Double-Blind, Placebo-Controlled Study of Two Doses of EPA-E in Patients With Non Alcoholic Steatohepatitis (NASH)

• Sponsor: Mochida Pharmaceutical Company, Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01154985
• Collaborator: (none)
• Enrollment: 243
• Locations: 34
• Arms: 3
• Duration (Months): 28
• Patients Per Site: 7.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This is a controlled study to determine the effectiveness and safety of ethyl icosapentate (EPA-E) in the treatment of adult patients with non-alcoholic steatohepatitis (NASH).

Condition or Disease	Intervention/Treatment	Phase
Steatohepatitis	Drug: Placebo capsule; Drug: EPA-E 300 mg capsule; Drug: EPA-E 300 mg capsule	Phase 2

Detailed Description

This is a phase II, double-blinded, placebo-controlled study to investigate the safety, efficacy, and pharmacokinetic profile of two doses of EPA-E in adult subjects with NASH. Subjects are required to have a liver biopsy with proven NASH in the 6 month period prior to screening. Up to 70 subjects will be enrolled into each treatment arm in a 1:1:1 ratio, for a total of 210 subjects. Subjects will be stratified at randomization by presence or absence of diabetes. Duration of treatment is 12 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 243 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase II Double-Blind, Placebo-Controlled Study of Two Doses of EPA-E in Patients With NASH
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo 3x placebo capsules TID	Drug: Placebo capsule; 3x Placebo capsules three times a day (TID) for 365 days
Experimental: EPA-E 1800 mg/day 2x EPA-E 300 mg capsules + 1placebo capsule TID	Drug: EPA-E 300 mg capsule; 2x 300 mg capsules + placebo capsule TID for 365 days
Experimental: EPA-E 2700 mg/day 3x EPA-E 300 mg capsules TID	Drug: EPA-E 300 mg capsule; 3x 300 mg capsules TID for 365 days

Outcome Measures

Primary Outcome Measures

1. Histological Response Defined by Change From Baseline in Standardized Scoring of Liver Biopsies [12 months]

   Patient is considered a responder if histological examination shows: Composite NAS of <=3 AND no worsening in Fibrosis OR Improvement in NAS by >=2 across at least 2 of the NAS components AND no worsening in fibrosis A priori threshold for statistical significance is p<0.05, 1-sided

2. Alanine Transaminase (ALT) Levels [3 month endpoint]

   Mean change from baseline at month 3 analyzed by Analysis of Covariance (ANCOVA) in the efficacy evaluable analysis set with treatment group as a factor and baseline ALT as a covariate. Principal comparisons were the response between; EPA-E 2700 mg and Placebo groups EPA-E 1800 mg and Placebo groups

3. Alanine Transaminase (ALT) Levels [6 months]

   Mean change from baseline at month 6 analyzed by Analysis of Covariance (ANCOVA) in the efficacy analysis set with treatment group as a factor and baseline ALT as a covariate. Principal comparisons were the response between; EPA-E 2700 mg and Placebo groups EPA-E 1800 mg and Placebo groups

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosis of definite NASH

• Patients with diabetes taking stable doses of anti-diabetic agents are eligible

• No significant concomitant medical illness

Exclusion Criteria:

• Diagnosis of cirrhosis.

• Serum ALT > 300 U/L

• Use of drugs associated with steatohepatitis

• Use of the following anit-NASH agents:

1. Vitamin E > 60 IU per day

2. Omega-3-acid ethyl esters or omega-3-polyunsaturated fatty acid (PUFA)-containing supplements > 200 mg per day

3. Thiazolidinediones (e.g. pioglitazone)

• Use of non-stable doses of the following anti-NASH agents: HMGCoA reductase inhibitors (statins), fibrates, probucol, ezetimibe, ursodiol (UDCA), taurine, betaine, N-acetylcysteine, s-adenosylmethionine (SAM-E), milk thistle, anti-TNF therapies, or probiotics.

