Study of Efficacy and Safety of Grazoprevir (MK-5172)/Elbasvir (MK-8742) Combination Regimen for Treatment-Naïve Participants With Chronic Hepatitis C Virus Genotypes 1, 4, and 6 (MK-5172-060)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02105467
• Collaborator: (none)
• Enrollment: 421
• Arms: 2
• Actual Duration (Months): 15

Study Details

Study Description

Brief Summary

This was an efficacy and safety study of grazoprevir (MK-5172) in combination with elbasvir (MK-8742) in treatment-naive participants with chronic hepatitis C virus (HCV) genotype (GT) 1, 4, or 6 infection. Participants were randomly assigned (3:1 ratio) to immediate treatment or deferred treatment (placebo control). The primary efficacy hypothesis was that the proportion of participants receiving combination therapy in the Immediate Treatment Arm who achieve sustained viral response at 12 weeks after the end of study treatment (SVR12) is superior to 73%.

Condition or Disease	Intervention/Treatment	Phase
Chronic Hepatitis C Virus	Drug: Grazoprevir 100mg / Elbasvir 50 mg FDC; Drug: Placebo to Grazoprevir / Elbasvir 50 mg FDC	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 421 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-5172/MK-8742 in Treatment-Naïve Subjects With Chronic HCV GT1, GT4, and GT6 Infection.
• Actual Study Start Date: Jun 5, 2014
• Actual Primary Completion Date: Feb 26, 2015
• Actual Study Completion Date: Sep 6, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Immediate Treatment Group Participants received blinded grazoprevir 100 mg / elbasvir 50 mg fixed-dose combination (FDC) tablet orally once daily for 12 weeks followed by a 24-week follow-up period	Drug: Grazoprevir 100mg / Elbasvir 50 mg FDC
Placebo Comparator: Deferred Treatment Group Participants received blinded placebo tablet orally once daily for 12 weeks; after a 4-week unblinding/washout period participants received open label grazoprevir 100 mg / elbasvir 50 mg FDC tablet orally once daily for 12 weeks. Follow-up was continued for an additional 24 weeks.	Drug: Grazoprevir 100mg / Elbasvir 50 mg FDC; Drug: Placebo to Grazoprevir / Elbasvir 50 mg FDC

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of Treatment (SVR12) [Week 24 (12 weeks after the end of treatment)]

   Hepatitis C Virus (HCV) ribonucleic acid (RNA) was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay. SVR12 was defined as HCV RNA <Lower Limit of Quantification (<15 IU/mL) 12 weeks after the end of all study therapy.

2. Percentage of Participants Experiencing at Least One Adverse Event [Up to Week 14 (14 days after the Blinded Treatment was completed)]

   An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event.

3. Percentage of Participants Discontinued From Study Treatment Because of an Adverse Event [Up to Week 12 (end of Blinded Treatment)]

   An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event.

Secondary Outcome Measures

1. Percentage of Participants Achieving Sustained Virologic Response at 24 Weeks After the End of Treatment (SVR24) [Week 36 (24 weeks after the end of treatment)]

   Hepatitis C Virus RNA was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay. SVR24 was defined as HCV RNA <Lower Limit of Quantitation (<15 IU/mL) 24 weeks after the end of all study therapy.

Other Outcome Measures

1. Percentage of Participants Achieving Sustained Virologic Response at 4 Weeks After the End of Treatment (SVR4) [Week 16 (4 weeks after the end of treatment)]

   Hepatitis C Virus RNA was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay. SVR4 was defined as HCV RNA <Lower Limit of Quantitation (<15 IU/mL) 4 weeks after the end of all study therapy.

