A Study of ALKS 5461 for Treatment Refractory Major Depressive Disorder (MDD)

• ALKS 5461 (Drug): Samidorphan + buprenorphine, administered sublingually
• ALKS 5461 Placebo (Drug): Placebo tablet, administered sublingually

Primary outcomes

• Change From Baseline to the End of Treatment (EOT) in the Montgomery Asberg Depression Rating Scale-10 (MADRS-10) Scores [Baseline and 5 weeks for Stage 1, Baseline and 6 weeks for Stage 2]: The MADRS-10 scale is a clinician-administered questionnaire comprised of 10 items used to measure the severity of Major Depressive Disorder (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.

Secondary outcomes

• Montgomery Asberg Depression Rating Scale (MADRS) Response Rate [Baseline and 5 weeks for Stage 1, Baseline and 6 weeks for Stage 2]: The percentage of subjects demonstrating a MADRS-10 treatment response, defined as a >/= 50% reduction in MADRS-10 score from baseline to the end of the efficacy period (Week 5 for Stage 1, Week 6 for Stage 2). The MADRS-10 scale is a measure of the severity of Major Depressive Disorder (MDD) symptoms and includes the following 10 items: Apparent Sadness, Reported Sadness, Inner Tension, Reduced Sleep, Reduced Appetite, Concentration Difficulties, Lassitude, Inability to Feel, Pessimistic Thoughts, and Suicidal Thoughts. Scores range from 0 (no apparent symptoms) to 60 (most severe symptoms).
• Montgomery Asberg Depression Rating Scale (MADRS) Remission Rate [5 weeks for Stage 1, 6 weeks for Stage 2]: The percentage of subjects achieving remission, defined as a subject with a score </= 10 at the end of the efficacy period (Week 5 for Stage 1, Week 6 for Stage 2). The MADRS-10 scale is a measure of the severity of Major Depressive Disorder (MDD) symptoms and includes the following 10 items: Apparent Sadness, Reported Sadness, Inner Tension, Reduced Sleep, Reduced Appetite, Concentration Difficulties, Lassitude, Inability to Feel, Pessimistic Thoughts, and Suicidal Thoughts. Scores range from 0 (no apparent symptoms) to 60 (most severe symptoms).the end of the efficacy period.

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

* Have a Major Depressive Disorder (MDD) primary diagnosis
* Have a body mass index (BMI) of 18.0 to </= 40.0 kg/m\^2
* Be willing and able to follow the study procedures and visits as outlined in the protocol (including agreeing not to enroll in any other clinical trials)
* Have inadequate responses to antidepressant therapy (ADT) in the current Major Depressive Episode (MDE)
* Additional criteria may apply

Exclusion Criteria:

* Has any finding that would compromise the safety of the subject or affect their ability to adhere to the protocol visit schedule or fulfill visit requirements
* Has any other significant medical condition (eg, neurological, psychiatric, or metabolic) or clinical symptom that could unduly risk the subject or affect the interpretation of study data
* Has any current primary diagnosis other than MDD, where primary diagnosis is defined as the primary source of current distress and functional impairment
* Has experienced hallucinations, delusions, or any psychotic symptoms in the current MDE
* Has been hospitalized for MDD within 3 months before screening
* Has used opioid agonists (eg, codeine, oxycodone, tramadol, morphine) or opioid antagonists (eg, naloxone, naltrexone) within 14 days prior to screening
* Has received electroconvulsive therapy treatment within the last 2 years or within the current MDE or failed a course of electroconvulsive treatment at any time
* Has a significant risk for suicide
* Has a positive breath alcohol test at screening
* Has a positive test for drugs of abuse at screening or visit 2
* Is pregnant, planning to become pregnant, or is breastfeeding during the study
* Additional criteria may apply

Participant flow

Outcome results

• Change From Baseline to the End of Treatment (EOT) in the Montgomery Asberg Depression Rating Scale-10 (MADRS-10) Scores (Primary), Least squares mean, score on a scale: S1: Placebo -11.4 +/- 0.70; S1: ALKS 5461 2mg/2mg -13.9 +/- 1.12; S2: Placebo -4.2 +/- 1.06; S2: ALKS 5461 2mg/2mg -4.7 +/- 1.11 (p 0.128)
• Montgomery Asberg Depression Rating Scale (MADRS) Response Rate (Secondary), Count of participants, Participants: S1: Placebo 53; S1: ALKS 5461 2mg/2mg 27; S2: Placebo 10; S2: ALKS 5461 2mg/2mg 11
• Montgomery Asberg Depression Rating Scale (MADRS) Remission Rate (Secondary), Count of participants, Participants: S1: Placebo 31; S1: ALKS 5461 2mg/2mg 14; S2: Placebo 10; S2: ALKS 5461 2mg/2mg 8

Adverse events

Time frame: 5 weeks for Stage 1 and 6 weeks for Stage 2

Serious adverse events by term

Other adverse events by term

• Study Protocol (PDF, 2018-01-25)
• Statistical Analysis Plan (PDF, 2019-10-02)

• Sanjeev Pathak, MD, Study director, Alkermes, Inc.