Schizophrenia
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGRisperidone ISM
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.
Sponsors
Rovi Pharmaceuticals Laboratories
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Capable of providing informed consent. 2. Male or female aged ≥18 years to ≤65 years. 3. Current diagnosis of schizophrenia, according to Diagnostic and Statistical Manual 4. Body mass index (BMI) ≥17 kg/m2 but ≤35 kg/m2. 5. Medically stable over the last month, and psychiatrically stable 6. On oral stable dosage of risperidone ≥4 mg daily as maintenance therapy. 7. Total score ≤70 on the Positive and Negative Syndrome Scale. 8. Using a medically accepted contraceptive method 9. Agrees to washout all prohibited medications prior to baseline (day -1)
Exclusion criteria
1. Informed consent obtained from a third party. 2. Prisoners or patients who are compulsorily detained. 3. Females who are breast-feeding and/or who have a positive pregnancy test. 4. Presence of an uncontrolled, unstable clinically significant medical condition. 5. Positive serology for Hepatitis B, Hepatitis C or anti-HIV 1 and 2 at screening. 6. History of neuroleptic malignant syndrome. 7. Current or past history of tardive dyskinesia. 8. Positive urine drug or alcohol screen finding. 9. Risk of committing self-harm or harm based on Columbia Suicidal Rating Scale. 10. Taking more than one antidepressant. 11. Use of depot antipsychotics within the last three months. 12. Use of strong or moderate cytochrome P450 isoenzyme 3A4inducers 13. Use of electroconvulsive therapy (ECT) within the last three months. 14. Receipt of any investigational drugs within the last three months. 15. Known or suspected allergy or hypersensitivity to risperidone 16. Previous non-responder to risperidone treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PTF for Active Moiety | 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. | Peak to Trough Fluctuation ratio for the Active Moiety |
| Time to Peak Concentration (Tmax) for Active Moiety | 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. | — |
| Terminal Half-life (t1/2) for Active Moiety | 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. | — |
| Peak Plasma Concentration (Cmax) for Active Moiety | 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. | — |
| Trough Plasma Concentration (Cmin) for Active Moiety | 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. | — |
| Area Under the Curve to the Last Quantified Concentration (AUClast) for Active Moiety | 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. | — |
| Area Under the Curve Extrapolated to Infinity (AUC∞) for Active Moiety | 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. | — |
| AUCτ for Active Moiety | 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. | AUCτ is the area under the curve over the dosing interval (τ), where the dosing interval is 28 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Accumulation Ratio (RA) for Active Moiety | 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. | Defined as AUC (0-28 days) after the 4th dose divided by the AUC (0-28 days) of the first dose. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Positive and Negative Syndrome Scale (PANSS) Total Score | 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. | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Gluteus (Risperidone ISM) Risperidone ISM (75 mg) injection in the gluteal muscle at 28-day intervals
Risperidone ISM | 34 |
| Deltoid (Risperdione ISM) Risperidone ISM (75 mg) injection in the deltoid muscle at 28-day intervals
Risperidone ISM | 33 |
| Total | 67 |
Baseline characteristics
| Characteristic | Deltoid (Risperdione ISM) | Total | Gluteus (Risperidone ISM) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants | 67 Participants | 34 Participants |
| Age, Continuous | 44 years STANDARD_DEVIATION 9.8 | 43 years STANDARD_DEVIATION 10.5 | 41 years STANDARD_DEVIATION 11.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 28 Participants | 53 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 11 Participants | 7 Participants |
| Region of Enrollment United States | 33 participants | 67 participants | 34 participants |
| Sex: Female, Male Female | 5 Participants | 12 Participants | 7 Participants |
| Sex: Female, Male Male | 28 Participants | 55 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 34 | 31 / 33 |
| serious Total, serious adverse events | 5 / 34 | 7 / 33 |
Outcome results
Primary
Area Under the Curve Extrapolated to Infinity (AUC∞) for Active Moiety
Time frame: 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.