• Other liver disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mochida Investigative Site	Dothan	Alabama	United States	36305
2	Mochida Investigative Site	Tucson	Arizona	United States	85712
3	Mochida Investigative Site	Anaheim	California	United States	92801
4	Mochida Investigative Site	Coronado	California	United States	92118
5	Mochida Investigative Site	LaJolla	California	United States	92037
6	Mochida Investigative Site	Los Angeles	California	United States	90048
7	Mochida Investigative Site	San Diego	California	United States	92123
8	Mochida Investigative Site	San Diego	California	United States	92161
9	Mochida Investigative Site	Littleton	Colorado	United States	80120
10	Mochida Investigative Site	Hialeah	Florida	United States	33016
11	Mochida Investigative Site	Chicago	Illinois	United States	60612
12	Mochida Investigative Site	Lexington	Kentucky	United States	40536
13	Mochida Investigative Site	New Orleans	Louisiana	United States	70112
14	Mochida Investigative Site	Chevy Chase	Maryland	United States	20815
15	Mochida Investigative Site	Detroit	Michigan	United States	48202
16	Mochida Investigative Site	Plymouth	Minnesota	United States	55446
17	Mochida Investigative Site	Jackson	Mississippi	United States	39202
18	Mochida Investigative Site	Tupelo	Mississippi	United States	38801
19	Mochida Investigative Site	Plainview	New York	United States	11803
20	Mochida Investigative Site	Asheville	North Carolina	United States	28801
21	Mochida Investigative Site	Durham	North Carolina	United States	27713
22	Mochida Investigative Site	Cincinnati	Ohio	United States	45219
23	Mochida Investigative Site	Cincinnati	Ohio	United States	45242
24	Mochida Investigative Site	Cleveland	Ohio	United States	44195
25	Mochida Investigative Site	Providence	Rhode Island	United States	02903
26	Mochida Investigative Site (2 sites)	Germantown	Tennessee	United States	38138
27	Mochida Investigative Site	Nashville	Tennessee	United States	37211
28	Mochida Investigative Site	Houston	Texas	United States	77005
29	Mochida Investigative Site (2 sites)	Houston	Texas	United States	77030
30	Mochida Investigative Site	San Antonio	Texas	United States	78234
31	Mochida Investigative Site	Newport News	Virginia	United States	23602
32	Mochida Investigative Site	Richmond	Virginia	United States	23298
33	Mochida Investigative Site	Seattle	Washington	United States	98101
34	Mochida Investigative Site	San Juan		Puerto Rico	00927

Sponsors and Collaborators

• Mochida Pharmaceutical Company, Ltd.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mochida Pharmaceutical Company, Ltd.
• ClinicalTrials.gov Identifier: NCT01154985
• Other Study ID Numbers: MCH-02-001
• First Posted: Jul 1, 2010
• Last Update Posted: Nov 20, 2014
• Last Verified: Oct 1, 2014

• Keywords provided by Mochida Pharmaceutical Company, Ltd.: omega-3 fatty acids; alanine transaminase; triglycerides; lipids; EPA; ethyl-EPA; ethyl icosapentate; Non Alcoholic steatohepatitis; Non Alcoholic fatty liver disease; fatty acids
• Additional relevant MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease

Study Results

Participant Flow

Arm/Group Title	Placebo	EPA-E 1800 mg/Day	EPA-E 2700 mg/Day
Arm/Group Description	Placebo: Placebo three times a day (TID) for 365 days	EPA-E: 600 mg TID for 365 days	EPA-E: 900 mg TID for 365 days
Period Title: Overall Study
STARTED	75	82	86
Full Analysis Set	75	82	86
Valid Biopsy -Baseline and Month 12.5	60	62	68
Efficacy Evaluable Analysis Set	55	55	64
COMPLETED	58	55	68
NOT COMPLETED	17	27	18

