Study to Evaluate the Efficacy and Safety of Risperidone in Situ Microparticle (ISM)® in Patients With Acute Schizophrenia

Inclusion Criteria: To be eligible for enrolment into the study, each patient must meet all of the followingcriteria at screening:

1. Capable of providing informed consent
2. A signed informed consent form must be provided before any study assessments areperformed
3. Patients must be fluent in the language that is spoken by the investigator andthe study site staff (including raters) and must be able to read and understandthe words in which the informed consent is written
4. Age ≥ 18 and ≤ 65 years
5. Body mass index 18.5 to 40.0 kg/m2 (inclusive)
6. Current diagnosis of schizophrenia, according to the Diagnostic and Statistical Manualof Mental Disorders, Fifth Edition (DSM-5) criteria
7. Currently experiencing an acute exacerbation or relapse with onset < 2 monthsbefore screening
8. If inpatient at screening, has been hospitalized for < 2 weeks for the currentexacerbation
9. ≥ 2 years have elapsed since initial onset of active-phase schizophrenia symptoms
10. Has been able to achieve outpatient status for > 4 months during the past year
11. Has previously had a clinically significant beneficial response (improvement inschizophrenia symptoms), as determined by the investigator, to treatment with anantipsychotic medication other than clozapine
12. Agrees to discontinue prohibited medications as applicable and as clinically indicatedaccording to investigator instructions
13. Dosages of all permitted medications are considered to have been stable (with theexception of medication to be used on an as-needed basis) for ≥ 2 weeks prior to thebaseline visit and to remain stable during participation in this study
14. Positive and Negative Syndrome Scale (PANSS) results at the screening and baselinevisits 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)
15. Clinical Global Impression - Severity (CGI-S) score of ≥ 4 (moderately ill or worse)
16. Resides in a stable living situation and is anticipated to return to that same stableliving situation after discharge from the inpatient study unit, in the opinion of theinvestigator
17. Has an identified reliable informant who is anticipated to remain the same after thepatient is discharged from the inpatient study unit, in the opinion of theinvestigator
18. Meets the following criteria: a. If a sexually active, is using a medically accepted contraceptive method, and willcontinue to use such throughout participation in this study (and for ≥ 6 months afterthe last dose of IM study drug has been administered); acceptable methods include thefollowing: i. Condoms (male or female) with or without a spermicidal agent ii.Diaphragm or cervical cap with spermicide iii. Intrauterine device iv. Hormonalcontraceptive b. If not currently sexually active, them meets the following criteria:i. Agrees that if sexually activity resumes while participating in this study, amedically accepted contraception method will be used
19. Willing and able to be confined to an inpatient study unit for up to 2 weeks (orlonger if clinically indicated), as applicable and as clinically indicated accordingto investigator instructions
20. Agrees not to post any personal medical data related to the study or informationrelated to the study on any website or social media site (eg, Facebook, Twitter, andothers) during the study duration

Exclusion Criteria: An individual who meets any of the following criteria at screening will not be permitted toenroll 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 adequatetrials (≥ 4 weeks with an adequate dose) of 2 different antipsychotic medications;history of clozapine use (exception: use was not because of treatment resistance orrefractory psychotic symptoms)
3. Improvement in PANSS total score 20% or greater between the initial screening visitand 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 unjustifiablerisk 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 thelast year
9. Current diagnosis or a history of substance use disorder according to DSM-5 criteriawithin 6 months prior to the screening visit (with the exception of tobacco, mildcannabis, or mild alcohol use disorder) or a positive drug screen test (with theexception 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 thefollowing:
12. Current untreated or unstable major depressive disorder
13. Clinically significant cognitive difficulties including dementia, delirium, oramnesic syndrome, within the past 2 years and would interfere with participationin the study
14. Any other psychiatric condition that would, in the judgment of the investigator,interfere with participation in the study
15. Clinically significant or unstable medical illness/condition/disorder that would beanticipated, in the investigator's opinion, to potentially compromise patient safetyor adversely affect the evaluation of efficacy, including (but not necessarily limitedto) the following:
16. Clinically significant hypotension or hypertension not stabilized by medicaltherapy (diastolic blood pressure > 105 mmHg)
17. Unstable thyroid dysfunction in the past 6 months
18. Malignant tumor within the last 5 years
19. Neurologic conditions including the following: i. History of seizure disorder or condition associated with seizures ii. History ofbrain tumor, subdural hematoma, or other clinically significant neurological conditionwithin the past 12 months iii. Head trauma with loss of consciousness within 12 monthsbefore 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 conductiondefect ii. History of myocardial infarction or unstable angina within the last 3months before screening, or clinically significant abnormality on screening orbaseline electrocardiogram (ECG) including but not limited to the following: QTinterval corrected for heart rate using Fridericia's formula (QTcF) > 465 msec if maleor > 485 msec if female
20. Laboratory abnormality that, in the opinion of the investigator, would compromise thewell-being of the patient, or any of the following laboratory abnormalities atscreening or baseline:
21. Aspartate aminotransferase or alanine aminotransferase value ≥ 2 times the upperlimit of the laboratory normal reference range
22. Hemoglobin A1c > 9%
23. Absolute neutrophil count ≤ 1.5 × 103 μL
24. Platelet count ≤ 75 × 103 μL
25. Creatinine clearance < 60 mL/min
26. Positive test result for human immunodeficiency virus, hepatitis B surfaceantigen, or antihepatitis C virus antibody
27. Positive pregnancy test result
28. Urine drug screen at screening or baseline shows a positive result for any of thetested substances (potential exceptions: results positive for benzodiazepine maynot be exclusionary if the investigator confirms that such medication wasmedically indicated and consults the medical monitor before enrolling a patientwith such a finding; results positive for Tetrahydrocannabinol (THC) may not beexclusionary in certain cases only if exclusion criterion 9 is not met and onlyif the medical monitor provides approval)
29. Pregnant, lactating, or breastfeeding
30. Inadequate gluteal or deltoid musculature or excessive fat, as determined by theinvestigator, that would interfere with IM study drug injections
31. Any contraindication for IM injections
32. Receipt of any long-acting antipsychotic medication by IM injection within 60 daysbefore screening
33. Current involuntary hospitalization or incarceration
34. Hospitalized for more than 30 days during the 90 days before screening
35. Participation in another clinical study in which the patient received an experimentalor investigational drug or agent within 6 months before screening
36. Participation in a clinical study with Risperidone ISM within 1 year before screening
37. Study site personnel and/or persons employed by the investigator or study site or isan immediate family member of such persons
38. Patients taking any prohibited concomitant medication (see Section 3.2.2.1.1) at thetime of randomization visit
39. Clinically significant ocular disease or visual impairment interfering with theplanned ophthalmological examinations or that in the investigator's opinion couldpotentially compromise patients' ocular safety
40. Patients with planned or anticipated need for ocular surgery during the treatmentperiod of the trial