A Study of ALKS 5461 for the Treatment of Major Depressive Disorder (MDD) - FORWARD-5 Study

• Sponsor: Alkermes, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02218008
• Collaborator: (none)
• Enrollment: 407
• Locations: 44
• Arms: 3
• Duration (Months): 27
• Patients Per Site: 9.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy and safety of ALKS 5461.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: ALKS 5461; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 407 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Efficacy and Safety Study of ALKS 5461 for the Adjunctive Treatment of Major Depressive Disorder (the FORWARD-5 Study)
• Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: Sep 1, 2016
• Actual Study Completion Date: Oct 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: High Dose	Drug: ALKS 5461; Sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant)
Experimental: Low Dose	Drug: ALKS 5461; Sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant)
Placebo Comparator: Placebo	Drug: Placebo; Sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant)

Outcome Measures

Primary Outcome Measures

1. Change in Montgomery Asberg Depression Rating Scale (MADRS)-6 Score Using Average of Changes From Baseline to Week 3 Through the End of Treatment Period (Week 5 for Stage 1, Week 6 for Stage 2) [Baseline and 5 weeks (Stage 1) and baseline and 6 weeks (Stage 2), combined together for the overall estimate of treatment effect]

   The MADRS-6 scale is a clinician-administered questionnaire used to measure the severity of MDD symptoms. The MADRS-6 scale is a subset of the MADRS-10 scale, comprised of the following individual questionnaire items: Apparent Sadness, Reported Sadness, Inner Tension, Lassitude, Inability to Feel, and Pessimistic Thoughts. Scores range from 0 (no apparent symptoms) to 36 (most severe symptoms).

2. Change in MADRS-10 Score Using Average of Changes From Baseline to Week 3 Through the End of Treatment Period (Week 5 for Stage 1, Week 6 for Stage 2) [5-6 Weeks (5 weeks for Stage 1 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 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.

3. Change From Baseline to End of Treatment in the MADRS-10 [5-6 Weeks (5 weeks for Stage 1 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 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 Outcome Measures

1. Proportion of Patients Who Exhibited Treatment Response (MADRS-10) [5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)]

   The proportion of subjects demonstrating MADRS-10 treatment response, defined as a ≥ 50% reduction in MADRS-10 score from baseline to the end of the efficacy period (week 5). 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.

2. Remission Rate [5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)]

   The proportion of subjects achieving remission, defined as a MADRS-10 score of ≤10 at the end of the efficacy period.

3. Number of Subjects With Adverse Events (AEs) [5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Have a BMI of 18.0 to 40.0 kg/m2, inclusive

• Agree to use an acceptable method of contraception for the duration of the study

• Have an MDD primary diagnosis

• Have no more than 2 inadequate responses to antidepressant therapy (ADT) in the current Major Depressive Episode (MDE)

• Additional criteria may apply

Exclusion Criteria:

• Have a current primary Axis-I disorder other than MDD

• Have used opioid agonists (eg, codeine, oxycodone, tramadol, morphine) or opioid antagonists (eg, naloxone, naltrexone) within 14 days

• Have received electroconvulsive therapy treatment within the last 2 years or received more than one course of electroconvulsive treatment during their lifetime

• Have attempted suicide within the past 2 years

• Have a positive test for drugs of abuse

• Are pregnant, planning to become pregnant, or breastfeeding

• Have a history of intolerance, allergy, or hypersensitivity to buprenorphine or opioid antagonists (eg, naltrexone, naloxone)