Baseline Characteristics

Arm/Group Title	Placebo	EPA-E 1800 mg/Day	EPA-E 2700 mg/Day	Total
Arm/Group Description	Placebo: Placebo three times a day (TID) for 365 days	EPA-E: 600 mg TID for 365 days	EPA-E: 900 mg TID for 365 days	Total of all reporting groups
Overall Participants	75	82	86	243
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	67 89.3%	74 90.2%	80 93%	221 90.9%
>=65 years	8 10.7%	8 9.8%	6 7%	22 9.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.5 (12.45)	47.8 (12.48)	47.8 (11.14)	48.6 (12.02)
Sex: Female, Male (Count of Participants)
Female	43 57.3%	48 58.5%	57 66.3%	148 60.9%
Male	32 42.7%	34 41.5%	29 33.7%	95 39.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	15 20%	15 18.3%	15 17.4%	45 18.5%
Not Hispanic or Latino	60 80%	67 81.7%	71 82.6%	198 81.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 1.2%	2 2.3%	3 1.2%
Asian	3 4%	1 1.2%	6 7%	10 4.1%
Native Hawaiian or Other Pacific Islander	1 1.3%	0 0%	1 1.2%	2 0.8%
Black or African American	3 4%	3 3.7%	2 2.3%	8 3.3%
White	68 90.7%	77 93.9%	75 87.2%	220 90.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Histological Response Defined by Change From Baseline in Standardized Scoring of Liver Biopsies
Description	Patient is considered a responder if histological examination shows: Composite NAS of <=3 AND no worsening in Fibrosis OR Improvement in NAS by >=2 across at least 2 of the NAS components AND no worsening in fibrosis A priori threshold for statistical significance is p<0.05, 1-sided
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Efficacy Evaluable Analysis Set - All patients in Full Analysis Set who have valid 12-month histological data without major protocol violations, including withdrawn patients with valid 12.5 month histological data after more than 6 months treatment

Arm/Group Title	Placebo	EPA-E 1800 mg/Day	EPA-E 2700 mg/Day
Arm/Group Description	Placebo: Placebo three times a day (TID) for 365 days	EPA-E: 600 mg TID for 365 days	EPA-E: 900 mg TID for 365 days
Measure Participants	55	55	64
Number [participants]	18 24%	18 22%	20 23.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, EPA-E 1800 mg/Day, EPA-E 2700 mg/Day
	Comments	Proportion of responders in the EPA-E 1800 mg and 2700 mg groups compared to the proportion of responders in the placebo group compared using the Cochran-Armitage trend test in the Efficacy Evaluable analysis set. P-value less than 5% 1-sided. A total sample size of 210 (70 per arm) was planned to give 80% power for detecting a positive dose-response slope among the 3 treatment arms at 12 months.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.57
	Comments
	Method	Cochran-Armitage trend test
	Comments

2. Primary Outcome

Title	Alanine Transaminase (ALT) Levels
Description	Mean change from baseline at month 3 analyzed by Analysis of Covariance (ANCOVA) in the efficacy evaluable analysis set with treatment group as a factor and baseline ALT as a covariate. Principal comparisons were the response between; EPA-E 2700 mg and Placebo groups EPA-E 1800 mg and Placebo groups
Time Frame	3 month endpoint

Outcome Measure Data

Analysis Population Description

Efficacy Evaluable Analysis Set - All patients in Full Analysis Set who have valid 12-month histological data without major protocol violations, including withdrawn patients with valid 12.5 month histological data after more than 6 months treatment

Arm/Group Title	Placebo	EPA-E 1800 mg/Day	EPA-E 2700 mg/Day
Arm/Group Description	Placebo: Placebo three times a day (TID) for 365 days	EPA-E: 600 mg TID for 365 days	EPA-E: 900 mg TID for 365 days
Measure Participants	55	55	64
Least Squares Mean (Standard Error) [U/L]	-19.3 (4.61)	-3.0 (4.61)	2.8 (4.27)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, EPA-E 1800 mg/Day
	Comments	Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 1,800 mg/day EPA-E treatment group compared to placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0137
	Comments	Two-sided p-values testing for significance was performed within treatment group change from baseline and comparisons between treatment groups. Multiple comparison techniques were not applied.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, EPA-E 1800 mg/Day
	Comments	Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 1,800 mg/day EPA-E treatment group compared to placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	16.2
	Confidence Interval	(2-Sided) 95%; 3.4 to 29.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, EPA-E 2700 mg/Day
	Comments	Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 2,700 mg/day EPA-E treatment group compared to placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments	Two-sided p-values testing for significance was performed within treatment group change from baseline and comparisons between treatment groups. Multiple comparison techniques were not applied.
	Method	ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, EPA-E 2700 mg/Day
	Comments	Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 2,700 mg/day EPA-E treatment group compared to placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	22.0
	Confidence Interval	(2-Sided) 95%; 9.6 to 34.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Alanine Transaminase (ALT) Levels
Description	Mean change from baseline at month 6 analyzed by Analysis of Covariance (ANCOVA) in the efficacy analysis set with treatment group as a factor and baseline ALT as a covariate. Principal comparisons were the response between; EPA-E 2700 mg and Placebo groups EPA-E 1800 mg and Placebo groups
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Efficacy Evaluable Analysis Set - All patients in Full Analysis Set who have valid 12-month histological data without major protocol violations, including withdrawn patients with valid 12.5 month histological data after more than 6 months treatment

