A Study of Duloxetine in Fibromyalgia

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01552057
• Collaborator: Shionogi (Industry)
• Enrollment: 393
• Location: 1
• Arms: 2
• Duration (Months): 21
• Patients Per Site Per Month: 18.7

Study Details

Study Description

Brief Summary

The purpose of the study is to assess the effectiveness and safety of duloxetine in participants with fibromyalgia.

Condition or Disease	Intervention/Treatment	Phase
Fibromyalgia	Drug: Duloxetine 60 mg; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 393 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III Clinical Trial of Duloxetine in Participants With Fibromyalgia
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Duloxetine 60 mg Duloxetine hydrochloride up to 60 milligrams (mg) orally for 15 weeks	Drug: Duloxetine 60 mg; Duloxetine 60 mg taken orally once every day for 15 weeks; Other Names: LY248686 Cymbalta
Placebo Comparator: Placebo Placebo orally for 15 weeks	Drug: Placebo; Placebo taken orally once every day for 15 weeks

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to 14-Week Endpoint in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM) [Baseline, 14 weeks]

   BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.

2. Change From Baseline to 2 Weeks in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM) [Baseline, 2 weeks]

   BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.

3. Change From Baseline to 4 Weeks in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM) [Baseline, 4 weeks]

   BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.

4. Change From Baseline to 6 Weeks in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM) [Baseline, 6 weeks]

   BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.

5. Change From Baseline to 10 Weeks in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM) [Baseline, 10 weeks]

   BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.

6. Change From Baseline up to 14-Week Endpoint in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (ANCOVA) [Baseline, up to 14 weeks]

   BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an analysis of covariance (ANCOVA) approach including administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates.

Secondary Outcome Measures

1. Patients Global Impression of Improvement (PGI-I) at Endpoint [14 weeks]

   PGI-I measures the participant's perception of improvement at the time of assessment compared with the start of treatment. Scores ranged from 1 (very much better) to 7 (very much worse). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.

2. Clinical Global Impression of Improvement (CGI-I) at Endpoint [14 weeks]

   CGI-I measures the clinician's perception of participant improvement at the time of assessment (compared with the start of treatment). Scores ranged from 1 (very much better) to 7 (very much worse). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.

3. Change From Baseline to 14-Week Endpoint in Fibromyalgia Impact Questionnaire (FIQ) [Baseline, 14 weeks]

   FIQ is a 20-item, self-administered questionnaire using Likert-type scales to measure participant (pt) outcomes over the past week. Items 1 through 11 measured physical functioning on 4-point scales. Items 12 and 13 measured the number of days a pt felt well and days a pt was unable to work due to fibromyalgia symptoms. Items 14 through 20 were 11-point scales on which a pt rated work difficulty, pain, fatigue, morning tiredness, stiffness, anxiety, and depression. If a pt did not do all the tasks listed, those items were deleted from scoring. Algorithms were used to determine total FIQ scores which ranged from 0 to 100; higher scores indicated a more negative impact. LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between administration groups as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.

4. Change From Baseline to 14-Week Endpoint in 36-Item Short-Form (SF-36) Health Survey Domain Scores [Baseline, up to 14 weeks]

   The SF-36 Health Survey is a generic, health-related survey assessing the participant's quality of life on 8 domains: physical functioning, daily functioning (physical), bodily pain, general health, vitality, social functioning, daily functioning (emotional), and mental health. Each domain was scored by summing individual items pertaining to that domain and transforming scores into a 0 to 100 scale, with higher scores indicating better health status or functioning. LS mean was calculated using an ANCOVA approach including administration groups as fixed effects, and baseline as well as the presence or absence of complication by major depressive disorder as covariates.

5. Change From Baseline to 14-Week Endpoint in Beck Depression Inventory-II (BDI-II) [Baseline, 14 weeks]

   The BDI-II is a 21-item self-administered questionnaire designed to assess the characteristics of depression. Each item was scored on a 4-point scale ranging from 0 (not present) to 3 (present in the extreme) and was summed to give a total BDI-II score. A total BDI-II score of 0 through 13 was considered minimal, 14 through 19 was mild, 20 through 28 was moderate, and 29 through 63 was severe depression symptoms. LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups and as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.

6. Change From Baseline to 14-Week Endpoint in Widespread Pain Index (WPI) and Symptom Severity (SS) in American College of Rheumatology (ACR) Fibromyalgia Diagnostic Criteria 2010 [Baseline, 14 weeks]

   WPI: Participant-reported areas (out of 19 points on the body) in which the participant had pain in the past week. WPI scores ranged from 0 (no areas) to 19 (all areas). SS: The sum of severity scores for fatigue, waking unrefreshed, and cognitive symptoms [each rated from 0 (no problem) to 3 (severe; life-disturbing problems)] plus the severity of somatic symptoms in general [rated from 0 (no symptoms) to 3 (a great deal of symptoms)]. The total SS score ranged from 0 and 12. LS mean was calculated using an MMRM approach including administration groups, observation points, interaction between the administration groups and the observation points as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.

