An Extension Study of Duloxetine in Fibromyalgia (Extension of F1J-JE-HMGZ, NCT01552057)

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01621191
• Collaborator: Shionogi (Industry)
• Enrollment: 149
• Location: 1
• Arm: 1
• Duration (Months): 20
• Patients Per Site Per Month: 7.4

Study Details

Study Description

Brief Summary

The purpose of the study is to assess the safety and efficacy of duloxetine in participants with fibromyalgia at long-term use.

Condition or Disease	Intervention/Treatment	Phase
Fibromyalgia	Drug: Duloxetine	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 149 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Extension Study of Phase 3 Trial of Duloxetine in Patients With Fibromyalgia
• Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: Feb 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 60 mg Duloxetine Duloxetine 20 milligrams (mg) taken orally once every day for 1 week, followed by 40 mg taken orally once every day for 1 week, and then 60 mg taken orally once every day for 48 weeks	Drug: Duloxetine; Administered Orally; Other Names: LY248686 Cymbalta Ariclaim Xeristar Yentreve

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Experienced an Adverse Event (AE) [Baseline through 53 weeks]

   A summary of serious and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.

Secondary Outcome Measures

1. Patient Global Impression-Improvement (PGI-I) at Endpoint [50 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).

2. Clinical Global Impression-Improvement (CGI-I) at Endpoint [50 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).

3. Change From Baseline to 50-Week Endpoint in Fibromyalgia Impact Questionnaire (FIQ) [Baseline, 50 weeks]

   FIQ is a 20-item, self-administered questionnaire using Likert-type scales to measure participant 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 participant felt well and days a participant was unable to work due to fibromyalgia symptoms, respectively. Items 14 through 20 were 11-point scales on which a participant rated work difficulty, pain, fatigue, morning tiredness, stiffness, anxiety, and depression, respectively. If a participant 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.

4. Change From Baseline to 50-Week Endpoint in Brief Pain Inventory-Severity (BPI-S) and Brief Pain Inventory-Interference (BPI-I) Scores on the BPI-Modified Short Form [Baseline, 50 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 average pain, 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.

5. Change From Baseline to 50-Week Endpoint in 36-Item Short-Form (SF-36) Health Survey Domain Scores [Baseline, 50 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.

6. Change From Baseline to 50-Week Endpoint in Beck Depression Inventory-II (BDI-II) [Baseline, 50 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.

7. Change From Baseline to 50-Week Endpoint in Widespread Pain Index (WPI) and Symptom Severity (SS) in American College of Rheumatology (ACR) Fibromyalgia Diagnostic Criteria 2010 [Baseline, 50 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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Participants who have completed the 15-week treatment in the preceding study HMGZ

• Participants who wish continuous treatment with duloxetine after the preceding study

• Participants are able to give their own written consent

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/Liter (IU/L) or total bilirubin of not less than 1.6 milligrams/deciliter (mg/dL) at Week 0 (Visit 8 of the preceding study)

• Participants with serum creatinine level of not less than 2.0 mg/dL, participant who has undergone kidney transplantation or hemodialysis at Week 0 (Visit 8 of the preceding study)

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

• Participants with thyroidal dysfunction, excluding those assessed by the investigator that the disorder is controlled as appropriate by three-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 uncontrolled angle closure glaucoma

• Participants who received monoamine oxidase (MAO) inhibitors within 14 days before Week 0 (Visit 8 of the preceding study) or need to receive a MAO inhibitor within 5 days after study discontinuation

• Participants who have experienced suicidal ideation or suicide attempt during the preceding study

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

• 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 cannot 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 assessed ineligible by the investigator (sub-investigator) for other reasons

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: NCT01621191
• Other Study ID Numbers: 14614; F1J-JE-HMHB
• First Posted: Jun 18, 2012
• Last Update Posted: Feb 11, 2015
• Last Verified: Jan 1, 2015

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

Study Results

Participant Flow

Recruitment Details	Participants who completed the 15-week treatment in the preceding study F1J-JE-HMGZ (HMGZ) (NCT01552057) were enrolled in this study.
Pre-assignment Detail	Enrolled participants who completed the 50-week treatment period were considered to have completed the study. After study completion or early discontinuation, participants completed a 2-week taper and were observed 1 week post-treatment for safety.

