A Trial of the Efficacy and the Safety of RO6889450 (Ralmitaront) vs Placebo in Patients With an Acute Exacerbation of Schizophrenia or Schizoaffective Disorder
Condition: Schizophrenia, Schizoaffective Disorder
MeSH terms: Schizophrenia; Psychotic Disorders
Intervention: RO6889450; Placebo; Risperidone
Intervention description: Participants will receive oral RO6889450 QD.; Participants will receive oral placebo QD.; Participants will receive oral risperidone QD.
Intervention MeSH terms: Risperidone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 287.0
Sex: All
Minimum age: 18 Years
Maximum age: 45 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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