7. Change From Baseline to 14-Week Endpoint in Average Pain and Worst Pain Severity Score Within 24-Hours in Participant Diary [Baseline, 14 weeks]

   Each morning participants rated their average pain and worst pain within the past 24 hours on separate 11-point Likert scales with scores ranging from 0 (no pain) through 10 (worst possible pain). These scores were then averaged for the week and compared to baseline. LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.

8. Change From Baseline to 14-Week Endpoint in Brief Pain Inventory-Severity (BPI-S) and Brief Pain Inventory-Interference (BPI-I) Scores on the BPI-Modified Short Form [Baseline, 14 weeks]

   BPI-S and BPI-I are self-reported scales measuring severity of pain and interference on function, respectively. Severity scores ranged from 0 (no pain) to 10 (severe pain) for each question assessing worst pain, least pain, and pain right now. Interference scores ranged from 0 (does not interfere) to 10 (completely interferes) for each question assessing interference of pain in past 24 hours with general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. Average interference was the average of non-missing scores of individual interference items. LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 74 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants fulfilling the following criteria in the American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia

• Participants with pain rated severity 4 or over by Brief Pain Inventory (BPI) - average pain severity item (Question 3)

Exclusion Criteria:

• Participants with serious cardiovascular, hepatic, renal, respiratory, or hematological disease, or clinically significant laboratory or electrocardiogram abnormality which indicate a serious medical problem or require significant intervention in the judgment of the investigators

• Participants with alanine aminotransferase/aspartate aminotransferase of not less than 100 international units per liter (IU/L) or total bilirubin of not less than 1.6 milligrams per deciliter (mg/dL)

• Participants with serum creatinine level of not less than 2.0 mg/dL, participant who has undergone kidney transplantation or hemodialysis

• Participants with pain difficult to discriminate from pain associated with fibromyalgia or disease which disturbs the assessment

• Participants with treatment-refractory fibromyalgia

• Participants with thyroidal dysfunction, excluding those assessed by the investigator that the disorder is controlled as appropriate by 3-month or longer drug therapy

• Participants with present or past history of rheumatoid arthritis, inflammatory arthritis, infectious arthritis, or auto immune disease rather than thyroid deficiency

• Participants with an axis I condition according to Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV), currently or within the past year, except for major depressive disorders

• Participants with a lifetime diagnosis of bipolar disorder or schizoaffective disorder; or any other disorder with psychotic symptoms - based on the clinical opinion of the investigator

• Participants with personality disorder or mental retardation

• Participants with uncontrolled angle closure glaucoma

• Participants with present or past history of uncontrolled seizures or convulsion disorders

• Participants with suicidal ideation within past 6 months, with suicidal attempt within past 1 year

• Participants answering "yes" to any of the questions about active suicidal ideation/intent/behaviors occurring within the past 6 months (Columbia Suicide Severity Rating Scale, Suicide Ideation section - Questions 4 and 5; Suicidal Behavior section)

• Participants with past history of multiple episodes of drug allergy

• Female participants who are pregnant, lactating, or who want to get pregnant during the study period. Male participants who want his partner to get pregnant

• Females of child-bearing potential who can't agree to utilize medically. acceptable and reliable means of birth control during the study and for 1 month following the last dose of the study

• Participants with a history of alcohol or any psychoactive substance abuse or dependence (including alcohol, but excluding nicotine and caffeine) within the past 1 year

• Participants who have a positive urine drug screen for any substance of abuse (phencyclidine, cocaine, antihypnotic agent, or cannabis)

• Participants previously treated with duloxetine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Miyagi		Japan	982-0032

Sponsors and Collaborators

• Eli Lilly and Company
• Shionogi

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01552057
• Other Study ID Numbers: 14377; F1J-JE-HMGZ
• First Posted: Mar 13, 2012
• Last Update Posted: Jan 16, 2015
• Last Verified: Jan 1, 2015

• Additional relevant MeSH terms: Fibromyalgia; Myofascial Pain Syndromes; Duloxetine Hydrochloride

Study Results

Participant Flow

Pre-assignment Detail	Randomized participants who completed the 14-week treatment period were considered to have completed the study. After study completion or early discontinuation, participants completed a 1-week taper and were observed 1 week post-treatment for safety.

