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Trial record 26 of 889 for:    "Depressive Disorder" [DISEASE] AND MADRS

A Study of ALKS 5461 for the Treatment of Major Depressive Disorder (MDD) - the FORWARD-4 Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02158533
Recruitment Status : Completed
First Posted : June 9, 2014
Results First Posted : March 27, 2019
Last Update Posted : August 14, 2019
Sponsor:
Information provided by (Responsible Party):
Alkermes, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Major Depressive Disorder
Interventions Drug: High Dose ALKS 5461
Drug: Low Dose ALKS 5461
Drug: Placebo
Enrollment 385
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 Details 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). One subject randomized to the PBO group in Stage 1 did not receive study drug.
Arm/Group Title Placebo S1 ALKS 5461 0.5mg/0.5mg S1 ALKS 5461 2mg/2mg S1 Placebo S2 ALKS 5461 0.5mg/0.5mg S2 ALKS 5461 2mg/2mg S2
Hide Arm/Group Description Randomized to placebo in Stage 1 Randomized to ALKS 5461 0.5mg/0.5mg in Stage 1 Randomized to ALKS 5461 2mg/2mg in Stage 1 Randomized to placebo in Stage 2 Randomized to ALKS 5461 0.5mg/0.5mg in Stage 2 Randomized to ALKS 5461 2mg/2mg in Stage 2
Period Title: Stage 1
Started 265 59 60 0 0 0
Completed 251 51 52 0 0 0
Not Completed 14 8 8 0 0 0
Reason Not Completed
Adverse Event             6             4             7             0             0             0
Withdrawal by Subject             3             2             1             0             0             0
Lack of Efficacy             1             0             0             0             0             0
Lost to Follow-up             3             1             0             0             0             0
Failure to Meet Eligibility Criteria             0             1             0             0             0             0
Non-compliance with study visits             1             0             0             0             0             0
Period Title: Stage 2
Started [1] 0 0 0 56 56 56
Completed 0 0 0 53 52 50
Not Completed 0 0 0 3 4 6
Reason Not Completed
Adverse Event             0             0             0             0             0             1
Lack of Efficacy             0             0             0             0             1             0
Lost to Follow-up             0             0             0             1             1             2
Withdrawal by Subject             0             0             0             0             1             2
Physician Decision             0             0             0             0             1             0
Pregnancy             0             0             0             1             0             0
Psychiatrist decision to try new tx             0             0             0             1             0             0
Non-adherence with study visits             0             0             0             0             0             1
[1]
Subjects randomized in Stage 2 are a subset of those randomized to placebo in Stage 1.
Arm/Group Title Placebo S1 ALKS 5461 0.5mg/0.5mg S1 ALKS 5461 2mg/2mg S1 Total
Hide Arm/Group Description Randomized to placebo in Stage 1 Randomized to ALKS 0.5mg/0.5mg in Stage 1 Randomized to ALKS 5461 2/2 in Stage 1 Total of all reporting groups
Overall Number of Baseline Participants 265 59 60 384
Hide Baseline Analysis Population Description
All subjects randomized to Stage 1 (i.e., all subjects randomized during the study) who received ≥ 1 dose of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 265 participants 59 participants 60 participants 384 participants
45.8  (11.50) 45.0  (13.89) 46.2  (12.14) 45.7  (11.97)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 265 participants 59 participants 60 participants 384 participants
Female
182
  68.7%
38
  64.4%
40
  66.7%
260
  67.7%
Male
83
  31.3%
21
  35.6%
20
  33.3%
124
  32.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 265 participants 59 participants 60 participants 384 participants
Hispanic or Latino
33
  12.5%
7
  11.9%
4
   6.7%
44
  11.5%
Not Hispanic or Latino
232
  87.5%
52
  88.1%
56
  93.3%
340
  88.5%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 265 participants 59 participants 60 participants 384 participants
American Indian or Alaska Native
1
   0.4%
0
   0.0%
0
   0.0%
1
   0.3%
Asian
3
   1.1%
1
   1.7%
2
   3.3%
6
   1.6%
Native Hawaiian or Other Pacific Islander
