A Study to Evaluate ALKS 5461 in Subjects With Major Depressive Disorder (MDD)

• Sponsor: Alkermes, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01500200
• Collaborator: (none)
• Enrollment: 142
• Locations: 27
• Arms: 2
• Duration (Months): 15
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy of ALKS 5461 when administered daily for 4 weeks to adults with Major Depressive Disorder (MDD) and inadequate response to antidepressant therapy.

Condition or Disease	Intervention/Treatment	Phase
Major Depressive Disorder	Drug: ALKS 5461; Drug: Placebo	Phase 2

Detailed Description

The study will measure efficacy using the HAM-D-17, the MADRS, and the CGI-S as well as using other scales and assessments.

Study Design

• Study Type: Interventional
• Actual Enrollment: 142 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate ALKS 5461 in Subjects With Major Depressive Disorder and Inadequate Response to Antidepressant Therapy
• Study Start Date: Dec 1, 2011
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ALKS 5461	Drug: ALKS 5461; Two active tablets, given daily
Placebo Comparator: Placebo	Drug: Placebo; Two placebo tablets, given daily

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 4 in Hamilton Rating Scale for Depression (HAM-D17) Total Score [Baseline and 4 weeks for each stage]

   The HAM-D17 scale is a clinician-administered questionnaire comprised of 17 items used to measure the severity of MDD symptoms. Scores range from 0 (no apparent symptoms) to 50 (most severe symptoms). Individual questionnaire items include depressed mood, work and activities, insomnia (early), insomnia (middle), insomnia (late), genital symptoms, somatic symptoms (gastrointestinal), loss of weight, somatic symptoms (general), feelings of guilt, suicide, anxiety (psychic), anxiety (somatic), hypochondriasis, insight, agitation, and retardation.

Secondary Outcome Measures

1. Proportion of Patients Who Exhibited Treatment Response (HAM-D17) [4 weeks for each stage]

   The proportion of subjects demonstrating HAM-D17 treatment response, defined as a ≥ 50% reduction in HAM-D17 score from baseline to the end of the efficacy period (Week 4). The HAM-D17 is a clinician administered questionnaire comprised of 17 questions used to assess the severity of a patient's depression. Scores range from 0 (no apparent symptoms) to 50 (most severe symptoms). Individual questionnaire items include depressed mood, work and activities, insomnia (early), insomnia (middle), insomnia (late), genital symptoms, somatic symptoms (gastrointestinal), loss of weight, somatic symptoms (general), feelings of guilt, suicide, anxiety (psychic), anxiety (somatic), hypochondriasis, insight, agitation, and retardation.

2. Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score [4 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.

3. Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score [4 weeks for each stage]

   The CGI-S is a 7-point scale that requires the clinician to assess how mentally ill the patient is at a specific point in time. Based on the scale, patients are categorized as follows: "1: normal, not at all ill"; "2: borderline mentally ill"; "3: mildly ill"; "4: moderately ill"; "5: markedly ill"; "6: severely ill"; and "7: among the most extremely ill patients."

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosed with a major depressive episode (MDE)

• Body mass index less than or equal to 40 kg/m2

• Have been treated with an adequate dose of SSRI/SNRI during the current MDE for at least 8 weeks, with the same, adequate dose over the last 4 weeks that is expected to remain stable throughout the study

• History of inadequate response during the entire current MDE to 1 or 2 adequate antidepressant treatments, including current treatment

• Be otherwise physically healthy

Exclusion Criteria:

• Have an axis I diagnosis of delirium, dementia, amnestic or other cognitive disorder, schizophrenia or other psychotic disorder, bipolar I or II disorder, eating disorder, obsessive-compulsive disorder, panic disorder, acute stress disorder, or posttraumatic stress disorder

• Have a clinically significant current axis II diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder

• Are experiencing hallucinations, delusions, or any psychotic symptomatology in the current MDE

• Receive new onset psychotherapy within 6 weeks of screening

• Use of opioid agonists (eg, codeine, oxycodone, morphine) within 14 days before screening