• Have had a significant blood loss or blood donation within 60 days

• Additional criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alkermes Investigational Site	Birmingham	Alabama	United States	35294
2	Alkermes Investigational Site	Colton	California	United States	92324
3	Alkermes Investigational Site	Garden Grove	California	United States	92845
4	Alkermes Investigational Site	Los Angeles	California	United States	90024
5	Alkermes Investigational Site	Oakland	California	United States	94612
6	Alkermes Investigational Site	Oceanside	California	United States	92056
7	Alkermes Investigational Site	Pico Rivera	California	United States	90660
8	Alkermes Investigational Site	San Gabriel	California	United States	91776
9	Alkermes Investigational Site	Colorado Springs	Colorado	United States	80910
10	Alkermes Investigational Site	Bradenton	Florida	United States	34201
11	Alkermes Investigational Site	Fort Myers	Florida	United States	33912
12	Alkermes Investigational Site	Melbourne	Florida	United States	32901
13	Alkermes Investigational Site	North Miami	Florida	United States	33161
14	Alkermes Investigational Site	Oakland Park	Florida	United States	33334
15	Alkermes Investigational Site	Winter Haven	Florida	United States	33880
16	Alkermes Investigational Site	Smyrna	Georgia	United States	30080
17	Alkermes Investigational Site	Hoffman Estates	Illinois	United States	60169
18	Alkermes Investigational Site	Flowood	Mississippi	United States	39232
19	Alkermes Investigational Site	Saint Charles	Missouri	United States	63304
20	Alkermes Investigational Site	Saint Louis	Missouri	United States	63141
21	Alkermes Investigational Site	Princeton	New Jersey	United States	08540
22	Alkermes Investigational Site	New York	New York	United States	10168
23	Alkermes Investigational Site	High Point	North Carolina	United States	27265
24	Alkermes Investigational Site	Canton	Ohio	United States	44718
25	Alkermes Investigational Site	Portland	Oregon	United States	97214
26	Alkermes Investigational Site	Memphis	Tennessee	United States	38119
27	Alkermes Investigational Site	DeSoto	Texas	United States	75115
28	Alkermes Investigational Site	Wichita Falls	Texas	United States	76309
29	Alkermes Investigational Site	Clinton	Utah	United States	84015
30	Alkermes Investigational Site	Bellevue	Washington	United States	98007
31	Alkermes Investigational Site	Seattle	Washington	United States	98104
32	Alkermes Investigational Site	Spokane	Washington	United States	99204
33	Alkermes Investigational Site	Gatineau		Canada	J8T 8J1
34	Alkermes Investigational Site	Halifax		Canada	B3S 1M7
35	Alkermes Investigational Site	Penticton		Canada	V2A 4M4
36	Alkermes Investigational Site	Quebec		Canada	G3K 2P8
37	Alkermes Investigational Site	Berlin		Germany	10245
38	Alkermes Investigational Site	Berlin		Germany	10629
39	Alkermes Investigational Site	Hannover		Germany	30159
40	Alkermes Investigational Site	Oranienburg		Germany	16515
41	Alkermes Investigational Site	Schwerin		Germany	19053
42	Alkermes Investigational Site	Stralsund		Germany	18439
43	Alkermes Investigational Site	San Juan		Puerto Rico	00918
44	Alkermes Investigational Site	San Juan		Puerto Rico	00926

Sponsors and Collaborators

• Alkermes, Inc.

Investigators

• Study Director: Sanjeev Pathak, MD, Alkermes, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alkermes, Inc.
• ClinicalTrials.gov Identifier: NCT02218008
• Other Study ID Numbers: ALK5461-207
• First Posted: Aug 15, 2014
• Last Update Posted: Aug 14, 2019
• Last Verified: Aug 1, 2019

• Keywords provided by Alkermes, Inc.: Major depressive disorder (MDD); depression; Alkermes; ALKS 5461; samidorphan
• Additional relevant MeSH terms: Disease; Depressive Disorder; Depression; Depressive Disorder, Major

Study Results

Participant Flow

Recruitment Details	Subjects were diagnosed with major depressive disorder (MDD), and had an inadequate response to 1 or 2 adequate courses of treatment with a commercially available antidepressant therapy (ADT) during the current major depressive episode (MDE). All subjects continued ADT for the duration of the study.
Pre-assignment Detail	This was a Sequential Parallel Comparison Design (SPCD) study comprised of 2 stages. In Stage 1 subjects were randomized to ALKS 5461 or placebo (2:2:9). In Stage 2 only placebo non-responders from Stage 1 were re-randomized to ALKS 5461 or placebo (1:1:1). 1 subject randomized to the placebo group in Stage 1 did not receive any study drug.