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-milligram (mg) dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules). During the 1-week taper, the daily dosage was gradually reduced. For the first 3 days: 40-mg dose of duloxetine (two 20-mg capsules) administered orally once daily. For the remaining 4 days: 20-mg dose of duloxetine (one 20-mg capsule) administered orally once daily.	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks. During the 1-week taper, the number of placebo capsules was gradually reduced. For the first 3 days: 2 placebo capsules administered orally once daily. For the remaining 4 days: 1 placebo capsule administered orally once daily.
Period Title: Overall Study
STARTED	196	197
Received at Least 1 Dose of Study Drug	194	196
COMPLETED	166	149
NOT COMPLETED	30	48

Baseline Characteristics

Arm/Group Title	Duloxetine 60 mg	Placebo	Total
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules). During the 1-week taper, the daily dosage was gradually reduced. For the first 3 days: 40-mg dose of duloxetine (two 20-mg capsules) administered orally once daily. For the remaining 4 days: 20-mg dose of duloxetine (one 20-mg capsule) administered orally once daily.	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks. During the 1-week taper, the number of placebo capsules was gradually reduced. For the first 3 days: 2 placebo capsules administered orally once daily. For the remaining 4 days: 1 placebo capsule administered orally once daily.	Total of all reporting groups
Overall Participants	191	195	386
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.8 (12.0)	49.5 (11.7)	48.7 (11.9)
Sex: Female, Male (Count of Participants)
Female	157 82.2%	164 84.1%	321 83.2%
Male	34 17.8%	31 15.9%	65 16.8%
Race/Ethnicity, Customized (participants) [Number]
Japanese	191 100%	195 100%	386 100%
Region of Enrollment (participants) [Number]
Japan	191 100%	195 100%	386 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to 14-Week Endpoint in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM)
Description	BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). Least squares (LS) mean was calculated using a mixed-effects model repeated measures (MMRM) approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.
Time Frame	Baseline, 14 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline measurement of primary efficacy (BPI 24-hour average pain severity).

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules).	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks.
Measure Participants	191	195
Least Squares Mean (Standard Error) [units on a scale]	-1.90 (0.23)	-1.58 (0.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0988
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -0.70 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Patients Global Impression of Improvement (PGI-I) at Endpoint
Description	PGI-I measures the participant's perception of improvement at the time of assessment compared with the start of treatment. Scores ranged from 1 (very much better) to 7 (very much worse). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline measurement of primary efficacy (BPI 24-hour average pain severity).

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules).	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks.
Measure Participants	191	195
Least Squares Mean (Standard Error) [units on a scale]	2.83 (0.16)	3.32 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -0.76 to -0.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Clinical Global Impression of Improvement (CGI-I) at Endpoint
Description	CGI-I measures the clinician's perception of participant improvement at the time of assessment (compared with the start of treatment). Scores ranged from 1 (very much better) to 7 (very much worse). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.
Time Frame	14 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline measurement of primary efficacy (BPI 24-hour average pain severity).

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules).	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks.
Measure Participants	191	195
Least Squares Mean (Standard Error) [units on a scale]	2.83 (0.15)	3.27 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0012
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95%; -0.71 to -0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline to 14-Week Endpoint in Fibromyalgia Impact Questionnaire (FIQ)
Description	FIQ is a 20-item, self-administered questionnaire using Likert-type scales to measure participant (pt) outcomes over the past week. Items 1 through 11 measured physical functioning on 4-point scales. Items 12 and 13 measured the number of days a pt felt well and days a pt was unable to work due to fibromyalgia symptoms. Items 14 through 20 were 11-point scales on which a pt rated work difficulty, pain, fatigue, morning tiredness, stiffness, anxiety, and depression. If a pt did not do all the tasks listed, those items were deleted from scoring. Algorithms were used to determine total FIQ scores which ranged from 0 to 100; higher scores indicated a more negative impact. LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between administration groups as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.
Time Frame	Baseline, 14 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline measurement of primary efficacy (BPI 24-hour average pain severity).

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules).	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks.
Measure Participants	191	195
Least Squares Mean (Standard Error) [units on a scale]	-18.41 (2.57)	-13.05 (2.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0073
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.35
	Confidence Interval	(2-Sided) 95%; -9.26 to -1.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline to 14-Week Endpoint in 36-Item Short-Form (SF-36) Health Survey Domain Scores
Description	The SF-36 Health Survey is a generic, health-related survey assessing the participant's quality of life on 8 domains: physical functioning, daily functioning (physical), bodily pain, general health, vitality, social functioning, daily functioning (emotional), and mental health. Each domain was scored by summing individual items pertaining to that domain and transforming scores into a 0 to 100 scale, with higher scores indicating better health status or functioning. LS mean was calculated using an ANCOVA approach including administration groups as fixed effects, and baseline as well as the presence or absence of complication by major depressive disorder as covariates.
Time Frame	Baseline, up to 14 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline measurement of primary efficacy (BPI 24-hour average pain severity); LOCF values were used.