• Have received electroconvulsive therapy during the current MDE

• Have attempted suicide within the past 2 years

• Have a thyroid pathology

• Have a history of a seizure disorder or of neuroleptic malignant syndrome/serotonin syndrome

• Have a positive test for human immunodeficiency virus (HIV)

Additional inclusion/exclusion 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	Oceanside	California	United States	92056
3	Alkermes Investigational Site	Santa Ana	California	United States	92701
4	Alkermes Investigational Site	Torrance	California	United States	90502
5	Alkermes Investigational Site	Fort Myers	Florida	United States	33912
6	Alkermes Investigational Site	Lauderhill	Florida	United States	33319
7	Alkermes Investigational Site	Leesburg	Florida	United States	34748
8	Alkermes Investigational Site	North Miami	Florida	United States	33161
9	Alkermes Investigational Site	Saint Petersburg	Florida	United States	33716
10	Alkermes Investigational Site	Atlanta	Georgia	United States	30308
11	Alkermes Investigational Site	Hoffman Estates	Illinois	United States	60169
12	Alkermes Investigational Site	Baltimore	Maryland	United States	21285
13	Alkermes Investigational Site	Boston	Massachusetts	United States	02135
14	Alkermes Investigational Site	Haverhill	Massachusetts	United States	01830
15	Alkermes Investigational Site	Berlin	New Jersey	United States	08009
16	Alkermes Investigational Site	Brooklyn	New York	United States	11241
17	Alkermes Investigational Site	New York	New York	United States	10021
18	Alkermes Investigational Site	Canton	Ohio	United States	44718
19	Alkermes Investigational Site	Dayton	Ohio	United States	45417
20	Alkermes Investigational Site	Oklahoma City	Oklahoma	United States	73112
21	Alkermes Investigational Site	Philadelphia	Pennsylvania	United States	19104
22	Alkermes Investigational Site	Charleston	South Carolina	United States	29407
23	Alkermes Investigational Site	Austin	Texas	United States	78754
24	Alkermes Investigational Site	Dallas	Texas	United States	75235
25	Alkermes Investigational Site	Houston	Texas	United States	77081
26	Alkermes Investigational Site	San Antonio	Texas	United States	78229
27	Alkermes Investigational Site	Bellevue	Washington	United States	98007

Sponsors and Collaborators

• Alkermes, Inc.

Investigators

• Study Director: Richard Leigh-Pemberton, MD, Alkermes, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alkermes, Inc.
• ClinicalTrials.gov Identifier: NCT01500200
• Other Study ID Numbers: ALK5461-202
• First Posted: Dec 28, 2011
• Last Update Posted: May 21, 2019
• Last Verified: Apr 1, 2019

• Additional relevant MeSH terms: 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). One subject randomized to placebo did not receive study drug.

Arm/Group Title	Placebo S1	ALKS 5461 2mg/2mg S1	ALKS 5461 8mg/8mg S1	Placebo S2	ALKS 5461 2mg/2mg S2	ALKS 5461 8mg/8mg S2
Arm/Group Description	Received placebo in Stage 1	Received ALKS 5461 2mg/2mg in Stage 1	Received ALKS 5461 8mg/8mg in Stage 1	Received placebo in Stage 2	Received ALKS 5461 2mg/2mg in Stage 2	Received ALKS 5461 8mg/8mg in Stage 2
Period Title: Stage 1
STARTED	98	24	19	0	0	0
COMPLETED	90	18	13	0	0	0
NOT COMPLETED	8	6	6	0	0	0
Period Title: Stage 1
STARTED	0	0	0	20	23	22
COMPLETED	0	0	0	20	18	18
NOT COMPLETED	0	0	0	0	5	4