Eligibility Criteria

Criteria

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

Inclusion criteria:

• Documented chronic HCV GT1, GT4, or GT6 with no evidence of non-typeable or mixed genotype infection (positive for anti-HCV antibody, HCV RNA, or any of the listed GTs at least 6 months prior to screening must be confirmed by screening lab results)

• Cirrhosis defined by: liver biopsy showing cirrhosis METAVIR F4; or Fibroscan showing cirrhosis with a result of >12.5 kiloPascals (kPa); or FibroSure® (Fibrotest®) score of >0.75 and an aspartate aminotransferase (AST): platelet ratio index (APRI) of >2

• Absence of cirrhosis defined by: liver biopsy showing absence of cirrhosis, or Fibroscan with a result of ≤12.5 kPa, or Fibrosure® (Fibrotest®) score of <= 0.48 and APRI of <=1

• HCV treatment status of treatment naïve (naïve to all anti-HCV treatment) and can also be ineligible to take pegylated interferon

• Female participant not of reproductive potential, or female of reproductive potential and agrees to avoid becoming pregnant while receiving study drug and for 14 days after the last dose of study drug (using abstinence or acceptable methods of contraception)

Exclusion criteria:

• Evidence of decompensated liver disease manifested by the presence of or history of ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy or other signs or symptoms of advanced liver disease. For cirrhotics, participants who are Child-Pugh Class B or C or who have a Pugh-Turcotte (CPT) score >6

• Co-infection with hepatitis B virus or human immunodeficiency virus (HIV)

• History of malignancy <=5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer or carcinoma in situ; or is under evaluation for other active or suspected malignancy

• Evidence of hepatocellular carcinoma (HCC) or under evaluation for HCC

• Currently participating or has participated in a study with an investigational compound within 30 days of signing informed consent and is not willing to refrain from participating in another such study during the course of this study

• Clinically-relevant drug or alcohol abuse within 12 months of screening

• Pregnant, breast-feeding, or expecting to conceive or donate eggs from Day 1 throughout treatment and 14 days after the last dose of study medication or longer if dictated by local regulations

• Organ transplant (including hematopoietic stem cell transplants) other than cornea and hair

• Poor venous access

• History of gastric surgery (e.g., stapling, bypass) or history of malabsorption disorder (e.g., celiac sprue disease)

• Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids, TNF antagonists, or other immunosuppressant drugs during the course of the trial

• Evidence of history of chronic hepatitis not caused by HCV, including but not limited to nonalcoholic steatohepatitis (NASH), drug-induced hepatitis, and autoimmune hepatitis

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

• Zeuzem S, Ghalib R, Reddy KR, Pockros PJ, Ben Ari Z, Zhao Y, Brown DD, Wan S, DiNubile MJ, Nguyen BY, Robertson MN, Wahl J, Barr E, Butterton JR. Grazoprevir-Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial. Ann Intern Med. 2015 Jul 7;163(1):1-13. doi: 10.7326/M15-0785.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02105467
• Other Study ID Numbers: 5172-060; 2014-000137-22
• First Posted: Apr 7, 2014
• Last Update Posted: Oct 2, 2018
• Last Verified: Sep 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Hepatitis, Chronic; Grazoprevir; Elbasvir-grazoprevir drug combination

Study Results

Participant Flow

Recruitment Details	For Subject Disposition, Period 1 covers Day 1 through Week 12 for both treatment groups. Period 2 covers Week 12 through Week 36 for the Immediate Treatment Group (ITG) and Week 12 through Week 28 for the Deferred Treatment Group (DTG). Period 3 covers Week 28 through Week 52 for the DTG; the ITG completed the study with Period 2.
Pre-assignment Detail	A total of 469 participants were screened and 421 were randomized.

