Safety, Tolerability, Pharmacokinetics and Efficacy of 180 mg Subcutaneous Risperidone From 6 mg Oral Risperidone

Cavg,ss for risperidone and total active moiety after oral and SC administration

Time frame: 0-12 hours post-dose on Day -1, and 0-672 hours after Dose 3

Population: The primary PK analysis was conducted in participants who received at least 3 doses of PERSERIS 180 mg and provided adequate blood samples for the determination of Cavg after the third dose (primary PK population).

Area under the plasma concentration-time curve (AUC) was measured for risperidone, 9-OH and total active moiety.

Time frame: Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4).

Population: PK population; actual number of participants analyzed for each period is reported

Injection site tolerability was measured by injection site grading for redness, induration, swelling and tenderness/pain. These were graded on a scale from 0 to 4 for severity (none, mild, moderate, severe and potentially life-threatening)

Time frame: First injection at Day 1 until last injection administered at Day 85

Population: The number of participants assessed is the actual number who received the injection at each visit. \*By the nature of this outcome measure (injection site), all results are reported for participants who had received PERSERIS

Average plasma concentration of risperidone, 9-hydroxyrisperidone (9-OH) and total active moiety over the dosing interval after oral dosing and SC doses 1, 3 and 4.

Time frame: Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4).

Population: PK population; actual number of participants analyzed for each period is reported

Clinical outcome (efficacy endpoint) as measured by change from baseline in CGI-S scores was measured. The CGI-S is a measurement of the total severity of illness where one question is assessed. Responses range from 0 (not assessed) to 7 (most extremely ill).

Time frame: Baseline through EOS (Day 113)

Population: Severity of illness observed values were measured and change from baseline calculated for those participants with results reported.

Significant changes from baseline in C-SSRS scores were reported as adverse events. The C-SSRS is based on a categorization of thoughts and behavior that are identified as related to suicidal behavior. The scale captures the occurrence, severity and frequency of suicide related thoughts and behaviors throughout lifetime at screening and for the time interval since last administration during a study. Responses are indicated as yes (thought or behavior did occur) or no (thought or behavior did not occur). If a yes response is received, then follow up questions are asked. The outcome of the C-SSRS is a numerical score obtained from each of the categories. Scores can range from 0-25, indicating the intensity rating, and any score greater than 0 may indicate the need for mental health intervention. Higher scores indicate greater intensity (i.e. worse outcome).

Time frame: Screening through EOS (Day 113)

Population: Only actual number of participants assessed at visit was reported. Only change in suicidal behavior from baseline at Dose 1/Day 8 (first measure after baseline) and EOS is reported as all numbers are zero.

Maximum observed plasma concentration of risperidone, 9-hydroxyrisperidone (9-OH) and total active moiety over the dosing interval after oral dosing and SC doses 1, 3 and 4

Time frame: Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4)

Population: Analysis population is the PK population. Actual number of participants analyzed for each period is reported.

Minimum observed plasma concentration of risperidone, 9-hydroxyrisperidone (9-OH) and total active moiety over the dosing interval after oral dosing and SC doses 1, 3 and 4

Time frame: Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4).

Population: PK population. Actual number of participants analyzed for each period is reported

Plasma concentration variation of risperidone, 9-OH and total active moiety over the dosing interval was measured by percent fluctuation after oral dosing and SC doses 1, 3 and 4 at steady state.

Time frame: Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4)

Population: PK population. Actual number of participants analyzed for each period is reported

Clinical outcome (efficacy endpoint) as measured by change from baseline in PANSS scores was measured. PANSS is a medical scale designed to measure schizophrenia symptom severity utilizing a 30 item, 7-point rating scheme. The PANSS Is scored by a summation of ratings across items, with a total potential range of 7-210; higher results indicate greater severity of illness. Only total score changes from baseline are reported here.

Time frame: Baseline, defined as last assessment prior to first injection, through Day 113 (EOS)

Population: PANSS total scores change from baseline measure from baseline through Day 113 for those participants with results reported

Safety of treatment was measured by characterization of thoughts and behavior related to suicidal behavior. This was assessed by administration of the C-SSRS at designated visits. The scale captures the occurrence, severity and frequency of suicide related thoughts and behaviours throughout lifetime at screening and for the time interval since last administration during a study. Questions solicit the type of information needed to determine if a suicide-related thought or behavior occurred.