Arm/Group Title	Placebo S1	ALKS 5461 1mg/1mg S1	ALKS 5461 2mg/2mg S1	Placebo S2	ALKS 5461 1mg/1mg S2	ALKS 5461 2mg/2mg S2
Arm/Group Description	Randomized to placebo in Stage 1	Randomized to ALKS 5461 1mg/1mg in Stage 1	Randomized to ALKS 5461 2mg/2mg in Stage 1	Randomized to placebo in Stage 2	Randomized to ALKS 5461 1mg/1mg in Stage 2	Randomized to ALKS 5461 2mg/2mg in Stage 2
Period Title: Stage 1 (S1)
STARTED	280	63	63	0	0	0
COMPLETED	258	56	48	0	0	0
NOT COMPLETED	22	7	15	0	0	0
Period Title: Stage 1 (S1)
STARTED	0	0	0	62	62	63
COMPLETED	0	0	0	58	58	57
NOT COMPLETED	0	0	0	4	4	6

Baseline Characteristics

Arm/Group Title	Placebo	ALKS 5461 1mg/1mg	ALKS 5461 2mg/2mg	Total
Arm/Group Description	Randomized to placebo in Stage 1	Randomized to ALKS 5461 1mg/1mg in Stage 1	Randomized to ALKS 5461 2mg/2mg in Stage 1	Total of all reporting groups
Overall Participants	280	63	63	406
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.7 (12.87)	45.1 (11.46)	42.9 (14.48)	45.2 (12.93)
Sex: Female, Male (Count of Participants)
Female	193 68.9%	42 66.7%	42 66.7%	277 68.2%
Male	87 31.1%	21 33.3%	21 33.3%	129 31.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	48 17.1%	10 15.9%	9 14.3%	67 16.5%
Not Hispanic or Latino	232 82.9%	53 84.1%	54 85.7%	339 83.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.4%	0 0%	0 0%	1 0.2%
Asian	5 1.8%	2 3.2%	2 3.2%	9 2.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	67 23.9%	17 27%	11 17.5%	95 23.4%
White	207 73.9%	44 69.8%	50 79.4%	301 74.1%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
Canada	5 1.8%	1 1.6%	1 1.6%	7 1.7%
United States	229 81.8%	54 85.7%	52 82.5%	335 82.5%
Germany	46 16.4%	8 12.7%	10 15.9%	64 15.8%

Outcome Measures

1. Primary Outcome

Title	Change in Montgomery Asberg Depression Rating Scale (MADRS)-6 Score Using Average of Changes From Baseline to Week 3 Through the End of Treatment Period (Week 5 for Stage 1, Week 6 for Stage 2)
Description	The MADRS-6 scale is a clinician-administered questionnaire used to measure the severity of MDD symptoms. The MADRS-6 scale is a subset of the MADRS-10 scale, comprised of the following individual questionnaire items: Apparent Sadness, Reported Sadness, Inner Tension, Lassitude, Inability to Feel, and Pessimistic Thoughts. Scores range from 0 (no apparent symptoms) to 36 (most severe symptoms).
Time Frame	Baseline and 5 weeks (Stage 1) and baseline and 6 weeks (Stage 2), combined together for the overall estimate of treatment effect

Outcome Measure Data

Analysis Population Description

Stage 1 and Stage 2 Full Analysis Sets (FAS) consisted of subjects who were randomized and took at least 1 dose of study drug and had at least 1 postbaseline MADRS assessment in the respective stage.