Arm/Group Title	Immediate Treatment Group	Deferred Treatment Group
Arm/Group Description	Participants received blinded grazoprevir 100 mg / elbasvir 50 mg fixed-dose combination (FDC) tablet orally once daily for 12 weeks (Period 1), followed by a 24-week follow-up period (Period 2)	Participants received blinded placebo tablet orally once daily for 12 weeks (Period 1), followed by a 4-week unblinding/washout period and 12 weeks of open label grazoprevir 100 mg / elbasvir 50 mg FDC tablet orally once daily (Period 2), followed by a 24-week follow-up period (Period 3).
Period Title: Period 1
STARTED	316	105
COMPLETED	314	105
NOT COMPLETED	2	0
Period Title: Period 1
STARTED	314	104
COMPLETED	312	102
NOT COMPLETED	2	2
Period Title: Period 1
STARTED	0	103
COMPLETED	0	102
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Immediate Treatment Group	Deferred Treatment Group	Total
Arm/Group Description	Participants received blinded grazoprevir 100 mg / elbasvir 50 mg fixed-dose combination (FDC) tablet orally once daily for 12 weeks followed by a 24-week follow-up period	Participants received blinded placebo tablet orally once daily for 12 weeks; after a 4-week unblinding/washout period participants received open label grazoprevir 100 mg / elbasvir 50 mg FDC tablet orally once daily for 12 weeks. Follow-up was for an additional 24 weeks.	Total of all reporting groups
Overall Participants	316	105	421
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	52.2 (11.1)	53.8 (11.2)	52.6 (11.2)
Sex: Female, Male (Count of Participants)
Female	145 45.9%	49 46.7%	194 46.1%
Male	171 54.1%	56 53.3%	227 53.9%
HCV Genotype (Number) [Number]
Genotype 1a	157 49.7%	54 51.4%	211 50.1%
Genotype 1b	131 41.5%	40 38.1%	171 40.6%
Genotype 4	18 5.7%	8 7.6%	26 6.2%
Genotype 6	10 3.2%	3 2.9%	13 3.1%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Achieving Sustained Virologic Response at 12 Weeks After the End of Treatment (SVR12)
Description	Hepatitis C Virus (HCV) ribonucleic acid (RNA) was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay. SVR12 was defined as HCV RNA <Lower Limit of Quantification (<15 IU/mL) 12 weeks after the end of all study therapy.
Time Frame	Week 24 (12 weeks after the end of treatment)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set included randomized participants who received at least one dose of study treatment. This outcome measure applied only to the Immediate Treatment group.

Arm/Group Title	Immediate Treatment Group
Arm/Group Description	Participants received blinded grazoprevir 100 mg / elbasvir 50 mg fixed-dose combination (FDC) tablet orally once daily for 12 weeks followed by a 24-week follow-up period
Measure Participants	316
Number (95% Confidence Interval) [Percentage of participants]	94.6 29.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Immediate Treatment Group
	Comments	Superiority of SVR12 in the Immediate Treatment group was tested against the historical response rate of 73%.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	One-sided, one-sample exact test
	Comments

2. Primary Outcome

Title	Percentage of Participants Experiencing at Least One Adverse Event
Description	An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event.
Time Frame	Up to Week 14 (14 days after the Blinded Treatment was completed)

Outcome Measure Data

Analysis Population Description

The All Subjects as Treated population included randomized participants who received at least one dose of study treatment. This outcome measure applied only to the blinded treatment period.

Arm/Group Title	Immediate Treatment Group	Deferred Treatment Group
Arm/Group Description	Participants received blinded grazoprevir 100 mg / elbasvir 50 mg fixed-dose combination (FDC) tablet orally once daily for 12 weeks followed by a 24-week follow-up period	Participants received blinded placebo tablet orally once daily for 12 weeks; after a 4-week unblinding/washout period participants received open label grazoprevir 100 mg / elbasvir 50 mg FDC tablet orally once daily for 12 weeks. Follow-up was for an additional 24 weeks.
Measure Participants	316	105
Number [Percentage of participants]	67.4 21.3%	68.6 65.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Immediate Treatment Group, Deferred Treatment Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -10.8 to 9.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Between-treatment difference (Immediate Treatment Group - Deferred Treatment Group) was analyzed using the Miettinen and Nurminen method.

