 45 years of age inclusive Participants with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of schizophrenia or schizoaffective disorder as confirmed by the Mini International Neuropsychiatric Interview (MINI) Disease duration </=10 years Have a current acute exacerbation of schizophrenia of no more than 8 weeks before screening visit and no current signs of apparent lack of treatment response At the time of screening, the participant needs to be either hospitalized or requiring inpatient psychiatric care according to clinical judgment. If the participant has been hospitalized for the current exacerbation, the hospitalization has to be of a maximum of 1 week prior to screening. In previous exacerbations and hospitalizations, the subject has shown a pattern of response to appropriate antipsychotic treatment Medically stable over a period of 3 months (non-psychiatric conditions) prior to screening visit and not expected to require hospitalization or change of treatment for non-psychiatric conditions for the duration of the study Screening and baseline CGI-S >/=4 (moderate or worse) Screening and baseline PANSS total score >= 80 Based on screening and baseline PANSS, scores of >/= 4 (moderate or worse) on 2 or more of the following items: delusions, conceptual disorganization, unusual thought content, hallucinatory behavior, or suspiciousness/persecution Body mass index between 18 and 35 kg/m2 inclusive Male and female participants; female participants 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 Additional inclusion criteria for optional 36-Week Safety Extension Phase Successful completion of the 12-week treatment period No signs or symptoms of worsening of the psychiatric or medical status that would preclude the patient from the participation in the 36-Week Safety Extension Phase or affect their ability to comply with the study requirements. Exclusion criteria Has been inpatient for > 1 week or had any other hospitalization for acute exacerbation of schizophrenia or schizoaffective disorder within the prior 8 weeks or signs of lack of response to antipsychotic treatment Disease duration > 10 years Is currently an inpatient on an involuntary basis Subject answers yes to Suicidal Ideation Item 4 (active suicidal ideation with some intent to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) or any suicidal behavior on the Columbia-Suicide Severity Rating Scale (C-SSRS) assessment within one month from screening or between screening and baseline Lifetime history of homicidal behavior Moderate to severe substance use disorder within six months (excluding nicotine) as defined by DSM-5 Other current DSM-5 diagnosis (e.g., bipolar disorder, major depressive disorder) A prior or current general medical condition that might be impairing cognition or other psychiatric functioning (e.g., migraine headaches requiring prophylaxis treatment, head trauma, dementia, seizure disorder, stroke; or neurodegenerative, inflammatory, infectious, neoplastic, toxic, metabolic, or endocrine conditions) Clinically significant abnormalities in laboratory safety test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis), including a) Aspartate aminotransferase (AST), OR alanine aminotransferase (ALT) 2 x upper limit of normal (ULN), OR total bilirubin > 1.5 ULN with the exception of known Gilbert syndrome. b) Serum creatinine > 1.5 ULN Positive result at screening for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV, untreated), or human immunodeficiency virus (HIV)-1 and -2. HCV participants who have been successfully treated and who test negative for HCV RNA are eligible for entry into the study Tardive dyskinesia that is moderate to severe or requires treatment History of neuroleptic malignant syndrome Average triplicate QTcF interval greater than 450 msec for males and 470 msec for females or other clinically significant abnormality on screening ECG based on centralized reading Participant for whom risperidone is contraindicated or who have a documented history of lack of response or intolerance to risperidone or paliperidone or participants with known hypersensitivity to risperidone, paliperidone, or to any excipients in Risperdal Participant treated with a long acting injectable antipsychotic or other antipsychotics that cannot be washed-out within the allotted screening period History of electro-convulsive therapy (ECT) for any reason Participant treated with clozapine at any dose within 12 months of screening visit or participants treated with clozapine at 200 mg/day or above at any time; low dose (< 200mg/day) use for insomnia or dyskinesia longer than 12 months prior to screening visit is permitted Participants currently receiving a psychotropic or other medication used as a psychotropic, which cannot be discontinued during the screening period Positive urine drug screen for amphetamines, methamphetamines, opiates, buprenorphine, methadone, cocaine and barbiturates. In case of positive urine drug screen for cannabinoids, the participant may be allowed to enter the study if approved by Medical Monitor Participant has previously received RO6889450 Participant received an investigational drug within 28 days or five times the half-life of the investigational drug prior to the first study drug administration 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: 45 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 150 mg Once Daily (QD) RO6889450<br>Participants will receive 150 mg of RO6889450 QD for 4 weeks or 12 weeks or 48 weeks. | Drug: RO6889450<br>* Participants will receive oral RO6889450 QD.<br>|
| Experimental: 45 mg QD RO6889450<br>Participants will receive 45 mg of RO6889450 QD for 4 weeks or 12 weeks or 48 weeks. | Drug: RO6889450<br>* Participants will receive oral RO6889450 QD.<br>|
| Placebo Comparator: Placebo<br>Participants will receive oral placebo QD for 4 weeks. Participants from this arm that continue to the extension period will be randomized to either 45 mg or 150 mg QD of RO6889450 for up to an additional 8 weeks or additional 44 weeks (optional 36-Week Safety Extension Phase). | Drug: Placebo<br>* Participants will receive oral placebo QD.<br>|
