Study to Evaluate the Efficacy and Safety of Risperidone in Situ Microparticle (ISM)® in Patients With Acute Schizophrenia
Condition: Acute Schizophrenia
MeSH terms: Schizophrenia
Intervention: Risperidone ISM 75 mg; Risperidone ISM 100 mg; Placebo of Risperidone ISM
Intervention description: Monthly (once every 4 weeks) IM injection in the gluteal or deltoid muscle.; Monthly (once every 4 weeks) IM injection in the gluteal or deltoid muscle.; Monthly (once every 4 weeks) IM injection in the gluteal or deltoid muscle.
Intervention MeSH terms: Risperidone
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking description: The study drug will be administered under double-blind conditions so that investigators, site staff, and patients will not be aware about the identity of the study drug (ie, blinded Risperidone ISM 75 mg, Risperidone ISM 100 mg, or placebo) administered to any given patient.
Enrollment: 438.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

Summary:

      This is a multicenter, randomized, double-blind, placebo-controlled study designed to
      evaluate the efficacy and safety of intramuscular (IM) injections of Risperidone ISM® (75 or
      100 mg) or placebo, in patients with acute exacerbation of schizophrenia.
    

Eligibility criteria:

        Inclusion Criteria:

        To be eligible for enrolment into the study, each patient must meet all of the following
        criteria at screening:

          1. Capable of providing informed consent

               1. A signed informed consent form must be provided before any study assessments are
                  performed

               2. Patients must be fluent in the language that is spoken by the investigator and
                  the study site staff (including raters) and must be able to read and understand
                  the words in which the informed consent is written

          2. Age ≥ 18 and ≤ 65 years

          3. Body mass index 18.5 to 40.0 kg/m2 (inclusive)

          4. Current diagnosis of schizophrenia, according to the Diagnostic and Statistical Manual
             of Mental Disorders, Fifth Edition (DSM-5) criteria

               1. Currently experiencing an acute exacerbation or relapse with onset < 2 months
                  before screening

               2. If inpatient at screening, has been hospitalized for < 2 weeks for the current
                  exacerbation

               3. ≥ 2 years have elapsed since initial onset of active-phase schizophrenia symptoms

          5. Has been able to achieve outpatient status for > 4 months during the past year

          6. Has previously had a clinically significant beneficial response (improvement in
             schizophrenia symptoms), as determined by the investigator, to treatment with an
             antipsychotic medication other than clozapine

          7. Agrees to discontinue prohibited medications as applicable and as clinically indicated
             according to investigator instructions

          8. Dosages of all permitted medications are considered to have been stable (with the
             exception of medication to be used on an as-needed basis) for ≥ 2 weeks prior to the
             baseline visit and to remain stable during participation in this study

          9. Positive and Negative Syndrome Scale (PANSS) results at the screening and baseline
             visits meets the following criteria:

             a. Total score between 80 and 120, inclusive b. Score of ≥ 4 (moderate or greater) for
             ≥ 2 of the following Positive Scale items: i. Item 1 (P1: delusions) ii. Item 2 (P2:
             conceptual disorganization) iii. Item 3 (P3: hallucinatory behavior) iv. Item 6 (P6:
             suspiciousness/persecution)

         10. Clinical Global Impression - Severity (CGI-S) score of ≥ 4 (moderately ill or worse)

         11. Resides in a stable living situation and is anticipated to return to that same stable
             living situation after discharge from the inpatient study unit, in the opinion of the
             investigator

         12. Has an identified reliable informant who is anticipated to remain the same after the
             patient is discharged from the inpatient study unit, in the opinion of the
             investigator

         13. Meets the following criteria:

             a. If a sexually active, is using a medically accepted contraceptive method, and will
             continue to use such throughout participation in this study (and for ≥ 6 months after
             the last dose of IM study drug has been administered); acceptable methods include the
             following: i. Condoms (male or female) with or without a spermicidal agent ii.
             Diaphragm or cervical cap with spermicide iii. Intrauterine device iv. Hormonal
             contraceptive b. If not currently sexually active, them meets the following criteria:
             i. Agrees that if sexually activity resumes while participating in this study, a
             medically accepted contraception method will be used

         14. Willing and able to be confined to an inpatient study unit for up to 2 weeks (or
             longer if clinically indicated), as applicable and as clinically indicated according
             to investigator instructions

         15. Agrees not to post any personal medical data related to the study or information
             related to the study on any website or social media site (eg, Facebook, Twitter, and
             others) during the study duration

        Exclusion Criteria:

        An individual who meets any of the following criteria at screening will not be permitted to
        enroll in the study:

          1. History of proven inadequate clinical response to treatment with therapeutic doses
             (with good compliance) of risperidone or paliperidone

          2. History of treatment resistance, defined as failure to respond to 2 discrete adequate
             trials (≥ 4 weeks with an adequate dose) of 2 different antipsychotic medications;
             history of clozapine use (exception: use was not because of treatment resistance or
             refractory psychotic symptoms)

