Schizophrenia
Conditions
Keywords
Schizophrenia, Olanzapine, Samidorphan, Alkermes
Brief summary
This is a Phase 2, randomized, placebo-controlled multicenter study, which will be conducted in 2 parts. The study duration for each subject will be approximately 33 weeks and will include 25 study visits.
Interventions
DRUGSamidorphan (Low Dose)
Tablets taken once daily
DRUGSamidorphan (Medium Dose)
Tablets taken once daily
DRUGSamidorphan (High Dose)
Tablets taken once daily
DRUGPlacebo
Tablets taken once daily
DRUGOlanzapine
Tablets taken once daily
Sponsors
Alkermes, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Age 18 to 50 years, inclusive * Body mass index (BMI) of 17-30 kg/m2, inclusive * Diagnosis of schizophrenia that is clinically stable
Exclusion criteria
* Initiated 1st antipsychotic treatment within the past 12 months and/or has had symptoms lasting \<2 years * Current diagnosis of alcohol or drug use disorder, moderate or severe * Clinically significant or unstable medical illness, condition, or disorder * Pregnant or breastfeeding * Significant changes in diet or exercise regimen or plans to join a weight management program during the study * Opioid medications taken within 14 days and/or need to take opioid medication during the study period * History of hypersensitivity to or intolerance of olanzapine * Use of olanzapine, clozapine, mesoridazine, chlorpromazine, or thioridazine for more than 1 week during the past year
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Total Positive and Negative Syndrome Scale (PANSS) Score | Baseline (Day 8) to Day 92 (end of study Part A) | Change from baseline (Day 8) to Day 92 (end of study Part A). The PANSS is a 30-item scale measuring severity of schizophrenia symptoms. Symptom severity for each item is rated on a 7-point scale (1 = absent; 7 = extreme), and the total score is added together, with a minimum score of 30 and a maximum score of 210. A higher score indicates more severe symptoms, while a lower score indicates less severe symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Body Weight (Kilogram) From Baseline to Day 92 | Baseline (Day 8) to Day 92 (end of study Part A) | Percent change from baseline (Day 8) to the end of Part A (Day 92) |
| Absolute Change in Body Weight (kg) From Baseline to Day 92 | Baseline (Day 8) to Day 92 (end of study Part A) | Change from randomization (Day 8) to the end of Part A (Week 12; Day 92) |
| Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | Baseline (Day 8) to Day 92 (end of study Part A) | Significant weight gain will include a \>=5%, \>= 7%, or \>=10% gain in body weight from baseline (Day 8) to Day 92 (end of study Part A) |
| Change in Clinical Global Impressions - Severity (CGI-S) From Baseline to Day 92 | Baseline (Day 8) to Day 92 (end of study Part A) | Change in CGI-S score from baseline (Day 8) to the end of Part A (Week 12; Day 92). The CGI-S is a 7-point scale intended to measure the severity of a patient's illness at the time of assessment. Scores range from 1 (normal) to 7(extremely ill), so a higher score is correlative to more severe illness. |
Countries
Bulgaria, Czechia, United States
Participant flow
Recruitment details
This study included subjects who had a diagnosis of schizophrenia and who had not been exposed to olanzapine, clozapine, mesoridazine, chlorpromazine, or thioridazine for more than 1 week within the previous year or at any time in the 3 months prior to screening. Subjects were enrolled in study sites located in 3 countries: United States, Bulgaria, and the Czech Republic.
