| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Major Depressive Disorder |
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| E.1.1.1 | Medical condition in easily understood language |
| Major Depressive Disorder |
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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 | 10025454 |
| E.1.2 | Term | Major depressive disorder, recurrent episode |
| 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 the efficacy of ALKS 5461 for the adjunctive treatment of major depressive disorder (MDD) in adults who have an inadequate response to antidepressant therapy (ADT)
• To evaluate the safety and tolerability of ALKS 5461 in adults who have MDD and an inadequate response to ADT |
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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 |
FOR All subjects:
1. Be willing and able to provide informed consent.
2. Be between 18 and 70 years of age, inclusive.
3. Have a body mass index (BMI) of 18.0 to 40.0 kg/m2, inclusive.
4. Agree to use an acceptable method of contraception for the duration of the study and at least 30 days after last dose of study drug unless surgically sterile or postmenopausal.
5. Have a Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) MDD primary diagnosis as assessed and confirmed by the Mini International Neuropsychiatric Interview (MINI; administered by qualified site staff); primary diagnosis is defined as the primary source of current distress and functional impairment, in the opinion of the investigator.
6. Have a current major depressive episode (MDE) lasting 8 weeks to 24 months.
7. Be willing and able to follow the study procedures as outlined in the protocol including adherence with both approved ADT and study drug regimen.
FOR Subjects entering the prospective lead-in:
8. Are not currently taking any ADT
9. Have no more than 1 inadequate response to ADT in the current MDE as of screening; an inadequate response at screening is defined as <50% reduction in depressive symptom severity during a course of treatment at an adequate dose at least 8 weeks in duration, with the same, adequate dose of ADT in the last 4 weeks, as assessed by the Massachusetts General Hospital Antidepressant Response Questionnaire (ATRQ).
10. Have a HAM-D total score ≥22 at screening.
FOR Subjects bypassing the prospective lead-in (Historical Inadequate Responder [HIR] subjects)
11. Have been treated with an adequate dose of an SSRI, SNRI, or bupropion during the current MDE for at least 8 weeks, with the same, adequate dose over the last 4 weeks that is expected to remain stable throughout the study
Note: if a subject had experienced an adequate response to an ADT, and now has relapsed (ie, a new MDE has begun) but remains on the same ADT at the same or lower dose, this would not represent an adequate trial of an ADT for this MDE.
12. Have no more than 2 inadequate responses to ADT (inclusive of current inadequate response) in the current MDE as of screening. Current inadequate response must be to an SSRI, SNRI or bupropion. Prior inadequate response within the current MDE (if applicable) must be to an antidepressant medication listed on the ATRQ.
13. Have an inadequate response to current ADT treatment; a current inadequate response in HIR subjects is defined as <50% reduction in depressive symptom severity during a course of treatment at least 8 weeks in duration with an adequate dose of an SSRI, SNRI, or bupropion, as assessed by the ATRQ.
14. Have a HAM-D total score ≥18 at screening.
At Visit 2 for All subjects
15. Have a site-administered HAM-D score ≥18 at Visit 2.
16. Be deemed eligible by independent qualification, as evidenced by an independent-rater administered SAFER, ATRQ, and HAM-D total score ≥18.
17. Have a Clinical Global Impression -Severity (CGI-S) score of ≥3 at Visit 2.
FOR Subjects that have participated in the prospective lead-in period
18. Have been treated during the prospective lead-in period with an adequate dose of escitalopram, sertraline, duloxetine, venlafaxine, bupropion, or fluoxetine for at least 8 weeks, with the same adequate dose over the last 4 weeks
19. Have met additional masked criteria for prospective inadequate response as determined by an interactive voice or web response system (IxRS). |
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| E.4 | Principal exclusion criteria |
1. Have any finding that in the view of the investigator or medical monitor would compromise the safety of the subject or affect their ability to adhere to the protocol visit schedule or fulfill visit requirements.
2. Have any current primary Axis I diagnosis other than MDD, where primary diagnosis is defined as the primary source of current distress and functional impairment, in the opinion of the investigator.
