Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment Experienced Subjects With Chronic Genotype 2 or 3 HCV Infection (FUSION) (FUSION)

• ClinicalTrials.gov Identifier: NCT01604850
• Recruitment Status: Completed
• First Posted: May 24, 2012
• Results First Posted: May 1, 2014
• Last Update Posted: May 28, 2014
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Chronic Hepatitis C
• Interventions: Drug: SOF; Drug: RBV; Drug: Placebo to match SOF; Drug: Placebo to match RBV
• Enrollment: 202

Participant Flow

Recruitment Details	Subjects were enrolled in a total of 57 study sites in the United States, Canada, and New Zealand. The first participant was screened on 04 June 2012. The last participant observation was on 08 May 2013.
Pre-assignment Details	277 participants were screened and 202 were randomized. Of those participants randomized, 201 received at least one dose of study drug, and comprise the Safety Analysis Set; 195 of those participants with genotypes 2 or 3 HCV infection were treated and comprise the Full Analysis Set.

Arm/Group Title	SOF+RBV+Placebo	SOF+RBV
Arm/Group Description	Participants were randomized to receive sofosbuvir (SOF)+ribavirin (RBV) for 12 weeks, followed by placebo to match sofosbuvir plus placebo to match RBV for 4 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets. Placebo to match sofosbuvir and placebo to match RBV were also administered as oral tablets.	Participants were randomized to receive sofosbuvir+RBV for 16 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets.
Period Title: Overall Study
Started	103	99
Enrolled and Treated	103	98
Completed	51	69
Not Completed	52	30
Reason Not Completed
Enrolled but never treated	0	1
Efficacy Failure	50	29
Lost to Follow-up	1	0
Subject withdrew consent	1	0

Baseline Characteristics

Arm/Group Title		SOF+RBV+Placebo	SOF+RBV	Total
Arm/Group Description		Participants were randomized to receive sofosbuvir+RBV for 12 weeks, followed by placebo to match sofosbuvir plus placebo to match RBV for 4 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets. Placebo to match sofosbuvir and placebo to match RBV were also administered as oral tablets.	Participants were randomized to receive sofosbuvir+RBV for 16 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets.	Total of all reporting groups
Overall Number of Baseline Participants		103	98	201
Baseline Analysis Population Description		Participants in the Safety Analysis Set (randomized and received at least 1 dose of study drug) were analyzed for baseline characteristics.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	103 participants	98 participants	201 participants
		54 (7.7)	54 (7.8)	54 (7.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	103 participants	98 participants	201 participants
	Female	30 29.1%	31 31.6%	61 30.3%
	Male	73 70.9%	67 68.4%	140 69.7%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	103 participants	98 participants	201 participants
Black or African American		5	1	6
White		88	86	174
Asian		7	5	12
American Indian/ Alaska Native/ First Nations		1	3	4
Hawaiian or Pacific Islander		0	1	1
Other		2	2	4
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	103 participants	98 participants	201 participants
United States		74	76	150
Canada		26	17	43
New Zealand		3	5	8
Hepatitis C Virus (HCV) genotype; Measure Type: Number; Unit of measure: Participants	Number Analyzed	103 participants	98 participants	201 participants
Genotype 1		3	3	6
Genotype 2		36	32	68
Genotype 3		64	63	127
HCV RNA; Mean (Standard Deviation); Unit of measure: Log10 IU/mL
	Number Analyzed	103 participants	98 participants	201 participants
		6.5 (0.67)	6.5 (0.63)	6.5 (0.65)
HCV RNA Category; Measure Type: Number; Unit of measure: Participants	Number Analyzed	103 participants	98 participants	201 participants
< 6 log10 IU/mL		26	29	55
≥ 6 log10 IU/mL		77	69	146
IL28 Genotype [1]; Measure Type: Number; Unit of measure: Participants	Number Analyzed	103 participants	98 participants	201 participants
CC		31	30	61
CT		53	56	109
TT		19	12	31
		[1] Measure Description: CC, CT, and TT alleles are different forms of the IL28b gene.
Cirrhosis (Y/N); Measure Type: Number; Unit of measure: Participants	Number Analyzed	103 participants	98 participants	201 participants
No		66	66	132
Yes		36	32	68
Missing		1	0	1
Response to Prior HCV Treatment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	103 participants	98 participants	201 participants
Nonresponse		25	25	50
Relapse/Breakthrough		78	73	151

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Achieving SVR12
Description	SVR12 was defined as HCV RNA < the lower limit of quantitation (LLOQ, ie, < 25 IU/mL) 12 weeks after cessation of therapy. For the purposes of this efficacy analysis, the posttreatment period began after the end of active treatment (following Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm).
Time Frame	Posttreatment Week 12

Outcome Measure Data

Analysis Population Description

The Full Analysis Set included all participants with genotype 2 or 3 HCV infection who were randomized and received at least 1 dose of study drug.