          3. Improvement in PANSS total score 20% or greater between the initial screening visit
             and first injection

          4. Known or suspected intolerance of or allergy or hypersensitivity to risperidone,
             paliperidone, or any of the excipients in the IM formulations of these

          5. History of neuroleptic malignant syndrome, clinically significant tardive dyskinesia,
             or tardive dystonia

          6. History of any other medical condition that is considered to pose any unjustifiable
             risk or interfere with study assessments

          7. Clinically significant extrapyramidal symptoms at screening or baseline

          8. Answer of "yes" on item 4 or on item 5 of the Columbia-Suicide Severity Rating Scale
             (C-SSRS) (ideation) with the most recent episode occurring within the past 2 months,
             or answer "yes" to any of the 5 items (behavior) with an episode occurring within the
             last year

          9. Current diagnosis or a history of substance use disorder according to DSM-5 criteria
             within 6 months prior to the screening visit (with the exception of tobacco, mild
             cannabis, or mild alcohol use disorder) or a positive drug screen test (with the
             exception of cannabis) verified by repeat testing

         10. Lifetime history of diagnosis of schizoaffective disorder or bipolar disorder

         11. Clinically significant comorbid neuropsychiatric disorders including any of the
             following:

               1. Current untreated or unstable major depressive disorder

               2. Clinically significant cognitive difficulties including dementia, delirium, or
                  amnesic syndrome, within the past 2 years and would interfere with participation
                  in the study

               3. Any other psychiatric condition that would, in the judgment of the investigator,
                  interfere with participation in the study

         12. Clinically significant or unstable medical illness/condition/disorder that would be
             anticipated, in the investigator's opinion, to potentially compromise patient safety
             or adversely affect the evaluation of efficacy, including (but not necessarily limited
             to) the following:

               1. Clinically significant hypotension or hypertension not stabilized by medical
                  therapy (diastolic blood pressure > 105 mmHg)

               2. Unstable thyroid dysfunction in the past 6 months

               3. Malignant tumor within the last 5 years

               4. Neurologic conditions including the following:

             i. History of seizure disorder or condition associated with seizures ii. History of
             brain tumor, subdural hematoma, or other clinically significant neurological condition
             within the past 12 months iii. Head trauma with loss of consciousness within 12 months
             before screening iv. Active acute or chronic central nervous system infection v.
             Stroke within 6 months before screening e. Cardiac conditions including the following:
             i. Clinically significant cardiac arrhythmia, cardiomyopathy, or cardiac conduction
             defect ii. History of myocardial infarction or unstable angina within the last 3
             months before screening, or clinically significant abnormality on screening or
             baseline electrocardiogram (ECG) including but not limited to the following: QT
             interval corrected for heart rate using Fridericia's formula (QTcF) > 465 msec if male
             or > 485 msec if female

         13. Laboratory abnormality that, in the opinion of the investigator, would compromise the
             well-being of the patient, or any of the following laboratory abnormalities at
             screening or baseline:

               1. Aspartate aminotransferase or alanine aminotransferase value ≥ 2 times the upper
                  limit of the laboratory normal reference range

               2. Hemoglobin A1c > 9%

               3. Absolute neutrophil count ≤ 1.5 × 103 μL

               4. Platelet count ≤ 75 × 103 μL

               5. Creatinine clearance < 60 mL/min

               6. Positive test result for human immunodeficiency virus, hepatitis B surface
                  antigen, or antihepatitis C virus antibody

               7. Positive pregnancy test result

               8. Urine drug screen at screening or baseline shows a positive result for any of the
                  tested substances (potential exceptions: results positive for benzodiazepine may
                  not be exclusionary if the investigator confirms that such medication was
                  medically indicated and consults the medical monitor before enrolling a patient
                  with such a finding; results positive for Tetrahydrocannabinol (THC) may not be
                  exclusionary in certain cases only if exclusion criterion 9 is not met and only
                  if the medical monitor provides approval)

         14. Pregnant, lactating, or breastfeeding

         15. Inadequate gluteal or deltoid musculature or excessive fat, as determined by the
             investigator, that would interfere with IM study drug injections

         16. Any contraindication for IM injections

         17. Receipt of any long-acting antipsychotic medication by IM injection within 60 days
             before screening

         18. Current involuntary hospitalization or incarceration

         19. Hospitalized for more than 30 days during the 90 days before screening

         20. Participation in another clinical study in which the patient received an experimental
             or investigational drug or agent within 6 months before screening

         21. Participation in a clinical study with Risperidone ISM within 1 year before screening

         22. Study site personnel and/or persons employed by the investigator or study site or is
             an immediate family member of such persons

         23. Patients taking any prohibited concomitant medication (see Section 3.2.2.1.1) at the
             time of randomization visit

         24. Clinically significant ocular disease or visual impairment interfering with the
             planned ophthalmological examinations or that in the investigator's opinion could
             potentially compromise patients' ocular safety

         25. Patients with planned or anticipated need for ocular surgery during the treatment
             period of the trial