Pharmacokinetics and Tolerability Study of Risperidone ISM® in Schizophrenia (PRISMA-2)

Multicenter, Open-label, Two-arm, Parallel-design, Repeat-dose Clinical Trial to Evaluate the PK, Safety, and Tolerability of Four Intramuscular Injections of Risperidone ISM® 75 mg, at 28 Day Intervals in Patients With Schizophrenia

To characterize the pharmacokinetics (PK) of the injectable intramuscular (IM) long-acting formulation (in situ microparticle, ISM) of risperidone over four IM injections in the gluteal and deltoid muscle at 28-day intervals and at one dose strength (75 mg) in patients with schizophrenia.

This was a multicenter, open-label, two-arm, parallel-design, repeat-dose clinical study designed to evaluate the PK, safety, and tolerability of Risperidone ISM®, a new long-acting injectable formulation of the licensed drug risperidone, administered in the gluteal muscle or the deltoid muscle. Participants were patients with a diagnosis of schizophrenia capable of understanding, signing, and consenting to study participation on their own. Objectives: Primary Objective • To characterize the pharmacokinetics (PK) of the injectable intramuscular (IM) long-acting formulation of risperidone over four IM injections in the gluteal and deltoid muscle at 28 day intervals and at one dose strength (75 mg) in patients with schizophrenia. Secondary Objectives To document the attainment of steady-state exposure by the injectable formulation ISM® of risperidone over four IM injections in the gluteal and deltoid muscle at 28-day intervals and at one dose strength (75 mg) in patients with schizophrenia. To perform a descriptive comparison of the PK data between the gluteal and the deltoid muscle administration of the injectable formulation ISM® of risperidone over four IM injections at 28-day intervals and at one dose strength (75 mg) in patients with schizophrenia. To evaluate the safety and tolerability of the injectable formulation ISM® of risperidone after four IM injections in the gluteal muscle or deltoid muscle at 28-day intervals at one dose strength (75 mg) in patients with schizophrenia. Exploratory Objectives To explore the efficacy of once every four weeks of the injectable formulation ISM® of risperidone after four IM injections in the gluteal muscle or deltoid muscle at 28-day (± 1 day) intervals at one dose strength (75 mg) in patients with schizophrenia. To characterize patients' metabolic phenotype (cytochrome P450 [CYP]2D6, CYP3A4) to explain any potential unexpected outlying PK value, and/or explore its relationship with any potential safety or tolerability issue.

Four doses of 75 mg of Risperidone ISM as intramuscular (IM) injection into the deltoid muscle at 28-day intervals. Four doses of 75 mg of Risperidone ISM as intramuscular injections into the gluteal muscle at 28-day intervals.

Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.

Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.

Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.

Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.

Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.

Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.

Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.

Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.

Dose 1, 2 and 3: Pre-dose; at 2, 8, 12, 24 and 48 hours post-dose; 5, 7, 10, 14, 18, and 21 days post-dose. Dose 4: Pre dose; at 2, 8, 12, 24, and 48 hours post-dose; at 5, 7, 10, 14, 18, 21, 25, 28, 32, 37, 42, 60, 75, 90, 105, and 120 days post-dose.

The change in PANSS score from Baseline by visit 48. The PANSS combines 3 subscales: The positive scale (7 items), the negative scale (7 items) and the general psychopathology scale (16 items). PANSS Items Scores: 1 = Absent, 2 = Minimal, 3 = Mild, 4 = Moderate, 5 = Moderate Severe, 6 = Severe, 7 = Extreme. Subscales are summed to compute a total score Range for each of the subscales: Positive scale (7-49); Negative scale (7-49); General psychopathology scale (16-112) Range for the PANSS total scale: 30-210 PANSS total score ≤70: stable schizophrenia PANSS total score between >70: decompensated schizophrenia

Baseline, Days 5, 7, 10, 14, 18, and 21 post Dose 1; Dose 2, 3 and 4 post dose; Days 5, 7, 10, 14, 18, and 21 post Dose 2, 3, and 4; Days 25, 28, 32, 37, 42, 60, 75, 90, and 105 post Dose 4; Day 120 post Dose 4 or early termination.

Inclusion Criteria: Capable of providing informed consent. Male or female aged ≥18 years to ≤65 years. Current diagnosis of schizophrenia, according to Diagnostic and Statistical Manual Body mass index (BMI) ≥17 kg/m2 but ≤35 kg/m2. Medically stable over the last month, and psychiatrically stable On oral stable dosage of risperidone ≥4 mg daily as maintenance therapy. Total score ≤70 on the Positive and Negative Syndrome Scale. Using a medically accepted contraceptive method Agrees to washout all prohibited medications prior to baseline (day -1) Exclusion Criteria: Informed consent obtained from a third party. Prisoners or patients who are compulsorily detained. Females who are breast-feeding and/or who have a positive pregnancy test. Presence of an uncontrolled, unstable clinically significant medical condition. Positive serology for Hepatitis B, Hepatitis C or anti-HIV 1 and 2 at screening. History of neuroleptic malignant syndrome. Current or past history of tardive dyskinesia. Positive urine drug or alcohol screen finding. Risk of committing self-harm or harm based on Columbia Suicidal Rating Scale. Taking more than one antidepressant. Use of depot antipsychotics within the last three months. Use of strong or moderate cytochrome P450 isoenzyme 3A4inducers Use of electroconvulsive therapy (ECT) within the last three months. Receipt of any investigational drugs within the last three months. Known or suspected allergy or hypersensitivity to risperidone Previous non-responder to risperidone treatment.