3. Have any of the following psychiatric conditions per DSM-IV-TR criteria, as assessed by the MINI. Conditions not assessable by the MINI should be assessed by clinical judgment.
a. Lifetime history of an Axis I diagnosis of delirium, dementia, schizophrenia or other psychotic disorder (including psychotic depression), or bipolar I or II disorder.
b. History within the past 12 months of an Axis I diagnosis of eating disorder,obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, or acute stress disorder.
c. Clinically significant current Axis II diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder.
d. Current diagnosis or clinical evidence of any cognitive disorder at screening
4. Have experienced hallucinations, delusions, or any psychotic symptoms in the current MDE.
5. Have been hospitalized related to MDD within 3 months before screening.
6. Have initiated psychotherapy within 6 weeks of screening or have an anticipated need for initiating psychotherapy during the trial. A stable course of psychotherapy initiated >6 weeks prior to screening is permitted to continue throughout the trial.
7. Have received adjunctive therapy at an adequate dose and duration in combination with an ADT for the purpose of augmenting the effects of the ADT at any time during the current MDE. Such adjunctive therapies include, but are not restricted to, atypical antipsychotics, monoamine oxidase inhibitors, lithium, tricyclic antidepressants, psychostimulants, bupropion, or BUP.
8. Have used opioid agonists or opioid antagonists within 14 days prior to screening, or have used an extended-release formulation of an opioid antagonist within 2 months prior to screening.
9. Have initiated a hypnotic agent for insomnia within 30 days of screening or at any time during the study. Have used a hypnotic agent for insomnia >3 times per week within 30 days of screening or expect to use any of these agents >3 times per week at any time during the study. Have used a hypnotic agent for
any indication other than insomnia within 30 days prior to screening.
10. Have initiated or had a dose adjustment to hormone replacement therapy or oral contraceptive within 30 days of screening.
11. Have used inducers or moderate to strong inhibitors of cytochrome P450 (CYP) 3A4 within 30 days prior to screening .
12. Have received electroconvulsive therapy treatment within the last 2 years or received more than one course of electroconvulsive treatment during the subject’s lifetime.
13. Pose a current suicide risk, as evidenced by any of the following:
a. it is the opinion of the investigator that the subject may be at risk for suicide
b. the subject responds “Yes” to Question # 4 or Question # 5 on the Baseline C-SSRS, if the most recent episode occurred within the past 12 months.
c. the subject has attempted suicide within the past 2 years.
14. Have a QT interval >450 msec for males and >470 msec for females, assessed in a relaxed state, as corrected by the Fridericia formula (QTcF) observed at Visit 1 or Visit 2.
15. Have an aspartate aminotransferase or alanine transaminase measurement of >2× the upper limit of normal at Visit 1.
16. Have current evidence of or history of any of the following:
a. compromised respiratory function
b. thyroid pathology (unless stabilized and euthyroid for >3 months at the time of screening)
c. seizure disorder
d. hepatitis or human immunodeficiency virus (HIV) infection
17. Have current evidence of or a history (in the past 12 months) of alcohol or substance abuse or dependence per DSM-IV-TR criteria as assessed by the MINI.
18. Have a positive breath alcohol test at screening.
19. Have a positive test for drugs of abuse at screening or Visit 2.
20. Are pregnant, planning to become pregnant, or breastfeeding during the study.
21. Have a history of intolerance, allergy, or hypersensitivity to BUP or opioid antagonists.
22. Have had a significant blood loss (>500 mL) or blood donation within 60 days of screening or between screening and randomization or anticipated blood donation at any time during the trial.
23. Have participated in either of the following:
a. >2 clinical studies of an investigational product with a central nervous system indication in the past the past 4 years
b. any clinical study of an investigational product and/or have received an investigational drug or device within 30 days of screening.
24. Have participated in a prior clinical study of ALKS 5461 within 2 years.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint will be the change from baseline to the end of the efficacy period in MADRS total score.
The primary efficacy endpoint will be evaluated using mixed model repeated measures (MMRM). Comparison of the active versus placebo arms will be made and the least-squares mean difference along with the corresponding 95% confidence interval will be reported.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy will be assessed as follows:
MADRS - all site visits during the treatment period (except FU on Day 85)
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| E.5.2 | Secondary end point(s) |
Safety and tolerability will be assessed on the basis of:
• Treatment-emergent adverse events (TEAEs)
• Clinical laboratory results
• Vital signs
• Weight
• ECG results
• C-SSRS results
• COWS, as applicable. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | 2 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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 |
| Bulgaria |
| Canada |
| Czech Republic |
| France |
| Hungary |
| Slovakia |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| Last Visit of the Last Subject (LVLS) |
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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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
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