2
   0.8%
0
   0.0%
0
   0.0%
2
   0.5%
Black or African American
77
  29.1%
16
  27.1%
16
  26.7%
109
  28.4%
White
182
  68.7%
42
  71.2%
42
  70.0%
266
  69.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 265 participants 59 participants 60 participants 384 participants
Canada
32
  12.1%
4
   6.8%
4
   6.7%
40
  10.4%
United States
218
  82.3%
53
  89.8%
52
  86.7%
323
  84.1%
Australia
15
   5.7%
2
   3.4%
4
   6.7%
21
   5.5%
1.Primary Outcome
Title Change From Baseline to Week 5 in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score
Hide 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 Baseline and 5 weeks for each stage
Hide Outcome Measure Data
Hide 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 0.5mg/0.5mg S1 ALKS 5461 2mg/2mg S1 Placebo S2 ALKS 5461 0.5mg/0.5mg S2 ALKS 5461 2mg/2mg S2
Hide Arm/Group Description:
Randomized to placebo in Stage 1
Randomized to ALKS 5461 0.5mg/0.5mg in Stage 1
Randomized to ALKS 5461 2mg/2mg in Stage 1
Randomized to placebo in Stage 2
Randomized to ALKS 5461 0.5mg/0.5mg in Stage 2
Randomized to ALKS 5461 2mg/2mg in Stage 2
Overall Number of Participants Analyzed 256 58 59 54 55 54
Least Squares Mean (Standard Error)
Unit of Measure: units on a scale
-11.1  (0.67) -8.4  (1.49) -13.0  (1.50) -2.2  (1.08) -4.8  (1.27) -3.9  (1.13)
Show Statistical Analysis 1 Hide 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 0.5mg/0.5mg compared to placebo.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.109
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 -1.8
Confidence Interval (2-Sided) 95%
-4.1 to 0.4
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.14
Estimation Comments Estimates below zero favor ALKS 5461.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo S1, ALKS 5461 0.5mg/0.5mg S1, Placebo S2, ALKS 5461 0.5mg/0.5mg 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 0.5mg/0.5mg was compared to placebo (i.e., ALKS 5461 0.5mg/0.5mg S1 vs Placebo S1; and ALKS 5461 0.5mg/0.5mg S2 vs Placebo S2). The pre-specified order of hypothesis tests was ALKS 5461 2/2 compared to placebo followed by ALKS 5461 0.5/0.5 compared to placebo.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.975
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 0.0
Confidence Interval (2-Sided) 95%
-2.3 to 2.3
Parameter Dispersion
Type: Standard Error of the Mean
Value: 1.17
Estimation Comments Estimates below zero favor ALKS 5461.
2.Secondary Outcome
Title Proportion of Patients Who Exhibited Treatment Response (MADRS-10)
Hide 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 measure of the severity of 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).
Time Frame Baseline and 5 weeks for each stage
Hide Outcome Measure Data
Hide Analysis Population Description
Stage 1 Full Analysis Set (FAS) consisted of subjects who took at least 1 dose of study drug and had at least 1 postbaseline assessment of MADRS in Stage 1. Stage 2 FAS consisted of Stage 1 placebo non-responders who entered Stage 2 and who received at least 1 dose of study drug and had at least 1 postbaseline assessment of MADRS in Stage 2.
Arm/Group Title Placebo S1 ALKS 5461 0.5mg/0.5mg S1 ALKS 5461 2mg/2mg S1 Placebo S2 ALKS 5461 0.5mg/0.5mg S2 ALKS 5461 2mg/2mg S2
Hide Arm/Group Description:
Randomized to placebo in Stage 1
Randomized to ALKS 5461 0.5mg/0.5mg in Stage 1
Randomized to ALKS 5461 2mg/2mg in Stage 1
Randomized to placebo in Stage 2
Randomized to ALKS 5461 0.5mg/0.5mg in Stage 2
Randomized to ALKS 5461 2mg/2mg in Stage 2
Overall Number of Participants Analyzed 256 58 59 54 55 54
Measure Type: Count of Participants
Unit of Measure: Participants
Yes
79
  30.9%
9
  15.5%
20
  33.9%
6
  11.1%
9
  16.4%
9
  16.7%
No
177
  69.1%
49
  84.5%
39
  66.1%
48
  88.9%
46
  83.6%
45
  83.3%
3.Secondary Outcome
Title Remission Rate
Hide Description The proportion of subjects achieving remission, defined as a MADRS-10 score of </= 10 at the end of the efficacy period.
Time Frame Baseline and 5 weeks for each stage
Hide Outcome Measure Data
Hide Analysis Population Description
Stage 1 Full Analysis Set (FAS) consisted of subjects who took at least 1 dose of study drug and had at least 1 postbaseline assessment of MADRS in Stage 1. Stage 2 FAS consisted of Stage 1 placebo non-responders who entered Stage 2 and who received at least 1 dose of study drug and had at least 1 postbaseline assessment of MADRS in Stage 2.