Arm/Group Title	Duloxetine 60 mg
Arm/Group Description	Treatment Period: Up to a 60-milligram (mg) dose of duloxetine was administered orally once daily for 50 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule), Week 2: 40-mg dose of duloxetine (two 20-mg capsules), and Weeks 3 through 50: 60-mg dose of duloxetine (three 20-mg capsules). During the 2-week taper, the daily dosage was gradually reduced. For the first week: 40-mg dose of duloxetine (two 20-mg capsules) administered orally once daily. For the second week: 20-mg dose of duloxetine (one 20-mg capsule) administered orally once daily.
Period Title: Overall Study
STARTED	149
Received at Least 1 Dose of Study Drug	149
Had at Least 1 Post-Baseline Observation	148
COMPLETED	124
NOT COMPLETED	25

Baseline Characteristics

Arm/Group Title	Duloxetine 60 mg
Arm/Group Description	Treatment Period: Up to a 60-mg dose of duloxetine was administered orally once daily for 50 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule), Week 2: 40-mg dose of duloxetine (two 20-mg capsules), and Weeks 3 through 50: 60-mg dose of duloxetine (three 20-mg capsules). During the 2-week taper, the daily dosage was gradually reduced. For the first week: 40-mg dose of duloxetine (two 20-mg capsules) administered orally once daily. For the second week: 20-mg dose of duloxetine (one 20-mg capsule) administered orally once daily.
Overall Participants	148
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.3 (11.9)
Sex: Female, Male (Count of Participants)
Female	121 81.8%
Male	27 18.2%
Race/Ethnicity, Customized (participants) [Number]
Japanese	148 100%
Region of Enrollment (participants) [Number]
Japan	148 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Experienced an Adverse Event (AE)
Description	A summary of serious and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Time Frame	Baseline through 53 weeks

Outcome Measure Data

Analysis Population Description

Enrolled participants who received at least 1 dose of study drug.

Arm/Group Title	Duloxetine 60 mg
Arm/Group Description	Treatment Period: Up to a 60-mg dose of duloxetine was administered orally once daily for 50 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule), Week 2: 40-mg dose of duloxetine (two 20-mg capsules), and Weeks 3 through 50: 60-mg dose of duloxetine (three 20-mg capsules). During the 2-week taper, the daily dosage was gradually reduced. For the first week: 40-mg dose of duloxetine (two 20-mg capsules) administered orally once daily. For the second week: 20-mg dose of duloxetine (one 20-mg capsule) administered orally once daily.
Measure Participants	149
Number [participants]	138 93.2%

2. Secondary Outcome

Title	Patient Global Impression-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).
Time Frame	50 weeks

Outcome Measure Data

Analysis Population Description

Enrolled participants who received at least 1 dose of study drug and had a Week 50 PGI-I assessment.

Arm/Group Title	Duloxetine 60 mg
Arm/Group Description	Treatment Period: Up to a 60-mg dose of duloxetine was administered orally once daily for 50 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule), Week 2: 40-mg dose of duloxetine (two 20-mg capsules), and Weeks 3 through 50: 60-mg dose of duloxetine (three 20-mg capsules).
Measure Participants	115
Mean (Standard Deviation) [units on a scale]	2.48 (1.31)

3. Secondary Outcome

Title	Clinical Global Impression-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).
Time Frame	50 weeks

Outcome Measure Data

Analysis Population Description

Enrolled participants who received at least 1 dose of study drug and had a Week 50 CGI-I assessment.

Arm/Group Title	Duloxetine 60 mg
Arm/Group Description	Treatment Period: Up to a 60-mg dose of duloxetine was administered orally once daily for 50 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule), Week 2: 40-mg dose of duloxetine (two 20-mg capsules), and Weeks 3 through 50: 60-mg dose of duloxetine (three 20-mg capsules).
Measure Participants	115
Mean (Standard Deviation) [units on a scale]	2.34 (1.08)

4. Secondary Outcome

Title	Change From Baseline to 50-Week Endpoint in Fibromyalgia Impact Questionnaire (FIQ)
Description	FIQ is a 20-item, self-administered questionnaire using Likert-type scales to measure participant 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 participant felt well and days a participant was unable to work due to fibromyalgia symptoms, respectively. Items 14 through 20 were 11-point scales on which a participant rated work difficulty, pain, fatigue, morning tiredness, stiffness, anxiety, and depression, respectively. If a participant 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.
Time Frame	Baseline, 50 weeks

Outcome Measure Data

Analysis Population Description

Enrolled participants who received at least 1 dose of study drug and had a Week 50 FIQ assessment.