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules).	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks.
Measure Participants	191	195
Physical Functioning	7.40 (2.13)	3.06 (2.15)
Role-Physical	8.20 (2.96)	0.44 (2.98)
Bodily Pain	10.95 (2.07)	5.28 (2.08)
General Health	6.55 (1.92)	3.31 (1.94)
Vitality	10.05 (2.51)	3.35 (2.53)
Social Functioning	10.32 (3.04)	3.28 (3.06)
Role-Emotional	5.50 (3.35)	-3.63 (3.36)
Mental Health	5.91 (2.51)	-2.00 (2.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Physical Functioning
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0049
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.34
	Confidence Interval	(2-Sided) 95%; 1.32 to 7.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Role-Physical
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.76
	Confidence Interval	(2-Sided) 95%; 3.57 to 11.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Bodily Pain
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.67
	Confidence Interval	(2-Sided) 95%; 2.76 to 8.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	General Health
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0192
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.25
	Confidence Interval	(2-Sided) 95%; 0.53 to 5.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Vitality
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.70
	Confidence Interval	(2-Sided) 95%; 3.15 to 10.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Social Functioning
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0014
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.04
	Confidence Interval	(2-Sided) 95%; 2.74 to 11.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Role-Emotional
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.12
	Confidence Interval	(2-Sided) 95%; 4.41 to 13.83
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Mental Health
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.91
	Confidence Interval	(2-Sided) 95%; 4.39 to 11.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline to 14-Week Endpoint in Beck Depression Inventory-II (BDI-II)
Description	The BDI-II is a 21-item self-administered questionnaire designed to assess the characteristics of depression. Each item was scored on a 4-point scale ranging from 0 (not present) to 3 (present in the extreme) and was summed to give a total BDI-II score. A total BDI-II score of 0 through 13 was considered minimal, 14 through 19 was mild, 20 through 28 was moderate, and 29 through 63 was severe depression symptoms. LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups and as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.
Time Frame	Baseline, 14 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline measurement of primary efficacy (BPI 24-hour average pain severity).

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules).	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks.
Measure Participants	191	195
Least Squares Mean (Standard Error) [units on a scale]	-4.07 (0.84)	-1.22 (0.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.85
	Confidence Interval	(2-Sided) 95%; -4.32 to -1.38
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline to 14-Week Endpoint in Widespread Pain Index (WPI) and Symptom Severity (SS) in American College of Rheumatology (ACR) Fibromyalgia Diagnostic Criteria 2010
Description	WPI: Participant-reported areas (out of 19 points on the body) in which the participant had pain in the past week. WPI scores ranged from 0 (no areas) to 19 (all areas). SS: The sum of severity scores for fatigue, waking unrefreshed, and cognitive symptoms [each rated from 0 (no problem) to 3 (severe; life-disturbing problems)] plus the severity of somatic symptoms in general [rated from 0 (no symptoms) to 3 (a great deal of symptoms)]. The total SS score ranged from 0 and 12. LS mean was calculated using an MMRM approach including administration groups, observation points, interaction between the administration groups and the observation points as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.
Time Frame	Baseline, 14 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline measurement of primary efficacy (BPI 24-hour average pain severity).

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules).	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks.
Measure Participants	191	195
WPI	-2.34 (0.58)	-1.06 (0.60)
SS	-1.37 (0.27)	-1.00 (0.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	WPI
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0029
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.28
	Confidence Interval	(2-Sided) 95%; -2.12 to -0.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Symptom Severity
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0906
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.36
	Confidence Interval	(2-Sided) 95%; -0.79 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline to 14-Week Endpoint in Average Pain and Worst Pain Severity Score Within 24-Hours in Participant Diary
Description	Each morning participants rated their average pain and worst pain within the past 24 hours on separate 11-point Likert scales with scores ranging from 0 (no pain) through 10 (worst possible pain). These scores were then averaged for the week and compared to baseline. LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.
Time Frame	Baseline, 14 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline measurement of primary efficacy (BPI 24-hour average pain severity).

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules).	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks.
Measure Participants	191	195
Average Pain	-1.82 (0.18)	-1.48 (0.18)
Worst Pain	-1.81 (0.19)	-1.34 (0.19)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Average Pain
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0755
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95%; -0.70 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Worst Pain
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0232
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.47
	Confidence Interval	(2-Sided) 95%; -0.88 to -0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline to 14-Week Endpoint in Brief Pain Inventory-Severity (BPI-S) and Brief Pain Inventory-Interference (BPI-I) Scores on the BPI-Modified Short Form
Description	BPI-S and BPI-I are self-reported scales measuring severity of pain and interference on function, respectively. Severity scores ranged from 0 (no pain) to 10 (severe pain) for each question assessing worst pain, least pain, and pain right now. Interference scores ranged from 0 (does not interfere) to 10 (completely interferes) for each question assessing interference of pain in past 24 hours with general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. Average interference was the average of non-missing scores of individual interference items. LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and baseline as well as the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.
Time Frame	Baseline, 14 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline measurement of primary efficacy (BPI 24-hour average pain severity).

