Alcohol Use Disorder, Schizophrenia
Conditions
Keywords
Alkermes, Schizophrenia, Alcohol Use Disorder, ALKS 3831
Brief summary
This double-blind, randomized study will evaluate the efficacy, safety and tolerability of ALKS 3831 in subjects with schizophrenia and alcohol use disorder (AUD).
Interventions
DRUGSamidorphan + olanzapine (ALKS 3831)
Oral tablet, taken once daily
DRUGPlacebo + olanzapine
Oral tablet, 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 65 Years
Healthy volunteers
No
Inclusion criteria
* Has a BMI between 18.0 and 40.0 kg/m2, inclusive * Has a diagnosis of schizophrenia * Has a diagnosis of alcohol use disorder (AUD) * Has experienced an acute exacerbation of schizophrenia within the past 6 months * Additional criteria may apply
Exclusion criteria
* Is pregnant or breastfeeding * Had first lifetime psychotic episode less than 1 year before screening or has experienced only a single lifetime psychotic episode * Has a known or suspected intolerance, allergy, or hypersensitivity to olanzapine * Has current or pending legal charges with the potential for incarceration * Has a positive drug screen for opiates * Additional criteria may apply
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Independent Adjudication Committee (IAC) Adjudicated Event of Exacerbation of Disease (EEDS) | Up to 15 months | EEDS was defined as any of the following occurring during the double-blind period & was related to worsening of disease symptoms, as confirmed by the Independent Adjudication Committee (IAC): 1. Hospitalization (includes psychiatric& treatment of alcohol intoxication/withdrawal) 2. \>= 25% or \>= 15 point increase from randomization in PANSS total score 3. PANSS items score of P1, P2, P3, P6, P7 or G8 that meets 1 of the following: 3a. Score \>= 5 for subjects at a 2nd ad hoc visit with a score \<=3 at randomization 3b. Score \>= 6 for subjects at a 2nd ad hoc visit with a score =4 at randomization 4. Engagement in self injury, aggressive behavior, or suicidal/homicidal ideation 5. Initiation of rescue medication, including increase in olanzapine dosage initially prescribed at randomization 6. ER visit 7. Subject withdraws or PI discontinues subject for lack of efficacy, lost to follow-up, or withdrawal by subject 8. Arrest or incarceration related to subject's underlying disease |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Events of Exacerbation of Disease (EEDS) | Up to 15 months | EEDS was defined as any of the following occurring during the double-blind period & was related to worsening of disease symptoms, as confirmed by the Independent Adjudication Committee (IAC): 1. Hospitalization(includes psychiatric & treatment of alcohol intoxication/withdrawal) 2. \>= 25% or \>= 15 point increase from randomization in PANSS total score 3. PANSS items score of P1, P2, P3, P6, P7 or G8 that meets 1 of the following: 3a. Score \>= 5 for subjects at a 2nd ad hoc visit with a score \<=3 at randomization 3b. Score \>= 6 for subjects at a 2nd ad hoc visit with a score =4 at randomization 4. Engagement in self injury, aggressive behavior, or suicidal/homicidal ideation 5. Initiation of rescue medication, including increase in olanzapine dosage initially prescribed at randomization 6. ER visit 7. Subject withdraws or PI discontinues subject for lack of efficacy, lost to follow-up, or withdrawal by subject 8. Arrest or incarceration related to subject's underlying disease |
| Number and Percentage of Subjects With at Least 1 Level Decrease in World Health Organization (WHO) Drinking Risk Level From Baseline to Week 24 of the Double-blind Treatment (Study Week 27) | 24 weeks | Alcohol consumption per day = (total number of drinks x 14 gram) / (total number of days) WHO criteria for risk of alcohol consumption on a single drinking day: Abstinence- Males: 0 g; Females- 0 g Low Risk- Males: 1-40 g; Females: 1-20 g Medium Risk- Males: 41- 60 g; Females: 21- 40 g High Risk- Males: 61-100 g; Females: 41-60 g Very High Risk- Males: \>= 101 g; Females: \>= 61 g |
Countries
Bulgaria, Poland, United States
Participant flow
Recruitment details
Subjects were adults with a diagnosis of schizophrenia and Alcohol Use Disorder (AUD). Subjects must also have recently experienced an exacerbation of disease symptoms (eg, hospitalization), but could not exceed a pre-defined level of symptom severity at the time of screening (as measured by assessments like the Positive and Negative Symptom Scale \[PANSS\] and Clinical Global Impression- Severity \[CGI-S\]).
Pre-assignment details
After screening, subjects began a 4-week open-label olanzapine dosing period followed by a 2- week open-label ALKS 3831 period. Subjects who did not tolerate ALKS 3831 during the second open-label period were discontinued from the study prior to randomization. A total of 300 subjects were enrolled in the study, and 255 completed the open-label olanzapine period. 234 subjects were randomized following the open-label ALKS 3831 period, however, 5 subjects discontinued prior to receiving treatment.