Arm/Group Title	Placebo S1	ALKS 5461 1mg/1mg S1	ALKS 5461 2mg/2mg S1	Placebo S2	ALKS 5461 1mg/1mg S2	ALKS 5461 2mg/2mg S2
Arm/Group Description	Randomized to placebo in Stage 1	Randomized to ALKS 5461 1mg/1mg in Stage 1	Randomized to ALKS 5461 2mg/2mg in Stage 1	Randomized to placebo in Stage 2	Randomized to ALKS 5461 1mg/1mg in Stage 2	Randomized to ALKS 5461 2mg/2mg in Stage 2
Measure Participants	273	62	63	60	62	63
Least Squares Mean (Standard Error) [Units on a scale]	-5.6 (0.34)	-6.0 (0.74)	-6.8 (0.75)	-1.5 (0.65)	-2.2 (0.67)	-3.2 (0.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo S1, ALKS 5461 2mg/2mg S1, Placebo S2, ALKS 5461 2mg/2mg S2
	Comments	Analysis was conducted for each stage separately and overall efficacy was based on combined stage analysis where stage-specific estimates were combined using pre-specified equal weights. Within each stage ALKS 5461 2mg/2mg was compared to placebo (i.e., ALKS 5461 2mg/2mg S1 vs Placebo S1; and ALKS 5461 2mg/2mg S2 vs Placebo S2. The pre-specified order of hypothesis tests was ALKS 5461 2/2 compared to placebo followed by ALKS 5461 1/1 compared to placebo.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments	Hypothesis tests were two-sided with an alpha of 0.05. Control of type 1 error inflation due to multiplicity was achieved by pre-specifying a fixed sequence for statistical tests.
	Method	Mixed Models Analysis
	Comments	ALKS 5461 was compared to pbo using stage-specific MMRM for MADRS-10 Change from Baseline. Model-derived estimates were combined using equal weights.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 95%; -2.7 to -0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates below zero favor ALKS 5461.

2. Primary Outcome

Title	Change in MADRS-10 Score Using Average of Changes From Baseline to Week 3 Through the End of Treatment Period (Week 5 for Stage 1, Week 6 for Stage 2)
Description	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.
Time Frame	5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)

Outcome Measure Data

Analysis Population Description

Stage 1 and Stage 2 Full Analysis Sets (FAS) consisted of subjects who were randomized and took at least 1 dose of study drug and had at least 1 postbaseline MADRS-10 assessment in the respective stage.

Arm/Group Title	Placebo S1	ALKS 5461 1mg/1mg S1	ALKS 5461 2mg/2mg S1	Placebo S2	ALKS 5461 1mg/1mg S2	ALKS 5461 2mg/2mg S2
Arm/Group Description	Randomized to placebo in Stage 1	Randomized to ALKS 5461 1mg/1mg in Stage 1	Randomized to ALKS 5461 2mg/2mg in Stage 1	Randomized to placebo in Stage 2	Randomized to ALKS 5461 1mg/1mg in Stage 2	Randomized to ALKS 5461 2mg/2mg in Stage 2
Measure Participants	273	62	63	60	62	63
Least Squares Mean (Standard Error) [Units on a scale]	-8.1 (0.48)	-8.8 (1.05)	-10.3 (1.06)	-2.1 (0.88)	-3.2 (0.91)	-3.7 (0.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo S1, ALKS 5461 2mg/2mg S1, Placebo S2, ALKS 5461 2mg/2mg S2
	Comments	Analysis was conducted for each stage separately and overall efficacy was based on combined stage analysis where stage-specific estimates were combined using pre-specified equal weights. Within each stage ALKS 5461 2mg/2mg was compared to placebo (i.e., ALKS 5461 2mg/2mg S1 vs Placebo S1; and ALKS 5461 2mg/2mg S2 vs Placebo S2. The pre-specified order of hypothesis tests was ALKS 5461 2/2 compared to placebo followed by ALKS 5461 1/1 compared to placebo.
	Type of Statistical Test	Superiority
	Comments	Hypothesis tests were two-sided with an alpha of 0.05. Control of type 1 error inflation due to multiplicity was achieved by pre-specifying a fixed sequence for statistical tests.
Statistical Test of Hypothesis	p-Value	0.026
	Comments	ALKS 5461 was compared to pbo using stage-specific MMRM for MADRS-10 Change from Baseline. Model-derived estimates were combined using equal weights.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-1.9
	Confidence Interval	(2-Sided) 95%; -3.6 to -0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimates below zero favor ALKS 5461.

