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

• Sponsor: Alkermes, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03188185
• Collaborator: (none)
• Enrollment: 278
• Locations: 35
• Arms: 2
• Actual Duration (Months): 32.8
• Patients Per Site: 7.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy, safety, and tolerability of adjunctive ALKS 5461 in adults who have treatment refractory MDD.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 278 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3b Efficacy and Safety Study of Adjunctive ALKS 5461 in Treatment Refractory Major Depressive Disorder
• Actual Study Start Date: Jun 12, 2017
• Actual Primary Completion Date: Feb 26, 2020
• Actual Study Completion Date: Mar 5, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ALKS 5461 Sublingual tablets	Drug: ALKS 5461; Samidorphan + buprenorphine, administered sublingually
Placebo Comparator: ALKS 5461 Placebo Sublingual tablets	Drug: ALKS 5461 Placebo; Placebo tablet, administered sublingually

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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).

2. 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.

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 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alkermes Investigational Site	Tucson	Arizona	United States	85712
2	Alkermes Investigational Site	Little Rock	Arkansas	United States	72211
3	Alkermes Investigational Site	Los Alamitos	California	United States	90720
4	Alkermes Investigational Site	Oceanside	California	United States	92056
5	Alkermes Investigational Site	Pico Rivera	California	United States	90660
6	Alkermes Investigational Site	Redlands	California	United States	92374
7	Alkermes Investigational Site	Santa Ana	California	United States	92705
8	Alkermes Investigational Site	Sherman Oaks	California	United States	91403
9	Alkermes Investigational Site	Temecula	California	United States	92591
10	Alkermes Investigative Site	Upland	California	United States	91786
11	Alkermes Investigational Site	Hollywood	Florida	United States	33024
12	Alkermes Investigational Site	Jacksonville	Florida	United States	32256
13	Alkermes Investigational Site	Lauderhill	Florida	United States	33319
14	Alkermes Investigational Site	Orlando	Florida	United States	32801
15	Alkermes Investigative Site	Palm Bay	Florida	United States	32905
16	Alkermes Investigational Site	Atlanta	Georgia	United States	30341
17	Alkermes Investigational Site	Decatur	Georgia	United States	30030
18	Alkermes Investigational Site	Pikesville	Maryland	United States	21208
19	Alkermes Investigational Site	O'Fallon	Missouri	United States	63368
20	Alkermes Investigational Site	Jamaica	New York	United States	11432
21	Alkermes Investigational Site	Mount Kisco	New York	United States	10549
22	Alkermes Investigational Site	Canton	Ohio	United States	44720
23	Alkermes Investigational Site	Cincinnati	Ohio	United States	45215
24	Alkermes Investigational Site	Oklahoma City	Oklahoma	United States	73112
25	Alkermes Investigational Site	Allentown	Pennsylvania	United States	18104
26	Alkermes Investigational Site	Memphis	Tennessee	United States	38119
27	Alkermes Investigational Site	Dallas	Texas	United States	75390
28	Alkermes Investigational Site	DeSoto	Texas	United States	75115
29	Alkermes Investigational Site	Woodstock	Vermont	United States	05091
30	Alkermes Investigative Site	Bellevue	Washington	United States	98007
31	Alkermes Investigational Site	Frankston	Victoria	Australia	3199
32	Alkermes Investigational Site	Noble Park	Victoria	Australia	3174
33	Alkermes Investigational Site	Richmond	Victoria	Australia	3121
34	Alkermes Investigational Site	San Juan		Puerto Rico	00918
35	Alkermes Investigational Site	San Juan		Puerto Rico	00926-3160

Sponsors and Collaborators

• Alkermes, Inc.

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Jan 25, 2018
• Statistical Analysis Plan - Oct 2, 2019

More Information

Publications

None provided.

