A Study to Evaluate ALKS 5461 in Subjects With Major Depressive Disorder (MDD)

The study will measure efficacy using the HAM-D-17, the MADRS, and the CGI-S as well as using other scales and assessments.

• ALKS 5461 (Drug): Two active tablets, given daily
• Placebo (Drug): Two placebo tablets, given daily

Primary outcomes

• Change From Baseline to Week 4 in Hamilton Rating Scale for Depression (HAM-D17) Total Score [Baseline and 4 weeks for each stage]: The HAM-D17 scale is a clinician-administered questionnaire comprised of 17 items used to measure the severity of MDD symptoms. Scores range from 0 (no apparent symptoms) to 50 (most severe symptoms). Individual questionnaire items include depressed mood, work and activities, insomnia (early), insomnia (middle), insomnia (late), genital symptoms, somatic symptoms (gastrointestinal), loss of weight, somatic symptoms (general), feelings of guilt, suicide, anxiety (psychic), anxiety (somatic), hypochondriasis, insight, agitation, and retardation.

Secondary outcomes

• Proportion of Patients Who Exhibited Treatment Response (HAM-D17) [4 weeks for each stage]: The proportion of subjects demonstrating HAM-D17 treatment response, defined as a ≥ 50% reduction in HAM-D17 score from baseline to the end of the efficacy period (Week 4). The HAM-D17 is a clinician administered questionnaire comprised of 17 questions used to assess the severity of a patient's depression. Scores range from 0 (no apparent symptoms) to 50 (most severe symptoms). Individual questionnaire items include depressed mood, work and activities, insomnia (early), insomnia (middle), insomnia (late), genital symptoms, somatic symptoms (gastrointestinal), loss of weight, somatic symptoms (general), feelings of guilt, suicide, anxiety (psychic), anxiety (somatic), hypochondriasis, insight, agitation, and retardation.
• Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score [4 weeks for each stage]: The MADRS-10 scale is a clinician-administered questionnaire comprised of 10 items used to measure the severity of MDD symptoms. Scores range from 0 (no apparent symptoms) to 60 (most severe symptoms). Individual questionnaire items include: Apparent Sadness, Reported Sadness, Inner Tension, Reduced Sleep, Reduced Appetite, Concentration Difficulties, Lassitude, Inability to Feel, Pessimistic Thoughts, and Suicidal Thoughts.
• Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score [4 weeks for each stage]: The CGI-S is a 7-point scale that requires the clinician to assess how mentally ill the patient is at a specific point in time. Based on the scale, patients are categorized as follows: "1: normal, not at all ill"; "2: borderline mentally ill"; "3: mildly ill"; "4: moderately ill"; "5: markedly ill"; "6: severely ill"; and "7: among the most extremely ill patients."

Sex: All, ages: 18 Years to 65 Years

Inclusion Criteria:

* Diagnosed with a major depressive episode (MDE)
* Body mass index less than or equal to 40 kg/m2
* Have been treated with an adequate dose of SSRI/SNRI 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
* History of inadequate response during the entire current MDE to 1 or 2 adequate antidepressant treatments, including current treatment
* Be otherwise physically healthy

Exclusion Criteria:

* Have an axis I diagnosis of delirium, dementia, amnestic or other cognitive disorder, schizophrenia or other psychotic disorder, bipolar I or II disorder, eating disorder, obsessive-compulsive disorder, panic disorder, acute stress disorder, or posttraumatic stress disorder
* Have a clinically significant current axis II diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder
* Are experiencing hallucinations, delusions, or any psychotic symptomatology in the current MDE
* Receive new onset psychotherapy within 6 weeks of screening
* Use of opioid agonists (eg, codeine, oxycodone, morphine) within 14 days before screening
* Have received electroconvulsive therapy during the current MDE
* Have attempted suicide within the past 2 years
* Have a thyroid pathology
* Have a history of a seizure disorder or of neuroleptic malignant syndrome/serotonin syndrome
* Have a positive test for human immunodeficiency virus (HIV)

Additional inclusion/exclusion criteria may apply

Participant flow

Outcome results

• Change From Baseline to Week 4 in Hamilton Rating Scale for Depression (HAM-D17) Total Score (Primary), Least squares mean, score on a scale: Placebo S1 -7.1 +/- 0.6; ALKS 5461 2mg/2mg S1 -9.3 +/- 1.5; ALKS 5461 8mg/8mg S1 -6.6 +/- 1.6; Placebo S2 -1.5 +/- 1.1; ALKS 5461 2mg/2mg S2 -5.2 +/- 1.2; ALKS 5461 8mg/8mg S2 -3.3 +/- 1.1 (p 0.014)
• Proportion of Patients Who Exhibited Treatment Response (HAM-D17) (Secondary), Count of participants, Participants: Placebo S1 23; ALKS 5461 2mg/2mg S1 8; ALKS 5461 8mg/8mg S1 5; Placebo S2 3; ALKS 5461 2mg/2mg S2 6; ALKS 5461 8mg/8mg S2 5
• Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score (Secondary), Least squares mean, score on a scale: Placebo S1 -9.6 +/- 0.9; ALKS 5461 2mg/2mg S1 -13.3 +/- 2.2; ALKS 5461 8mg/8mg S1 -11.3 +/- 2.3; Placebo S2 -2.1 +/- 1.6; ALKS 5461 2mg/2mg S2 -8.8 +/- 1.7; ALKS 5461 8mg/8mg S2 -4.7 +/- 1.7
• Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score (Secondary), Least squares mean, score on a scale: Placebo S1 -1.0 +/- 0.1; ALKS 5461 2mg/2mg S1 -1.3 +/- 0.2; ALKS 5461 8mg/8mg S1 -1.2 +/- 0.3; Placebo S2 -0.5 +/- 0.2; ALKS 5461 2mg/2mg S2 -1.1 +/- 0.2; ALKS 5461 8mg/8mg S2 -0.6 +/- 0.2

Adverse events

Time frame: 4 weeks for each stage

Serious adverse events by term

Other adverse events by term

Limitations and caveats: Two subjects randomized to 8/8 received 2/2 and are presented in the Participant Flow, Baseline, and AE tables by actual treatment received. For the outcome measures, subjects were analyzed by randomization treatment assignment.

• Results publication: Fava M, Memisoglu A, Thase ME, Bodkin JA, Trivedi MH, de Somer M, Du Y, Leigh-Pemberton R, DiPetrillo L, Silverman B, Ehrich E. Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial. Am J Psychiatry. 2016 May 1;173(5):499-508. doi: 10.1176/appi.ajp.2015.15070921. Epub 2016 Feb 12. PMID 26869247

• Richard Leigh-Pemberton, MD, Study director, Alkermes, Inc.