Population: The analysis was conducted in the PK population (patients who had at least 1 PK sample taken and had no major protocol deviations that would exclude them from PK analysis). As determined by the pharmacokineticist, for this analysis, 11 patients in the gluteal and 18 in the deltoids had concentration amenable to evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Gluteus (Risperidone ISM) | Area Under the Curve Extrapolated to Infinity (AUC∞) for Active Moiety | 21100 h*ng/mL | Geometric Coefficient of Variation 27.4 |
| Deltoid (Risperdione ISM) | Area Under the Curve Extrapolated to Infinity (AUC∞) for Active Moiety | 22700 h*ng/mL | Geometric Coefficient of Variation 40.4 |
Primary
Area Under the Curve to the Last Quantified Concentration (AUClast) for Active Moiety
Time frame: 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.
Population: The analysis was conducted in the PK population (patients who had at least 1 PK sample taken and had no major protocol deviations that would exclude them from PK analysis). As determined by the pharmacokineticist, for this analysis, 18 patients in the gluteal and 22 in the deltoids had concentration amenable to evaluation..
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Gluteus (Risperidone ISM) | Area Under the Curve to the Last Quantified Concentration (AUClast) for Active Moiety | 21300 h*ng/mL | Geometric Coefficient of Variation 35.2 |
| Deltoid (Risperdione ISM) | Area Under the Curve to the Last Quantified Concentration (AUClast) for Active Moiety | 23300 h*ng/mL | Geometric Coefficient of Variation 43.3 |
Primary
AUCτ for Active Moiety
AUCτ is the area under the curve over the dosing interval (τ), where the dosing interval is 28 days
Time frame: 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.
Population: The analysis was conducted in the PK population: 43 patients (20 in the gluteal and 23 in the deltoid site injection group). As determined by the pharmacokineticist, for Dose 4th analysis, 18 patients in the gluteal and 22 in the deltoid group had concentration amenable to evaluation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Gluteus (Risperidone ISM) | AUCτ for Active Moiety | Dose 1 | 14100 h*ng/mL | Geometric Coefficient of Variation 39.5 |
| Gluteus (Risperidone ISM) | AUCτ for Active Moiety | Dose 2 | 15400 h*ng/mL | Geometric Coefficient of Variation 59.3 |
| Gluteus (Risperidone ISM) | AUCτ for Active Moiety | Dose 3 | 16600 h*ng/mL | Geometric Coefficient of Variation 24.2 |
| Gluteus (Risperidone ISM) | AUCτ for Active Moiety | Dose 4 | 17300 h*ng/mL | Geometric Coefficient of Variation 27.1 |
| Deltoid (Risperdione ISM) | AUCτ for Active Moiety | Dose 4 | 18500 h*ng/mL | Geometric Coefficient of Variation 35.9 |
| Deltoid (Risperdione ISM) | AUCτ for Active Moiety | Dose 1 | 16300 h*ng/mL | Geometric Coefficient of Variation 42.6 |
| Deltoid (Risperdione ISM) | AUCτ for Active Moiety | Dose 3 | 18200 h*ng/mL | Geometric Coefficient of Variation 32.5 |
| Deltoid (Risperdione ISM) | AUCτ for Active Moiety | Dose 2 | 18000 h*ng/mL | Geometric Coefficient of Variation 40.2 |
Primary
Peak Plasma Concentration (Cmax) for Active Moiety
Time frame: 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.
Population: The analysis was conducted in the PK population, which includes 43 patients (20 in the gluteal and 23 in the deltoid site injection group) who had at least 1 PK sample taken and had no major protocol deviations that would exclude them from PK analysis. They also had concentration data amenable to evaluation as determined by the pharmacokineticist.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Gluteus (Risperidone ISM) | Peak Plasma Concentration (Cmax) for Active Moiety | Dose 1 | 39.6 ng/mL | Geometric Coefficient of Variation 33.7 |
| Gluteus (Risperidone ISM) | Peak Plasma Concentration (Cmax) for Active Moiety | Dose 2 | 53.2 ng/mL | Geometric Coefficient of Variation 52.7 |
| Gluteus (Risperidone ISM) | Peak Plasma Concentration (Cmax) for Active Moiety | Dose 3 | 48.6 ng/mL | Geometric Coefficient of Variation 33.3 |
| Gluteus (Risperidone ISM) | Peak Plasma Concentration (Cmax) for Active Moiety | Dose 4 | 47.4 ng/mL | Geometric Coefficient of Variation 38.9 |
| Deltoid (Risperdione ISM) | Peak Plasma Concentration (Cmax) for Active Moiety | Dose 4 | 57.7 ng/mL | Geometric Coefficient of Variation 39.3 |
| Deltoid (Risperdione ISM) | Peak Plasma Concentration (Cmax) for Active Moiety | Dose 1 | 54.1 ng/mL | Geometric Coefficient of Variation 48.9 |
| Deltoid (Risperdione ISM) | Peak Plasma Concentration (Cmax) for Active Moiety | Dose 3 | 61.0 ng/mL | Geometric Coefficient of Variation 36.9 |
| Deltoid (Risperdione ISM) | Peak Plasma Concentration (Cmax) for Active Moiety | Dose 2 | 61.0 ng/mL | Geometric Coefficient of Variation 38.4 |
Primary
PTF for Active Moiety
Peak to Trough Fluctuation ratio for the Active Moiety
Time frame: 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.
