A Study of ALKS 5461 for the Treatment of Major Depressiv... | NCT02218008

A Study of ALKS 5461 for the Treatment of Major Depressiv... | NCT02218008 | Trialant

Arms/Interventions Module

Label	Type	Intervention Names
High Dose	Experimental	Drug: ALKS 5461
Low Dose	Experimental	Drug: ALKS 5461
Placebo	Placebo Comparator	Drug: Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
ALKS 5461	Drug	Sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant)	High Dose Low Dose

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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)	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).	Baseline and 5 weeks (Stage 1) and baseline and 6 weeks (Stage 2), combined together for the overall estimate of treatment effect
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)	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.	5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)
Change From Baseline to End of Treatment in the MADRS-10	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.	5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)

Secondary Outcomes

Measure	Description	Time Frame
Proportion of Patients Who Exhibited Treatment Response (MADRS-10)	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.

Contacts/Locations Module

Name	Affiliation	Role
Sanjeev Pathak, MD	Alkermes, Inc.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Alkermes Investigational Site		Birmingham	Alabama	35294	United States
Alkermes Investigational Site

Label	URL
Study-specific website	View source

Results Section

Participant Flow Module

ID	Title	Description
FG000	Placebo S1	Randomized to placebo in Stage 1
FG001	ALKS 5461 1mg/1mg S1	Randomized to ALKS 5461 1mg/1mg in Stage 1

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Comment	Reasons
Adverse Event		FG0006 subjects FG0015 subjects FG00211 subjects FG0030 subjects FG0040 subjects FG0050 subjects
Withdrawal by Subject		FG0006 subjects FG0011 subjects FG0021 subjects FG0030 subjects FG004
Lack of Efficacy		FG0003 subjects FG0010 subjects FG0020 subjects FG0030 subjects FG004
Lost to Follow-up		FG0003 subjects FG0010 subjects FG0021 subjects FG0030 subjects FG004
Non-compliance with Study Drug		FG0002 subjects FG0011 subjects FG0020 subjects FG0030 subjects FG004
Non-compliance; drug use		FG0001 subjects FG0010 subjects FG0020 subjects FG0030 subjects FG004
Pregnancy		FG0000 subjects FG0010 subjects FG0021 subjects FG0030 subjects FG004
Protocol Violation		FG0000 subjects FG0010 subjects FG0021 subjects FG0030 subjects FG004
Failure to Meet Eligibility Criteria		FG0001 subjects FG0010 subjects FG0020 subjects FG0030 subjects FG004

Stage 2 (S2)

Type	Comment	Milestone Data
STARTED	Subjects randomized in Stage 2 are a subset of those randomized to placebo in Stage 1.	FG0000 subjects FG0010 subjects FG0020 subjects FG00362 subjects FG00462 subjects FG00563 subjects
COMPLETED		FG0000 subjects FG0010 subjects FG0020 subjects FG00358 subjects FG004
NOT COMPLETED		FG0000 subjects FG0010 subjects FG0020 subjects FG0034 subjects FG004

Type	Comment	Reasons
Adverse Event		FG0000 subjects FG0010 subjects FG0020 subjects FG003

Arm/Group Information

ID	Title	Description
BG000	Placebo	Randomized to placebo in Stage 1
BG001	ALKS 5461 1mg/1mg	Randomized to ALKS 5461 1mg/1mg in Stage 1
BG002	ALKS 5461 2mg/2mg	Randomized to ALKS 5461 2mg/2mg in Stage 1
BG003	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00045.7± 12.87 BG00145.1± 11.46 BG00242.9± 14.48 BG003

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG000193 BG00142 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG00048 BG00110 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0001 BG0010 BG002

Region of Enrollment

Count of Participants

Participants

Title

Denominators

Categories

Canada

Title	Measurements
	BG0005 BG0011 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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)

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).

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.