3. Primary Outcome

Title	Change From Baseline to End of Treatment in the MADRS-10
Description	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.
Time Frame	5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)

Outcome Measure Data

Analysis Population Description

Stage 1 and Stage 2 Full Analysis Sets (FAS) consisted of subjects who were randomized and took at least 1 dose of study drug and had at least 1 postbaseline MADRS-10 assessment in the respective stage.

Arm/Group Title	Placebo S1	ALKS 5461 1mg/1mg S1	ALKS 5461 2mg/2mg S1	Placebo S2	ALKS 5461 1mg/1mg S2	ALKS 5461 2mg/2mg S2
Arm/Group Description	Randomized to placebo in Stage 1	Randomized to ALKS 5461 1mg/1mg in Stage 1	Randomized to ALKS 5461 2mg/2mg in Stage 1	Randomized to placebo in Stage 2	Randomized to ALKS 5461 1mg/1mg in Stage 2	Randomized to ALKS 5461 2mg/2mg in Stage 2
Measure Participants	273	62	63	60	62	63
Least Squares Mean (Standard Error) [Units on a scale]	-9.2 (0.55)	-10.3 (1.19)	-10.8 (1.22)	-1.9 (0.96)	-3.4 (0.98)	-3.6 (0.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo S1, ALKS 5461 2mg/2mg S1, Placebo S2, ALKS 5461 2mg/2mg S2
	Comments	ALKS 5461 is compared to placebo within each of the 2 stages (i.e., ALKS 5461 2/2 S1 vs Placebo S1; and ALKS 5461 2/2 S2 vs Placebo S2). Efficacy was estimated as a weighted average across 2 stages using equal weights.
	Type of Statistical Test	Superiority
	Comments	The primary hypotheses were evaluated using a 6-step, fixed sequence approach to adjust for multiple comparisons. Using this method, hypothesis testing (using alpha=0.05) continued through the sequence until statistical significance was not achieved. Steps 1-3 included testing the ALKS 5461 2mg/2mg dose vs placebo for the 3 primary endpoints.
Statistical Test of Hypothesis	p-Value	0.076
	Comments	ALKS 5461 is compared to placebo within each of the 2 stages, and resulting treatment effects from each stage are combined for a single hypothesis test using equal weights of 0.5 for both stages.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-1.7
	Confidence Interval	(2-Sided) 95%; -3.6 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Proportion of Patients Who Exhibited Treatment Response (MADRS-10)
Description	The proportion of subjects demonstrating MADRS-10 treatment response, defined as a ≥ 50% reduction in MADRS-10 score from baseline to the end of the efficacy period (week 5). 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.
Time Frame	5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)

Outcome Measure Data

Analysis Population Description

Stage 1 and Stage 2 Full Analysis Sets (FAS) consisted of subjects who were randomized and took at least 1 dose of study drug and had at least 1 postbaseline MADRS-10 assessment in the respective stage.

