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

Study Overview
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Brief Summary
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This study evaluates PERSERIS at a higher dose than what has been administered in previous clinical trials. Subjects with stable schizophrenia on a dose of 5-6 mg oral risperidone will be switched to PERSERIS at the higher dose, which is believed to be similar to the oral dose

Detailed Description
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PERSERIS is an extended-release subcutaneous (SC) injectable suspension administered monthly for the treatment of schizophrenia in adults. PERSERIS was approved by the FDA at doses equivalent to 3 mg and 4 mg oral risperidone. Many patients require doses of 5-6 mg oral risperidone and above, and this study will test a higher dose of PERSERIS in order to meet this need. Eligible subjects will initially be stabilized in the clinical unit on 6 mg oral risperidone for 5 days and transition to an approximate dose of PERSERIS by SC injection. PERSERIS will be administered every 28 days and subjects will be admitted to the clinical unit the day before, and remain in the unit for 3 days after each injection for pharmacokinetics (PK) and safety evaluations (a total of 8 days for the first injection including the stabilization period). Subjects will return to the clinic between injections for additional PK, safety and efficacy assessments at scheduled intervals until the next injection. A total of 4 doses of PERSERIS will be administered. The 4th dose will evaluate an alternate site for injection, and will be administered in the back of the upper arm. Subjects will return to the clinical unit for an end of study visit and will receive a follow up phone call to assess for adverse events one week after the end of study visit.