Baseline Characteristics

Arm/Group Title	Placebo S1	ALKS 5461 2mg/2mg S1	ALKS 5461 8mg/8mg S1	Total
Arm/Group Description	Received placebo in Stage 1	Received ALKS 5461 2mg/2mg in Stage 1	Received ALKS 5461 8mg/8mg in Stage 1	Total of all reporting groups
Overall Participants	98	24	19	141
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.6 (11.0)	45.2 (10.9)	45.8 (11.9)	46.3 (11.1)
Sex: Female, Male (Count of Participants)
Female	68 69.4%	17 70.8%	11 57.9%	96 68.1%
Male	30 30.6%	7 29.2%	8 42.1%	45 31.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	1 1%	0 0%	0 0%	1 0.7%
Black or African American	23 23.5%	9 37.5%	6 31.6%	38 27%
White	74 75.5%	15 62.5%	13 68.4%	102 72.3%
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) [Number]
United States	98 100%	24 100%	19 100%	141 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 4 in Hamilton Rating Scale for Depression (HAM-D17) Total Score
Description	The HAM-D17 scale is a clinician-administered questionnaire comprised of 17 items used to measure the severity of MDD symptoms. Scores range from 0 (no apparent symptoms) to 50 (most severe symptoms). Individual questionnaire items include depressed mood, work and activities, insomnia (early), insomnia (middle), insomnia (late), genital symptoms, somatic symptoms (gastrointestinal), loss of weight, somatic symptoms (general), feelings of guilt, suicide, anxiety (psychic), anxiety (somatic), hypochondriasis, insight, agitation, and retardation.
Time Frame	Baseline and 4 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 HAM-D17 assessment in the respective stage. Two subjects randomized to 8/8 in Stage 1 received 2/2. These subjects are included in the 8/8 group for efficacy analysis.

Arm/Group Title	Placebo S1	ALKS 5461 2mg/2mg S1	ALKS 5461 8mg/8mg S1	Placebo S2	ALKS 5461 2mg/2mg S2	ALKS 5461 8mg/8mg S2
Arm/Group Description	Subjects randomized to placebo in Stage 1	Subjects randomized to ALKS 5461 2mg/2mg in Stage 1	Subjects randomized to ALKS 5461 8mg/8mg in Stage 1	Subjects randomized to placebo in Stage 2	Subjects randomized to ALKS 5461 2mg/2mg in Stage 2	Subjects randomized to ALKS 5461 8mg/8mg in Stage 2
Measure Participants	95	20	20	20	23	22
Least Squares Mean (Standard Error) [score on a scale]	-7.1 (0.6)	-9.3 (1.5)	-6.6 (1.6)	-1.5 (1.1)	-5.2 (1.2)	-3.3 (1.1)

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 weights (0.6/0.4 for Stage 1/Stage 2). 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
Statistical Test of Hypothesis	p-Value	0.014
	Comments	Hypothesis tests were two-sided with an alpha of 0.5.
	Method	Mixed Models Analysis
	Comments	ALKS 5461 was compared to PBO using stage-specific MMRM for change from Baseline. Model-derived estimates were combined using pre-specified weights.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo S1, ALKS 5461 8mg/8mg S1, Placebo S2, ALKS 5461 8mg/8mg 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 weights (0.6/0.4 for Stage 1/Stage 2). Within each stage ALKS 5461 8mg/8mg was compared to placebo (i.e., ALKS 5461 8mg/8mg S1 vs Placebo S1; and ALKS 5461 8mg/8mg S2 vs Placebo S2.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.699
	Comments	Hypothesis tests were two-sided with an alpha of 0.05.
	Method	Mixed Models Analysis
	Comments	ALKS 5461 was compared to PBO using stage-specific MMRM for change from Baseline. Model-derived estimates were combined using pre-specified weights.

2. Secondary Outcome

Title	Proportion of Patients Who Exhibited Treatment Response (HAM-D17)
Description	The proportion of subjects demonstrating HAM-D17 treatment response, defined as a ≥ 50% reduction in HAM-D17 score from baseline to the end of the efficacy period (Week 4). The HAM-D17 is a clinician administered questionnaire comprised of 17 questions used to assess the severity of a patient's depression. Scores range from 0 (no apparent symptoms) to 50 (most severe symptoms). Individual questionnaire items include depressed mood, work and activities, insomnia (early), insomnia (middle), insomnia (late), genital symptoms, somatic symptoms (gastrointestinal), loss of weight, somatic symptoms (general), feelings of guilt, suicide, anxiety (psychic), anxiety (somatic), hypochondriasis, insight, agitation, and retardation.
Time Frame	4 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 HAM-D17 assessment in the respective stage.