Time frame: Screening through EOS (Day 113)

Population: Only actual number of participants assessed at visit was reported. Only results for lifetime, past 6 months and EOS are reported as all responses are 'no' after lifetime.

Body weight, with shoes off, was measured and clinically significant changes in weight was reported as adverse events (AE). Determination of whether the changes were AEs was made by the investigator or a medically qualified designee. If determined to be an AE, the measurement was repeated at appropriate intervals until the value returned to an acceptable range and the subject was clinically stable, a specific diagnosis was established, or the condition otherwise explained.

Time frame: Time subjects sign the informed consent form throughout the study until EOS (Day 113)

ECGs were performed, and clinically significant changes in parameters were reported as adverse events (AE). ECGs were performed after 5 minutes of rest, and ECG parameters including QT interval, PR interval, QRS interval and heart rate was recorded. The ECG measurements were evaluated during the visit and determination of whether any abnormalities were AEs was made by the investigator or a medically qualified designee. If determined to be an AE, the measurement was repeated at appropriate intervals until the value returned to an acceptable range and the subject was clinically stable, a specific diagnosis was established, or the condition otherwise explained.

Time frame: Time participants sign the informed consent form throughout the study until EOS (Day 113)

Laboratory testing was performed by the local clinical laboratory accredited by the College of American Pathologists, and clinically significant changes from baseline were reported as AEs. Subjects were expected to fast for a minimum of 8 hours prior to blood draws for all laboratory assessments except at the screening visit. Prior to entering the study, any abnormal laboratory test results were to be considered not clinically significant. Any abnormal hematology, serum chemistry or urinalysis test result after study drug intake that was determined by the investigator or a medically qualified designee to be clinically significant was reported as an AE. If determined to be an AE, the measurement was repeated at appropriate intervals until the value returned to an acceptable range or it was determined that resolution was not expected.

Time frame: Time subjects sign the informed consent form throughout the study until end of study (EOS) visit (Day 113)

Vital sign measurement was performed, including orthostatic blood pressure, and clinically significant changes were reported as adverse events (AE). Vital sign measurement also included measurement of pulse rate, oral temperature and respiratory rate. Determination of whether the changes were AEs was made by the investigator or a medically qualified designee. If determined to be an AE, the measurement was repeated at appropriate intervals until the value returned to an acceptable range and the subject was clinically stable, a specific diagnosis was established, or the condition otherwise explained.

Time frame: Time subjects sign the informed consent form throughout the study until EOS (Day 113)

Safety of treatment was measured by administration of symptom questionnaires including AIMS, Barnes Akathisia Rating Scale (BARS) and Simpson-Angus Scale (SAS), as well as by assessment by the investigator or suitably qualified medical designee. The AIMS is a tool that aids in early detection and ongoing monitoring of tardive dyskinesia, a movement disorder. The BARS is a 4-item scale that detects the presence and severity of any drug-induced restlessness. The SAS is a 10-item scale used to detect the presence of drug-induced Parkinsonism (movement disorder seen in Parkinson's disease) and extrapyramidal side effects and evaluates symptom severity. Extrapyramidal symptoms include involuntary or uncontrollable movements, tremors, and muscle contractions.

Time frame: Time subjects sign the informed consent form throughout the study until EOS (Day 113)

Population: There were no clinically important differences in mean scores across study visits. TEAEs related to EPS are reported below

The injection site was evaluated for adverse events by observation and examination by appropriately trained personnel.

Time frame: First injection at Day 1 until Day 120

Population: \*By the nature of this outcome measure (injection site), all results are reported for participants who had received PERSERIS

Time to maximal observed plasma concentration (Tmax) for risperidone, 9-OH, and total active moiety after oral dosing and SC doses 1, 3 and 4.

Time frame: Calculated over the overall dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4).

Population: PK population; actual number of participants analyzed for each period is reported

Trough (pre-dose) plasma concentrations were measured for risperidone, 9-OH and total active moiety for SC doses 1, 3 and 4

Time frame: Calculated over the dosing interval (0-672 hours) after Dose 1, 3 or 4.

Population: PK population; actual number of participants analyzed for each period is reported.