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

• Sponsor: Alkermes, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02158533
• Collaborator: (none)
• Enrollment: 385
• Locations: 49
• Arms: 3
• Duration (Months): 19
• Patients Per Site: 7.9
• Patients Per Site Per Month: 0.4

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: High Dose ALKS 5461; Drug: Low Dose ALKS 5461; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 385 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-4 Study)
• Study Start Date: May 1, 2014
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: High Dose	Drug: High Dose ALKS 5461; Sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant); Other Names: ALKS 5461
Experimental: Low Dose	Drug: Low Dose ALKS 5461; Sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant); Other Names: ALKS 5461
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 From Baseline to Week 5 in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score [Baseline and 5 weeks for each stage]

   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) [Baseline and 5 weeks for each stage]

   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).

2. Remission Rate [Baseline and 5 weeks for each stage]

   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 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 Body Mass Index (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 a Major Depressive Disorder (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 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	35226
2	Alkermes Investigational Site	Tucson	Arizona	United States	85712
3	Alkermes Investigational Site	Carson	California	United States	90746
4	Alkermes Investigational Site	National City	California	United States	91950
5	Alkermes Investigational Site	Orange	California	United States	92868
6	Alkermes Investigational Site	Sherman Oaks	California	United States	91403
7	Alkermes Investigational Site	Torrance	California	United States	90502
8	Alkermes Investigational Site	Upland	California	United States	91786
9	Alkermes Investigational Site	Hartford	Connecticut	United States	06106
10	Alkermes Investigational Site	Norwich	Connecticut	United States	06360
11	Alkermes Investigational Site	Coral Springs	Florida	United States	33067
12	Alkermes Investigational Site	Gainesville	Florida	United States	32607
13	Alkermes Investigational Site	Lauderhill	Florida	United States	33319
14	Alkermes Investigational Site	Orlando	Florida	United States	32801
15	Alkermes, Investigational Site	Alpharetta	Georgia	United States	30005
16	Alkermes Investigational Site	Decatur	Georgia	United States	30030
17	Alkermes Investigational Site	Chicago	Illinois	United States	60640
18	Alkermes Investigational Site	Joliet	Illinois	United States	60435
19	Alkermes Investigational Site	Skokie	Illinois	United States	60076
20	Alkermes Investigational Site	Newburgh	Indiana	United States	47630
21	Alkermes Investigational Site	Valparaiso	Indiana	United States	46383
22	Alkermes Investigational Site	Owensboro	Kentucky	United States	42301
23	Alkermes Investigational Site	Baltimore	Maryland	United States	21208
24	Alkermes Investigational Site	Baltimore	Maryland	United States	21285
25	Alkermes Investigational Site	Berlin	New Jersey	United States	08009
26	Alkermes Investigational Site	Brooklyn	New York	United States	11241
27	Alkermes Investigational Site	Mount Kisco	New York	United States	10549
28	Alkermes Investigational Site	New York	New York	United States	10128
29	Alkermes Investigational Site	Staten Island	New York	United States	10305
30	Alkermes Investigational Site	Canton	Ohio	United States	44718
31	Alkermes Investigational Site	Dayton	Ohio	United States	45417
32	Alkermes Investigational Site	Oklahoma City	Oklahoma	United States	73103
33	Alkermes Investigational Site	Oklahoma City	Oklahoma	United States	73112
34	Alkermes Investigational Site	Allentown	Pennsylvania	United States	18104
35	Alkermes Investigational Site	Media	Pennsylvania	United States	19063
36	Alkermes Investigational Site	Philadelphia	Pennsylvania	United States	19107
37	Alkermes Investigational Site	Lincoln	Rhode Island	United States	02865
38	Alkermes Investigational Site	Austin	Texas	United States	78731
39	Alkermes Investigational Site	Houston	Texas	United States	77081
40	Alkermes Investigational Site	San Antonio	Texas	United States	78229
41	Alkermes Investigational Site	Woodstock	Vermont	United States	05091
42	Alkermes Investigational Site	Middleton	Wisconsin	United States	53562
43	Alkermes Investigational Site	Brisbane	Queensland	Australia	4000
44	Alkermes Investigational Site	Towong	Queensland	Australia	4066
45	Alkermes Investigational Site	Frankston	Victoria	Australia	3199
46	Alkermes Investigational Site	Melbourne	Victoria	Australia	3004
47	Alkermes Investigational Site	Penticton	British Columbia	Canada
48	Alkermes Investigational Site	Gatineau	Quebec	Canada
49	Alkermes Investigational Site	Quebec		Canada

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: NCT02158533
• Other Study ID Numbers: ALK5461-205
• First Posted: Jun 9, 2014
• Last Update Posted: Aug 14, 2019
• Last Verified: Aug 1, 2019

• Keywords provided by Alkermes, Inc.: Major Depressive Disorder; Depression; Alkermes; ALKS 5461; Samidorphan
• Additional relevant MeSH terms: Disease; Depressive Disorder; Depression; Depressive Disorder, Major; Naltrexone; Buprenorphine

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). 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
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
Period Title: Stage 1
STARTED	0	0	0	56	56	56
COMPLETED	0	0	0	53	52	50
NOT COMPLETED	0	0	0	3	4	6

Baseline Characteristics

Arm/Group Title	Placebo S1	ALKS 5461 0.5mg/0.5mg S1	ALKS 5461 2mg/2mg S1	Total
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 Participants	265	59	60	384
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.8 (11.50)	45.0 (13.89)	46.2 (12.14)	45.7 (11.97)
Sex: Female, Male (Count of 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) (Count of 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%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.4%	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%	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%	266 69.3%
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	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%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 5 in the Montgomery Asberg Depression Rating Scale (MADRS) Total Score
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

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 0.5mg/0.5mg S1	ALKS 5461 2mg/2mg S1	Placebo S2	ALKS 5461 0.5mg/0.5mg S2	ALKS 5461 2mg/2mg S2
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
Measure Participants	256	58	59	54	55	54
Least Squares Mean (Standard Error) [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)

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
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.