Arm/Group Title	Placebo S1	ALKS 5461 2mg/2mg S1	ALKS 5461 8mg/8mg S1	Placebo S2	ALKS 5461 2mg/2mg S2	ALKS 5461 8mg/8mg S2
Arm/Group Description	Subjects randomized to placebo in Stage 1	Subjects randomized to ALKS 5461 2mg/2mg in Stage 1	Subjects randomized to ALKS 5461 8mg/8mg in Stage 1	Subjects randomized to placebo in Stage 2	Subjects randomized to ALKS 5461 2mg/2mg in Stage 2	Subjects randomized to ALKS 5461 8mg/8mg in Stage 2
Measure Participants	90	17	14	20	18	18
Yes	23 23.5%	8 33.3%	5 26.3%	3 2.1%	6 NaN	5 NaN
No	67 68.4%	9 37.5%	9 47.4%	17 12.1%	12 NaN	13 NaN

3. Secondary Outcome

Title	Change From Baseline in 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	4 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 HAM-D17 assessment in the respective stage. Two subjects randomized to 8/8 in Stage 1 received 2/2. These subjects are included in the 8/8 group for efficacy analysis.

Arm/Group Title	Placebo S1	ALKS 5461 2mg/2mg S1	ALKS 5461 8mg/8mg S1	Placebo S2	ALKS 5461 2mg/2mg S2	ALKS 5461 8mg/8mg S2
Arm/Group Description	Subjects randomized to placebo in Stage 1	Subjects randomized to ALKS 5461 2mg/2mg in Stage 1	Subjects randomized to ALKS 5461 8mg/8mg in Stage 1	Subjects randomized to placebo in Stage 2	Subjects randomized to ALKS 5461 2mg/2mg in Stage 2	Subjects randomized to ALKS 5461 8mg/8mg in Stage 2
Measure Participants	95	20	20	20	23	22
Least Squares Mean (Standard Error) [score on a scale]	-9.6 (0.9)	-13.3 (2.2)	-11.3 (2.3)	-2.1 (1.6)	-8.8 (1.7)	-4.7 (1.7)

4. Secondary Outcome

Title	Change From Baseline in Clinical Global Impression - Severity (CGI-S) Total Score
Description	The CGI-S is a 7-point scale that requires the clinician to assess how mentally ill the patient is at a specific point in time. Based on the scale, patients are categorized as follows: "1: normal, not at all ill"; "2: borderline mentally ill"; "3: mildly ill"; "4: moderately ill"; "5: markedly ill"; "6: severely ill"; and "7: among the most extremely ill patients."
Time Frame	4 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 HAM-D17 assessment in the respective stage. Two subjects randomized to 8/8 in Stage 1 received 2/2. These subjects are included in the 8/8 group for efficacy analysis.

Arm/Group Title	Placebo S1	ALKS 5461 2mg/2mg S1	ALKS 5461 8mg/8mg S1	Placebo S2	ALKS 5461 2mg/2mg S2	ALKS 5461 8mg/8mg S2
Arm/Group Description	Subjects randomized to placebo in Stage 1	Subjects randomized to ALKS 5461 2mg/2mg in Stage 1	Subjects randomized to ALKS 5461 8mg/8mg in Stage 1	Subjects randomized to placebo in Stage 2	Subjects randomized to ALKS 5461 2mg/2mg in Stage 2	Subjects randomized to ALKS 5461 8mg/8mg in Stage 2
Measure Participants	95	20	20	20	23	22
Least Squares Mean (Standard Error) [score on a scale]	-1.0 (0.1)	-1.3 (0.2)	-1.2 (0.3)	-0.5 (0.2)	-1.1 (0.2)	-0.6 (0.2)