Pre-assignment details
Subjects completed a seven-day lead-in period on open-label olanzapine before being randomized into the 12-week double-blind treatment period. Baseline data includes subjects who completed the lead-in period and were randomized to a treatment group. A total of 347 subjects were enrolled in the study; 309 subjects completed the 1-week olanzapine lead-in period and were randomized to one of the 4 treatment groups in Part A
Participants by arm
| Arm | Count |
|---|---|
| Olz + Placebo Olanzapine (dose level determined by Investigator) and placebo tablets taken once daily | 75 |
| Olz + Sam 5mg Olanzapine (dose level determined by Investigator) and 5mg Samidorphan tablets taken once daily | 80 |
| Olz + Sam 10mg Olanzapine (dose level determined by Investigator) and 10mg Samidorphan tablets taken once daily | 86 |
| Olz + Sam 20mg Olanzapine (dose level determined by Investigator) and 20mg Samidorphan tablets taken once daily | 68 |
| Total | 309 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part A | Adverse Event | 3 | 6 | 9 | 6 |
| Part A | Lost to Follow-up | 9 | 7 | 7 | 2 |
| Part A | Non-compliance with study drug | 1 | 4 | 4 | 0 |
| Part A | Physician Decision | 1 | 1 | 0 | 0 |
| Part A | Protocol Violation | 1 | 1 | 0 | 0 |
| Part A | Withdrawal by Subject | 4 | 9 | 8 | 5 |
| Part B | Adverse Event | 3 | 0 | 2 | 0 |
| Part B | Incarceration | 2 | 0 | 0 | 1 |
| Part B | Lack of Efficacy | 0 | 1 | 0 | 0 |
| Part B | Lost to Follow-up | 0 | 3 | 3 | 4 |
| Part B | Non-compliance with study drug | 2 | 0 | 0 | 1 |
| Part B | Physician Decision | 1 | 0 | 0 | 2 |
| Part B | Withdrawal by Subject | 1 | 2 | 0 | 3 |
Baseline characteristics
| Characteristic | Olz + Sam 5mg | Total | Olz + Placebo | Olz + Sam 20mg | Olz + Sam 10mg |
|---|---|---|---|---|---|
| Age, Continuous | 37.9 years STANDARD_DEVIATION 8.62 | 38.8 years STANDARD_DEVIATION 8.3 | 40.3 years STANDARD_DEVIATION 8.14 | 39.3 years STANDARD_DEVIATION 8.38 | 38.1 years STANDARD_DEVIATION 8 |
| Body Mass Index (BMI) | 25.7 kilograms/meters^2 STANDARD_DEVIATION 3.18 | 25.2 kilograms/meters^2 STANDARD_DEVIATION 3.3 | 25.1 kilograms/meters^2 STANDARD_DEVIATION 3.4 | 24.8 kilograms/meters^2 STANDARD_DEVIATION 3.41 | 25.0 kilograms/meters^2 STANDARD_DEVIATION 3.23 |
| Body Mass Index (BMI) Group Normal (18.5 to <25) | 31 Participants | 137 Participants | 32 Participants | 32 Participants | 42 Participants |
| Body Mass Index (BMI) Group Obese (>=30) | 3 Participants | 4 Participants | 0 Participants | 1 Participants | 0 Participants |
| Body Mass Index (BMI) Group Overweight (25 to <30) | 46 Participants | 165 Participants | 42 Participants | 34 Participants | 43 Participants |
| Body Mass Index (BMI) Group Underweight (<18.5) | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 17 Participants | 4 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 75 Participants | 292 Participants | 71 Participants | 65 Participants | 81 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 173.5 centimeters STANDARD_DEVIATION 10.76 | 174 centimeters STANDARD_DEVIATION 9.82 | 173.4 centimeters STANDARD_DEVIATION 8.07 | 174.1 centimeters STANDARD_DEVIATION 9.99 | 174.8 centimeters STANDARD_DEVIATION 10.27 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 4 Participants | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 53 Participants | 189 Participants | 44 Participants | 42 Participants | 50 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 26 Participants | 112 Participants | 28 Participants | 23 Participants | 35 Participants |
| Region of Enrollment Bulgaria | 12 Participants | 50 Participants | 15 Participants | 8 Participants | 15 Participants |
| Region of Enrollment Czechia | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 68 Participants | 258 Participants | 60 Participants | 60 Participants | 70 Participants |
| Sex: Female, Male Female | 20 Participants | 81 Participants | 22 Participants | 18 Participants | 21 Participants |
| Sex: Female, Male Male | 60 Participants | 228 Participants | 53 Participants | 50 Participants | 65 Participants |
| Weight | 77.5 kilograms STANDARD_DEVIATION 13.07 | 76.4 kilograms STANDARD_DEVIATION 12.96 | 75.6 kilograms STANDARD_DEVIATION 12.3 | 75.4 kilograms STANDARD_DEVIATION 12.81 | 76.7 kilograms STANDARD_DEVIATION 13.67 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 75 | 0 / 80 | 0 / 86 | 0 / 68 | 0 / 54 | 0 / 52 | 0 / 57 | 0 / 55 |
| other Total, other adverse events | 33 / 75 | 25 / 80 | 33 / 86 | 33 / 68 | 11 / 54 | 10 / 52 | 11 / 57 | 12 / 55 |
| serious Total, serious adverse events | 2 / 75 | 3 / 80 | 4 / 86 | 4 / 68 | 1 / 54 | 1 / 52 | 1 / 57 | 0 / 55 |
Outcome results
Primary
Absolute Change in Total Positive and Negative Syndrome Scale (PANSS) Score
Change from baseline (Day 8) to Day 92 (end of study Part A). The PANSS is a 30-item scale measuring severity of schizophrenia symptoms. Symptom severity for each item is rated on a 7-point scale (1 = absent; 7 = extreme), and the total score is added together, with a minimum score of 30 and a maximum score of 210. A higher score indicates more severe symptoms, while a lower score indicates less severe symptoms.