Posted

Least Squares Mean

Standard Error

Units on a scale

Baseline and 5 weeks (Stage 1) and baseline and 6 weeks (Stage 2), combined together for the overall estimate of treatment effect

ID	Title	Description
OG000	Placebo S1	Randomized to placebo in Stage 1
OG001	ALKS 5461 1mg/1mg S1	Randomized to ALKS 5461 1mg/1mg in Stage 1
OG002	ALKS 5461 2mg/2mg S1	Randomized to ALKS 5461 2mg/2mg in Stage 1
OG003	Placebo S2	Randomized to placebo in Stage 2
OG004	ALKS 5461 1mg/1mg S2	Randomized to ALKS 5461 1mg/1mg in Stage 2
OG005	ALKS 5461 2mg/2mg S2	Randomized to ALKS 5461 2mg/2mg in Stage 2

Units	Counts
Participants	OG000273 OG00162 OG00263 OG003

Title

Denominators

Categories

Title	Measurements
	OG000-5.6± 0.34 OG001-6.0± 0.74 OG002-6.8± 0.75 OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002 OG003 OG005	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.	Mixed Models Analysis	ALKS 5461 was compared to pbo using stage-specific MMRM for MADRS-10 Change from Baseline. Model-derived estimates were combined using equal weights.	0.018	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.	Least Squares Mean Difference	-1.5			2-Sided	95	-2.7	-0.3

Primary

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)

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.

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.

Posted

Least Squares Mean

Standard Error

Units on a scale

5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)

ID	Title	Description
OG000	Placebo S1	Randomized to placebo in Stage 1
OG001	ALKS 5461 1mg/1mg S1	Randomized to ALKS 5461 1mg/1mg in Stage 1
OG002	ALKS 5461 2mg/2mg S1	Randomized to ALKS 5461 2mg/2mg in Stage 1

Primary

Change From Baseline to End of Treatment in the MADRS-10

Posted

Least Squares Mean

Standard Error

Units on a scale

5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)

ID	Title	Description
OG000	Placebo S1	Randomized to placebo in Stage 1
OG001	ALKS 5461 1mg/1mg S1	Randomized to ALKS 5461 1mg/1mg in Stage 1
OG002	ALKS 5461 2mg/2mg S1	Randomized to ALKS 5461 2mg/2mg in Stage 1
OG003	Placebo S2

Secondary

Proportion of Patients Who Exhibited Treatment Response (MADRS-10)

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.

Posted

Count of Participants

Participants

5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)

ID	Title	Description
OG000	Placebo S1	Randomized to placebo in Stage 1
OG001	ALKS 5461 1mg/1mg S1	Randomized to ALKS 5461 1mg/1mg in Stage 1
OG002	ALKS 5461 2mg/2mg S1	Randomized to ALKS 5461 2mg/2mg in Stage 1

Secondary

Remission Rate

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

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.

Posted

Count of Participants

Participants

5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)

ID	Title	Description
OG000	Placebo S1	Randomized to placebo in Stage 1
OG001	ALKS 5461 1mg/1mg S1	Randomized to ALKS 5461 1mg/1mg in Stage 1
OG002	ALKS 5461 2mg/2mg S1	Randomized to ALKS 5461 2mg/2mg in Stage 1
OG003	Placebo S2	Randomized to placebo in Stage 2
OG004	ALKS 5461 1mg/1mg S2

Secondary

Number of Subjects With Adverse Events (AEs)

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

Posted

Count of Participants

Participants

5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2)

ID	Title	Description
OG000	Placebo S1	Randomized to placebo in Stage 1
OG001	ALKS 5461 1mg/1mg S1	Randomized to ALKS 5461 1mg/1mg in Stage 1
OG002	ALKS 5461 2mg/2mg S1	Randomized to ALKS 5461 2mg/2mg in Stage 1
OG003	Placebo S2	Randomized to placebo in Stage 2
OG004	ALKS 5461 1mg/1mg S2	Randomized to ALKS 5461 1mg/1mg in Stage 2
OG005