Population: The analysis was conduct in the PK population, which includes 43 patients (20 in the gluteal and 23 in the deltoid site injection group) who had at least 1 PK sample taken and had no major protocol deviations that would exclude them from PK analysis. They also had concentration data amenable to evaluation as determined by the pharmacokineticist.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Gluteus (Risperidone ISM) | PTF for Active Moiety | Dose 1 | 0.999 Ratio | Geometric Coefficient of Variation 181.6 |
| Gluteus (Risperidone ISM) | PTF for Active Moiety | Dose 2 | 1.89 Ratio | Geometric Coefficient of Variation 38.1 |
| Gluteus (Risperidone ISM) | PTF for Active Moiety | Dose 3 | 1.39 Ratio | Geometric Coefficient of Variation 51.9 |
| Deltoid (Risperdione ISM) | PTF for Active Moiety | Dose 3 | 1.82 Ratio | Geometric Coefficient of Variation 29.6 |
| Deltoid (Risperdione ISM) | PTF for Active Moiety | Dose 1 | 1.76 Ratio | Geometric Coefficient of Variation 47.6 |
| Deltoid (Risperdione ISM) | PTF for Active Moiety | Dose 2 | 1.88 Ratio | Geometric Coefficient of Variation 23 |
Primary
Terminal Half-life (t1/2) for Active Moiety
Time frame: 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.
Population: The analysis was conducted in the PK population (patients who had at least 1 PK sample taken and had no major protocol deviations that would exclude them from PK analysis). As determined by the pharmacokineticist, for this analysis, 12 patients in the gluteal and 19 in the deltoid group had concentration amenable to evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Gluteus (Risperidone ISM) | Terminal Half-life (t1/2) for Active Moiety | 163 h | Geometric Coefficient of Variation 80.5 |
| Deltoid (Risperdione ISM) | Terminal Half-life (t1/2) for Active Moiety | 269 h | Geometric Coefficient of Variation 71.6 |
Primary
Time to Peak Concentration (Tmax) for Active Moiety
Time frame: 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.
Population: The analysis was conducted in the PK population, which includes 43 patients (20 in the gluteal and 23 in the deltoid site injection group) who had at least 1 PK sample taken and had no major protocol deviations that would exclude them from PK analysis. They also had concentration data amenable to evaluation as determined by the pharmacokineticist.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Gluteus (Risperidone ISM) | Time to Peak Concentration (Tmax) for Active Moiety | Dose 2 | 24.0 h |
| Gluteus (Risperidone ISM) | Time to Peak Concentration (Tmax) for Active Moiety | Dose 1 | 48.0 h |
| Gluteus (Risperidone ISM) | Time to Peak Concentration (Tmax) for Active Moiety | Dose 3 | 48.0 h |
| Gluteus (Risperidone ISM) | Time to Peak Concentration (Tmax) for Active Moiety | Dose 4 | 24.0 h |
| Deltoid (Risperdione ISM) | Time to Peak Concentration (Tmax) for Active Moiety | Dose 4 | 48.0 h |
| Deltoid (Risperdione ISM) | Time to Peak Concentration (Tmax) for Active Moiety | Dose 1 | 48.0 h |
| Deltoid (Risperdione ISM) | Time to Peak Concentration (Tmax) for Active Moiety | Dose 2 | 24.0 h |
| Deltoid (Risperdione ISM) | Time to Peak Concentration (Tmax) for Active Moiety | Dose 3 | 24.0 h |
Primary
Trough Plasma Concentration (Cmin) for Active Moiety
Time frame: 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.