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules).	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks.
Measure Participants	191	195
Worst Pain	-1.91 (0.26)	-1.35 (0.26)
Least Pain	-1.72 (0.22)	-1.23 (0.22)
Pain Right Now	-1.77 (0.26)	-1.20 (0.26)
Interference With General Activity	-2.22 (0.31)	-1.76 (0.32)
Interference With Mood	-2.17 (0.32)	-1.42 (0.33)
Interference With Walking Ability	-1.67 (0.29)	-1.29 (0.30)
Interference With Normal Work	-2.18 (0.31)	-1.76 (0.32)
Interference With Relations With Other People	-1.09 (0.30)	-0.53 (0.30)
Interference With Sleep	-1.82 (0.35)	-1.57 (0.36)
Interference With Enjoyment of Life	-1.90 (0.31)	-1.24 (0.32)
Average Interference	-1.95 (0.27)	-1.44 (0.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Worst Pain
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0126
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.56
	Confidence Interval	(2-Sided) 95%; -0.99 to -0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Least Pain
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0092
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -0.87 to -0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Pain Right Now
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0083
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.57
	Confidence Interval	(2-Sided) 95%; -1.00 to -0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Interference With General Activity
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0807
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.46
	Confidence Interval	(2-Sided) 95%; -0.98 to 0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Interference With Mood
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0057
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.75
	Confidence Interval	(2-Sided) 95%; -1.29 to -0.22
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Interference With Walking Ability
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1114
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -0.84 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Interference With Normal Work
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1081
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95%; -0.94 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Interference With Relationships With Other People
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0264
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.55
	Confidence Interval	(2-Sided) 95%; -1.04 to -0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Interference With Sleep
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3959
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.81 to 0.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Interference With Enjoyment of Life
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0119
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.66
	Confidence Interval	(2-Sided) 95%; -1.18 to -0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments	Average Interference
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0222
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.52
	Confidence Interval	(2-Sided) 95%; -0.96 to -0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Primary Outcome

Title	Change From Baseline to 2 Weeks in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM)
Description	BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.
Time Frame	Baseline, 2 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline measurement of primary efficacy (BPI 24-hour average pain severity).

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules).	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks.
Measure Participants	191	195
Least Squares Mean (Standard Error) [units on a scale]	-1.00 (0.21)	-0.60 (0.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0113
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.40
	Confidence Interval	(2-Sided) 95%; -0.71 to -0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Primary Outcome

Title	Change From Baseline to 4 Weeks in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM)
Description	BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline measurement of primary efficacy (BPI 24-hour average pain severity).

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules).	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks.
Measure Participants	191	195
Least Squares Mean (Standard Error) [units on a scale]	-1.55 (0.22)	-0.94 (0.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.61
	Confidence Interval	(2-Sided) 95%; -0.94 to -0.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Primary Outcome

Title	Change From Baseline to 6 Weeks in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM)
Description	BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.
Time Frame	Baseline, 6 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline measurement of primary efficacy (BPI 24-hour average pain severity).

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules).	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks.
Measure Participants	191	195
Least Squares Mean (Standard Error) [units on a scale]	-1.81 (0.22)	-1.09 (0.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.72
	Confidence Interval	(2-Sided) 95%; -1.07 to -0.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Primary Outcome

Title	Change From Baseline to 10 Weeks in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (MMRM)
Description	BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an MMRM approach including administration groups, observation points, and interaction between the administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates; a linear model with unstructured error variance was applied.
Time Frame	Baseline, 10 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline measurement of primary efficacy (BPI 24-hour average pain severity).

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules).	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks.
Measure Participants	191	195
Least Squares Mean (Standard Error) [units on a scale]	-1.85 (0.23)	-1.41 (0.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0226
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	MMRM
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95%; -0.82 to -0.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Primary Outcome

Title	Change From Baseline up to 14-Week Endpoint in the BPI 24-Hour Average Pain Severity Item of the BPI-Modified Short Form Score (ANCOVA)
Description	BPI 24-hour average pain severity is a self-reported scale that measures the severity of pain based on the average pain over the past 24-hours. Severity scores ranged from 0 (no pain) to 10 (severe pain). LS mean was calculated using an analysis of covariance (ANCOVA) approach including administration groups as fixed effects, and BPI average pain severity at baseline and the presence or absence of major depressive disorder as covariates.
Time Frame	Baseline, up to 14 weeks

Outcome Measure Data

Analysis Population Description

Randomized participants who received at least 1 dose of study drug and had at least 1 post-baseline measurement of primary efficacy (BPI 24-hour average pain severity); Last Observation Carried Forward (LOCF) values were used.