Participants by arm
| Arm | Count |
|---|---|
| ALKS 3831 Oral tablet, taken once daily
ALKS 3831: Olanzapine (dose level determined by investigator) + Samidorphan (10mg) | 112 |
| Olanzapine + Placebo Oral tablet, taken once daily
Olanzapine dose level determined by investigator | 117 |
| Total | 229 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Open-Label ALKS 3831 Period | Adverse Event | 3 | 0 | 0 |
| Open-Label ALKS 3831 Period | Failure to meet randomization criteria | 6 | 0 | 0 |
| Open-Label ALKS 3831 Period | Lack of Efficacy | 1 | 0 | 0 |
| Open-Label ALKS 3831 Period | Lost to Follow-up | 3 | 0 | 0 |
| Open-Label ALKS 3831 Period | Non-compliance with study drug | 1 | 0 | 0 |
| Open-Label ALKS 3831 Period | Physician Decision | 1 | 0 | 0 |
| Open-Label ALKS 3831 Period | Protocol Violation | 2 | 0 | 0 |
| Open-Label ALKS 3831 Period | Withdrawal by Subject | 4 | 0 | 0 |
| Post- Randomization Period | Adverse Event | 0 | 9 | 10 |
| Post- Randomization Period | Lack of Efficacy | 0 | 0 | 1 |
| Post- Randomization Period | Lost to Follow-up | 0 | 9 | 15 |
| Post- Randomization Period | Non- compliance with study drug | 0 | 8 | 2 |
| Post- Randomization Period | Non-compliance with study procedures | 0 | 2 | 4 |
| Post- Randomization Period | Physician Decision | 0 | 2 | 4 |
| Post- Randomization Period | Protocol Violation | 0 | 2 | 3 |
| Post- Randomization Period | Received prohibitive treatment | 0 | 1 | 2 |
| Post- Randomization Period | Relocation | 0 | 3 | 0 |
| Post- Randomization Period | Withdrawal by Subject | 0 | 23 | 18 |
Baseline characteristics
| Characteristic | Olanzapine + Placebo | Total | ALKS 3831 |
|---|---|---|---|
| Age, Continuous | 45.1 years STANDARD_DEVIATION 10.22 | 45.7 years STANDARD_DEVIATION 10.4 | 46.4 years STANDARD_DEVIATION 10.6 |
| Body Mass Index (BMI) | 28.5 kg/m^2 STANDARD_DEVIATION 5.4 | 28.6 kg/m^2 STANDARD_DEVIATION 5.6 | 28.6 kg/m^2 STANDARD_DEVIATION 5.7 |
| Body Mass Index (BMI) Group Normal (18.5 to <25) | 29 Participants | 63 Participants | 34 Participants |
| Body Mass Index (BMI) Group Obese (>= 30) | 39 Participants | 81 Participants | 42 Participants |
| Body Mass Index (BMI) Group Overweight (25 to <30) | 49 Participants | 82 Participants | 33 Participants |
| Body Mass Index (BMI) Group Underweight (<18.5) | 0 Participants | 3 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 11 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 109 Participants | 217 Participants | 108 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Height | 174.4 centimeters STANDARD_DEVIATION 8.4 | 173.9 centimeters STANDARD_DEVIATION 9 | 173.4 centimeters STANDARD_DEVIATION 9.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 57 Participants | 122 Participants | 65 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 | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 58 Participants | 101 Participants | 43 Participants |
| Region of Enrollment Bulgaria | 36 participants | 60 participants | 24 participants |
| Region of Enrollment Poland | 5 participants | 8 participants | 3 participants |
| Region of Enrollment United States | 76 participants | 161 participants | 85 participants |
| Sex: Female, Male Female | 26 Participants | 49 Participants | 23 Participants |
| Sex: Female, Male Male | 91 Participants | 180 Participants | 89 Participants |
| Weight | 86.8 kilograms STANDARD_DEVIATION 18.1 | 86.5 kilograms STANDARD_DEVIATION 18.9 | 86.2 kilograms STANDARD_DEVIATION 19.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 255 | 1 / 117 | 1 / 112 |
| other Total, other adverse events | 0 / 255 | 19 / 117 | 26 / 112 |
| serious Total, serious adverse events | 4 / 255 | 12 / 117 | 7 / 112 |
Outcome results
Primary
Number of Participants With Independent Adjudication Committee (IAC) Adjudicated Event of Exacerbation of Disease (EEDS)
EEDS was defined as any of the following occurring during the double-blind period & was related to worsening of disease symptoms, as confirmed by the Independent Adjudication Committee (IAC): 1. Hospitalization (includes psychiatric& treatment of alcohol intoxication/withdrawal) 2. \>= 25% or \>= 15 point increase from randomization in PANSS total score 3. PANSS items score of P1, P2, P3, P6, P7 or G8 that meets 1 of the following: 3a. Score \>= 5 for subjects at a 2nd ad hoc visit with a score \<=3 at randomization 3b. Score \>= 6 for subjects at a 2nd ad hoc visit with a score =4 at randomization 4. Engagement in self injury, aggressive behavior, or suicidal/homicidal ideation 5. Initiation of rescue medication, including increase in olanzapine dosage initially prescribed at randomization 6. ER visit 7. Subject withdraws or PI discontinues subject for lack of efficacy, lost to follow-up, or withdrawal by subject 8. Arrest or incarceration related to subject's underlying disease