• Responsible Party: Alkermes, Inc.
• ClinicalTrials.gov Identifier: NCT03188185
• Other Study ID Numbers: ALK5461-217
• First Posted: Jun 15, 2017
• Last Update Posted: Apr 8, 2021
• Last Verified: Mar 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Alkermes, Inc.: Alkermes; Major Depressive Disorder; Treatment Refractory MDD; ALKS 5461
• Additional relevant MeSH terms: Disease; Depressive Disorder; Depression; Depressive Disorder, Major; Naltrexone; Buprenorphine

Study Results

Participant Flow

Recruitment Details	Subjects were diagnosed with treatment refractory major depressive disorder (MDD), defined as having at least 2 inadequate responses to commercially available antidepressant therapies (ADTs) during the current major depressive episode (MDE). All subjects continued to take an approved 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. In Stage 2 only placebo non-responders from Stage 1 were re-randomized to ALKS 5461 or placebo.

Arm/Group Title	S1: Placebo	S1: ALKS 5461 2mg/2mg	S2: Placebo	S2: ALKS 5461 2mg/2mg
Arm/Group Description	Randomized to placebo in Stage 1	Randomized to ALKS 5461 2mg/2mg in Stage 1	Randomized to placebo in Stage 2	Randomized to ALKS 5461 2mg/2mg in Stage 2
Period Title: Stage 1
STARTED	198	80	0	0
COMPLETED	179	64	0	0
NOT COMPLETED	19	16	0	0
Period Title: Stage 1
STARTED	0	0	64	63
COMPLETED	0	0	55	57
NOT COMPLETED	0	0	9	6

Baseline Characteristics

Arm/Group Title	S1: Placebo	S1: ALKS 5461 2mg/2mg	Total
Arm/Group Description	Randomized to placebo in Stage 1.	Randomized to ALKS 5461 2mg/2mg in Stage 1.	Total of all reporting groups
Overall Participants	198	80	278
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	44	40.5	43
Sex: Female, Male (Count of Participants)
Female	139 70.2%	57 71.3%	196 70.5%
Male	59 29.8%	23 28.8%	82 29.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	31 15.7%	10 12.5%	41 14.7%
Not Hispanic or Latino	167 84.3%	70 87.5%	237 85.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	5 2.5%	4 5%	9 3.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	24 12.1%	9 11.3%	33 11.9%
White	160 80.8%	63 78.8%	223 80.2%
More than one race	4 2%	2 2.5%	6 2.2%
Unknown or Not Reported	5 2.5%	2 2.5%	7 2.5%
Region of Enrollment (Count of Participants)
United States	176 88.9%	72 90%	248 89.2%
Australia	22 11.1%	8 10%	30 10.8%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to the End of Treatment (EOT) in the Montgomery Asberg Depression Rating Scale-10 (MADRS-10) Scores
Description	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.
Time Frame	Baseline and 5 weeks for Stage 1, Baseline 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 assessment in the respective stage.

Arm/Group Title	S1: Placebo	S1: ALKS 5461 2mg/2mg	S2: Placebo	S2: ALKS 5461 2mg/2mg
Arm/Group Description	Randomized to placebo in Stage 1	Randomized to ALKS 5461 2mg/2mg in Stage 1	Randomized to placebo in Stage 2	Randomized to ALKS 5461 2mg/2mg in Stage 2
Measure Participants	195	76	64	63
Least Squares Mean (Standard Error) [score on a scale]	-11.4 (0.70)	-13.9 (1.12)	-4.2 (1.06)	-4.7 (1.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S1: Placebo, S1: ALKS 5461 2mg/2mg, S2: Placebo, S2: ALKS 5461 2mg/2mg
	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).
	Type of Statistical Test	Superiority
	Comments	Hypothesis tests were two-sided with an alpha of 0.05 .
Statistical Test of Hypothesis	p-Value	0.128
	Comments	ALK 5461 was compared to placebo 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	-1.5
	Confidence Interval	(2-Sided) 95%; -3.5 to 0.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.99
	Estimation Comments

2. Secondary Outcome

Title	Montgomery Asberg Depression Rating Scale (MADRS) Response Rate
Description	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).
Time Frame	Baseline and 5 weeks for Stage 1, Baseline 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 assessment in the respective stage.