Arm/Group Title	Duloxetine 60 mg
Arm/Group Description	Treatment Period: Up to a 60-mg dose of duloxetine was administered orally once daily for 50 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule), Week 2: 40-mg dose of duloxetine (two 20-mg capsules), and Weeks 3 through 50: 60-mg dose of duloxetine (three 20-mg capsules).
Measure Participants	115
Mean (Standard Deviation) [units on a scale]	-6.00 (15.12)

5. Secondary Outcome

Title	Change From Baseline to 50-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 average pain, 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.
Time Frame	Baseline, 50 weeks

Outcome Measure Data

Analysis Population Description

Enrolled participants who received at least 1 dose of study drug and had a Week 50 BPI-S or BPI-W assessment.

Arm/Group Title	Duloxetine 60 mg
Arm/Group Description	Treatment Period: Up to a 60-mg dose of duloxetine was administered orally once daily for 50 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule), Week 2: 40-mg dose of duloxetine (two 20-mg capsules), and Weeks 3 through 50: 60-mg dose of duloxetine (three 20-mg capsules).
Measure Participants	115
Average Pain	-1.31 (1.70)
Worst Pain	-1.53 (1.87)
Least Pain	-1.26 (1.82)
Pain Right Now	-1.47 (2.03)
Interference With General Activity	-0.72 (2.04)
Interference With Mood	-0.82 (1.82)
Interference With Walking Ability	-0.73 (2.04)
Interference With Normal Work	-0.66 (2.01)
Interference With Relations With Other People	-0.38 (1.95)
Interference With Sleep	-1.00 (2.26)
Interference With Enjoyment of Life	-0.68 (2.00)
Average Interference	-0.71 (1.65)

6. Secondary Outcome

Title	Change From Baseline to 50-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.
Time Frame	Baseline, 50 weeks

Outcome Measure Data

Analysis Population Description

Enrolled participants who received at least 1 dose of study drug and had a Week 50 SF-36 assessment.

Arm/Group Title	Duloxetine 60 mg
Arm/Group Description	Treatment Period: Up to a 60-mg dose of duloxetine was administered orally once daily for 50 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule), Week 2: 40-mg dose of duloxetine (two 20-mg capsules), and Weeks 3 through 50: 60-mg dose of duloxetine (three 20-mg capsules).
Measure Participants	115
Physical Functioning	4.26 (14.54)
Role-Physical	4.02 (17.05)
Bodily Pain	6.89 (14.89)
General Health	4.14 (11.88)
Vitality	0.16 (18.13)
Social Functioning	3.26 (21.47)
Role-Emotional	3.55 (18.83)
Mental Health	2.13 (14.00)

7. Secondary Outcome

Title	Change From Baseline to 50-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.
Time Frame	Baseline, 50 weeks

Outcome Measure Data

Analysis Population Description

Enrolled participants who received at least 1 dose of study drug and had a Week 50 BDI-II assessment.

Arm/Group Title	Duloxetine 60 mg
Arm/Group Description	Treatment Period: Up to a 60-mg dose of duloxetine was administered orally once daily for 50 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule), Week 2: 40-mg dose of duloxetine (two 20-mg capsules), and Weeks 3 through 50: 60-mg dose of duloxetine (three 20-mg capsules).
Measure Participants	115
Mean (Standard Deviation) [units on a scale]	-0.94 (5.22)

8. Secondary Outcome

Title	Change From Baseline to 50-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.
Time Frame	Baseline, 50 weeks

Outcome Measure Data

Analysis Population Description

Enrolled participants who received at least 1 dose of study drug and had a Week 50 WPI or SS assessment.