Time frame: Baseline (Day 8) to Day 92 (end of study Part A)
Population: Full Analysis Set (FAS) 1 efficacy analysis population included all randomized subjects who received at least one dose of study drug and had at least one postbaseline assessment of Positive and Negative Syndrome Scale (PANSS) total score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A FAS 1 - Olz + Placebo | Absolute Change in Total Positive and Negative Syndrome Scale (PANSS) Score | -2.9 units on a scale | Standard Error 0.82 |
| Part A FAS 1 - Olz + Sam 5mg | Absolute Change in Total Positive and Negative Syndrome Scale (PANSS) Score | -1.5 units on a scale | Standard Error 0.85 |
| Part A FAS 1- Olz+ Sam 10mg | Absolute Change in Total Positive and Negative Syndrome Scale (PANSS) Score | -2.7 units on a scale | Standard Error 0.79 |
| Part A FAS 1- Olz+ Sam 20mg | Absolute Change in Total Positive and Negative Syndrome Scale (PANSS) Score | -2.5 units on a scale | Standard Error 0.83 |
p-value: 0.395% CI: [-2, 2.6]Least Square Mean Difference
Secondary
Absolute Change in Body Weight (kg) From Baseline to Day 92
Change from randomization (Day 8) to the end of Part A (Week 12; Day 92)
Time frame: Baseline (Day 8) to Day 92 (end of study Part A)
Population: Full Analysis Set (FAS) 1 efficacy analysis population included all randomized subjects who received at least one dose of study drug and had at least one postbaseline assessment of Positive and Negative Syndrome Scale (PANSS) total score. FAS 2 efficacy analysis population included all FAS 1 subjects who gained weight during the 1-week OLZ lead-in period prior to randomization and had at least one postbaseline weight assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A FAS 1 - Olz + Placebo | Absolute Change in Body Weight (kg) From Baseline to Day 92 | 2.9 kg |
| Part A FAS 1 - Olz + Sam 5mg | Absolute Change in Body Weight (kg) From Baseline to Day 92 | 2.1 kg |
| Part A FAS 1- Olz+ Sam 10mg | Absolute Change in Body Weight (kg) From Baseline to Day 92 | 1.5 kg |
| Part A FAS 1- Olz+ Sam 20mg | Absolute Change in Body Weight (kg) From Baseline to Day 92 | 2.2 kg |
| Part A FAS 2- Olz + Placebo | Absolute Change in Body Weight (kg) From Baseline to Day 92 | 3.8 kg |
| Part A FAS 2- Olz + Sam 5mg | Absolute Change in Body Weight (kg) From Baseline to Day 92 | 2.9 kg |
| Part A FAS 2- Olz + Sam 10mg | Absolute Change in Body Weight (kg) From Baseline to Day 92 | 1.5 kg |
| Part A FAS 2- Olz + 20mg | Absolute Change in Body Weight (kg) From Baseline to Day 92 | 1.2 kg |
p-value: 0.018Mixed Models Analysis
p-value: <0.001Mixed Models Analysis
Secondary
Change in Clinical Global Impressions - Severity (CGI-S) From Baseline to Day 92
Change in CGI-S score from baseline (Day 8) to the end of Part A (Week 12; Day 92). The CGI-S is a 7-point scale intended to measure the severity of a patient's illness at the time of assessment. Scores range from 1 (normal) to 7(extremely ill), so a higher score is correlative to more severe illness.