| Active Comparator: 4 mg QD Risperidone<br>Participants will receive 4 mg of risperidone QD for 4 weeks or 12 weeks or 48 weeks. | Drug: Risperidone<br>* Participants will receive oral risperidone QD.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score at Week 4 | The PANSS is a 30-item rating scale that evaluates positive, negative, and other symptoms in patients with schizophrenia. The Positive subscale is a 7-item scale that assesses features in schizophrenia that are not present in a normal mental state. The Negative subscale is a 7-item scale that assesses features absent in schizophrenia but present in those with a normal mental state. Items are rated on a 7-point scale, where 1 = absent and 7 = extreme, for a maximum score of 49 for each scale. The General subscale is a 16-item scale that assesses the overall severity of schizophrenia and the risk of aggression. Items are rated on the same scale, with a minimum score of 16 and a maximum score of 112. Total scores are calculated by adding subscale scores together, for a minimum score of 30 and a maximum score of 210. Higher scores indicate higher severity. | Week 4 (Day 28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in PANSS Factor Scores at Week 4 | PANSS factors are modified groupings of the 30 PANSS items from the original three subscales (positive, negative, and general psychopathology). Each item is rated on a scale of 1 (absent) to 7 (most extreme). The positive symptom factor contains 8 items (score range 8-56); the negative symptom and disorganized thought/cognition factors contain 7 items (score range 7-49); the uncontrolled hostility/excitement, expressive deficit, and anxiety/depression factors contain 4 items (score range 4-28); and the avolition domain contains 3 items (score range 3-21). The negative and positive totals each have a range of 7-49 and the general total has a range of 16-112. Higher scores indicate higher symptom severity. | Week 4 (Day 28) | 
| Proportion of Participants With at Least 20% or 50% Improvement From Baseline in the PANSS Total Score | The PANSS is a 30-item rating scale that evaluates positive, negative, and other symptoms in patients with schizophrenia. The Positive subscale is a 7-item scale that assesses features in schizophrenia that are not present in a normal mental state. The Negative subscale is a 7-item scale that assesses features absent in schizophrenia but present in those with a normal mental state. Items are rated on a 7-point scale, where 1 = absent and 7 = extreme, for a maximum score of 49 for each scale. The General subscale is a 16-item scale that assesses the overall severity of schizophrenia and the risk of aggression. Items are rated on the same scale, with a minimum score of 16 and a maximum score of 112. Total scores are calculated by adding subscale scores together, for a minimum score of 30 and a maximum score of 210. Higher scores indicate higher severity. | Baseline to Week 12 | 
| Change From Baseline in Clinical Global Impression Severity (CGI-S) Scores | The CGI-S measures global severity of illness at a given point in time using a 7-point scale, where 1 = no symptoms and 7 = very severe symptoms. | Week 4 (Day 28) | 
| Clinical Global Impression - Improvement (CGI-I) Scores | The CGI-I measures change from the baseline state at subsequent visits using a 7-point scale, where 1 = very much improved and 7 = very much worse. | Week 4 (Day 28) | 
| PANSS Total Score at Week 12 | The PANSS is a 30-item rating scale that evaluates positive, negative, and other symptoms in patients with schizophrenia. The Positive subscale is a 7-item scale that assesses features in schizophrenia that are not present in a normal mental state. The Negative subscale is a 7-item scale that assesses features absent in schizophrenia but present in those with a normal mental state. Items are rated on a 7-point scale, where 1 = absent and 7 = extreme, for a maximum score of 49 for each scale. The General subscale is a 16-item scale that assesses the overall severity of schizophrenia and the risk of aggression. Items are rated on the same scale, with a minimum score of 16 and a maximum score of 112. Total scores are calculated by adding subscale scores together, for a minimum score of 30 and a maximum score of 210. Higher scores indicate higher severity. | Week 12 | 
| Proportion of Participants With at Least 20% or 50% Improvement in the PANSS Total Score up to Week 12 | The PANSS is a 30-item rating scale that evaluates positive, negative, and other symptoms in patients with schizophrenia. The Positive subscale is a 7-item scale that assesses features in schizophrenia that are not present in a normal mental state. The Negative subscale is a 7-item scale that assesses features absent in schizophrenia but present in those with a normal mental state. Items are rated on a 7-point scale, where 1 = absent and 7 = extreme, for a maximum score of 49 for each scale. The General subscale is a 16-item scale that assesses the overall severity of schizophrenia and the risk of aggression. Items are rated on the same scale, with a minimum score of 16 and a maximum score of 112. Total scores are calculated by adding subscale scores together, for a minimum score of 30 and a maximum score of 210. Higher scores indicate higher severity. | Weeks 4, 8, and 12 | 
| CGI-S up to Week 12 | The CGI-S measures global severity of illness at a given point in time using a 7-point scale, where 1 = no symptoms and 7 = very severe symptoms. | Up to Week 12 | 
| CGI-I up to Week 12 | The CGI-I measures change from the baseline state at subsequent visits using a 7-point scale, where 1 = very much improved and 7 = very much worse. | Up to Week 12 | 
| Participants Ready for Discharge From First Randomized Treatment Intake to Readiness for Discharge as Assessed by the Readiness for Discharge Questionnaire (RDQ) at 4-Week Treatment | The RDQ is a tool used to assess inpatients with schizophrenia on their readiness for discharge from inpatient treatment. It consists of five items that assess suicidality/homicidality, control of aggression/impulsivity, activities of daily living, medication-taking, and delusions/hallucinations interfering with functioning and global status. An additional item examines the overall clinical state of the patient and the final question assesses readiness for discharge. The values reported are the proportion (expressed as a percentage) of participants in each analysis group considered ready for discharge according to the RDQ. | after 4-week treatment | 
| Plasma Concentration of RO6889450 |  | Day 7 - Day 336 |