Arm/Group Title Placebo S1 ALKS 5461 0.5mg/0.5mg S1 ALKS 5461 2mg/2mg S1 Placebo S2 ALKS 5461 0.5mg/0.5mg S2 ALKS 5461 2mg/2mg S2
Hide Arm/Group Description:
Randomized to placebo in Stage 1
Randomized to ALKS 5461 0.5mg/0.5mg in Stage 1
Randomized to ALKS 5461 2mg/2mg in Stage 1
Randomized to placebo in Stage 2
Randomized to ALKS 5461 0.5mg/0.5mg in Stage 2
Randomized to ALKS 5461 2mg/2mg in Stage 2
Overall Number of Participants Analyzed 256 58 59 54 55 54
Measure Type: Count of Participants
Unit of Measure: Participants
Yes
47
  18.4%
6
  10.3%
13
  22.0%
4
   7.4%
7
  12.7%
7
  13.0%
No
209
  81.6%
52
  89.7%
46
  78.0%
50
  92.6%
48
  87.3%
47
  87.0%
4.Secondary Outcome
Title Number of Subjects With Adverse Events (AEs)
Hide Description [Not Specified]
Time Frame 5 weeks for Stage 1 and 6 weeks for Stage 2
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population consists of all randomized subjects who received at least 1 dose of study drug.
Arm/Group Title Placebo S1 ALKS 5461 0.5mg/0.5mg S1 ALKS 5461 2mg/2mg S1 Placebo S2 ALKS 5461 0.5mg/0.5mg S2 ALKS 5461 2mg/2mg S2
Hide Arm/Group Description:
Randomized to placebo in Stage 1
Randomized to ALKS 5461 0.5mg/0.5mg in Stage 1
Randomized to ALKS 5461 2mg/2mg in Stage 1
Randomized to placebo in Stage 2
Randomized to ALKS 5461 0.5mg/0.5mg in Stage 2
Randomized to ALKS 5461 2mg/2mg in Stage 2
Overall Number of Participants Analyzed 265 59 60 56 56 56
Measure Type: Count of Participants
Unit of Measure: Participants
142
  53.6%
34
  57.6%
41
  68.3%
29
  51.8%
27
  48.2%
29
  51.8%
Time Frame 5 weeks for Stage 1 and 6 weeks for Stage 2
Adverse Event Reporting Description Safety population consists of all randomized subjects who received at least 1 dose of study drug.
 
Arm/Group Title Placebo S1 ALKS 5461 0.5mg/0.5mg S1 ALKS 5461 2mg/2mg S1 Placebo S2 ALKS 5461 0.5mg/0.5mg S2 ALKS 5461 2mg/2mg S2
Hide Arm/Group Description Randomized to placebo in Stage 1 Randomized to ALKS 5461 0.5mg/0.5mg in Stage 1 Randomized to ALKS 5461 2mg/2mg in Stage 1 Randomized to placebo in Stage 2 Randomized to ALKS 5461 0.5mg/0.5mg in Stage 2 Randomized to ALKS 5461 2mg/2mg in Stage 2
All-Cause Mortality
Placebo S1 ALKS 5461 0.5mg/0.5mg S1 ALKS 5461 2mg/2mg S1 Placebo S2 ALKS 5461 0.5mg/0.5mg S2 ALKS 5461 2mg/2mg S2
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/265 (0.00%)      0/59 (0.00%)      0/60 (0.00%)      0/56 (0.00%)      0/56 (0.00%)      0/56 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo S1 ALKS 5461 0.5mg/0.5mg S1 ALKS 5461 2mg/2mg S1 Placebo S2 ALKS 5461 0.5mg/0.5mg 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   1/265 (0.38%)      0/59 (0.00%)      0/60 (0.00%)      0/56 (0.00%)      0/56 (0.00%)      0/56 (0.00%)    
Metabolism and nutrition disorders             
Hypoglycaemia * 1  1/265 (0.38%)  1 0/59 (0.00%)  0 0/60 (0.00%)  0 0/56 (0.00%)  0 0/56 (0.00%)  0 0/56 (0.00%)  0
1
Term from vocabulary, MedDRA 18.0
*