Official Title
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An Open-label Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of 180 mg Risperidone Subcutaneous Injection (PERSERIS) Following a Switch From 6 mg Oral Risperidone in Patients With Clinically Stable Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: PERSERIS
* Drug: Risperidone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of schizophrenia Clinically stable as defined as no hospitalizations for acute exacerbations within 3 months of screening and Screening PANSS score ≤70 Total body mass index (BMI) between 18 and 35 kg/m2 Given written informed consent Exclusion Criteria: Received a once-monthly long-acting injectable (LAI) antipsychotic within 60 days of screening and a once every 3 month LAI antipsychotic within 120 days of screening Taking the following concurrent or over the counter (OTC) products: Inducers or inhibitors of CYP2D6 within 14 days or 5 half-lives whichever is greater prior to study screening Bupropion, chlorpheniramine, cimetidine, clomipramine, doxepin or quinidine within 30 days prior to study screening Clozapine, phenothiazines, aripiprazole, haloperidol or any other antipsychotic other than oral risperidone within 14 days prior to study screening Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) within 30 days prior to study screening Opioids or opioid-containing analgesics within 14 days prior to study screening Medications, in the addition to those listed above which in the opinion of the Investigator in conjunction with the medical monitor, may be expected to significantly interfere with the metabolism or excretion of risperidone and/or 9-hydroxyrisperidone, that may be associated with a significant drug interaction with risperidone, or that may pose a significant risk to subjects' participation in the study. The medical monitor should be contacted with any questions regarding the use of CYP2D6 or 3A4 inducers or inhibitors in particular. History of cancer (with the exception of resected basal cell or squamous cell carcinoma of the skin) unless they have been disease free for ≥5 years. Another active medical condition or organ disease that may either compromise subject safety or interfere with the safety and/or outcome evaluation of the study drug. Evidence or history of a significant hepatic disorder that may either compromise subject safety or interfere with the safety and/or outcome evaluation of the study drug. Individuals with acute or chronic hepatitis (including but not limited to hepatitis B or C); or individuals with 1) total bilirubin >1.5x the upper limit of normal (ULN) and/or 2) alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3x ULN will be excluded. A history of renal disease, or a creatinine clearance of less than 60 mL/min (as determined by the Cockcroft-Gault formula). A history of orthostatic hypotension, syncope, significant low white blood cell (WBC) count (i.e., based on absolute neutrophil count or drug-induced leukopenia or other medical conditions including, but not limited to, history of heart attack (i.e., myocardial infarction) or brain injury (i.e., traumatic with loss of consciousness and/or cardiovascular accident) within a year of Screening and clinically significant low blood pressure or arrhythmias as interpreted by the principal investigator (PI). Corrected QT interval [Fridericia's calculation (QTcF)] >450 msec (male) or >470 msec (female) at screening or prior to administration of the 1st dose of PERSERIS, or with a known history of Torsades de Points, or family member with sudden unexplained cardiac death. Known to have AIDS (acquired immunodeficiency syndrome) or to be HIV (human immunodeficiency virus) positive. Suicidal ideation with intent and plan, as assessed by affirmative answers to C-SSRS questions 4 and 5 of the ideation section,or suicide attempts within the last 6 months as noted on the C-SSRS, or subjects with uncontrolled depression in the opinion of the Investigator. Known diagnosis of type 1 diabetes or subjects with Haemoglobin A1c (HbA1c) >8.0% at screening. Participated in a clinical trial within 30 days prior to study screening. Significant traumatic injury, major surgery or open biopsy within 30 days prior to study screening. Meet the criteria for the diagnosis of current moderate or severe substance use disorder. Prior allergic reactions, sensitivities, or other known contraindications to any component of PERSERIS. Women of childbearing potential who are pregnant or breastfeeding, seeking pregnancy or failing to use adequate contraceptive methods during the study. Positive urine drug screen (UDS) anytime through Day -1 for opioids, cocaine, amphetamines, methadone, cannabinoids, barbiturates, benzodiazepines, methamphetamine and phencyclidine, unless the positive screen is determined to be secondary to an allowable concomitant medication. If a positive UDS is possibly the result of a subject's use of OTC or prescription medications, a repeat urine drug screen may be permissible. Study site personnel should contact the medical monitor for approval to retest. Tardive dyskinesia as assessed by a score of ≥2 on Item 8 of the Abnormal Involuntary Movement Scale (AIMS) at Screening. Epilepsy or other seizure disorders, Parkinson's disease or dementia. History of neuroleptic malignant syndrome. Previously injected with PERSERIS within 6 months prior to screening. Unable, in the opinion of the PI, to comply fully with the study requirements. Determined to be poor metabolisers, intermediate metabolisers or ultra-rapid metabolisers for CYP2D6 genotype.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Interventional Model Description: The study will enroll subjects currently on a stable dose of 5 or 6 mg of oral risperidone. After screening, eligible subjects will be admitted to the clinical unit and stabilized on 6 mg daily (3 mg oral risperidone twice a day) for 5 days, followed by an additional 3 days, during which the first injection of PERSERIS will be administered. Subjects will then return to the clinical unit every 28 days for an additional 3 admit periods for subsequent PERSERIS injections (2 injections per visit).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral Risperidone followed by PERSERIS<br>All subjects will receive 2 SC injections of PERSERIS at each study visit every 28 days for a total of 4 visits of 2 injections each. The first 3 visit injections will be administered in the abdomen and the final visit injections will be administered in the back of the upper arm. | Drug: PERSERIS<br>* PERSERIS is an extended-release SC injectable suspension administered once-monthly<br>* Other names: long acting risperidone;Drug: Risperidone<br>* Oral risperidone<br>* Other names: Risperdal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Steady-state Average Plasma Concentration (Cavg,ss) of Risperidone and Total Active Moiety | Cavg,ss for risperidone and total active moiety after oral and SC administration | 0-12 hours post-dose on Day -1, and 0-672 hours after Dose 3 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of Local Injection Site Tolerability* | 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) | First injection at Day 1 until last injection administered at Day 85 | 
| The Number of Participants With TEAEs as Assessed by Local Injection Site* | The injection site was evaluated for adverse events by observation and examination by appropriately trained personnel. | First injection at Day 1 until Day 120 | 
| The Number of Participants With TEAEs as Assessed by Changes in Vital Signs | 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 subjects sign the informed consent form throughout the study until EOS (Day 113) | 
| The Number of Participants With TEAEs as Assessed by Changes in ECG | 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 participants sign the informed consent form throughout the study until EOS (Day 113) | 
| The Number of Participants With TEAEs as Assessed by Changes in Body Weight | 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 subjects sign the informed consent form throughout the study until EOS (Day 113) | 
| The Number of Participants With TEAEs as Assessed by Changes in Laboratory Testing | 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 subjects sign the informed consent form throughout the study until end of study (EOS) visit (Day 113) | 
| The Number of Participants With TEAEs as Assessed by Extrapyramidal Symptoms (EPS) of Anti-psychotic Drug Treatment | 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 subjects sign the informed consent form throughout the study until EOS (Day 113) | 
| Positive and Negative Syndrome Scale (PANSS) | 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. | Baseline, defined as last assessment prior to first injection, through Day 113 (EOS) | 
| Clinical Global Impression-Severity of Illness Scale (CGI-S) | 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). | Baseline through EOS (Day 113) | 
| Columbia-Suicide Severity Rating Scale (C-SSRS)-Change | 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). | Screening through EOS (Day 113) | 
| Safety as Measured by Columbia-Suicide Severity Rating Scale (C-SSRS) Scores | 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. | Screening through EOS (Day 113) | 
| Minimum Plasma Concentration Over the Dosing Interval | 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 | Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4). | 
| Maximum Plasma Concentration Over the Dosing Interval | 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 | Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4) | 
| Percent Fluctuation in Concentration Over the Dosing Interval | 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. | Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4) | 
| Area Under the Plasma Concentration-time Curve Over the Dosing Interval | Area under the plasma concentration-time curve (AUC) was measured for risperidone, 9-OH and total active moiety. | Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4). | 
| Average Plasma Concentration (Cavg) Over the Dosing Interval of Risperidone, 9-OH and Total Active Moiety | 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. | Calculated over the dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4). | 
| Trough Plasma Concentration | Trough (pre-dose) plasma concentrations were measured for risperidone, 9-OH and total active moiety for SC doses 1, 3 and 4 | Calculated over the dosing interval (0-672 hours) after Dose 1, 3 or 4. | 
| Time to Occurrence of Maximum Concentration | 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. | Calculated over the overall dosing interval (0-12 hours on Day -1, or 0-672 hours after Dose 1, 3 or 4). |