Arm/Group Title	SOF+RBV+Placebo	SOF+RBV
Arm/Group Description:	Participants were randomized to receive sofosbuvir+RBV for 12 weeks, followed by placebo to match sofosbuvir plus placebo to match RBV for 4 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets. Placebo to match sofosbuvir and placebo to match RBV were also administered as oral tablets.	Participants were randomized to receive sofosbuvir+RBV for 16 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets.
Overall Number of Participants Analyzed	100	95
Measure Type: Number; Unit of Measure: percentage of participants
	51.0	72.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	SOF+RBV+Placebo, SOF+RBV
	Comments	A sample size of 100 subjects in each group would provide over 97% power to detect at least 20% improvement in SVR12 rate from the assumed null rate of 25% using 2-sided exact 1-sample binomial test at significance level of 0.025.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	< 0.001
	Comments	P-value is from the Cochran-Mantel-Haenszel (CMH) test stratified by the randomization stratification factor (ie, presence/absence of cirrhosis, genotype 2 or 3).
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Proportion difference
	Estimated Value	-22.4
	Confidence Interval	(2-Sided) 95%; -34.4 to -10.3
	Estimation Comments	The difference in proportions between treatment groups and associated 95% confidence interval (CI) are calculated based on stratum-adjusted Mantel-Haenszel proportions.

2. Primary Outcome

Title	Adverse Events Leading to Permanent Discontinuation of Study Drug
Description	Adverse events which led to permanent discontinuation of study drug may or may not have been related to study treatment.
Time Frame	Baseline to Week 16

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included participants who were randomized and received at least 1 dose of study drug.

Arm/Group Title	SOF+RBV+Placebo	SOF+RBV
Arm/Group Description:	Participants were randomized to receive sofosbuvir+RBV for 12 weeks, followed by placebo to match sofosbuvir plus placebo to match RBV for 4 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets. Placebo to match sofosbuvir and placebo to match RBV were also administered as oral tablets.	Participants were randomized to receive sofosbuvir+RBV for 16 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets.
Overall Number of Participants Analyzed	103	98
Measure Type: Number; Unit of Measure: participants
	1	0

3. Secondary Outcome

Title	Percentage of Participants Achieving SVR4
Description	SVR4 was defined as HCV RNA < LLOQ 4 weeks after cessation of therapy. For the purposes of this efficacy analysis, the posttreatment period began after the end of active treatment (following Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm).
Time Frame	Posttreatment Week 4

Outcome Measure Data

Analysis Population Description

The Full Analysis Set included all participants with genotype 2 or 3 HCV infection who were randomized and received at least 1 dose of study drug.

Arm/Group Title	SOF+RBV+Placebo	SOF+RBV
Arm/Group Description:	Participants were randomized to receive sofosbuvir+RBV for 12 weeks, followed by placebo to match sofosbuvir plus placebo to match RBV for 4 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets. Placebo to match sofosbuvir and placebo to match RBV were also administered as oral tablets.	Participants were randomized to receive sofosbuvir+RBV for 16 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets.
Overall Number of Participants Analyzed	100	95
Measure Type: Number; Unit of Measure: percentage of participants
	56.0	76.8

4. Secondary Outcome

Title	Percentage of Participants Achieving SVR24
Description	SVR24 was defined as HCV RNA < LLOQ 24 weeks after cessation of therapy. For the purposes of this efficacy analysis, the posttreatment period began after the end of active treatment (following Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm).
Time Frame	Posttreatment Week 24

Outcome Measure Data

Analysis Population Description

The Full Analysis Set included all participants with genotype 2 or 3 HCV infection who were randomized and received at least 1 dose of study drug.