Indicates events were collected by non-systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo S1 ALKS 5461 0.5mg/0.5mg S1 ALKS 5461 2mg/2mg S1 Placebo S2 ALKS 5461 0.5mg/0.5mg 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   81/265 (30.57%)      32/59 (54.24%)      36/60 (60.00%)      11/56 (19.64%)      13/56 (23.21%)      22/56 (39.29%)    
Gastrointestinal disorders             
Nausea * 1  17/265 (6.42%)  17 14/59 (23.73%)  15 17/60 (28.33%)  24 1/56 (1.79%)  1 5/56 (8.93%)  6 8/56 (14.29%)  8
Constipation * 2  4/265 (1.51%)  4 4/59 (6.78%)  4 10/60 (16.67%)  10 1/56 (1.79%)  1 1/56 (1.79%)  1 2/56 (3.57%)  2
Vomiting * 2  4/265 (1.51%)  4 4/59 (6.78%)  4 6/60 (10.00%)  6 0/56 (0.00%)  0 2/56 (3.57%)  2 4/56 (7.14%)  4
Dry mouth * 2  11/265 (4.15%)  11 2/59 (3.39%)  2 5/60 (8.33%)  6 0/56 (0.00%)  0 0/56 (0.00%)  0 2/56 (3.57%)  2
General disorders             
Fatigue * 2  5/265 (1.89%)  5 3/59 (5.08%)  4 2/60 (3.33%)  2 1/56 (1.79%)  1 0/56 (0.00%)  0 3/56 (5.36%)  3
Infections and infestations             
Upper respiratory tract infection * 2  6/265 (2.26%)  6 1/59 (1.69%)  1 2/60 (3.33%)  2 4/56 (7.14%)  4 0/56 (0.00%)  0 2/56 (3.57%)  2
Nasopharyngitis * 2  6/265 (2.26%)  7 1/59 (1.69%)  1 0/60 (0.00%)  0 2/56 (3.57%)  2 1/56 (1.79%)  1 3/56 (5.36%)  3
Musculoskeletal and connective tissue disorders             
Muscle spasms * 2  1/265 (0.38%)  1 0/59 (0.00%)  0 3/60 (5.00%)  3 1/56 (1.79%)  1 0/56 (0.00%)  0 0/56 (0.00%)  0
Nervous system disorders             
Dizziness * 2  9/265 (3.40%)  10 4/59 (6.78%)  4 8/60 (13.33%)  9 1/56 (1.79%)  2 4/56 (7.14%)  4 2/56 (3.57%)  2
Somnolence * 2  7/265 (2.64%)  7 5/59 (8.47%)  5 6/60 (10.00%)  6 0/56 (0.00%)  0 1/56 (1.79%)  1 0/56 (0.00%)  0
Headache * 2  22/265 (8.30%)  23 7/59 (11.86%)  10 5/60 (8.33%)  5 1/56 (1.79%)  1 1/56 (1.79%)  1 2/56 (3.57%)  2
Sedation * 2  3/265 (1.13%)  3 2/59 (3.39%)  2 5/60 (8.33%)  6 0/56 (0.00%)  0 0/56 (0.00%)  0 0/56 (0.00%)  0
Psychiatric disorders             
Insomnia * 2  7/265 (2.64%)  7 1/59 (1.69%)  1 5/60 (8.33%)  5 1/56 (1.79%)  1 0/56 (0.00%)  0 0/56 (0.00%)  0
Abnormal dreams * 2  7/265 (2.64%)  7 3/59 (5.08%)  3 3/60 (5.00%)  3 0/56 (0.00%)  0 0/56 (0.00%)  0 0/56 (0.00%)  0
Irritability * 2  0/265 (0.00%)  0 0/59 (0.00%)  0 3/60 (5.00%)  3 0/56 (0.00%)  0 0/56 (0.00%)  0 1/56 (1.79%)  1
Skin and subcutaneous tissue disorders             
Hyperhidrosis * 2  4/265 (1.51%)  4 0/59 (0.00%)  0 4/60 (6.67%)  4 0/56 (0.00%)  0 0/56 (0.00%)  0 1/56 (1.79%)  1
Vascular disorders             
Hot flush * 2  5/265 (1.89%)  5 0/59 (0.00%)  0 3/60 (5.00%)  3 0/56 (0.00%)  0 0/56 (0.00%)  0 1/56 (1.79%)  1
1
Term from vocabulary, MedDRA 18.0
2
Term from vocabulary, MedDRA (18.0)
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Eva Stroynowski
Organization: Alkermes
Phone: 781-609-7000
EMail: Eva.Stroynowski@alkermes.com
Layout table for additonal information
Responsible Party: Alkermes, Inc.
ClinicalTrials.gov Identifier: NCT02158533     History of Changes
Other Study ID Numbers: ALK5461-205
First Submitted: June 5, 2014
First Posted: June 9, 2014
Results First Submitted: March 1, 2019
Results First Posted: March 27, 2019
Last Update Posted: August 14, 2019