Arm/Group Title	Duloxetine 60 mg	Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules).	Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks.
Measure Participants	191	195
Least Squares Mean (Standard Error) [units on a scale]	-1.60 (0.26)	-1.22 (0.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine 60 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0408
	Comments	Statistical tests were conducted at a 2-sided alpha level of 0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -0.74 to -0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Baseline through 1 week post last dose
Adverse Event Reporting Description	Randomized who received at least 1 dose of study drug.
Arm/Group Title	Duloxetine 60 mg		Placebo
Arm/Group Description	Treatment Period: Up to 60-mg dose of duloxetine administered orally once daily for 14 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule, and 2 placebo capsules), Week 2: 40-mg dose of duloxetine (two 20-mg capsules and 1 placebo capsule), Weeks 3 to 14: 60-mg dose of duloxetine (three 20-mg capsules). During the 1-week taper, the daily dosage was gradually reduced. For the first 3 days: 40-mg dose of duloxetine (two 20-mg capsules) administered orally once daily. For the remaining 4 days: 20-mg dose of duloxetine (one 20-mg capsule) administered orally once daily.		Treatment Period: 3 placebo capsules administered orally once daily for 14 weeks. During the 1-week taper, the number of placebo capsules was gradually reduced. For the first 3 days: 2 placebo capsules administered orally once daily. For the remaining 4 days: 1 placebo capsule administered orally once daily.
All Cause Mortality
	Duloxetine 60 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Duloxetine 60 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/194 (0.5%)		1/196 (0.5%)
Hepatobiliary disorders
Liver disorder	1/194 (0.5%)	1	0/196 (0%)	0
Infections and infestations
Pneumonia	0/194 (0%)	0	1/196 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	0/194 (0%)	0	1/196 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Duloxetine 60 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	147/194 (75.8%)		122/196 (62.2%)
Blood and lymphatic system disorders
Anaemia	1/194 (0.5%)	1	0/196 (0%)	0
Cardiac disorders
Palpitations	5/194 (2.6%)	5	1/196 (0.5%)	1
Tachycardia	1/194 (0.5%)	1	1/196 (0.5%)	1
Ear and labyrinth disorders
Tinnitus	1/194 (0.5%)	1	1/196 (0.5%)	1
Vertigo	4/194 (2.1%)	4	0/196 (0%)	0
Eye disorders
Conjunctival haemorrhage	0/194 (0%)	0	1/196 (0.5%)	1
Eye irritation	0/194 (0%)	0	1/196 (0.5%)	1
Vitreous floaters	1/194 (0.5%)	1	0/196 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	5/194 (2.6%)	6	5/196 (2.6%)	5
Abdominal distension	4/194 (2.1%)	4	1/196 (0.5%)	1
Abdominal pain	1/194 (0.5%)	1	0/196 (0%)	0
Abdominal pain upper	6/194 (3.1%)	6	4/196 (2%)	4
Constipation	29/194 (14.9%)	29	8/196 (4.1%)	8
Dental caries	0/194 (0%)	0	1/196 (0.5%)	1
Diarrhoea	8/194 (4.1%)	8	7/196 (3.6%)	8
Dyschezia	0/194 (0%)	0	1/196 (0.5%)	1
Dyspepsia	2/194 (1%)	2	1/196 (0.5%)	1
Enterocolitis	0/194 (0%)	0	1/196 (0.5%)	1
Food poisoning	1/194 (0.5%)	1	0/196 (0%)	0
Gastritis	2/194 (1%)	2	1/196 (0.5%)	1
Gastrooesophageal reflux disease	1/194 (0.5%)	1	1/196 (0.5%)	1
Glossitis	0/194 (0%)	0	1/196 (0.5%)	1
Irritable bowel syndrome	1/194 (0.5%)	1	1/196 (0.5%)	1
Nausea	42/194 (21.6%)	44	9/196 (4.6%)	9
Periodontal disease	0/194 (0%)	0	1/196 (0.5%)	1
Stomatitis	4/194 (2.1%)	5	3/196 (1.5%)	3
Toothache	0/194 (0%)	0	1/196 (0.5%)	1
Vomiting	7/194 (3.6%)	7	4/196 (2%)	4
General disorders
Asthenia	4/194 (2.1%)	4	0/196 (0%)	0
Chest discomfort	1/194 (0.5%)	1	0/196 (0%)	0
Chills	1/194 (0.5%)	1	1/196 (0.5%)	1
Fatigue	1/194 (0.5%)	1	0/196 (0%)	0
Feeling abnormal	2/194 (1%)	3	1/196 (0.5%)	1
Feeling cold	0/194 (0%)	0	1/196 (0.5%)	1
Malaise	9/194 (4.6%)	9	6/196 (3.1%)	6
Oedema	0/194 (0%)	0	1/196 (0.5%)	1
Pyrexia	2/194 (1%)	2	0/196 (0%)	0
Thirst	14/194 (7.2%)	14	7/196 (3.6%)	7
Hepatobiliary disorders
Hepatic function abnormal	5/194 (2.6%)	5	4/196 (2%)	4
Infections and infestations
Bronchitis	2/194 (1%)	2	1/196 (0.5%)	1
Cystitis	3/194 (1.5%)	4	3/196 (1.5%)	3
Ear infection	0/194 (0%)	0	1/196 (0.5%)	1
Folliculitis	1/194 (0.5%)	1	0/196 (0%)	0
Gastroenteritis	2/194 (1%)	2	2/196 (1%)	2
Gastroenteritis viral	0/194 (0%)	0	1/196 (0.5%)	1
Gingivitis	1/194 (0.5%)	1	1/196 (0.5%)	1
Hand-foot-and-mouth disease	1/194 (0.5%)	1	0/196 (0%)	0
Herpes simplex	0/194 (0%)	0	1/196 (0.5%)	1
Herpes zoster	2/194 (1%)	2	1/196 (0.5%)	1
Hordeolum	1/194 (0.5%)	1	0/196 (0%)	0
Impetigo	0/194 (0%)	0	1/196 (0.5%)	1
Influenza	3/194 (1.5%)	3	0/196 (0%)	0
Keratitis bacterial	1/194 (0.5%)	1	0/196 (0%)	0
Nasopharyngitis	26/194 (13.4%)	39	29/196 (14.8%)	37
Otitis media	0/194 (0%)	0	1/196 (0.5%)	1
Paronychia	1/194 (0.5%)	1	0/196 (0%)	0
Periodontitis	0/194 (0%)	0	1/196 (0.5%)	1
Pertussis	1/194 (0.5%)	1	0/196 (0%)	0
Pharyngitis	1/194 (0.5%)	1	1/196 (0.5%)	1
Pneumonia	0/194 (0%)	0	1/196 (0.5%)	1
Tinea pedis	0/194 (0%)	0	1/196 (0.5%)	1
Upper respiratory tract infection	2/194 (1%)	4	0/196 (0%)	0
Injury, poisoning and procedural complications
Contusion	3/194 (1.5%)	3	2/196 (1%)	2
Excoriation	0/194 (0%)	0	1/196 (0.5%)	1
Hand fracture	0/194 (0%)	0	1/196 (0.5%)	1
Heat illness	1/194 (0.5%)	1	0/196 (0%)	0
Ligament sprain	3/194 (1.5%)	3	3/196 (1.5%)	3
Thermal burn	0/194 (0%)	0	2/196 (1%)	2
Wound	0/194 (0%)	0	1/196 (0.5%)	1
Investigations
Alanine aminotransferase increased	2/194 (1%)	2	0/196 (0%)	0
Blood alkaline phosphatase increased	2/194 (1%)	2	0/196 (0%)	0
Blood bilirubin increased	5/194 (2.6%)	6	4/196 (2%)	4
Blood cholesterol increased	2/194 (1%)	2	1/196 (0.5%)	1
Blood creatine phosphokinase increased	3/194 (1.5%)	3	3/196 (1.5%)	3
Blood potassium increased	0/194 (0%)	0	1/196 (0.5%)	1
Blood triglycerides increased	2/194 (1%)	2	2/196 (1%)	2
Blood uric acid increased	1/194 (0.5%)	1	0/196 (0%)	0
Blood urine present	1/194 (0.5%)	1	1/196 (0.5%)	1
Eosinophil count increased	0/194 (0%)	0	1/196 (0.5%)	1
Gamma-glutamyltransferase increased	4/194 (2.1%)	4	4/196 (2%)	4
Haematocrit decreased	0/194 (0%)	0	1/196 (0.5%)	1
Haematocrit increased	1/194 (0.5%)	1	0/196 (0%)	0
Haemoglobin decreased	0/194 (0%)	0	1/196 (0.5%)	1
Haemoglobin increased	1/194 (0.5%)	1	0/196 (0%)	0
Heart rate increased	1/194 (0.5%)	1	0/196 (0%)	0
Lymphocyte count decreased	0/194 (0%)	0	1/196 (0.5%)	1
Protein total decreased	0/194 (0%)	0	1/196 (0.5%)	1
Protein urine present	1/194 (0.5%)	1	1/196 (0.5%)	1
Red blood cell count decreased	1/194 (0.5%)	1	1/196 (0.5%)	1
Red blood cell count increased	1/194 (0.5%)	1	0/196 (0%)	0
Weight decreased	2/194 (1%)	2	1/196 (0.5%)	1
Weight increased	1/194 (0.5%)	1	2/196 (1%)	2