Adverse Events

Time Frame	4 weeks for each stage
Adverse Event Reporting Description	The safety population includes all subjects who were randomized and received at least 1 dose of study drug. Two subjects randomized to 8/8 in Stage 1 received 2/2. These subjects are included in the 2/2 group for the safety analysis.
Arm/Group Title	Placebo S1		ALKS 5461 2mg/2mg S1		ALKS 5461 8mg/8mg S1		Placebo S2		ALKS 5461 2mg/2mg S2		ALKS 5461 8mg/8mg S2
Arm/Group Description	Received placebo in Stage 1		Received ALKS 5461 2mg/2mg in Stage 1		Received ALKS 5461 8mg/8mg in Stage 1		Received placebo in Stage 2		Received ALKS 5461 2mg/2mg in Stage 1		Received ALKS 5461 8mg/8mg in Stage 1
All Cause Mortality
	Placebo S1		ALKS 5461 2mg/2mg S1		ALKS 5461 8mg/8mg S1		Placebo S2		ALKS 5461 2mg/2mg S2		ALKS 5461 8mg/8mg 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	0/98 (0%)		0/24 (0%)		0/19 (0%)		0/20 (0%)		0/23 (0%)		0/22 (0%)
Serious Adverse Events
	Placebo S1		ALKS 5461 2mg/2mg S1		ALKS 5461 8mg/8mg S1		Placebo S2		ALKS 5461 2mg/2mg S2		ALKS 5461 8mg/8mg 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	1/98 (1%)		1/24 (4.2%)		0/19 (0%)		0/20 (0%)		1/23 (4.3%)		0/22 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intraocular melanoma	0/98 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/20 (0%)	0	1/23 (4.3%)	1	0/22 (0%)	0
Psychiatric disorders
Multiple drug overdose intentional	1/98 (1%)	1	0/24 (0%)	0	0/19 (0%)	0	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Drug withdrawal syndrome	0/98 (0%)	0	1/24 (4.2%)	1	0/19 (0%)	0	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo S1		ALKS 5461 2mg/2mg S1		ALKS 5461 8mg/8mg S1		Placebo S2		ALKS 5461 2mg/2mg S2		ALKS 5461 8mg/8mg 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	42/98 (42.9%)		15/24 (62.5%)		18/19 (94.7%)		11/20 (55%)		19/23 (82.6%)		17/22 (77.3%)
Eye disorders
Dry eye	0/98 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Miosis	0/98 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Vision blurred	0/98 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	1/23 (4.3%)	1	0/22 (0%)	0
Gastrointestinal disorders
Nausea	6/98 (6.1%)	7	5/24 (20.8%)	6	9/19 (47.4%)	10	2/20 (10%)	2	10/23 (43.5%)	11	5/22 (22.7%)	5
Constipation	5/98 (5.1%)	6	2/24 (8.3%)	2	1/19 (5.3%)	1	1/20 (5%)	1	2/23 (8.7%)	2	2/22 (9.1%)	2
Vomiting	0/98 (0%)	0	3/24 (12.5%)	5	7/19 (36.8%)	7	1/20 (5%)	1	5/23 (21.7%)	6	2/22 (9.1%)	2
Dry mouth	6/98 (6.1%)	6	2/24 (8.3%)	2	2/19 (10.5%)	2	2/20 (10%)	2	2/23 (8.7%)	2	1/22 (4.5%)	1
Dyspepsia	4/98 (4.1%)	4	0/24 (0%)	0	2/19 (10.5%)	2	0/20 (0%)	0	1/23 (4.3%)	1	0/22 (0%)	0
Abdominal pain	0/98 (0%)	0	1/24 (4.2%)	1	1/19 (5.3%)	1	0/20 (0%)	0	1/23 (4.3%)	1	1/22 (4.5%)	1
Abdominal pain upper	1/98 (1%)	1	0/24 (0%)	0	0/19 (0%)	0	1/20 (5%)	1	3/23 (13%)	3	1/22 (4.5%)	1
Hypoaesthesia oral	0/98 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	1/22 (4.5%)	1
Diarrhoea	5/98 (5.1%)	6	1/24 (4.2%)	1	0/19 (0%)	0	2/20 (10%)	2	1/23 (4.3%)	1	0/22 (0%)	0
General disorders
Fatigue	4/98 (4.1%)	4	2/24 (8.3%)	2	1/19 (5.3%)	1	1/20 (5%)	1	2/23 (8.7%)	2	1/22 (4.5%)	1