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
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)
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

Outcome Measure Data

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
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
Measure Participants	256	58	59	54	55	54
Yes	79 29.8%	9 15.3%	20 33.3%	6 1.6%	9 NaN	9 NaN
No	177 66.8%	49 83.1%	39 65%	48 12.5%	46 NaN	45 NaN

3. 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	Baseline and 5 weeks for each stage

Outcome Measure Data

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
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
Measure Participants	256	58	59	54	55	54
Yes	47 17.7%	6 10.2%	13 21.7%	4 1%	7 NaN	7 NaN
No	209 78.9%	52 88.1%	46 76.7%	50 13%	48 NaN	47 NaN

4. Secondary Outcome

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

Outcome Measure Data

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
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
Measure Participants	265	59	60	56	56	56
Count of Participants [Participants]	142 53.6%	34 57.6%	41 68.3%	29 7.6%	27 NaN	29 NaN

Adverse Events

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
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/265 (0%)		0/59 (0%)		0/60 (0%)		0/56 (0%)		0/56 (0%)		0/56 (0%)
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 (0.4%)		0/59 (0%)		0/60 (0%)		0/56 (0%)		0/56 (0%)		0/56 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	1/265 (0.4%)	1	0/59 (0%)	0	0/60 (0%)	0	0/56 (0%)	0	0/56 (0%)	0	0/56 (0%)	0
Other (Not Including 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	81/265 (30.6%)		32/59 (54.2%)		36/60 (60%)		11/56 (19.6%)		13/56 (23.2%)		22/56 (39.3%)
Gastrointestinal disorders
Nausea	17/265 (6.4%)	17	14/59 (23.7%)	15	17/60 (28.3%)	24	1/56 (1.8%)	1	5/56 (8.9%)	6	8/56 (14.3%)	8
Constipation	4/265 (1.5%)	4	4/59 (6.8%)	4	10/60 (16.7%)	10	1/56 (1.8%)	1	1/56 (1.8%)	1	2/56 (3.6%)	2
Vomiting	4/265 (1.5%)	4	4/59 (6.8%)	4	6/60 (10%)	6	0/56 (0%)	0	2/56 (3.6%)	2	4/56 (7.1%)	4
Dry mouth	11/265 (4.2%)	11	2/59 (3.4%)	2	5/60 (8.3%)	6	0/56 (0%)	0	0/56 (0%)	0	2/56 (3.6%)	2
General disorders
Fatigue	5/265 (1.9%)	5	3/59 (5.1%)	4	2/60 (3.3%)	2	1/56 (1.8%)	1	0/56 (0%)	0	3/56 (5.4%)	3
Infections and infestations
Upper respiratory tract infection	6/265 (2.3%)	6	1/59 (1.7%)	1	2/60 (3.3%)	2	4/56 (7.1%)	4	0/56 (0%)	0	2/56 (3.6%)	2
Nasopharyngitis	6/265 (2.3%)	7	1/59 (1.7%)	1	0/60 (0%)	0	2/56 (3.6%)	2	1/56 (1.8%)	1	3/56 (5.4%)	3
Musculoskeletal and connective tissue disorders
Muscle spasms	1/265 (0.4%)	1	0/59 (0%)	0	3/60 (5%)	3	1/56 (1.8%)	1	0/56 (0%)	0	0/56 (0%)	0
Nervous system disorders
Dizziness	9/265 (3.4%)	10	4/59 (6.8%)	4	8/60 (13.3%)	9	1/56 (1.8%)	2	4/56 (7.1%)	4	2/56 (3.6%)	2
Somnolence	7/265 (2.6%)	7	5/59 (8.5%)	5	6/60 (10%)	6	0/56 (0%)	0	1/56 (1.8%)	1	0/56 (0%)	0
Headache	22/265 (8.3%)	23	7/59 (11.9%)	10	5/60 (8.3%)	5	1/56 (1.8%)	1	1/56 (1.8%)	1	2/56 (3.6%)	2
Sedation	3/265 (1.1%)	3	2/59 (3.4%)	2	5/60 (8.3%)	6	0/56 (0%)	0	0/56 (0%)	0	0/56 (0%)	0
Psychiatric disorders
Insomnia	7/265 (2.6%)	7	1/59 (1.7%)	1	5/60 (8.3%)	5	1/56 (1.8%)	1	0/56 (0%)	0	0/56 (0%)	0
Abnormal dreams	7/265 (2.6%)	7	3/59 (5.1%)	3	3/60 (5%)	3	0/56 (0%)	0	0/56 (0%)	0	0/56 (0%)	0
Irritability	0/265 (0%)	0	0/59 (0%)	0	3/60 (5%)	3	0/56 (0%)	0	0/56 (0%)	0	1/56 (1.8%)	1
Skin and subcutaneous tissue disorders
Hyperhidrosis	4/265 (1.5%)	4	0/59 (0%)	0	4/60 (6.7%)	4	0/56 (0%)	0	0/56 (0%)	0	1/56 (1.8%)	1
Vascular disorders
Hot flush	5/265 (1.9%)	5	0/59 (0%)	0	3/60 (5%)	3	0/56 (0%)	0	0/56 (0%)	0	1/56 (1.8%)	1

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.