Arm/Group Title	SOF+RBV+Placebo	SOF+RBV
Arm/Group Description:	Participants were randomized to receive sofosbuvir+RBV for 12 weeks, followed by placebo to match sofosbuvir plus placebo to match RBV for 4 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets. Placebo to match sofosbuvir and placebo to match RBV were also administered as oral tablets.	Participants were randomized to receive sofosbuvir+RBV for 16 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets.
Overall Number of Participants Analyzed	100	95
Measure Type: Number; Unit of Measure: percentage of participants
	50.0	71.6

5. Secondary Outcome

Title	Percentage of Participants With Viral Breakthrough
Description	Viral breakthrough was defined as HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ while receiving treatment, confirmed with 2 consecutive values (second confirmation value could be posttreatment), or last available on-treatment measurement with no subsequent follow-up values. For the purposes of this efficacy analysis, assessments were made during active treatment (up to Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm).
Time Frame	Up to 16 weeks

Outcome Measure Data

Analysis Population Description

The Full Analysis Set included all participants with genotype 2 or 3 HCV infection who were randomized and received at least 1 dose of study drug.

Arm/Group Title	SOF+RBV+Placebo	SOF+RBV
Arm/Group Description:	Participants were randomized to receive sofosbuvir+RBV for 12 weeks, followed by placebo to match sofosbuvir plus placebo to match RBV for 4 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets. Placebo to match sofosbuvir and placebo to match RBV were also administered as oral tablets.	Participants were randomized to receive sofosbuvir+RBV for 16 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets.
Overall Number of Participants Analyzed	100	95
Measure Type: Number; Unit of Measure: percentage of participants
	0.0	0.0

6. Secondary Outcome

Title	Percentage of Participants With Viral Relapse
Description	Viral relapse was defined as HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at end of treatment, confirmed with 2 consecutive values or last available posttreatment measurement. For the purposes of this efficacy analysis, the posttreatment period began after the end of active treatment (following Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm).
Time Frame	End of treatment to posttreatment Week 24

Outcome Measure Data

Analysis Population Description

The Full Analysis Set included all participants with genotype 2 or 3 HCV infection who were randomized and received at least 1 dose of study drug.

Arm/Group Title	SOF+RBV+Placebo	SOF+RBV
Arm/Group Description:	Participants were randomized to receive sofosbuvir+RBV for 12 weeks, followed by placebo to match sofosbuvir plus placebo to match RBV for 4 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets. Placebo to match sofosbuvir and placebo to match RBV were also administered as oral tablets.	Participants were randomized to receive sofosbuvir+RBV for 16 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets.
Overall Number of Participants Analyzed	100	95
Measure Type: Number; Unit of Measure: participants
	47	26

