| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Major Depressive Disorder |
|
| E.1.1.1 | Medical condition in easily understood language |
| Major Depressive Disorder |
|
| 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 |
|
| 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 assess the long-term safety and tolerability of ALKS 5461 for use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
All Subjects
In order to qualify for participation in this study, all subjects must meet all of the following criteria:
1. Be willing and able to provide informed consent
2. Be willing and able to follow the study procedures as outlined in the protocol, including adherence with both approved antidepressant therapy (ADT) and study drug regimen
3. Agree to use an approved method of contraception for the duration of the study unless surgically sterile or postmenopausal
4. Have the potential to safely benefit from the administration of ALKS 5461, in the opinion of the investigator
New Subjects
In order to qualify for participation in this study, in addition to meeting the criteria for all subjects, New Subjects must also meet all of the following criteria:
5. Be between 18 and 70 years of age, inclusive
6. Have a body mass index (BMI) 18.0 - 40.0 kg/m2
7. Have not participated in a prior study of ALKS 5461 within 2 years
8. Have a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) MDD diagnosis at screening, as assessed and confirmed by the Mini International Neuropsychiatric Interview (MINI) administered by qualified site staff. The diagnosis of MDD must be considered by the investigator as the primary source of current distress and functional impairment.
9. Have a current major depressive episode (MDE) lasting 8 weeks to 24 months
10. Have been treated with an adequate dose of an approved ADT during the current MDE for at least 8 weeks, with the same, adequate dose over the last 4 weeks, which is expected to remain stable throughout the study
11. Have an inadequate response to current ADT and up to 1 prior ADT during the current MDE. An inadequate response is defined as less than a 50% reduction in depressive symptom severity during a course of treatment at least 8 weeks in duration with an adequate dose of an approved ADT, as assessed on-site using the Massachusetts General Hospital Antidepressant Treatment Questionnaire (ATRQ).
(NOTE: If a subject had an adequate response to an ADT in the past, but now has relapsed on the same ADT at the same or lower dose and is experiencing anew MDE, this would not represent an adequate trial of an ADT for this new MDE.)
12. Have a HAM-D total score of ≥14 at Visit 1 and ≥10 at Visit 2
Continuing Subjects
In order to qualify for participation in this study, in addition to meeting the criteria for all subjects, Continuing Subjects must also meet the following criterion:
13. Have completed the treatment period of ALK5461-205, ALK5461-206, ALK5461-207,
or ALK5461-210 within 10 days of Visit 2.
Lead-in Subjects
In order to qualify for participation in this study, in addition to meeting the criteria for all subjects, Lead-in Subjects must also meet all of the following criteria:
14. Have completed the prospective lead-in (PLI) of study ALK5461-205, ALK5461-206, or ALK5461-207 within the past 10 days
15. Have demonstrated a treatment response during the PLI of the antecedent study, but failed to achieve remission from MDD, as determined in an interactive voice or web response system (IxRS) using masked criteria.
|
|
| E.4 | Principal exclusion criteria |
All Subjects
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 fulfill the protocol visit schedule or visit requirements
2. Have a positive test for drugs of abuse at screening or Visit 2 (exception: a positive screen for benzodiazepine may not be exclusionary when such medication is medically indicated).
3. Are pregnant, planning to become pregnant, or breastfeeding during the study
New Subjects
4. Have any current “primary” Axis I diagnosis other than MDD, where “primary” is defined by the investigator as the primary source of current distress and functional impairment
5. 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 dementia, schizophrenia or other psychotic disorder (including psychotic depression), or bipolar disorder (I or II)
b. History within the past 12 months of an Axis I diagnosis of eating 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
6. Have experienced hallucinations, delusions, or any psychotic symptoms in the current MDE
7. Have initiated psychotherapy within 6 weeks of screening
8. Have received adjunctive therapy at an adequate dose and duration in combination with their approved ADT for the purpose of augmenting the effects of the ADT at any time during the current MDE
9. Have been hospitalized for MDD within 3 months prior to screening
10. Have used opioid agonists or opioid antagonists within 14 days before screening, or have an anticipated need for opioid use at any point during the study
11. Have used an extended-release formulation of an opioid antagonist within 2 months prior to screening
12. Have initiated a hypnotic agent for insomnia within 30 days prior to screening. Have used a hypnotic agent for insomnia >3 times/week within 30 days of screening, or expect to use any of these agents at >3 times/week at any time during the study. Have used a hypnotic agent for any indication other than insomnia within 30 days prior to screening.
13. Have initiated or had dose adjustment to hormone replacement therapy (including testosterone) or an oral contraceptive within 30 days of screening
14. Have used inducers or moderate to strong inhibitors of cytochrome P450 (CYP) 3A4 (prescription medications, over-the-counter medications [OTC], or dietary supplements) within 30 days prior to screening
15. Have received electroconvulsive therapy treatment within the last 2 years, or received more than 1 course of electroconvulsive treatment during their lifetime
16. 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
17. Have a QT interval >450 msec for men and >470 msec for women, assessed in a relaxed state, as corrected by the Fridericia formula (QTcF) observed at Visit 1 or Visit 2
18. Have an aspartate aminotransferase or alanine transaminase measurement of >2 times the upper limit of normal at Visit 1.
19. Have current evidence of or history of any of the following:
a. compromised respiratory function
b. thyroid pathology
c. seizure disorder
d. hepatitis or HIV
20. Have current evidence of, or a history in the past 12 months of, alcohol or substance abuse or dependence (excluding nicotine) per DSM-IV-TR criteria as assessed by the MINI
21. Have a positive breath alcohol test at screening
22. Have a history of intolerance, allergy or hypersensitivity to BUP or opioid antagonists
23. Have had a significant blood loss (>500 mL) or blood donation (including platelets or plasma) within 60 days of screening or between screening and randomization, or anticipated blood donation at any time during the trial
24. Have participated in any clinical trial of an investigational product and/or have received an investigational drug or device within 30 days prior to screening
25. Are an employee of the investigator or study center, or immediate family* of such employees or the investigator
26. Are an employee or an immediate family member* of an employee (permanent, temporary contract worker, or designee responsible for the conduct of the study) of Alkermes or the contract research organization (CRO) executing this study or any prior ALKS 5461 study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety and tolerability analyses will be performed using data from the safety population, defined as all subjects who receive at least 1 dose of ALKS 5461. Reported AE terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) preferred terms and system organ class categories.
Safety assessments will be summarized using descriptive statistics along with supportive listings. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| ALKS 5461 treatment effect over time will be assessed in an exploratory manner based on change from baseline in MADRS total score, HAM-A score, and CGI-S score. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
MADRS at: all site visits
HAM-A at: baseline, week 4, week 8, week 14, week 26, week 38, week 52,
CGI-S at: all visits during the treatment period |
|
| 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 | No |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 51 |
| 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 |
| Australia |
| Bulgaria |
| Canada |
| Czech Republic |
| Germany |
| Hungary |
| Lithuania |
| Poland |
| Puerto Rico |
| Slovakia |
| United States |
|
| 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) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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