| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10040706 |
| E.1.2 | Term | Simple type schizophrenia |
| E.1.2 | System Organ Class | 100000004873 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate 3 doses of samidorphan co-administered with olanzapine (ALKS3831) in subjects with schizophrenia to:
(1) evaluate ALKS3831 as a treatment of schizophrenia; (2) assess the safety and tolerability of ALKS3831; (3)characterize the impact of samidorphan component of ALKS3831 on weight and other metabolic factors |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is willing and able to provide informed consent; subject has signed the main informed consent form (ICF) before initiation of any study specific procedures
2. Subject is age 18 to 50 years, inclusive, at screening
3. Subject has a body mass index (BMI) of 17.0-30.0kg/m2, inclusive, at screening
4. Subject has a diagnosis of schizophrenia (based on Diagnostic and Statistical Manual of Mental Disorders [DSM] criteria) that is clinically stable as evidenced by both of the following:
• No hospitalizations for acute exacerbations of schizophrenia within 2 months before screening
• Clinical Global Impressions-Severity (CGI-S) score of ≤3 (mild) at screening and Visit 2
5. Subject has a total Positive and Negative Syndrome Scale (PANSS) score ≤80 at screening and Visit 2
6. Subject has stable positive symptoms, as shown by a score ≤ 4 on PANSS for items related to delusion, hallucination, conceptual disorganization, and unusual thought content, at screening and Visit 2.
7. Subject currently resides in a stable residence or living arrangement, has been in this residence/living arrangement for at least 8 weeks prior to screening, and the residence/living arrangement is not anticipated to change during the study.
8. Subject agrees to maintain current level of fitness or exercise regimen for the duration of the study
9. Subject reports a stable body weight for at least 3 months prior to screening
(change ≤5%) and from screening to Visit 2 (change ≤1 kg)
10. Subject agrees to use an acceptable method of contraception for the duration of the study |
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| E.4 | Principal exclusion criteria |
1. Subject does not meet duration of illness eligibility requirements for one of the following reasons:
•Subject initiated first antipsychotic treatment within the past 12 months.
•Subject has had symptoms lasting <2 years
2. Subject presents with comorbid neuropsychiatric disorders including the following:
• Axis I (according to DSM criteria) diagnosis of schizoaffective disorder or bipolar disorder, or current major depressive disorder that is untreated and/or unstable. Current major depressive disorder that is treated and stable is not a criterion for exclusion.
• Clinically significant cognitive difficulties that could interfere with participation in the study
• Drug induced or toxic psychosis
• Any other psychiatric condition that could interfere with participation in the study
3. Subject has a diagnosis (based on DSM-5 criteria) of moderate or severe alcohol or drug use disorder currently or at any time during the 3 months prior to screening.
4. Subject poses a current suicide risk as confirmed by the baseline Columbia-Suicide Severity Rating Scale (C-SSRS) by a response of “Yes” to question #4 or 5 with ideation or suicidal behavior occurring in the past year
5. Subject reports positive human immunodeficiency virus (HIV) status at screening
6. Subject has diabetes or meets any of the following criteria:
• Hemoglobin A1c (HbA1c) ≥6.5% at Visit 1,
• Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L) at Visit 2,
• A random plasma glucose ≥200 mg/dL (11.1 mmol/L) at Visit 1.
7. Subject has a clinically significant or unstable medical illness, condition, would be anticipated to potentially compromise subject safety or adversely
evaluation of efficacy, including (but not necessarily limited to) the following:
• Clinically significant hypotension or hypertension not controlled by medical therapy
• Unstable thyroid dysfunction in the past 6 months or a TSH value outside of the normal range at screening
• Personal or family history of neuroleptic malignant syndrome
• Dyslipidemia, defined for this study as total cholesterol >280 mg/dL>500 mg/dL, at screening
• Inflammatory bowel disease or any other gastrointestinal (GI) disorder with weight loss, anorexia nervosa, bulimia nervosa, or binge eating
• Neurologic conditions including the following:
− History of seizure disorder or a condition associated with seizures
− History of brain tumor, subdural hematoma or other clinically significant neurological condition within the 12 months prior to screening
− Head trauma with loss of consciousness within the 12 months prior to screening
− Active acute or chronic central nervous system (CNS) infection
− Stroke within the 6 months prior to screening
8. Subject has a cardiac condition that might confound the results of the study or pose additional risk when administering the investigational agents to the subject or preclude successful completion of the study. Such conditions include the following:
• Clinically significant cardiac arrhythmia, cardiomyopathy, or cardiac conduction
defect, a history of myocardial infarction or unstable angina, or clinically significant ECG abnormality at Visit 1 or Visit 2.
• QT interval >450 msec for men and >470 msec for women, as corrected by the
Fridericia formula (QTcF), observed at Visit 1 or Visit 2.
9. Subject has a laboratory abnormality that would compromise the well-being of the subject, or has any of the following specific laboratory results at Visit 1 or Visit 2:
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value ≥3 times the upper limit of the laboratory normal reference range
• Absolute neutrophil count ≤1.5 × 103 μL at Visit 1 and <1.0 ×103 μL at Visit 2
• Platelet count ≤75 × 103 μL
• Serum creatinine >2.5 mg/dL
• Positive pregnancy test result
10. Subject is pregnant or breastfeeding or is planning to become pregnant within 60 days of the last study drug administration
11. Subject has had any GI surgical procedures within one year prior to screening
12. Subject has had a surgical procedure for weight loss or is planning to have liposuction during the study
13. Subject has had significant changes in diet or exercise regimen within the 6 weeks prior to screening or plans to join a weight management program during the study.
14. Subject has started a smoking cessation program within the 6 months prior to screening or anticipates quitting smoking during the study
15. Subject requires or has had electroconvulsive therapy (ECT) treatment in the 2 month period prior to randomization
16. Subject has a positive urine drug screen for benzodiazepines, opioids,
amphetamine/methamphetamine, or cocaine at screening |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the absolute change in PANSS total score from randomization to the end of Part A.. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| AEs will be monitored continuously from the time the subjects signs the informed consent at every visit |
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| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include the following:
- Percent change in body weight
-Absolute change in body weight
-Proportion of subjects exhibiting signifficant weight gain (definitions of significant weight gain will include body weight gain greater than 7%)
- - Absolute change in CGI-S
Additional endpoints include the following:
- Change in waist circumference
- Change in IWQOL-Lite scales (physical function, self-esteem, sexual life, public distress and work) and total score
- Change in PSP
- Change in FCI
- Change in alcohol and drug use |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The timepoints will be evaluated at each visit or on specified visits as per schedule of assessments (Part A and Part B) |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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