Adverse Events

Time Frame	Baseline to posttreatment Week 24 plus 30 days
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	SOF+RBV+Placebo	SOF+RBV
Arm/Group Description	Participants were randomized to receive sofosbuvir+RBV for 12 weeks, followed by placebo to match sofosbuvir plus placebo to match RBV for 4 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets. Placebo to match sofosbuvir and placebo to match RBV were also administered as oral tablets.	Participants were randomized to receive sofosbuvir+RBV for 16 weeks. Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets.
All-Cause Mortality
	SOF+RBV+Placebo	SOF+RBV
	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--
Serious Adverse Events
	SOF+RBV+Placebo	SOF+RBV
	Affected / at Risk (%)	Affected / at Risk (%)
Total	5/103 (4.85%)	3/98 (3.06%)
Gastrointestinal disorders
Abdominal pain † 1	1/103 (0.97%)	0/98 (0.00%)
Oesophageal varices haemorrhage † 1	1/103 (0.97%)	0/98 (0.00%)
General disorders
Non-cardiac chest pain † 1	0/103 (0.00%)	1/98 (1.02%)
Pyrexia † 1	1/103 (0.97%)	0/98 (0.00%)
Hepatobiliary disorders
Portal vein thrombosis † 1	1/103 (0.97%)	0/98 (0.00%)
Injury, poisoning and procedural complications
Overdose † 1	0/103 (0.00%)	1/98 (1.02%)
Upper limb fracture † 1	1/103 (0.97%)	0/98 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic neoplasm malignant † 1	3/103 (2.91%)	0/98 (0.00%)
Basal cell carcinoma † 1	1/103 (0.97%)	0/98 (0.00%)
Psychiatric disorders
Suicide attempt † 1	0/103 (0.00%)	1/98 (1.02%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA Version 15.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	SOF+RBV+Placebo	SOF+RBV
	Affected / at Risk (%)	Affected / at Risk (%)
Total	92/103 (89.32%)	86/98 (87.76%)
Blood and lymphatic system disorders
Anaemia † 1	11/103 (10.68%)	4/98 (4.08%)
Gastrointestinal disorders
Nausea † 1	22/103 (21.36%)	20/98 (20.41%)
Diarrhoea † 1	15/103 (14.56%)	6/98 (6.12%)
Abdominal pain † 1	6/103 (5.83%)	5/98 (5.10%)
Dyspepsia † 1	6/103 (5.83%)	3/98 (3.06%)
Constipation † 1	2/103 (1.94%)	5/98 (5.10%)
General disorders
Fatigue † 1	46/103 (44.66%)	46/98 (46.94%)
Irritability † 1	15/103 (14.56%)	11/98 (11.22%)
Pain † 1	4/103 (3.88%)	5/98 (5.10%)
Infections and infestations
Upper respiratory tract infection † 1	6/103 (5.83%)	5/98 (5.10%)
Injury, poisoning and procedural complications
Contusion † 1	4/103 (3.88%)	8/98 (8.16%)
Metabolism and nutrition disorders
Decreased Appetite † 1	9/103 (8.74%)	5/98 (5.10%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	11/103 (10.68%)	9/98 (9.18%)
Myalgia † 1	8/103 (7.77%)	9/98 (9.18%)
Muscle spasms † 1	8/103 (7.77%)	8/98 (8.16%)
Back pain † 1	5/103 (4.85%)	5/98 (5.10%)
Nervous system disorders
Headache † 1	26/103 (25.24%)	32/98 (32.65%)
Dizziness † 1	6/103 (5.83%)	5/98 (5.10%)
Dysgeusia † 1	3/103 (2.91%)	6/98 (6.12%)
Disturbance in attention † 1	6/103 (5.83%)	1/98 (1.02%)
Psychiatric disorders
Insomnia † 1	21/103 (20.39%)	28/98 (28.57%)
Anxiety † 1	8/103 (7.77%)	9/98 (9.18%)
Depression † 1	6/103 (5.83%)	6/98 (6.12%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	10/103 (9.71%)	13/98 (13.27%)
Dyspnoea † 1	8/103 (7.77%)	5/98 (5.10%)
Skin and subcutaneous tissue disorders
Pruritus † 1	12/103 (11.65%)	7/98 (7.14%)
Rash † 1	7/103 (6.80%)	12/98 (12.24%)
Dry skin † 1	7/103 (6.80%)	5/98 (5.10%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, MedDRA Version 15.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met:

• The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or
• The study has been completed at all study sites for at least 2 years

Results Point of Contact

• Name/Title: Clinical Trial Disclosures
• Organization: Gilead Sciences, Inc.
• EMail: ClinicalTrialDisclosures@gilead.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Younossi ZM, Stepanova M, Sulkowski M, Naggie S, Puoti M, Orkin C, Hunt SL. Sofosbuvir and Ribavirin for Treatment of Chronic Hepatitis C in Patients Coinfected With Hepatitis C Virus and HIV: The Impact on Patient-Reported Outcomes. J Infect Dis. 2015 Aug 1;212(3):367-77. doi: 10.1093/infdis/jiv005. Epub 2015 Jan 12.

Stepanova M, Nader F, Cure S, Bourhis F, Hunt S, Younossi ZM. Patients' preferences and health utility assessment with SF-6D and EQ-5D in patients with chronic hepatitis C treated with sofosbuvir regimens. Aliment Pharmacol Ther. 2014 Sep;40(6):676-85. doi: 10.1111/apt.12880. Epub 2014 Jul 15.

Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, Shiffman ML, Lawitz E, Everson G, Bennett M, Schiff E, Al-Assi MT, Subramanian GM, An D, Lin M, McNally J, Brainard D, Symonds WT, McHutchison JG, Patel K, Feld J, Pianko S, Nelson DR; POSITRON Study; FUSION Study. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med. 2013 May 16;368(20):1867-77. doi: 10.1056/NEJMoa1214854. Epub 2013 Apr 23.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT01604850
• Other Study ID Numbers: GS-US-334-0108
• First Submitted: May 21, 2012
• First Posted: May 24, 2012
• Results First Submitted: March 31, 2014
• Results First Posted: May 1, 2014
• Last Update Posted: May 28, 2014