Arm/Group Title	Placebo S1	ALKS 5461 1mg/1mg S1	ALKS 5461 2mg/2mg S1	Placebo S2	ALKS 5461 1mg/1mg S2	ALKS 5461 2mg/2mg S2
Arm/Group Description	Randomized to placebo in Stage 1	Randomized to ALKS 5461 1mg/1mg in Stage 1	Randomized to ALKS 5461 2mg/2mg in Stage 1	Randomized to placebo in Stage 2	Randomized to ALKS 5461 1mg/1mg in Stage 2	Randomized to ALKS 5461 2mg/2mg in Stage 2
Measure Participants	273	62	63	60	62	63
Yes	61 21.8%	17 27%	16 25.4%	7 1.7%	7 NaN	6 NaN
No	212 75.7%	45 71.4%	47 74.6%	53 13.1%	55 NaN	57 NaN

5. Secondary Outcome

Title	Remission Rate
Description	The proportion of subjects achieving remission, defined as a MADRS-10 score of ≤10 at the end of the efficacy period.
Time Frame	5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)

Outcome Measure Data

Analysis Population Description

Stage 1 and Stage 2 Full Analysis Sets (FAS) consisted of subjects who were randomized and took at least 1 dose of study drug and had at least 1 postbaseline MADRS-10 (or HAM-D17) assessment in the respective stage.

Arm/Group Title	Placebo S1	ALKS 5461 1mg/1mg S1	ALKS 5461 2mg/2mg S1	Placebo S2	ALKS 5461 1mg/1mg S2	ALKS 5461 2mg/2mg S2
Arm/Group Description	Randomized to placebo in Stage 1	Randomized to ALKS 5461 1mg/1mg in Stage 1	Randomized to ALKS 5461 2mg/2mg in Stage 1	Randomized to placebo in Stage 2	Randomized to ALKS 5461 1mg/1mg in Stage 2	Randomized to ALKS 5461 2mg/2mg in Stage 2
Measure Participants	273	62	63	60	62	63
Yes	31 11.1%	8 12.7%	8 12.7%	4 1%	6 NaN	5 NaN
No	242 86.4%	54 85.7%	55 87.3%	56 13.8%	56 NaN	58 NaN

6. Secondary Outcome

Title	Number of Subjects With Adverse Events (AEs)
Time Frame	5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)

Outcome Measure Data

Analysis Population Description

The safety population includes all subjects who were randomized and received at least 1 dose of study drug.

Arm/Group Title	Placebo S1	ALKS 5461 1mg/1mg S1	ALKS 5461 2mg/2mg S1	Placebo S2	ALKS 5461 1mg/1mg S2	ALKS 5461 2mg/2mg S2
Arm/Group Description	Randomized to placebo in Stage 1	Randomized to ALKS 5461 1mg/1mg in Stage 1	Randomized to ALKS 5461 2mg/2mg in Stage 1	Randomized to placebo in Stage 2	Randomized to ALKS 5461 1mg/1mg in Stage 2	Randomized to ALKS 5461 2mg/2mg in Stage 2
Measure Participants	280	63	63	62	62	63
Count of Participants [Participants]	151 53.9%	37 58.7%	42 66.7%	25 6.2%	29 NaN	25 NaN