Arm/Group Title	Placebo	EPA-E 1800 mg/Day	EPA-E 2700 mg/Day
Arm/Group Description	Placebo: Placebo three times a day (TID) for 365 days	EPA-E: 600 mg TID for 365 days	EPA-E: 900 mg TID for 365 days
Measure Participants	55	55	64
Mean (Standard Deviation) [U/L]	-19.1 (4.79)	-9.5 (4.80)	-3.0 (4.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, EPA-E 1800 mg/Day
	Comments	Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 1,800 mg/day EPA-E treatment group compared to placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1592
	Comments	Two-sided p-values testing for significance was performed within treatment group change from baseline and comparisons between treatment groups. Multiple comparison techniques were not applied.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, EPA-E 1800 mg/Day
	Comments	Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 1,800 mg/day EPA-E treatment group compared to placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.6
	Confidence Interval	(2-Sided) 95%; -3.8 to 23.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, EPA-E 2700 mg/Day
	Comments	Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 2,700 mg/day EPA-E treatment group compared to placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0153
	Comments	Two-sided p-values testing for significance was performed within treatment group change from baseline and comparisons between treatment groups. Multiple comparison techniques were not applied.
	Method	ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, EPA-E 2700 mg/Day
	Comments	Least Squares (LS) mean, 95% CI and 2-sided p-value obtained from ANCOVA model with treatment group as a factor and baseline ALT as a covariate. 2,700 mg/day EPA-E treatment group compared to placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	16.0
	Confidence Interval	(2-Sided) 95%; 3.1 to 28.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	Adverse events solicited at each study visit.
Arm/Group Title	Placebo		EPA-E 1800 mg/Day		EPA-E 2700 mg/Day
Arm/Group Description	Placebo: Placebo three times a day (TID) for 365 days		EPA-E: 600 mg TID for 365 days		EPA-E: 900 mg TID for 365 days
All Cause Mortality
	Placebo		EPA-E 1800 mg/Day		EPA-E 2700 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		EPA-E 1800 mg/Day		EPA-E 2700 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/75 (5.3%)		8/82 (9.8%)		5/86 (5.8%)
Blood and lymphatic system disorders
Thrombocytopenia	1/75 (1.3%)		0/82 (0%)		0/86 (0%)
Cardiac disorders
Angina pectoris	0/75 (0%)		1/82 (1.2%)		0/86 (0%)
Gastrointestinal disorders
Abdominal pain	0/75 (0%)		2/82 (2.4%)		1/86 (1.2%)
Pancreatitis	0/75 (0%)		2/82 (2.4%)		0/86 (0%)
pancreatitis relapsing	0/75 (0%)		1/82 (1.2%)		0/86 (0%)
General disorders
Non-cardiac chest pain	0/75 (0%)		2/82 (2.4%)		0/86 (0%)
Asthenia	0/75 (0%)		1/82 (1.2%)		0/86 (0%)
Chest pain	0/75 (0%)		1/82 (1.2%)		0/86 (0%)
Pyrexia	1/75 (1.3%)		0/82 (0%)		0/86 (0%)
Infections and infestations
Appendicitis	0/75 (0%)		1/82 (1.2%)		0/86 (0%)