Arm/Group Title	S1: Placebo	S1: ALKS 5461 2mg/2mg	S2: Placebo	S2: ALKS 5461 2mg/2mg
Arm/Group Description	Randomized to placebo in Stage 1	Randomized to ALKS 5461 2mg/2mg in Stage 1	Randomized to placebo in Stage 2	Randomized to ALKS 5461 2mg/2mg in Stage 2
Measure Participants	195	76	64	63
Yes	53 26.8%	27 33.8%	10 3.6%	11 NaN
No	142 71.7%	49 61.3%	54 19.4%	52 NaN

3. Secondary Outcome

Title	Montgomery Asberg Depression Rating Scale (MADRS) Remission Rate
Description	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.
Time Frame	5 weeks for Stage 1, 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 assessment in the respective stage.

Arm/Group Title	S1: Placebo	S1: ALKS 5461 2mg/2mg	S2: Placebo	S2: ALKS 5461 2mg/2mg
Arm/Group Description	Randomized to placebo in Stage 1	Randomized to ALKS 5461 2mg/2mg in Stage 1	Randomized to placebo in Stage 2	Randomized to ALKS 5461 2mg/2mg in Stage 2
Measure Participants	195	76	64	63
Yes	31 15.7%	14 17.5%	10 3.6%	8 NaN
No	164 82.8%	62 77.5%	54 19.4%	55 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	S1: Placebo		S1: ALKS 5461 2mg/2mg		S2: Placebo		S2: ALKS 5461 2mg/2mg
Arm/Group Description	Randomized to placebo in Stage 1		Randomized to ALKS 5461 2mg/2mg in Stage 1		Randomized to placebo in Stage 2		Randomized to ALKS 5461 2mg/2mg in Stage 2
All Cause Mortality
	S1: Placebo		S1: ALKS 5461 2mg/2mg		S2: Placebo		S2: ALKS 5461 2mg/2mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/198 (0%)		0/80 (0%)		0/64 (0%)		0/63 (0%)
Serious Adverse Events
	S1: Placebo		S1: ALKS 5461 2mg/2mg		S2: Placebo		S2: ALKS 5461 2mg/2mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/198 (0%)		1/80 (1.3%)		1/64 (1.6%)		0/63 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Meningioma	0/198 (0%)		0/80 (0%)		1/64 (1.6%)		0/63 (0%)
Nervous system disorders
Serotonin Syndrome	0/198 (0%)		1/80 (1.3%)		0/64 (0%)		0/63 (0%)
Other (Not Including Serious) Adverse Events
	S1: Placebo		S1: ALKS 5461 2mg/2mg		S2: Placebo		S2: ALKS 5461 2mg/2mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/198 (21.7%)		56/80 (70%)		3/64 (4.7%)		29/63 (46%)
Gastrointestinal disorders
Nausea	10/198 (5.1%)		29/80 (36.3%)		0/64 (0%)		16/63 (25.4%)
Constipation	2/198 (1%)		9/80 (11.3%)		0/64 (0%)		3/63 (4.8%)
Vomiting	4/198 (2%)		5/80 (6.3%)		0/64 (0%)		6/63 (9.5%)
General disorders
Fatigue	3/198 (1.5%)		4/80 (5%)		1/64 (1.6%)		2/63 (3.2%)
Infections and infestations
Nasopharyngitis	5/198 (2.5%)		4/80 (5%)		1/64 (1.6%)		1/63 (1.6%)
Nervous system disorders
Dizziness	4/198 (2%)		18/80 (22.5%)		0/64 (0%)		8/63 (12.7%)
Somnolence	5/198 (2.5%)		10/80 (12.5%)		1/64 (1.6%)		3/63 (4.8%)
Headache	14/198 (7.1%)		9/80 (11.3%)		0/64 (0%)		7/63 (11.1%)
Sedation	5/198 (2.5%)		8/80 (10%)		0/64 (0%)		3/63 (4.8%)
Psychiatric disorders
Abnormal dreams	3/198 (1.5%)		4/80 (5%)		0/64 (0%)		3/63 (4.8%)

Limitations/Caveats

[Not Specified]

More Information

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.