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo S1	Randomized to placebo in Stage 1	280	1	280	72	280
EG001	ALKS 5461 1mg/1mg S1	Randomized to ALKS 5461 1mg/1mg in Stage 1	63	0	63	25	63
EG002	ALKS 5461 2mg/2mg S1	Randomized to ALKS 5461 2mg/2mg in Stage 1	63	2	63	28	63
EG003	Placebo S2	Randomized to placebo in Stage 2	62	1	62	11	62
EG004	ALKS 5461 1mg/1mg S2	Randomized to ALKS 5461 1mg/1mg in Stage 2	62	0	62	6	62
EG005	ALKS 5461 2mg/2mg S2	Randomized to ALKS 5461 2mg/2mg in Stage 2	63	0	63	10	63

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abdominal Pain	Gastrointestinal disorders	MedDRA (18.0)	Non-systematic Assessment	EG0001 events1 affected280 at risk EG0010 events0 affected63 at risk EG0020 events0 affected63 at risk EG0030 events0 affected62 at risk EG0040 events0 affected62 at risk EG0050 events0 affected63 at risk
Muscle strain	Musculoskeletal and connective tissue disorders	MedDRA (18.0)	Non-systematic Assessment	EG0000 events0 affected280 at risk EG0010 events0 affected63 at risk EG0021 events1 affected63 at risk EG003
Wrist Fracture	Injury, poisoning and procedural complications	MedDRA (18.0)	Non-systematic Assessment	EG0000 events0 affected280 at risk EG0010 events0 affected63 at risk EG0021 events1 affected63 at risk EG003
Suicide Attempt	Psychiatric disorders	MedDRA (18.0)	Non-systematic Assessment	EG0000 events0 affected280 at risk EG0010 events0 affected63 at risk EG0020 events0 affected63 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Nausea	Gastrointestinal disorders	MedDRA (18.0)	Non-systematic Assessment	EG00021 events20 affected280 at risk EG00111 events9 affected63 at risk EG00220 events17 affected63 at risk EG0031 events1 affected62 at risk EG0042 events2 affected62 at risk EG0055 events5 affected63 at risk
Dizziness	Nervous system disorders	MedDRA (18.0)	Non-systematic Assessment	EG00013 events12 affected280 at risk EG0016 events6 affected63 at risk EG0027 events7 affected63 at risk EG003
Fatigue	General disorders	MedDRA (18.0)	Non-systematic Assessment	EG0001 events1 affected280 at risk EG0015 events5 affected63 at risk EG0028 events7 affected63 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA (18.0)	Non-systematic Assessment	EG0008 events7 affected280 at risk EG0013 events3 affected63 at risk EG0026 events6 affected63 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA (18.0)	Non-systematic Assessment	EG00010 events9 affected280 at risk EG00110 events9 affected63 at risk EG0025 events5 affected63 at risk EG003
Headache	Nervous system disorders	MedDRA (18.0)	Non-systematic Assessment	EG00023 events22 affected280 at risk EG0015 events4 affected63 at risk EG0025 events5 affected63 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA (18.0)	Non-systematic Assessment	EG0008 events8 affected280 at risk EG0011 events1 affected63 at risk EG0023 events3 affected63 at risk EG003
Somnolence	Nervous system disorders	MedDRA (18.0)	Non-systematic Assessment	EG00012 events12 affected280 at risk EG0014 events4 affected63 at risk EG0023 events3 affected63 at risk EG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002 OG003 OG005	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.	Mixed Models Analysis		0.026	ALKS 5461 was compared to pbo using stage-specific MMRM for MADRS-10 Change from Baseline. Model-derived estimates were combined using equal weights.	Least Squares Mean Difference	-1.9			2-Sided	95	-3.6	-0.2			Estimates below zero favor ALKS 5461.		Superiority	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.

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG002 OG003 OG005	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.	Mixed Models Analysis		0.076	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.	Least Squares Mean Difference	-1.7			2-Sided	95	-3.6	0.2					Superiority	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.

ID	Term
D003866	Depressive Disorder
D019964	Mood Disorders
D001523	Mental Disorders
D001526	Behavioral Symptoms
D001519	Behavior