Adverse Events

Time Frame	5 weeks for Stage 1 and 6 weeks for Stage 2
Adverse Event Reporting Description	The safety population includes all subjects who were randomized and received at least 1 dose of study drug.
Arm/Group Title	Placebo S1		ALKS 5461 1mg/1mg S1		ALKS 5461 2mg/2mg S1		Placebo S2		ALKS 5461 1mg/1mg S2		ALKS 5461 2mg/2mg S2
Arm/Group Description	Randomized to placebo in Stage 1		Randomized to ALKS 5461 1mg/1mg in Stage 1		Randomized to ALKS 5461 2mg/2mg in Stage 1		Randomized to placebo in Stage 2		Randomized to ALKS 5461 1mg/1mg in Stage 2		Randomized to ALKS 5461 2mg/2mg in Stage 2
All Cause Mortality
	Placebo S1		ALKS 5461 1mg/1mg S1		ALKS 5461 2mg/2mg S1		Placebo S2		ALKS 5461 1mg/1mg S2		ALKS 5461 2mg/2mg S2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/280 (0%)		0/63 (0%)		0/63 (0%)		0/62 (0%)		0/62 (0%)		0/63 (0%)
Serious Adverse Events
	Placebo S1		ALKS 5461 1mg/1mg S1		ALKS 5461 2mg/2mg S1		Placebo S2		ALKS 5461 1mg/1mg S2		ALKS 5461 2mg/2mg S2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/280 (0.4%)		0/63 (0%)		2/63 (3.2%)		1/62 (1.6%)		0/62 (0%)		0/63 (0%)
Gastrointestinal disorders
Abdominal Pain	1/280 (0.4%)	1	0/63 (0%)	0	0/63 (0%)	0	0/62 (0%)	0	0/62 (0%)	0	0/63 (0%)	0
Injury, poisoning and procedural complications
Wrist Fracture	0/280 (0%)	0	0/63 (0%)	0	1/63 (1.6%)	1	0/62 (0%)	0	0/62 (0%)	0	0/63 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle strain	0/280 (0%)	0	0/63 (0%)	0	1/63 (1.6%)	1	0/62 (0%)	0	0/62 (0%)	0	0/63 (0%)	0
Psychiatric disorders
Suicide Attempt	0/280 (0%)	0	0/63 (0%)	0	0/63 (0%)	0	1/62 (1.6%)	1	0/62 (0%)	0	0/63 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo S1		ALKS 5461 1mg/1mg S1		ALKS 5461 2mg/2mg S1		Placebo S2		ALKS 5461 1mg/1mg S2		ALKS 5461 2mg/2mg S2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	72/280 (25.7%)		25/63 (39.7%)		28/63 (44.4%)		11/62 (17.7%)		6/62 (9.7%)		10/63 (15.9%)
Gastrointestinal disorders
Nausea	20/280 (7.1%)	21	9/63 (14.3%)	11	17/63 (27%)	20	1/62 (1.6%)	1	2/62 (3.2%)	2	5/63 (7.9%)	5
Vomiting	7/280 (2.5%)	8	3/63 (4.8%)	3	6/63 (9.5%)	6	1/62 (1.6%)	1	0/62 (0%)	0	1/63 (1.6%)	2
Constipation	9/280 (3.2%)	10	9/63 (14.3%)	10	5/63 (7.9%)	5	0/62 (0%)	0	2/62 (3.2%)	2	4/63 (6.3%)	4
General disorders
Fatigue	1/280 (0.4%)	1	5/63 (7.9%)	5	7/63 (11.1%)	8	1/62 (1.6%)	1	0/62 (0%)	0	1/63 (1.6%)	1
Infections and infestations
Nasopharyngitis	8/280 (2.9%)	8	1/63 (1.6%)	1	3/63 (4.8%)	3	4/62 (6.5%)	4	2/62 (3.2%)	2	1/63 (1.6%)	1
Nervous system disorders
Dizziness	12/280 (4.3%)	13	6/63 (9.5%)	6	7/63 (11.1%)	7	1/62 (1.6%)	1	1/62 (1.6%)	1	2/63 (3.2%)	2
Headache	22/280 (7.9%)	23	4/63 (6.3%)	5	5/63 (7.9%)	5	4/62 (6.5%)	6	0/62 (0%)	0	2/63 (3.2%)	2
Somnolence	12/280 (4.3%)	12	4/63 (6.3%)	4	3/63 (4.8%)	3	0/62 (0%)	0	0/62 (0%)	0	0/63 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Should an Investigator desire to disclose study results, Sponsor will review the results disclosure prior to public release and can embargo the disclosure for a period of at least 60 days. Revisions to the disclosure will be negotiated in good faith. For a multicenter study the Investigators agree to publish/publicly present the results together with the other sites for the 12 month period after study results are available unless Sponsor grants written permission in advance.