Arm/Group Title	Duloxetine 60 mg
Arm/Group Description	Treatment Period: Up to a 60-mg dose of duloxetine was administered orally once daily for 50 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule), Week 2: 40-mg dose of duloxetine (two 20-mg capsules), and Weeks 3 through 50: 60-mg dose of duloxetine (three 20-mg capsules).
Measure Participants	115
WPI	-1.46 (3.74)
SS	-0.37 (1.27)

Adverse Events

Time Frame	Baseline through 53 weeks
Arm/Group Title	60 mg Duloxetine
Arm/Group Description	Treatment Period: Up to a 60-mg dose of duloxetine was administered orally once daily for 50 weeks. During the first 2 weeks of treatment, participants gradually increased their dosage. Week 1: 20-mg dose of duloxetine (one 20-mg capsule), Week 2: 40-mg dose of duloxetine (two 20-mg capsules), and Weeks 3 through 50: 60-mg dose of duloxetine (three 20-mg capsules). During the 2-week taper, the daily dosage was gradually reduced. For the first week: 40-mg dose of duloxetine (two 20-mg capsules) administered orally once daily. For the second week: 20-mg dose of duloxetine (one 20-mg capsule) administered orally once daily.
All Cause Mortality
	60 mg Duloxetine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	60 mg Duloxetine
	Affected / at Risk (%)	# Events
Total	8/149 (5.4%)
Eye disorders
Retinal detachment	1/149 (0.7%)	1
Gastrointestinal disorders
Subileus	1/149 (0.7%)	1
Injury, poisoning and procedural complications
Clavicle fracture	1/149 (0.7%)	1
Rib fracture	1/149 (0.7%)	1
Skull fracture	1/149 (0.7%)	1
Thoracic vertebral fracture	1/149 (0.7%)	1
Traumatic intracranial haemorrhage	1/149 (0.7%)	1
Wound	1/149 (0.7%)	1
Metabolism and nutrition disorders
Diabetes mellitus inadequate control	1/149 (0.7%)	1
Musculoskeletal and connective tissue disorders
Spinal osteoarthritis	1/149 (0.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Rectal cancer	1/149 (0.7%)	1
Psychiatric disorders
Schizoaffective disorder	1/149 (0.7%)	1
Self injurious behaviour	1/149 (0.7%)	1
Other (Not Including Serious) Adverse Events
	60 mg Duloxetine
	Affected / at Risk (%)	# Events
Total	138/149 (92.6%)
Blood and lymphatic system disorders
Anaemia	2/149 (1.3%)	3
Cardiac disorders
Bundle branch block left	1/149 (0.7%)	1
Bundle branch block right	1/149 (0.7%)	1
Palpitations	4/149 (2.7%)	4
Prinzmetal angina	1/149 (0.7%)	1
Sinus tachycardia	1/149 (0.7%)	1
Ear and labyrinth disorders
Meniere's disease	1/149 (0.7%)	2
Tinnitus	3/149 (2%)	3
Vertigo	9/149 (6%)	9
Eye disorders
Blepharitis allergic	1/149 (0.7%)	1
Cataract	1/149 (0.7%)	1
Conjunctival haemorrhage	2/149 (1.3%)	2
Conjunctivitis allergic	2/149 (1.3%)	2
Corneal degeneration	1/149 (0.7%)	1
Diplopia	1/149 (0.7%)	1
Dry eye	2/149 (1.3%)	2
Glaucoma	1/149 (0.7%)	1
Scleral haemorrhage	1/149 (0.7%)	1
Uveitis	1/149 (0.7%)	1
Vitreous floaters	1/149 (0.7%)	1