3. Primary Outcome

Title	Percentage of Participants Discontinued From Study Treatment Because of an Adverse Event
Description	An adverse event is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event.
Time Frame	Up to Week 12 (end of Blinded Treatment)

Outcome Measure Data

Analysis Population Description

The All Subjects as Treated population included randomized participants who received at least one dose of study treatment. This outcome measure applied only to the blinded treatment period.

Arm/Group Title	Immediate Treatment Group	Deferred Treatment Group
Arm/Group Description	Participants received blinded grazoprevir 100 mg / elbasvir 50 mg fixed-dose combination (FDC) tablet orally once daily for 12 weeks followed by a 24-week follow-up period	Participants received blinded placebo tablet orally once daily for 12 weeks; after a 4-week unblinding/washout period participants received open label grazoprevir 100 mg / elbasvir 50 mg FDC tablet orally once daily for 12 weeks. Follow-up was for an additional 24 weeks.
Measure Participants	316	105
Number [Percentage of participants]	0.9 0.3%	1.0 1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Immediate Treatment Group, Deferred Treatment Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.0
	Confidence Interval	(2-Sided) 95%; -4.4 to 2.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Between-treatment difference (Immediate Treatment Group - Deferred Treatment Group) was analyzed using the Miettinen and Nurminen method.

4. Other Pre-specified Outcome

Title	Percentage of Participants Achieving Sustained Virologic Response at 4 Weeks After the End of Treatment (SVR4)
Description	Hepatitis C Virus RNA was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay. SVR4 was defined as HCV RNA <Lower Limit of Quantitation (<15 IU/mL) 4 weeks after the end of all study therapy.
Time Frame	Week 16 (4 weeks after the end of treatment)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set included randomized participants who received at least one dose of study treatment. This outcome measure applied only to the Immediate Treatment group.

Arm/Group Title	Immediate Treatment Group
Arm/Group Description	Participants received blinded grazoprevir 100 mg / elbasvir 50 mg fixed-dose combination (FDC) tablet orally once daily for 12 weeks followed by a 24-week follow-up period
Measure Participants	316
Number (95% Confidence Interval) [Percentage of participants]	97.2 30.8%

5. Secondary Outcome

Title	Percentage of Participants Achieving Sustained Virologic Response at 24 Weeks After the End of Treatment (SVR24)
Description	Hepatitis C Virus RNA was measured using the Roche COBAS® Taqman® HCV Test, v2.0 assay. SVR24 was defined as HCV RNA <Lower Limit of Quantitation (<15 IU/mL) 24 weeks after the end of all study therapy.
Time Frame	Week 36 (24 weeks after the end of treatment)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set included randomized participants who received at least one dose of study treatment. This outcome measure applied only to the Immediate Treatment group.

Arm/Group Title	Immediate Treatment Group
Arm/Group Description	Participants received blinded grazoprevir 100 mg / elbasvir 50 mg fixed-dose combination (FDC) tablet orally once daily for 12 weeks followed by a 24-week follow-up period
Measure Participants	316
Number (95% Confidence Interval) [Percentage of participants]	94.3 29.8%