Feeling abnormal	0/98 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Product taste abnormal	0/98 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/20 (0%)	0	3/23 (13%)	3	2/22 (9.1%)	2
Infections and infestations
Bronchitis	0/98 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Urinary tract infection	0/98 (0%)	0	1/24 (4.2%)	1	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Nasopharyngitis	2/98 (2%)	2	0/24 (0%)	0	0/19 (0%)	0	1/20 (5%)	1	0/23 (0%)	0	0/22 (0%)	0
Injury, poisoning and procedural complications
Poisoning	0/98 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Investigations
Blood pressure increased	0/98 (0%)	0	1/24 (4.2%)	1	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Blood thyroid stimulating hormone increased	0/98 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Electrocardiogram RR interval prolonged	0/98 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Weight increased	1/98 (1%)	1	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	1/98 (1%)	1	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Musculoskeletal and connective tissue disorders
Neck pain	0/98 (0%)	0	0/24 (0%)	0	2/19 (10.5%)	2	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Back pain	1/98 (1%)	1	0/24 (0%)	0	1/19 (5.3%)	2	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Muscle twitching	0/98 (0%)	0	0/24 (0%)	0	0/19 (0%)	0	0/20 (0%)	0	2/23 (8.7%)	2	0/22 (0%)	0
Nervous system disorders
Dizziness	5/98 (5.1%)	5	4/24 (16.7%)	5	9/19 (47.4%)	10	1/20 (5%)	1	5/23 (21.7%)	5	4/22 (18.2%)	4
Headache	14/98 (14.3%)	19	1/24 (4.2%)	1	5/19 (26.3%)	8	4/20 (20%)	5	1/23 (4.3%)	2	5/22 (22.7%)	8
Sedation	2/98 (2%)	2	3/24 (12.5%)	4	5/19 (26.3%)	5	0/20 (0%)	0	4/23 (17.4%)	5	1/22 (4.5%)	1
Dysgeusia	0/98 (0%)	0	0/24 (0%)	0	3/19 (15.8%)	3	0/20 (0%)	0	1/23 (4.3%)	1	2/22 (9.1%)	2
Hypoaesthesia	0/98 (0%)	0	0/24 (0%)	0	2/19 (10.5%)	2	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Somnolence	2/98 (2%)	2	0/24 (0%)	0	2/19 (10.5%)	2	0/20 (0%)	0	2/23 (8.7%)	2	2/22 (9.1%)	3
Psychiatric disorders
Agitation	0/98 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Anxiety	1/98 (1%)	1	0/24 (0%)	0	1/19 (5.3%)	1	1/20 (5%)	1	1/23 (4.3%)	1	0/22 (0%)	0
Suicidal ideation	1/98 (1%)	3	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Euphoric mood	0/98 (0%)	0	2/24 (8.3%)	2	0/19 (0%)	0	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Skin and subcutaneous tissue disorders
Hyperhidrosis	3/98 (3.1%)	3	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	4/23 (17.4%)	4	1/22 (4.5%)	1
Night sweats	0/98 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0
Rash	0/98 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	1/22 (4.5%)	1
Urticaria	0/98 (0%)	0	0/24 (0%)	0	1/19 (5.3%)	1	0/20 (0%)	0	0/23 (0%)	0	0/22 (0%)	0

Limitations/Caveats

Two subjects randomized to 8/8 received 2/2 and are presented in the Participant Flow, Baseline, and AE tables by actual treatment received. For the outcome measures, subjects were analyzed by randomization treatment assignment.

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.