Time frame: Baseline (Day 8) to Day 92 (end of study Part A)
Population: Full Analysis Set (FAS) 1 efficacy analysis population included all randomized subjects who received at least one dose of study drug and had at least one postbaseline assessment of Positive and Negative Syndrome Scale (PANSS) total score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Part A FAS 1 - Olz + Placebo | Change in Clinical Global Impressions - Severity (CGI-S) From Baseline to Day 92 | -0.0 units on a scale | Standard Error 0.05 |
| Part A FAS 1 - Olz + Sam 5mg | Change in Clinical Global Impressions - Severity (CGI-S) From Baseline to Day 92 | -0.1 units on a scale | Standard Error 0.05 |
| Part A FAS 1- Olz+ Sam 10mg | Change in Clinical Global Impressions - Severity (CGI-S) From Baseline to Day 92 | -0.0 units on a scale | Standard Error 0.05 |
| Part A FAS 1- Olz+ Sam 20mg | Change in Clinical Global Impressions - Severity (CGI-S) From Baseline to Day 92 | -0.1 units on a scale | Standard Error 0.05 |
Secondary
Percentage of Subjects Exhibiting Significant Weight Gain at Day 92
Significant weight gain will include a \>=5%, \>= 7%, or \>=10% gain in body weight from baseline (Day 8) to Day 92 (end of study Part A)
Time frame: Baseline (Day 8) to Day 92 (end of study Part A)
Population: Full Analysis Set (FAS) 1 efficacy analysis population included all randomized subjects who received at least one dose of study drug and had at least one postbaseline assessment of Positive and Negative Syndrome Scale (PANSS) total score. FAS 2 efficacy analysis population included all FAS 1 subjects who gained weight during the 1-week OLZ lead-in period prior to randomization and had at least one postbaseline weight assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A FAS 1 - Olz + Placebo | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >=10% weight gain | 10 Participants |
| Part A FAS 1 - Olz + Placebo | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 5% weight gain | 20 Participants |
| Part A FAS 1 - Olz + Placebo | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 7% weight gain | 14 Participants |
| Part A FAS 1 - Olz + Sam 5mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >=10% weight gain | 3 Participants |
| Part A FAS 1 - Olz + Sam 5mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 5% weight gain | 18 Participants |
| Part A FAS 1 - Olz + Sam 5mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 7% weight gain | 8 Participants |
| Part A FAS 1- Olz+ Sam 10mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 7% weight gain | 9 Participants |
| Part A FAS 1- Olz+ Sam 10mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 5% weight gain | 16 Participants |
| Part A FAS 1- Olz+ Sam 10mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >=10% weight gain | 4 Participants |
| Part A FAS 1- Olz+ Sam 20mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >=10% weight gain | 5 Participants |
| Part A FAS 1- Olz+ Sam 20mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 5% weight gain | 16 Participants |
| Part A FAS 1- Olz+ Sam 20mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 7% weight gain | 12 Participants |
| Part A FAS 2- Olz + Placebo | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >=10% weight gain | 8 Participants |
| Part A FAS 2- Olz + Placebo | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 5% weight gain | 14 Participants |
| Part A FAS 2- Olz + Placebo | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 7% weight gain | 11 Participants |
| Part A FAS 2- Olz + Sam 5mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 7% weight gain | 7 Participants |
| Part A FAS 2- Olz + Sam 5mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 5% weight gain | 13 Participants |
| Part A FAS 2- Olz + Sam 5mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >=10% weight gain | 3 Participants |
| Part A FAS 2- Olz + Sam 10mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 7% weight gain | 4 Participants |
| Part A FAS 2- Olz + Sam 10mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 5% weight gain | 8 Participants |
| Part A FAS 2- Olz + Sam 10mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >=10% weight gain | 3 Participants |
| Part A FAS 2- Olz + 20mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >=10% weight gain | 1 Participants |
| Part A FAS 2- Olz + 20mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 5% weight gain | 8 Participants |
| Part A FAS 2- Olz + 20mg | Percentage of Subjects Exhibiting Significant Weight Gain at Day 92 | >= 7% weight gain | 7 Participants |
Secondary
Percent Change in Body Weight (Kilogram) From Baseline to Day 92
Percent change from baseline (Day 8) to the end of Part A (Day 92)
Time frame: Baseline (Day 8) to Day 92 (end of study Part A)
Population: Full Analysis Set (FAS) 1 efficacy analysis population included all randomized subjects who received at least one dose of study drug and had at least one postbaseline assessment of Positive and Negative Syndrome Scale (PANSS) total score. FAS 2 efficacy analysis population included all FAS 1 subjects who gained weight during the 1-week OLZ lead-in period prior to randomization and had at least one postbaseline weight assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A FAS 1 - Olz + Placebo | Percent Change in Body Weight (Kilogram) From Baseline to Day 92 | 4.1 percent change |
| Part A FAS 1 - Olz + Sam 5mg | Percent Change in Body Weight (Kilogram) From Baseline to Day 92 | 2.8 percent change |
| Part A FAS 1- Olz+ Sam 10mg | Percent Change in Body Weight (Kilogram) From Baseline to Day 92 | 2.1 percent change |
| Part A FAS 1- Olz+ Sam 20mg | Percent Change in Body Weight (Kilogram) From Baseline to Day 92 | 2.9 percent change |
| Part A FAS 2- Olz + Placebo | Percent Change in Body Weight (Kilogram) From Baseline to Day 92 | 5.3 percent change |
| Part A FAS 2- Olz + Sam 5mg | Percent Change in Body Weight (Kilogram) From Baseline to Day 92 | 3.8 percent change |
| Part A FAS 2- Olz + Sam 10mg | Percent Change in Body Weight (Kilogram) From Baseline to Day 92 | 2.2 percent change |
| Part A FAS 2- Olz + 20mg | Percent Change in Body Weight (Kilogram) From Baseline to Day 92 | 1.6 percent change |
p-value: 0.006Mixed Models Analysis
p-value: <0.001Mixed Models Analysis