Adverse Events

Time Frame	Immediate Treatment Group: Up to Week 36; Deferred Treatment Group (Blinded Treatment): Up to Week 16; Deferred Treatment Group (Open-label Treatment): Week 16 to Week 52
Arm/Group Title	Immediate Treatment Group		Deferred Treatment Group (Blinded Treatment)		Deferred Treatment Group (Open-label Treatment)
Arm/Group Description	Participants received blinded grazoprevir 100 mg / elbasvir 50 mg fixed-dose combination (FDC) tablet orally once daily for 12 weeks followed by a 24-week follow-up period. Adverse event reporting covers Day 1 through Week 36.		Participants received blinded placebo tablet orally once daily for 12 weeks; after a 4-week unblinding/washout period participants received open label grazoprevir 100 mg / elbasvir 50 mg FDC tablet orally once daily for 12 weeks. Follow-up was for an additional 24 weeks. Adverse event reporting covers Day 1 through Week 16.		Participants received blinded placebo tablet orally once daily for 12 weeks; after a 4-week unblinding/washout period participants received open label grazoprevir 100 mg / elbasvir 50 mg FDC tablet orally once daily for 12 weeks. Follow-up was for an additional 24 weeks. Adverse event reporting covers Week 16 through Week 52.
All Cause Mortality
	Immediate Treatment Group		Deferred Treatment Group (Blinded Treatment)		Deferred Treatment Group (Open-label Treatment)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Immediate Treatment Group		Deferred Treatment Group (Blinded Treatment)		Deferred Treatment Group (Open-label Treatment)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/316 (4.7%)		4/105 (3.8%)		3/103 (2.9%)
Cardiac disorders
Myocardial infarction	1/316 (0.3%)	1	1/105 (1%)	1	0/103 (0%)	0
Ventricular arrhythmia	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Acute Myocardial Infarction	0/316 (0%)	0	0/105 (0%)	0	1/103 (1%)	1
Ear and labyrinth disorders
Meniere's disease	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Eye disorders
Retinal haemorrhage	0/316 (0%)	0	1/105 (1%)	1	0/103 (0%)	0
Gastrointestinal disorders
Abdominal pain upper	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Hiatus hernia strangulated	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Pancreatitis acute	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
General disorders
Asthenia	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Chest pain	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Infections and infestations
Peritoneal abscess	0/316 (0%)	0	0/105 (0%)	0	1/103 (1%)	1
Tooth abscess	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Injury, poisoning and procedural complications
Accidental overdose	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Multiple fractures	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/316 (0%)	0	1/105 (1%)	2	0/103 (0%)	0
Muscular weakness	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Rotator cuff syndrome	0/316 (0%)	0	1/105 (1%)	1	0/103 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma pancreas	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Bladder cancer	0/316 (0%)	0	0/105 (0%)	0	1/103 (1%)	1
Pancreatic carcinoma	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Prostate cancer	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Renal and urinary disorders
Renal colic	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Skin and subcutaneous tissue disorders
Skin ulcer	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Vascular disorders
Hypotension	1/316 (0.3%)	1	0/105 (0%)	0	0/103 (0%)	0
Other (Not Including Serious) Adverse Events
	Immediate Treatment Group		Deferred Treatment Group (Blinded Treatment)		Deferred Treatment Group (Open-label Treatment)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	147/316 (46.5%)		60/105 (57.1%)		42/103 (40.8%)
Gastrointestinal disorders
Diarrhoea	14/316 (4.4%)	15	7/105 (6.7%)	7	5/103 (4.9%)	5
Nausea	29/316 (9.2%)	32	8/105 (7.6%)	8	8/103 (7.8%)	8
General disorders
Fatigue	49/316 (15.5%)	53	18/105 (17.1%)	19	12/103 (11.7%)	13
Infections and infestations
Nasopharyngitis	20/316 (6.3%)	23	7/105 (6.7%)	8	7/103 (6.8%)	8
Upper respiratory tract infection	17/316 (5.4%)	18	2/105 (1.9%)	2	5/103 (4.9%)	6
Musculoskeletal and connective tissue disorders
Arthralgia	20/316 (6.3%)	22	6/105 (5.7%)	6	3/103 (2.9%)	3
Back pain	10/316 (3.2%)	10	3/105 (2.9%)	3	7/103 (6.8%)	7
Nervous system disorders
Dizziness	9/316 (2.8%)	9	7/105 (6.7%)	9	0/103 (0%)	0
Headache	51/316 (16.1%)	61	18/105 (17.1%)	19	17/103 (16.5%)	19
Psychiatric disorders
Insomnia	6/316 (1.9%)	6	6/105 (5.7%)	6	3/103 (2.9%)	3
Skin and subcutaneous tissue disorders
Pruritus	7/316 (2.2%)	7	8/105 (7.6%)	9	1/103 (1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results.