Time frame: Up to 15 months
Population: Efficacy analyses were carried out using the intent to treat (ITT) population, i.e. all randomized subjects who received at least one dose of study drug post-randomization
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ALKS 3831 | Number of Participants With Independent Adjudication Committee (IAC) Adjudicated Event of Exacerbation of Disease (EEDS) | Number of Subjects with IAC Adjudicated EEDS | 25 Participants |
| ALKS 3831 | Number of Participants With Independent Adjudication Committee (IAC) Adjudicated Event of Exacerbation of Disease (EEDS) | Number of Subjects Censored | 87 Participants |
| Olanzapine + Placebo | Number of Participants With Independent Adjudication Committee (IAC) Adjudicated Event of Exacerbation of Disease (EEDS) | Number of Subjects Censored | 88 Participants |
| Olanzapine + Placebo | Number of Participants With Independent Adjudication Committee (IAC) Adjudicated Event of Exacerbation of Disease (EEDS) | Number of Subjects with IAC Adjudicated EEDS | 29 Participants |
p-value: 0.74695% CI: [0.53, 1.56]Log Rank
Secondary
Number and Percentage of Subjects With at Least 1 Level Decrease in World Health Organization (WHO) Drinking Risk Level From Baseline to Week 24 of the Double-blind Treatment (Study Week 27)
Alcohol consumption per day = (total number of drinks x 14 gram) / (total number of days) WHO criteria for risk of alcohol consumption on a single drinking day: Abstinence- Males: 0 g; Females- 0 g Low Risk- Males: 1-40 g; Females: 1-20 g Medium Risk- Males: 41- 60 g; Females: 21- 40 g High Risk- Males: 61-100 g; Females: 41-60 g Very High Risk- Males: \>= 101 g; Females: \>= 61 g
Time frame: 24 weeks
Population: Efficacy analyses were carried out using subjects from the intent to treat (ITT) population with postbaseline data on drinking habits.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ALKS 3831 | Number and Percentage of Subjects With at Least 1 Level Decrease in World Health Organization (WHO) Drinking Risk Level From Baseline to Week 24 of the Double-blind Treatment (Study Week 27) | >= 1 Level Decrease from Baseline | 45 Participants |
| ALKS 3831 | Number and Percentage of Subjects With at Least 1 Level Decrease in World Health Organization (WHO) Drinking Risk Level From Baseline to Week 24 of the Double-blind Treatment (Study Week 27) | < 1 Level Decrease from Baseline | 66 Participants |
| Olanzapine + Placebo | Number and Percentage of Subjects With at Least 1 Level Decrease in World Health Organization (WHO) Drinking Risk Level From Baseline to Week 24 of the Double-blind Treatment (Study Week 27) | >= 1 Level Decrease from Baseline | 44 Participants |
| Olanzapine + Placebo | Number and Percentage of Subjects With at Least 1 Level Decrease in World Health Organization (WHO) Drinking Risk Level From Baseline to Week 24 of the Double-blind Treatment (Study Week 27) | < 1 Level Decrease from Baseline | 72 Participants |
p-value: 0.96395% CI: [0.56, 1.73]Regression, Logistic
Secondary
Number of Events of Exacerbation of Disease (EEDS)
EEDS was defined as any of the following occurring during the double-blind period & was related to worsening of disease symptoms, as confirmed by the Independent Adjudication Committee (IAC): 1. Hospitalization(includes psychiatric & treatment of alcohol intoxication/withdrawal) 2. \>= 25% or \>= 15 point increase from randomization in PANSS total score 3. PANSS items score of P1, P2, P3, P6, P7 or G8 that meets 1 of the following: 3a. Score \>= 5 for subjects at a 2nd ad hoc visit with a score \<=3 at randomization 3b. Score \>= 6 for subjects at a 2nd ad hoc visit with a score =4 at randomization 4. Engagement in self injury, aggressive behavior, or suicidal/homicidal ideation 5. Initiation of rescue medication, including increase in olanzapine dosage initially prescribed at randomization 6. ER visit 7. Subject withdraws or PI discontinues subject for lack of efficacy, lost to follow-up, or withdrawal by subject 8. Arrest or incarceration related to subject's underlying disease
Time frame: Up to 15 months
Population: Efficacy analyses were carried out using the intent to treat (ITT) population, i.e. all randomized subjects who received at least one dose of study drug post-randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ALKS 3831 | Number of Events of Exacerbation of Disease (EEDS) | 35 Events |
| Olanzapine + Placebo | Number of Events of Exacerbation of Disease (EEDS) | 49 Events |
p-value: 0.37295% CI: [0.43, 1.37]Andersen-Gill Recurrent-Event Cox Model