Population: The analysis was conducted in the PK population, which includes 43 patients (20 in the gluteal and 23 in the deltoid site injection group) who had at least 1 PK sample taken and had no major protocol deviations that would exclude them from PK analysis. They also had concentration data amenable to evaluation as determined by the pharmacokineticist.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Gluteus (Risperidone ISM) | Trough Plasma Concentration (Cmin) for Active Moiety | Dose 1 | 11.1 ng/mL | Geometric Coefficient of Variation 72.6 |
| Gluteus (Risperidone ISM) | Trough Plasma Concentration (Cmin) for Active Moiety | Dose 2 | 7.86 ng/mL | Geometric Coefficient of Variation 90.1 |
| Gluteus (Risperidone ISM) | Trough Plasma Concentration (Cmin) for Active Moiety | Dose 3 | 9.97 ng/mL | Geometric Coefficient of Variation 70.7 |
| Gluteus (Risperidone ISM) | Trough Plasma Concentration (Cmin) for Active Moiety | Dose 4 | 12.6 ng/mL | Geometric Coefficient of Variation 59.1 |
| Deltoid (Risperdione ISM) | Trough Plasma Concentration (Cmin) for Active Moiety | Dose 4 | 9.52 ng/mL | Geometric Coefficient of Variation 56.5 |
| Deltoid (Risperdione ISM) | Trough Plasma Concentration (Cmin) for Active Moiety | Dose 1 | 7.0 ng/mL | Geometric Coefficient of Variation 87.6 |
| Deltoid (Risperdione ISM) | Trough Plasma Concentration (Cmin) for Active Moiety | Dose 3 | 10.2 ng/mL | Geometric Coefficient of Variation 57.6 |
| Deltoid (Risperdione ISM) | Trough Plasma Concentration (Cmin) for Active Moiety | Dose 2 | 8.60 ng/mL | Geometric Coefficient of Variation 49.4 |
Secondary
Accumulation Ratio (RA) for Active Moiety
Defined as AUC (0-28 days) after the 4th dose divided by the AUC (0-28 days) of the first dose.
Time frame: 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.
Population: The analysis was conducted in the PK population (patients who had at least 1 PK sample taken and had no major protocol deviations that would exclude them from PK analysis). As determined by the pharmacokineticist, for this analysis, 18 patients in the gluteal and 22 in the deltoid group had concentration amenable to evaluation.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Gluteus (Risperidone ISM) | Accumulation Ratio (RA) for Active Moiety | 1.15 Ratio | Geometric Coefficient of Variation 25.1 |
| Deltoid (Risperdione ISM) | Accumulation Ratio (RA) for Active Moiety | 1.14 Ratio | Geometric Coefficient of Variation 26.2 |
Other Pre-specified
Positive and Negative Syndrome Scale (PANSS) Total Score
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
Time frame: 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.
Population: The analysis was conduct in the Intent-to-Treat (ITT) Population, which includes all patients in Safety Population with baseline (Day -1) efficacy data and at least 1 post-baseline efficacy evaluation. ITT Population includes 66 patients; 33 on each arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Gluteus (Risperidone ISM) | Positive and Negative Syndrome Scale (PANSS) Total Score | Baseline (Day -1) | 58 points | Standard Deviation 10.4 |
| Gluteus (Risperidone ISM) | Positive and Negative Syndrome Scale (PANSS) Total Score | Visit 48 (Day 120 post Dose 4) | 59 points | Standard Deviation 16.4 |
| Deltoid (Risperdione ISM) | Positive and Negative Syndrome Scale (PANSS) Total Score | Baseline (Day -1) | 60 points | Standard Deviation 9.8 |
| Deltoid (Risperdione ISM) | Positive and Negative Syndrome Scale (PANSS) Total Score | Visit 48 (Day 120 post Dose 4) | 61 points | Standard Deviation 10.8 |