Efficacy of Sofosbuvir With Ribavirin Administered Pre-Transplant in Preventing Hepatitis C Virus (HCV) Recurrence Post-Transplant

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01559844
• Collaborator: (none)
• Enrollment: 61
• Locations: 15
• Arm: 1
• Duration (Months): 31
• Patients Per Site: 4.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective is to determine if the administration of a combination of sofosbuvir (SOF; GS-7977; PSI-7977) and ribavirin (RBV) to HCV-infected adults with hepatocellular carcinoma (HCC) meeting the MILAN criteria prior to undergoing liver transplantation could prevent post-transplant re-infection as determined by a sustained post-transplant virological response (HCV RNA < LLoQ) at 12 weeks post-transplant.

Participants will enroll in the pretransplant treatment phase (24 or 48 weeks). Participants enrolling for 24 weeks in the pretransplant treatment phase may receive treatment for up to an additional 24 weeks in the pretransplant retreatment phase. Participants enrolling for 48 weeks in the pretransplant treatment will have a second baseline at Week 24 for combined analysis in the pretransplant retreatment phase.

Participants who undergo liver transplant will stop all study drug 24 hours prior to transplant, and enter a 48-week follow-up phase to monitor for recurrent HCV infection.

Condition or Disease	Intervention/Treatment	Phase
Hepatitis C; Hepatocellular Carcinoma	Drug: Sofosbuvir; Drug: Ribavirin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Study to Explore the Clinical Efficacy of GS-7977 With Ribavirin Administered Pre-Transplant in Preventing Hepatitis C Virus (HCV) Recurrence Post-Transplant
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SOF+RBV Sofosbuvir plus ribavirin for up to 48 weeks or until time of transplant, whichever occurs first.	Drug: Sofosbuvir; Sofosbuvir 400 mg (2 x 200 mg tablets) administered orally once daily; Other Names: GS-7977 PSI-7977 Sovaldi® ; Drug: Ribavirin; Ribavirin (RBV) tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75kg = 1000 mg and ≥ 75 kg = 1200 mg)

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Posttransplant Virologic Response (pTVR) at Posttransplant Week 12 [Posttransplant Week 12]

   pTVR was defined as HCV RNA < the lower limit of quantification (LLOQ, ie, 25 mL/IU) at Week 12 after transplant.

2. Percentage of Participants Experiencing Any Adverse Event Leading to Permanent Discontinuation of Sofosbuvir Prior to Receiving Transplant [Up to 48 weeks prior to transplant]

3. Percentage of Participants With Graft Loss Following Transplant [Up to 48 weeks following transplant]

4. Number of Participants Who Died [Up to 48 weeks following transplant]

   Treatment-emergent deaths were those that occurred while taking study drug or to the minimum of 1) date of transplantation, 2) retreatment 1st dose date, or 3) last dose date + 30 days. Only those participants who underwent liver transplantation were analyzed for death post-transplantation.

Secondary Outcome Measures

1. Percentage of Participants With Posttransplant Virologic Response (pTVR) Through Posttransplant Week 48 [Up to 48 weeks following transplant]

   pTVR was defined as HCV RNA < the lower limit of quantification (LLOQ, ie, 25 mL/IU) at the relevant time point after transplant.

2. Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48 [Up to 48 weeks prior to transplant]

3. HCV RNA and Change From Baseline in HCV RNA Through Week 8 [Up to 8 weeks prior to transplant]

4. Proportion of Participants With Virologic Failure Prior to Transplant [Up to 48 weeks prior to transplant]

   Virologic failure (VF) in the pretransplant phase was defined by: Breakthrough (HCV RNA ≥ 25 IU/ml after having previously had HCV RNA < 25 IU/ml, while on treatment) Rebound (breakthrough or > 1 log10 IU/ml increase in HCV RNA from nadir while on treatment) Non-response (HCV RNA ≥ 25 IU/ml through 8 weeks of treatment) Pre-transplant relapse (HCV RNA ≥ 25 IU/ml during the Pre-Transplant off-treatment follow-up period after having achieved HCV RNA < 25 IU/ml at last observed HCV RNA on treatment)

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Willing and able to provide written informed consent

2. Males or females, age > 18 years old

3. Males must agree to consistently and correctly use a condom while their female partner agrees to use an approved form of birth control from the date of screening until 7 months after their last dose of ribavirin.

4. Confirmation of chronic HCV infection documented by at least one measurement of serum

HCV RNA above the LLOQ measured at screening, and at least one of the following:

• Positive anti-HCV antibody test, HCV RNA or HCV genotyping test at least 6 months prior to the baseline/Day 1 visit together with positive HCV RNA test and anti-HCV antibody at the time of screening, or

• Positive HCV RNA test and anti-HCV antibody test at the time of screening together with either a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed before enrollment with evidence of chronic HCV infection, such as the presence of fibrosis)

1. HCV RNA > 10^4 IU/mL at screening

2. Patients meeting the MILAN criteria undergoing liver transplant for HCC secondary to HCV with a MELD of < 22 and a HCC weighted MELD of ≥ 22.

3. Child-Pugh Score (CPT) ≤ 7

4. Planned management of the subject to meet United Network for Organ Sharing (UNOS) criteria, with imaging studies made available for review if required.

5. Has not been treated with any investigational drug or device within 30 days of the screening visit.

Exclusion Criteria:

1. Females of child-bearing potential who is pregnant or nursing

2. Prior exposure to a direct-acting antiviral targeting the HCV nonstructural (NS)5B polymerase

3. Any transplant patient who has agreed to a liver transplant from a live donor.

4. