A Study in Participants With Diabetic Peripheral Neuropathic Pain in China

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01179672
• Collaborator: (none)
• Enrollment: 405
• Locations: 15
• Arms: 2
• Duration (Months): 28
• Patients Per Site: 27
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

The purpose of this trial is to assess the efficacy of duloxetine 60 milligrams (mg) once daily (QD) compared with placebo, on the change in pain severity from baseline to 12 weeks as measured by the weekly mean of the daily pain scores recorded in the participant's diary in participants with diabetic peripheral neuropathic pain.

Condition or Disease	Intervention/Treatment	Phase
Diabetic Neuropathy, Painful	Drug: Duloxetine; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 405 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Treatment of Patients With Diabetic Peripheral Neuropathic Pain in China: Duloxetine Versus Placebo
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Duloxetine	Drug: Duloxetine; 30 mg administered orally (po), QD for 1 week; 60 mg administered po, QD for remaining 11 weeks; 30 mg administered po, QD for 1 week during taper period; Other Names: Cymbalta LY248686
Placebo Comparator: Placebo	Drug: Placebo; Administered po, QD for 12 weeks; administered po, QD for 1 week during taper period

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline at 12-Week Endpoint in the Weekly Mean of Pain Severity Score [Baseline, 12 weeks]

   24-hour average pain severity scores were recorded daily by the participant on an 11-point Likert scale, an ordinal scale, with scores ranging from 0 (no pain) to 10 (worst possible pain). The weekly mean was calculated. A negative change indicated an improvement in participant's condition. Least squares (LS) mean was calculated using mixed model repeating measures (MMRM) and adjusted for treatment, pooled investigator, visit, and treatment-by-visit interaction, as well as baseline score and baseline score-by-visit interaction.

Secondary Outcome Measures

1. Mean Change From Baseline at 12-Week Endpoint in Weekly Mean of Night Pain and Worst Pain [Baseline, 12 weeks]

   24-hour average night pain and worst pain severity scores were recorded daily on an 11-point Likert scale, an ordinal scale, with scores ranging from 0 (no pain) to 10 (worst possible pain). A negative change indicated an improvement in the participant's condition. LS mean was calculated using MMRM and adjusted for treatment, pooled investigator, visit, and treatment-by-visit interaction, as well as the baseline score and baseline score-by-visit interaction.

2. Mean Change From Baseline at 12-Week Endpoint in the BPI-Severity Scale [Baseline, 12 weeks]

   BPI-Severity Scale was a self-reported scale that measured the severity of pain based on the average pain over the past 24-hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). A negative change indicated an improvement in the participant's condition. LS mean was calculated using MMRM and adjusted for treatment, pooled investigator, visit, and treatment-by-visit interaction, as well as baseline score and baseline score-by-visit interaction.

3. Mean Change From Baseline at 12-Week Endpoint in the CGI-S Scale [Baseline, 12 weeks]

   CGI-S was administered by the investigator in the presence of the participant and measured the severity of illness at the time of assessment compared with start of treatment; CGI-S scores ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). A negative change indicated an improvement in the participant's condition. LS mean was calculated using MMRM and adjusted for treatment, pooled investigator, visit, and treatment-by-visit interaction, as well as baseline score and baseline score-by-visit interaction.

4. Patient Global Impression of Improvement (PGI-I) Scale at 12-Week Endpoint [12 weeks]

   PGI-I was self-reported and measured a 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 MMRM and adjusted for treatment, pooled investigator, visit, and treatment-by-visit interaction, as well as baseline score and baseline score-by-visit interaction.

5. Mean Change From Baseline at 12-Week Endpoint in the Sensory Subscale of the SF-MPQ [Baseline, 12 weeks]

   SF-MPQ was a self-reported instrument that consisted of 11 sensory descriptors describing pain. The descriptors were rated on an intensity scale from 0 (none), 1 (mild), 2 (moderate) or 3 (severe). Three (3) pain scores were derived from the sum of the intensity rank values of the words chosen for sensory descriptors. The SF-MPQ sensory subscale was the sum of the 11 scores (ranged from 0 to 33, with 33 being the worst pain). A negative change indicates an improvement. LS mean was calculated using analysis of covariance (ANCOVA) adjusted for treatment, pooled investigator and baseline.

6. Percentage of Participants Who Experience Equal to or Greater Than 30%, 50% or 75% Reduction From Baseline at 12-Week Endpoint in Weekly Mean of Average Daily Pain [Baseline, 12 weeks]

   24-hour self-assessment of average daily pain was recorded in the participants diary based on an 11 point Likert scale with scores ranging from 0 (no pain) to 10 (worst possible pain). Percentage of participants was calculated as: (number of participants with 30% [or 50% or 75%] reduction in average daily pain) divided by (number of participants) multiplied by 100.

7. Percentage of Participants Who Experienced Equal to or Greater Than 30%, 50% or 75% Reduction From Baseline at 12-week Endpoint in BPI-Severity Average Pain Score [Baseline, 12 weeks]

   BPI-Severity scale was a self-reported scale that measured the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). A negative change indicated an improvement in the participant's condition. Percentage of participants was calculated as: (number of participants with 30% [or 50% or 75%] reduction in BPI-Severity average pain) divided by (number of participants) multiplied by 100.

8. Mean Change From Baseline at 12-week Endpoint in the BPI Interference Score [Baseline, 12 weeks]

   BPI-Interference Score was a self-reported scale that measured the interference of pain based on the average of the 7 questions assessing the interference of pain for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. The average interference scores ranged from 0 (does not interfere) to 10 (completely interferes). A negative change indicates an improvement in the participant's condition. LS means was calculated using MMRM and adjusted treatment, pooled investigator, visit, and treatment-by-visit interaction, baseline score and baseline score-by-visit interaction.

9. Mean Change From Baseline at 12 Week Endpoint in the SDS Total Score [Baseline, 12 weeks]

   SDS was self-reported and used to assess the effect of the participant's symptoms on their work (Item 1), social life (Item 2), and family life (Item 3). Each item was measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. SDS total score was the sum of the 3 items and ranged from 0 to 30, with higher values indicating greater disruption in the participant's work/social/family life. Scores ≥5 were associated with significant functional impairment. A negative change indicated an improvement in the participant's condition. LS mean was adjusted using MMRM and adjusted for treatment, pooled investigator, visit, and treatment-by-visit interaction, baseline score and baseline score-by-visit interaction.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Present with pain due to bilateral peripheral neuropathy

• Participants must have pain caused by Type 1 or Type 2 diabetes mellitus

• Pain must begin in the feet with relatively symmetrical onset

• Daily pain should be present for at least 6 months

• Diagnosis must be confirmed by a score of at least 3 on the Michigan Neuropathy Screening Inventory (MNSI)

• Females must test negative for a serum pregnancy test at Screening. Females of child-bearing potential (who are not surgically sterilized and between menarche and 1 year postmenopause) must agree to use a medically acceptable and reliable means of birth control, during the study and for 1 month following the last study dose.

• Stable glycemic control as assessed by a physician investigator and a glycosylated hemoglobin (HbA1c) <12% before randomization

• Score of greater than or equal to 4 on the Brief Pain Inventory (BPI) 24-hour average pain item at Screening.

• Full completion of the daily diaries for at least 80% of the days between the second and third time you come to the hospital (Screening).

Exclusion Criteria:

• Currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational drug or device or off-label use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study

• Current (less than or equal to 1 year) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) Axis I diagnosis of major depressive disorder, dysthymia, anxiety disorders (excluding phobias), alcohol or eating disorders as determined by the Mini-International Neuropsychiatric Interview (MINI) or a previous diagnosis

• DSM-IV diagnosis of mania, bipolar disorder, or psychosis determined either by participant history or by diagnosis using specific MNSI modules

• Serious or unstable cardiovascular, hepatic, renal, respiratory, or hematologic illness, symptomatic peripheral vascular disease, or other medical condition or psychological conditions that in the opinion of investigator would compromise participation or be likely to lead to hospitalization during the course of the study.

• At Screening alanine transaminase (ALT) greater than 2 times upper limit of normal (ULN), based on central laboratory reference ranges times ULN, based on central laboratory reference ranges

• Prior renal transplant, current renal dialysis, or serum creatinine laboratory value

1.5 times ULN, based on central laboratory reference ranges at Screening.

• Historical exposure to drugs known to cause neuropathy, or a history of a medical condition, including pernicious anemia and hypothyroidism, that could have been responsible for neuropathy

• Pain that cannot be clearly differentiated from or conditions that interfere with the assessment of the diabetic neuropathy pain. Examples of painful conditions that could be confused with diabetic neuropathy pain include peripheral vascular disease, neurological disorders unrelated to diabetic neuropathy, skin condition in the area of the neuropathy that could alter sensation, other painful conditions

• Participants who have previously completed or withdrawn from this study or have been previously treated with duloxetine, including participants who participated in study F1J-MC-HMEQ (NCT00408993), even those in the placebo arm

• Participants taking excluded medications that cannot be stopped at Screening

• Treatment with a monoamine oxidase inhibitor (MAOI) or fluoxetine within 30 days of the third Screening

• Participants with a positive Hepatitis B surface antigen and/or Hepatitis C antibody are to be excluded if they have any of the following:

• Hepatic dysfunction as determined by the investigator or

• Clinical manifestations of liver disease within the previous year such as unexplained pruritus, unexplained dark urine, jaundice, unexplained right upper quadrant tenderness, unexplained "flu-like" symptoms or

• Aspartate transaminase (AST), ALT, or bilirubin above the normal reference range.

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.	Beijing		China	100730
2	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.	Bengbu		China	233004
3	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.	Changchun		China	130021
4	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.	Chengdu		China	610072
5	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.	Chongqing		China
6	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.	Guang Zhou		China	510515
7	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.	Jinan		China	250001
8	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.	Nanjin		China	210006
9	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.	Qingdao		China	266003
10	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.	Shanghai		China	200040
11	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.	Shantou		China	515041
12	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.	Shi Jia Zhuang		China	050051
13	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.	Tianjin		China	300211
14	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.	Xi'An		China	710061
15	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.	Yueyang		China	414000

Sponsors and Collaborators

• Eli Lilly and Company

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: NCT01179672
• Other Study ID Numbers: 13649; F1J-MC-HMGV
• First Posted: Aug 11, 2010
• Last Update Posted: Oct 13, 2014
• Last Verified: Oct 1, 2014

• Keywords provided by Eli Lilly and Company: Diabetic Peripheral Neuropathic Pain
• Additional relevant MeSH terms: Neuralgia; Diabetic Neuropathies; Duloxetine Hydrochloride

Study Results

Participant Flow

Pre-assignment Detail	Participants tapered off study drug after either completing the 12 weeks of treatment or discontinued treatment early.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	30 milligrams (mg) duloxetine capsule administered orally, once daily (QD) during Week 1 then 60 mg duloxetine capsule orally, QD for the remaining 11 weeks of treatment. After a total 12 weeks of treatment or early discontinuation participants tapered off study drug (30 mg duloxetine capsule QD) for 1 week during taper.	Placebo administered orally, QD for 12 weeks of the treatment and orally, QD for 1 week during taper.
Period Title: Overall Study
STARTED	203	202
Received at Least 1 Dose of Study Drug	202	202
Entered Taper	181	177
COMPLETED	173	176
NOT COMPLETED	30	26

Baseline Characteristics

Arm/Group Title	Duloxetine	Placebo	Total
Arm/Group Description	30 mg duloxetine capsule administered orally, QD during Week 1 then 60 mg duloxetine capsule orally, QD for remaining 11 weeks of the treatment. After a total 12 weeks of treatment or early discontinuation, participants tapered off study drug (30 mg duloxetine capsule orally, QD) for 1 week during taper.	Placebo administered orally, QD for 12 weeks of the treatment and orally, QD for 1 week during taper.	Total of all reporting groups
Overall Participants	203	202	405
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.56 (9.65)	61.17 (9.42)	61.37 (9.52)
Sex: Female, Male (Count of Participants)
Female	112 55.2%	111 55%	223 55.1%
Male	91 44.8%	91 45%	182 44.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	203 100%	202 100%	405 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	203 100%	202 100%	405 100%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
China	203 100%	202 100%	405 100%
Diabetes Disease Characteristics-Types of Diabetes (participants) [Number]
Type I Diabetes	3 1.5%	3 1.5%	6 1.5%
Type II Diabetes	200 98.5%	199 98.5%	399 98.5%
Diabetes Disease Characteristics (years) [Mean (Standard Deviation) ]
Duration of Diabetes	11.53 (6.81)	11.38 (7.47)	11.45 (7.14)
Duration of Diabetic Neuropathy	3.47 (3.91)	3.07 (3.13)	3.27 (3.55)
Duration of Diabetic Neuropathy Pain	3.06 (3.70)	2.59 (2.69)	2.83 (3.24)
Weekly Mean of 24-Hour Average Pain (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	5.72 (1.72)	5.62 (1.66)	5.67 (1.69)
Brief Pain Inventory (BPI)-Severity Average Pain in the Last Week (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	5.97 (1.70)	5.86 (1.64)	5.91 (1.67)
Clinical Global Impression of Severity (CGI-S) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.76 (1.22)	4.66 (1.07)	4.71 (1.14)
Short Form-McGill Pain Questionnaire (SF-MPQ), Sensory Portion Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	12.24 (6.39)	11.81 (5.52)	12.02 (5.97)
BPI-Interference Average Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	4.38 (2.29)	4.08 (2.30)	4.23 (2.30)
Sheehan Disability Scale (SDS) Total Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	11.16 (7.59)	10.54 (7.31)	10.85 (7.45)

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline at 12-Week Endpoint in the Weekly Mean of Pain Severity Score
Description	24-hour average pain severity scores were recorded daily by the participant on an 11-point Likert scale, an ordinal scale, with scores ranging from 0 (no pain) to 10 (worst possible pain). The weekly mean was calculated. A negative change indicated an improvement in participant's condition. Least squares (LS) mean was calculated using mixed model repeating measures (MMRM) and adjusted for treatment, pooled investigator, visit, and treatment-by-visit interaction, as well as baseline score and baseline score-by-visit interaction.
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) principle was applied: All participants with a baseline and 12-week 24-hour average pain score based on the randomized group were analyzed.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	30 mg duloxetine capsule administered orally, QD during Week 1, then 60 mg duloxetine capsule orally QD for remaining 11 weeks of the treatment. After a total 12 weeks of treatment or early discontinuation, participants tapered off study drug (30 mg duloxetine capsule orally, QD) for 1 week during taper.	Placebo administered orally, QD for 12 weeks of the treatment and orally, QD for 1 week during taper.
Measure Participants	172	173
Least Squares Mean (Standard Error) [units on a scale]	-2.40 (0.14)	-1.97 (0.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.43
	Confidence Interval	(2-Sided) 95%; -0.82 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mean Change From Baseline at 12-Week Endpoint in Weekly Mean of Night Pain and Worst Pain
Description	24-hour average night pain and worst pain severity scores were recorded daily on an 11-point Likert scale, an ordinal scale, with scores ranging from 0 (no pain) to 10 (worst possible pain). A negative change indicated an improvement in the participant's condition. LS mean was calculated using MMRM and adjusted for treatment, pooled investigator, visit, and treatment-by-visit interaction, as well as the baseline score and baseline score-by-visit interaction.
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

ITT principle was applied: All participants with a baseline and 12-week 24-hour night pain score and worst pain score based on the randomized group were analyzed.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	30 mg duloxetine capsule administered orally, QD during Week 1, then 60 mg duloxetine capsule orally, QD for remaining 11 weeks of the treatment. After a total 12 weeks of treatment or early discontinuation, participants tapered off study drug (30 mg duloxetine capsule orally, QD) for 1 week during taper.	Placebo administered orally, QD for 12 weeks of the treatment and orally, QD for 1 week during taper.
Measure Participants	172	173
Night Pain	-2.65 (0.15)	-2.11 (0.15)
Worst Pain	-2.80 (0.16)	-2.25 (0.17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	P-value is for mean change from baseline to 12-week endpoint in night pain.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.54
	Confidence Interval	(2-Sided) 95%; -0.95 to -0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments	P-value is for mean change from baseline to 12 week endpoint in worst pain.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.55
	Confidence Interval	(2-Sided) 95%; -1.00 to -0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Mean Change From Baseline at 12-Week Endpoint in the BPI-Severity Scale
Description	BPI-Severity Scale was a self-reported scale that measured the severity of pain based on the average pain over the past 24-hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). A negative change indicated an improvement in the participant's condition. LS mean was calculated using MMRM and adjusted for treatment, pooled investigator, visit, and treatment-by-visit interaction, as well as baseline score and baseline score-by-visit interaction.
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

ITT principle was applied: All participants with a baseline and 12-week, 24-hour BPI-Severity score based on the randomized group were analyzed.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	30 mg duloxetine capsule administered orally, QD during Week 1, then 60 mg duloxetine capsule orally, QD for remaining 11 weeks of the treatment. After a total 12 weeks of treatment or early discontinuation, participants tapered off study drug (30 mg duloxetine capsule orally, QD) for 1 week during taper.	Placebo administered orally, QD for 12 weeks of the treatment and orally, QD for 1 week during taper.
Measure Participants	175	173
Least Squares Mean (Standard Error) [units on a scale]	-2.50 (0.15)	-2.00 (0.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.50
	Confidence Interval	(2-Sided) 95%; -0.90 to -0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Mean Change From Baseline at 12-Week Endpoint in the CGI-S Scale
Description	CGI-S was administered by the investigator in the presence of the participant and measured the severity of illness at the time of assessment compared with start of treatment; CGI-S scores ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). A negative change indicated an improvement in the participant's condition. LS mean was calculated using MMRM and adjusted for treatment, pooled investigator, visit, and treatment-by-visit interaction, as well as baseline score and baseline score-by-visit interaction.
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

ITT principle was applied: All participants with a baseline and 12-week CGI-S score based on the randomized group were analyzed. Data from 9 sites was not included in analysis due to wrong questionnaire used.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	30 mg duloxetine capsule administered orally, QD during Week 1, then 60 mg duloxetine capsule orally, QD for remaining 11 weeks of the treatment. After a total 12 weeks of treatment or early discontinuation, participants tapered off study drug (30 mg duloxetine capsule orally, QD) for 1 week during taper.	Placebo administered orally, QD for 12 weeks of the treatment and orally, QD for 1 week during taper.
Measure Participants	108	118
Least Squares Mean (Standard Error) [units on a scale]	-1.40 (0.10)	-1.17 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.081
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.48 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Patient Global Impression of Improvement (PGI-I) Scale at 12-Week Endpoint
Description	PGI-I was self-reported and measured a 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 MMRM and adjusted for treatment, pooled investigator, visit, and treatment-by-visit interaction, as well as baseline score and baseline score-by-visit interaction.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

All participants with a baseline and 12-week PGI-I score.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	30 mg duloxetine capsule administered orally, QD during Week 1, then 60 mg duloxetine capsule orally, QD for remaining 11 weeks of the treatment. After a total 12 weeks of treatment or early discontinuation, participants tapered off study drug (30 mg duloxetine capsule orally, QD) for 1 week during taper.	Placebo administered orally, QD for 12 weeks of the treatment and orally, QD for 1 week during taper.
Measure Participants	173	176
Least Squares Mean (Standard Error) [units on a scale]	2.44 (0.07)	2.65 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.40 to -0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Mean Change From Baseline at 12-Week Endpoint in the Sensory Subscale of the SF-MPQ
Description	SF-MPQ was a self-reported instrument that consisted of 11 sensory descriptors describing pain. The descriptors were rated on an intensity scale from 0 (none), 1 (mild), 2 (moderate) or 3 (severe). Three (3) pain scores were derived from the sum of the intensity rank values of the words chosen for sensory descriptors. The SF-MPQ sensory subscale was the sum of the 11 scores (ranged from 0 to 33, with 33 being the worst pain). A negative change indicates an improvement. LS mean was calculated using analysis of covariance (ANCOVA) adjusted for treatment, pooled investigator and baseline.
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

ITT principle was applied: All participants with a baseline and 12 weeks SF-MPQ score based on the randomized group were analyzed; last observation carried forward (LOCF).

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	30 mg duloxetine capsule administered orally, QD during Week 1, then 60 mg duloxetine capsule orally, QD for remaining 11 weeks of the treatment. After a total 12 weeks of treatment or early discontinuation, participants tapered off study drug (30 mg duloxetine capsule orally, QD) for 1 week during taper	Placebo administered orally, QD for 12 weeks of the treatment and orally, QD for 1 week during taper.
Measure Participants	188	180
Least Squares Mean (Standard Error) [units on a scale]	-6.45 (0.36)	-5.33 (0.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments
	Method	ANCOVA
	Comments	ANCOVA adjusted for treatment, pooled investigator and baseline.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.12
	Confidence Interval	(2-Sided) 95%; -2.07 to -0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Participants Who Experience Equal to or Greater Than 30%, 50% or 75% Reduction From Baseline at 12-Week Endpoint in Weekly Mean of Average Daily Pain
Description	24-hour self-assessment of average daily pain was recorded in the participants diary based on an 11 point Likert scale with scores ranging from 0 (no pain) to 10 (worst possible pain). Percentage of participants was calculated as: (number of participants with 30% [or 50% or 75%] reduction in average daily pain) divided by (number of participants) multiplied by 100.
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

All participants with a baseline and postbaseline 24-hour average pain score.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	30 mg duloxetine capsule administered orally, QD during Week 1, then 60 mg duloxetine capsule orally, QD for remaining 11 weeks of the treatment. After a total 12 weeks of treatment or early discontinuation, participants tapered off study drug (30 mg duloxetine capsule orally, QD) for 1 week during taper.	Placebo administered orally, QD for 12 weeks of the treatment and orally, QD for 1 week during taper.
Measure Participants	200	198
≥30% Reduction	61.5 30.3%	49.0 24.3%
≥50% Reduction	42.0 20.7%	28.8 14.3%
≥75% Reduction	14.5 7.1%	9.6 4.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments	P-value is for ≥30% reduction in 24-hour average pain.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test was stratified by pooled investigator.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	P-value is for ≥50% reduction in 24-hour average pain.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test was stratified by pooled investigator.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.193
	Comments	P-value is for ≥75% reduction in 24-hour average pain.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test was stratified by pooled investigator.

8. Secondary Outcome

Title	Percentage of Participants Who Experienced Equal to or Greater Than 30%, 50% or 75% Reduction From Baseline at 12-week Endpoint in BPI-Severity Average Pain Score
Description	BPI-Severity scale was a self-reported scale that measured the severity of pain based on the average pain experienced over the past 24 hours. The severity scores range from 0 (no pain) to 10 (pain as severe as you can imagine). A negative change indicated an improvement in the participant's condition. Percentage of participants was calculated as: (number of participants with 30% [or 50% or 75%] reduction in BPI-Severity average pain) divided by (number of participants) multiplied by 100.
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

All participants with a baseline and postbaseline BPI-Severity average pain scores.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	30 mg duloxetine capsule administered orally, QD during Week 1, then 60 mg duloxetine capsule orally, QD for remaining 11 weeks of the treatment. After a total 12 weeks of treatment or early discontinuation, participants tapered off study drug (30 mg duloxetine capsule orally, QD) for 1 week during taper.	Placebo administered orally, QD for 12 weeks of the treatment and orally, QD for 1 week during taper.
Measure Participants	200	197
≥30% Reduction	63.0 31%	46.7 23.1%
≥50% Reduction	46.0 22.7%	29.4 14.6%
≥75% Reduction	15.0 7.4%	9.6 4.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	P-value is for ≥30% reduction in 24-hour BPI-Severity average pain.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test was stratified by pooled investigator.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	P-value is for ≥50% reduction in 24-hour BPI-Severity average pain.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test was stratified by pooled investigator.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.168
	Comments	P-value is for ≥75% reduction in 24-hour BPI-Severity average pain.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran Mantel Haenszel test was stratified by pooled investigator.

9. Secondary Outcome

Title	Mean Change From Baseline at 12-week Endpoint in the BPI Interference Score
Description	BPI-Interference Score was a self-reported scale that measured the interference of pain based on the average of the 7 questions assessing the interference of pain for general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. The average interference scores ranged from 0 (does not interfere) to 10 (completely interferes). A negative change indicates an improvement in the participant's condition. LS means was calculated using MMRM and adjusted treatment, pooled investigator, visit, and treatment-by-visit interaction, baseline score and baseline score-by-visit interaction.
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

All participants with non-missing BPI-Interference score at baseline and 12 weeks.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	30 mg duloxetine capsule administered orally, QD during Week 1, then 60 mg duloxetine capsule orally, QD for remaining 11 weeks of the treatment. After a total 12 weeks of treatment or early discontinuation, participants tapered off study drug (30 mg duloxetine capsule orally, QD) for 1 week during taper.	Placebo administered orally, QD for 12 weeks of the treatment and orally, QD for 1 week during taper.
Measure Participants	173	176
Least Squares Mean (Standard Error) [units on a scale]	-2.42 (0.13)	-1.82 (0.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.60
	Confidence Interval	(2-Sided) 95%; -0.96 to -0.24
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Mean Change From Baseline at 12 Week Endpoint in the SDS Total Score
Description	SDS was self-reported and used to assess the effect of the participant's symptoms on their work (Item 1), social life (Item 2), and family life (Item 3). Each item was measured on a 0 (not at all) to 10 (extremely) point scale with higher values indicating greater disruption. SDS total score was the sum of the 3 items and ranged from 0 to 30, with higher values indicating greater disruption in the participant's work/social/family life. Scores ≥5 were associated with significant functional impairment. A negative change indicated an improvement in the participant's condition. LS mean was adjusted using MMRM and adjusted for treatment, pooled investigator, visit, and treatment-by-visit interaction, baseline score and baseline score-by-visit interaction.
Time Frame	Baseline, 12 weeks

Outcome Measure Data

Analysis Population Description

All participants with non-missing SDS Total Score at baseline and 12 weeks.

Arm/Group Title	Duloxetine	Placebo
Arm/Group Description	30 mg duloxetine capsule administered orally, QD during Week 1, then 60 mg duloxetine capsule orally, QD for remaining 11 weeks of the treatment. After a total 12 weeks of treatment or early discontinuation, participants tapered off study drug (30 mg duloxetine capsule orally, QD) for 1 week during taper.	Placebo administered orally, QD for 12 weeks of the treatment and orally, QD for 1 week during taper.
Measure Participants	172	175
Least Squares Mean (Standard Error) [units on a scale]	-6.36 (0.40)	-5.09 (0.42)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Duloxetine, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.26
	Confidence Interval	(2-Sided) 95%; -2.33 to -0.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	Duloxetine Treatment		Placebo Treatment		Duloxetine Taper		Placebo Taper
Arm/Group Description	30 mg duloxetine capsule administered orally, QD during Week 1 of the treatment; 60 mg capsule administered orally, QD for remaining 11 weeks of the treatment;		Placebo administered orally, QD for 12 weeks of the treatment.		After 12 weeks of treatment or early discontinuation, 30 mg duloxetine capsule administered orally, QD for 1 week during taper.		After 12 weeks of treatment or early discontinuation, placebo administered orally, QD for 1 week during taper.
All Cause Mortality
	Duloxetine Treatment		Placebo Treatment		Duloxetine Taper		Placebo Taper
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Duloxetine Treatment		Placebo Treatment		Duloxetine Taper		Placebo Taper
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/202 (2%)		3/202 (1.5%)		3/181 (1.7%)		1/177 (0.6%)
Cardiac disorders
Coronary artery disease	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Nodal arrhythmia	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
General disorders
Asthenia	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Hepatobiliary disorders
Cholecystitis chronic	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	1/177 (0.6%)	1
Metabolism and nutrition disorders
Diabetes mellitus	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Non-hodgkin's lymphoma	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Nervous system disorders
Cerebral infarction	0/202 (0%)	0	0/202 (0%)	0	1/181 (0.6%)	1	0/177 (0%)	0
Diabetic neuropathy	2/202 (1%)	2	0/202 (0%)	0	2/181 (1.1%)	2	0/177 (0%)	0
Other (Not Including Serious) Adverse Events
	Duloxetine Treatment		Placebo Treatment		Duloxetine Taper		Placebo Taper
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	93/202 (46%)		71/202 (35.1%)		8/181 (4.4%)		5/177 (2.8%)
Blood and lymphatic system disorders
Anaemia	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	1/177 (0.6%)	1
Leukopenia	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Neutropenia	0/202 (0%)	0	0/202 (0%)	0	1/181 (0.6%)	1	0/177 (0%)	0
Cardiac disorders
Coronary artery disease	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Palpitations	5/202 (2.5%)	5	4/202 (2%)	4	0/181 (0%)	0	0/177 (0%)	0
Ear and labyrinth disorders
Hypoacusis	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Tinnitus	1/202 (0.5%)	1	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Vertigo	2/202 (1%)	2	3/202 (1.5%)	3	0/181 (0%)	0	0/177 (0%)	0
Eye disorders
Amaurosis	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Diabetic retinopathy	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Photophobia	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Vision blurred	3/202 (1.5%)	3	2/202 (1%)	2	0/181 (0%)	0	0/177 (0%)	0
Visual impairment	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	7/202 (3.5%)	7	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Abdominal distension	1/202 (0.5%)	1	2/202 (1%)	2	0/181 (0%)	0	0/177 (0%)	0
Abdominal pain	2/202 (1%)	2	3/202 (1.5%)	3	0/181 (0%)	0	0/177 (0%)	0
Abdominal pain upper	3/202 (1.5%)	3	2/202 (1%)	2	0/181 (0%)	0	0/177 (0%)	0
Constipation	10/202 (5%)	10	4/202 (2%)	4	0/181 (0%)	0	0/177 (0%)	0
Diarrhoea	2/202 (1%)	2	3/202 (1.5%)	3	1/181 (0.6%)	1	0/177 (0%)	0
Dry mouth	5/202 (2.5%)	5	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Dyspepsia	5/202 (2.5%)	5	4/202 (2%)	4	0/181 (0%)	0	0/177 (0%)	0
Epigastric discomfort	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Eructation	1/202 (0.5%)	1	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Faeces hard	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Gastric ulcer	0/202 (0%)	0	0/202 (0%)	0	0/181 (0%)	0	1/177 (0.6%)	1
Gastritis	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Gastrointestinal disorder	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Hiatus hernia	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Hypoaesthesia oral	2/202 (1%)	2	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Infrequent bowel movements	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Nausea	21/202 (10.4%)	23	7/202 (3.5%)	7	1/181 (0.6%)	1	0/177 (0%)	0
Regurgitation	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Tongue discolouration	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Toothache	0/202 (0%)	0	2/202 (1%)	2	0/181 (0%)	0	0/177 (0%)	0
Vomiting	3/202 (1.5%)	3	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
General disorders
Asthenia	9/202 (4.5%)	10	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Chest discomfort	0/202 (0%)	0	4/202 (2%)	4	0/181 (0%)	0	0/177 (0%)	0
Chest pain	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Chills	2/202 (1%)	2	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Fatigue	10/202 (5%)	10	4/202 (2%)	6	0/181 (0%)	0	0/177 (0%)	0
Hunger	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Malaise	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Oedema peripheral	2/202 (1%)	2	2/202 (1%)	2	0/181 (0%)	0	0/177 (0%)	0
Sluggishness	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Thirst	2/202 (1%)	2	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Hepatobiliary disorders
Fatty liver alcoholic	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Hepatic function abnormal	2/202 (1%)	2	1/202 (0.5%)	1	0/181 (0%)	0	1/177 (0.6%)	1
Hepatic lesion	1/202 (0.5%)	1	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Liver injury	2/202 (1%)	2	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Infections and infestations
Influenza	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Nasopharyngitis	4/202 (2%)	4	2/202 (1%)	3	0/181 (0%)	0	0/177 (0%)	0
Upper respiratory tract infection	1/202 (0.5%)	1	3/202 (1.5%)	3	0/181 (0%)	0	0/177 (0%)	0
Urinary tract infection	0/202 (0%)	0	3/202 (1.5%)	3	0/181 (0%)	0	0/177 (0%)	0
Injury, poisoning and procedural complications
Head injury	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Joint dislocation	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Spinal cord injury cauda equina	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Investigations
Alanine aminotransferase increased	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Blood alkaline phosphatase increased	0/202 (0%)	0	0/202 (0%)	0	1/181 (0.6%)	1	0/177 (0%)	0
Blood bicarbonate decreased	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Blood cholesterol decreased	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Blood creatine phosphokinase increased	2/202 (1%)	2	2/202 (1%)	2	0/181 (0%)	0	0/177 (0%)	0
Blood potassium decreased	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Blood potassium increased	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Blood pressure increased	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Blood triglycerides increased	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Blood uric acid increased	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Gamma-glutamyltransferase increased	2/202 (1%)	2	2/202 (1%)	2	0/181 (0%)	0	0/177 (0%)	0
Transaminases increased	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Weight increased	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
White blood cell count decreased	1/202 (0.5%)	1	0/202 (0%)	0	1/181 (0.6%)	1	0/177 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	11/202 (5.4%)	11	8/202 (4%)	8	0/181 (0%)	0	0/177 (0%)	0
Dyslipidaemia	1/202 (0.5%)	1	2/202 (1%)	2	0/181 (0%)	0	0/177 (0%)	0
Hypercalcaemia	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Hypercholesterolaemia	2/202 (1%)	2	2/202 (1%)	2	0/181 (0%)	0	0/177 (0%)	0
Hyperkalaemia	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Hyperlipidaemia	9/202 (4.5%)	9	5/202 (2.5%)	5	1/181 (0.6%)	1	0/177 (0%)	0
Hypertriglyceridaemia	3/202 (1.5%)	3	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Hyperuricaemia	1/202 (0.5%)	1	1/202 (0.5%)	1	2/181 (1.1%)	2	1/177 (0.6%)	1
Hypoglycaemia	1/202 (0.5%)	2	3/202 (1.5%)	3	1/181 (0.6%)	1	0/177 (0%)	0
Hypokalaemia	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Back pain	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Fasciitis	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Myalgia	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Osteoporosis	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Pain in extremity	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Nervous system disorders
Autonomic neuropathy	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Cerebral infarction	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Clonus	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Convulsion	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Diabetic autonomic neuropathy	1/202 (0.5%)	1	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Disturbance in attention	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Dizziness	17/202 (8.4%)	18	9/202 (4.5%)	9	0/181 (0%)	0	0/177 (0%)	0
Dreamy state	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Dysgeusia	2/202 (1%)	2	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Formication	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Headache	6/202 (3%)	6	3/202 (1.5%)	4	1/181 (0.6%)	1	1/177 (0.6%)	1
Hypersomnia	2/202 (1%)	2	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Hypoaesthesia	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Lacunar infarction	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Lethargy	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Memory impairment	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Poor quality sleep	3/202 (1.5%)	3	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Sciatica	0/202 (0%)	0	0/202 (0%)	0	1/181 (0.6%)	1	0/177 (0%)	0
Somnolence	17/202 (8.4%)	18	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Tremor	3/202 (1.5%)	3	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Psychiatric disorders
Agitation	2/202 (1%)	2	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Anxiety	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Dysphoria	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Fear	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Food aversion	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Illusion	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Insomnia	3/202 (1.5%)	3	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Mutism	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Nervousness	2/202 (1%)	2	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Nightmare	0/202 (0%)	0	2/202 (1%)	2	0/181 (0%)	0	0/177 (0%)	0
Panic attack	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Sleep disorder	2/202 (1%)	2	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Tic	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Renal and urinary disorders
Dysuria	4/202 (2%)	4	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Nephrolithiasis	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Pollakiuria	2/202 (1%)	2	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Renal failure chronic	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Urinary retention	1/202 (0.5%)	2	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Urine flow decreased	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/91 (1.1%)	1	0/91 (0%)	0	0/85 (0%)	0	0/76 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/202 (0.5%)	1	2/202 (1%)	2	0/181 (0%)	0	0/177 (0%)	0
Dry throat	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Dyspnoea	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis allergic	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Diabetic foot	0/202 (0%)	0	0/202 (0%)	0	0/181 (0%)	0	1/177 (0.6%)	1
Eczema	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Erythema	1/202 (0.5%)	2	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Hyperhidrosis	8/202 (4%)	8	3/202 (1.5%)	3	0/181 (0%)	0	0/177 (0%)	0
Night sweats	1/202 (0.5%)	1	0/202 (0%)	0	0/181 (0%)	0	0/177 (0%)	0
Pruritus	2/202 (1%)	2	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Rash	2/202 (1%)	2	2/202 (1%)	2	0/181 (0%)	0	0/177 (0%)	0
Skin swelling	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Surgical and medical procedures
Haemorrhoid operation	0/202 (0%)	0	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0
Vascular disorders
Hypertension	1/202 (0.5%)	1	1/202 (0.5%)	1	0/181 (0%)	0	0/177 (0%)	0

Limitations/Caveats

[Not Specified]

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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.