Pneumonia	1/75 (1.3%)		0/82 (0%)		0/86 (0%)
Post procedural pneumonia	0/75 (0%)		0/82 (0%)		1/86 (1.2%)
Injury, poisoning and procedural complications
Post procedural bile leak	0/75 (0%)		0/82 (0%)		1/86 (1.2%)
Post procedural hematoma	0/75 (0%)		1/82 (1.2%)		0/86 (0%)
Investigations
Electrocardiogram T wave inversion	0/75 (0%)		1/82 (1.2%)		0/86 (0%)
Metabolism and nutrition disorders
Dehydration	1/75 (1.3%)		0/82 (0%)		0/86 (0%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/75 (0%)		0/82 (0%)		1/86 (1.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Carcinoid tumor	0/75 (0%)		1/82 (1.2%)		0/86 (0%)
Chronic myelomonocytic leukaemia	0/75 (0%)		1/82 (1.2%)		0/86 (0%)
Multiple myeloma	0/75 (0%)		1/82 (1.2%)		0/86 (0%)
Nervous system disorders
Transient ischemic attack	0/75 (0%)		2/82 (2.4%)		0/86 (0%)
Complicated migraine	0/75 (0%)		1/82 (1.2%)		0/86 (0%)
Multiple sclerosis relapse	1/75 (1.3%)		0/82 (0%)		0/86 (0%)
Syncope	1/75 (1.3%)		0/82 (0%)		1/86 (1.2%)
Psychiatric disorders
Panic attack	1/75 (1.3%)		0/82 (0%)		0/86 (0%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	0/75 (0%)		1/82 (1.2%)		1/86 (1.2%)
Pleural effusion	0/75 (0%)		1/82 (1.2%)		0/86 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		EPA-E 1800 mg/Day		EPA-E 2700 mg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	71/75 (94.7%)		65/82 (79.3%)		74/86 (86%)
Blood and lymphatic system disorders
Anaemia	4/75 (5.3%)		3/82 (3.7%)		2/86 (2.3%)
Gastrointestinal disorders
Nausea	7/75 (9.3%)		8/82 (9.8%)		16/86 (18.6%)
Diarrhoea	13/75 (17.3%)		6/82 (7.3%)		11/86 (12.8%)
Vomiting	4/75 (5.3%)		3/82 (3.7%)		10/86 (11.6%)
Abdominal pain	4/75 (5.3%)		5/82 (6.1%)		2/86 (2.3%)
Abdominal pain upper	1/75 (1.3%)		3/82 (3.7%)		6/86 (7%)
Gastroesphageal reflux disease	4/75 (5.3%)		2/82 (2.4%)		4/86 (4.7%)
General disorders
Fatigue	6/75 (8%)		3/82 (3.7%)		4/86 (4.7%)
Oedema peripheral	6/75 (8%)		3/82 (3.7%)		4/86 (4.7%)
Pyrexia	4/75 (5.3%)		2/82 (2.4%)		3/86 (3.5%)
Infections and infestations
Urinary tract infection	11/75 (14.7%)		11/82 (13.4%)		8/86 (9.3%)
Nasopharyngitis	9/75 (12%)		3/82 (3.7%)		6/86 (7%)
Sinusitis	5/75 (6.7%)		4/82 (4.9%)		7/86 (8.1%)
Gastroenteritis viral	3/75 (4%)		2/82 (2.4%)		8/86 (9.3%)
Upper respiratory tract infection	3/75 (4%)		5/82 (6.1%)		5/86 (5.8%)
Bronchitis	5/75 (6.7%)		1/82 (1.2%)		4/86 (4.7%)
Diverticulitis	4/75 (5.3%)		0/82 (0%)		1/86 (1.2%)
Injury, poisoning and procedural complications
Procedural pain	4/75 (5.3%)		2/82 (2.4%)		1/86 (1.2%)
Investigations
Blood creatine phosphokinase increased	4/75 (5.3%)		2/82 (2.4%)		0/86 (0%)
Musculoskeletal and connective tissue disorders
Back pain	6/75 (8%)		3/82 (3.7%)		5/86 (5.8%)
Arthralgia	0/75 (0%)		3/82 (3.7%)		5/86 (5.8%)
Nervous system disorders
Dizziness	4/75 (5.3%)		4/82 (4.9%)		1/86 (1.2%)
Psychiatric disorders
Depression	4/75 (5.3%)		4/82 (4.9%)		4/86 (4.7%)
Vascular disorders
Hypertension	5/75 (6.7%)		4/82 (4.9%)		4/86 (4.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.