Vitreous haemorrhage	1/149 (0.7%)	1
Gastrointestinal disorders
Abdominal discomfort	5/149 (3.4%)	7
Abdominal distension	3/149 (2%)	3
Abdominal pain	2/149 (1.3%)	2
Abdominal pain upper	8/149 (5.4%)	9
Constipation	27/149 (18.1%)	31
Dental caries	5/149 (3.4%)	5
Diarrhoea	3/149 (2%)	3
Dyspepsia	1/149 (0.7%)	1
Faeces hard	1/149 (0.7%)	1
Food poisoning	1/149 (0.7%)	1
Gastric ulcer	1/149 (0.7%)	1
Gastritis	4/149 (2.7%)	5
Gastrointestinal motility disorder	1/149 (0.7%)	1
Gastrooesophageal reflux disease	3/149 (2%)	3
Haemorrhoids	1/149 (0.7%)	1
Irritable bowel syndrome	3/149 (2%)	3
Large intestine polyp	2/149 (1.3%)	2
Nausea	22/149 (14.8%)	24
Periodontal disease	3/149 (2%)	3
Sensitivity of teeth	1/149 (0.7%)	1
Stomatitis	4/149 (2.7%)	4
Toothache	1/149 (0.7%)	1
Vomiting	4/149 (2.7%)	5
General disorders
Asthenia	1/149 (0.7%)	1
Drug withdrawal syndrome	5/149 (3.4%)	5
Fatigue	2/149 (1.3%)	2
Feeling abnormal	4/149 (2.7%)	4
Local swelling	2/149 (1.3%)	2
Malaise	8/149 (5.4%)	8
Oedema	3/149 (2%)	3
Oedema peripheral	1/149 (0.7%)	1
Pyrexia	2/149 (1.3%)	2
Submandibular mass	1/149 (0.7%)	1
Thirst	11/149 (7.4%)	11
Hepatobiliary disorders
Cholelithiasis	1/149 (0.7%)	1
Hepatic function abnormal	1/149 (0.7%)	1
Immune system disorders
Drug hypersensitivity	1/149 (0.7%)	1
Seasonal allergy	9/149 (6%)	10
Infections and infestations
Body tinea	2/149 (1.3%)	2
Bronchitis	4/149 (2.7%)	4
Cystitis	6/149 (4%)	6
Gastroenteritis	3/149 (2%)	4
Gastroenteritis viral	3/149 (2%)	3
Gingivitis	2/149 (1.3%)	2
Herpes zoster	2/149 (1.3%)	2
Hordeolum	2/149 (1.3%)	3
Infected dermal cyst	1/149 (0.7%)	1
Influenza	6/149 (4%)	6
Nasopharyngitis	58/149 (38.9%)	102
Oral candidiasis	1/149 (0.7%)	1
Oral herpes	5/149 (3.4%)	6
Paronychia	4/149 (2.7%)	5
Periodontitis	1/149 (0.7%)	1
Peritonitis	1/149 (0.7%)	1
Pertussis	1/149 (0.7%)	1
Pharyngitis	5/149 (3.4%)	5
Pulpitis dental	1/149 (0.7%)	1
Pyelonephritis	1/149 (0.7%)	1
Rhinitis	3/149 (2%)	3
Subcutaneous abscess	1/149 (0.7%)	2
Tinea infection	1/149 (0.7%)	1
Tonsillitis	1/149 (0.7%)	1
Upper respiratory tract infection	4/149 (2.7%)	7
Injury, poisoning and procedural complications
Arthropod sting	2/149 (1.3%)	2
Cartilage injury	1/149 (0.7%)	1
Chillblains	2/149 (1.3%)	2
Contusion	6/149 (4%)	8
Fall	1/149 (0.7%)	1
Ligament sprain	5/149 (3.4%)	6
Limb injury	1/149 (0.7%)	1
Patella fracture	1/149 (0.7%)	1
Post-traumatic neck syndrome	1/149 (0.7%)	1
Scratch	2/149 (1.3%)	2
Tooth fracture	1/149 (0.7%)	1
Tooth injury	1/149 (0.7%)	1
Wound	1/149 (0.7%)	1
Investigations
Alanine aminotransferase increased	1/149 (0.7%)	1
Blood bilirubin increased	3/149 (2%)	6
Blood cholesterol increased	1/149 (0.7%)	2
Blood creatine phosphokinase increased	1/149 (0.7%)	1
Blood glucose increased	1/149 (0.7%)	1
Blood triglycerides increased	4/149 (2.7%)	5
Blood uric acid increased	2/149 (1.3%)	2