White blood cell count decreased	1/194 (0.5%)	1	1/196 (0.5%)	1
Metabolism and nutrition disorders
Decreased appetite	13/194 (6.7%)	13	1/196 (0.5%)	1
Dyslipidaemia	0/194 (0%)	0	1/196 (0.5%)	1
Hypouricaemia	0/194 (0%)	0	1/196 (0.5%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/194 (0%)	0	2/196 (1%)	2
Arthritis	1/194 (0.5%)	1	0/196 (0%)	0
Back pain	2/194 (1%)	2	4/196 (2%)	4
Intervertebral disc protrusion	1/194 (0.5%)	1	1/196 (0.5%)	1
Musculoskeletal stiffness	1/194 (0.5%)	1	0/196 (0%)	0
Myalgia	1/194 (0.5%)	1	0/196 (0%)	0
Neck mass	1/194 (0.5%)	1	0/196 (0%)	0
Nodal osteoarthritis	1/194 (0.5%)	1	0/196 (0%)	0
Periarthritis	1/194 (0.5%)	1	0/196 (0%)	0
Plantar fasciitis	1/194 (0.5%)	1	0/196 (0%)	0
Synovial cyst	1/194 (0.5%)	1	0/196 (0%)	0
Tenosynovitis	1/194 (0.5%)	1	0/196 (0%)	0
Trigger finger	2/194 (1%)	2	0/196 (0%)	0
Nervous system disorders
Autonomic nervous system imbalance	1/194 (0.5%)	1	0/196 (0%)	0
Depressed level of consciousness	0/194 (0%)	0	1/196 (0.5%)	1
Dizziness	11/194 (5.7%)	11	2/196 (1%)	2
Dizziness postural	2/194 (1%)	2	1/196 (0.5%)	1
Dysgeusia	1/194 (0.5%)	1	0/196 (0%)	0
Dyskinesia	1/194 (0.5%)	1	0/196 (0%)	0
Head discomfort	1/194 (0.5%)	1	0/196 (0%)	0
Headache	9/194 (4.6%)	11	6/196 (3.1%)	6
Hypoaesthesia	1/194 (0.5%)	1	0/196 (0%)	0
Migraine	1/194 (0.5%)	1	2/196 (1%)	2
Sensory disturbance	1/194 (0.5%)	1	0/196 (0%)	0
Sleep paralysis	1/194 (0.5%)	1	0/196 (0%)	0
Somnolence	51/194 (26.3%)	52	21/196 (10.7%)	21
Syncope	1/194 (0.5%)	1	0/196 (0%)	0
Tremor	1/194 (0.5%)	1	0/196 (0%)	0
Psychiatric disorders
Anxiety	0/194 (0%)	0	2/196 (1%)	2
Depression	0/194 (0%)	0	1/196 (0.5%)	1
Insomnia	2/194 (1%)	2	5/196 (2.6%)	5
Limited symptom panic attack	0/194 (0%)	0	1/196 (0.5%)	1
Middle insomnia	2/194 (1%)	2	0/196 (0%)	0
Nightmare	1/194 (0.5%)	1	0/196 (0%)	0
Panic attack	0/194 (0%)	0	1/196 (0.5%)	1
Renal and urinary disorders
Dysuria	3/194 (1.5%)	3	0/196 (0%)	0
Hypertonic bladder	1/194 (0.5%)	1	0/196 (0%)	0
Oliguria	0/194 (0%)	0	1/196 (0.5%)	1
Pollakiuria	2/194 (1%)	2	0/196 (0%)	0
Reproductive system and breast disorders
Erectile dysfunction	0/35 (0%)	0	1/31 (3.2%)	1
Menopausal symptoms	1/159 (0.6%)	1	0/165 (0%)	0
Metrorrhagia	1/159 (0.6%)	1	0/165 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	0/194 (0%)	0	2/196 (1%)	2
Cough	1/194 (0.5%)	1	1/196 (0.5%)	1
Epistaxis	1/194 (0.5%)	2	0/196 (0%)	0
Hyperventilation	1/194 (0.5%)	1	0/196 (0%)	0
Oropharyngeal discomfort	1/194 (0.5%)	1	0/196 (0%)	0
Oropharyngeal pain	1/194 (0.5%)	1	0/196 (0%)	0
Rhinitis allergic	1/194 (0.5%)	1	0/196 (0%)	0
Upper respiratory tract inflammation	0/194 (0%)	0	1/196 (0.5%)	1
Yawning	1/194 (0.5%)	1	0/196 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	0/194 (0%)	0	1/196 (0.5%)	1
Dermatitis	1/194 (0.5%)	1	2/196 (1%)	2
Dermatitis atopic	1/194 (0.5%)	1	0/196 (0%)	0
Dermatitis contact	0/194 (0%)	0	2/196 (1%)	2
Drug eruption	1/194 (0.5%)	1	0/196 (0%)	0
Eczema	1/194 (0.5%)	1	8/196 (4.1%)	8
Erythema	0/194 (0%)	0	2/196 (1%)	2
Hyperhidrosis	2/194 (1%)	2	0/196 (0%)	0
Miliaria	1/194 (0.5%)	1	0/196 (0%)	0
Prurigo	0/194 (0%)	0	1/196 (0.5%)	1
Pruritus	5/194 (2.6%)	5	2/196 (1%)	2
Purpura	1/194 (0.5%)	1	0/196 (0%)	0
Rash	4/194 (2.1%)	5	2/196 (1%)	2
Rash papular	1/194 (0.5%)	1	0/196 (0%)	0
Urticaria	0/194 (0%)	0	4/196 (2%)	4
Vascular disorders
Hot flush	1/194 (0.5%)	1	0/196 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.