Eosinophil count increased	2/149 (1.3%)	2
Gamma-glutamyltransferase increased	7/149 (4.7%)	8
Haematocrit decreased	1/149 (0.7%)	1
Haemoglobin decreased	1/149 (0.7%)	1
Protein total decreased	2/149 (1.3%)	2
Weight decreased	2/149 (1.3%)	2
Weight increased	14/149 (9.4%)	14
White blood cell count decreased	1/149 (0.7%)	1
Metabolism and nutrition disorders
Decreased appetite	3/149 (2%)	3
Dehydration	1/149 (0.7%)	1
Diabetes mellitus	1/149 (0.7%)	1
Dyslipidaemia	2/149 (1.3%)	2
Increased appetite	1/149 (0.7%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	4/149 (2.7%)	4
Back pain	10/149 (6.7%)	11
Lumbar spinal stenosis	1/149 (0.7%)	1
Muscle spasms	1/149 (0.7%)	1
Musculoskeletal pain	1/149 (0.7%)	1
Musculoskeletal stiffness	3/149 (2%)	3
Myofascitis	1/149 (0.7%)	1
Neck mass	1/149 (0.7%)	1
Neck pain	1/149 (0.7%)	1
Osteoarthritis	2/149 (1.3%)	3
Pain in extremity	2/149 (1.3%)	2
Periarthritis	4/149 (2.7%)	4
Rotator cuff syndrome	1/149 (0.7%)	1
Spinal column stenosis	1/149 (0.7%)	1
Spinal osteoarthritis	1/149 (0.7%)	1
Synovial cyst	2/149 (1.3%)	2
Temporomandibular joint syndrome	1/149 (0.7%)	1
Tenosynovitis	2/149 (1.3%)	2
Nervous system disorders
Autonomic neuropathy	1/149 (0.7%)	1
Cubital tunnel syndrome	1/149 (0.7%)	1
Dizziness	9/149 (6%)	10
Dysgeusia	2/149 (1.3%)	2
Head discomfort	1/149 (0.7%)	1
Headache	8/149 (5.4%)	9
Hypoaesthesia	2/149 (1.3%)	2
Loss of consciousness	1/149 (0.7%)	1
Parosmia	1/149 (0.7%)	1
Poor quality sleep	1/149 (0.7%)	1
Radial nerve palsy	1/149 (0.7%)	1
Sciatica	1/149 (0.7%)	1
Sedation	1/149 (0.7%)	1
Somnolence	34/149 (22.8%)	34
Visual field defect	1/149 (0.7%)	1
Psychiatric disorders
Anxiety	1/149 (0.7%)	1
Delirium	1/149 (0.7%)	1
Insomnia	9/149 (6%)	9
Nightmare	3/149 (2%)	3
Somatoform disorder gastrointestinal	1/149 (0.7%)	1
Renal and urinary disorders
Dysuria	1/149 (0.7%)	1
Pollakiuria	1/149 (0.7%)	1
Reproductive system and breast disorders
Dysmenorrhoea	1/122 (0.8%)	1
Menopausal symptoms	1/122 (0.8%)	2
Respiratory, thoracic and mediastinal disorders
Asthma	5/149 (3.4%)	6
Cough	2/149 (1.3%)	2
Dyspnoea	1/149 (0.7%)	1
Oropharyngeal pain	4/149 (2.7%)	5
Rhinitis allergic	5/149 (3.4%)	5
Rhinorrhoea	1/149 (0.7%)	1
Upper respiratory tract inflammation	2/149 (1.3%)	2
Skin and subcutaneous tissue disorders
Alopecia areata	1/149 (0.7%)	1
Dermatitis	2/149 (1.3%)	3
Dermatitis allergic	1/149 (0.7%)	1
Dermatitis contact	2/149 (1.3%)	2
Eczema	5/149 (3.4%)	5
Erythema	2/149 (1.3%)	2
Haemorrhage subcutaneous	3/149 (2%)	3
Hyperhidrosis	1/149 (0.7%)	1
Miliaria	7/149 (4.7%)	7
Pityriasis rosea	1/149 (0.7%)	1
Prurigo	1/149 (0.7%)	1
Pruritus	3/149 (2%)	3
Purpura	1/149 (0.7%)	1
Pustular psoriasis	1/149 (0.7%)	1
Rash	1/149 (0.7%)	1
Urticaria	4/149 (2.7%)	4
Vascular disorders
Hypertension	6/149 (4%)	7

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.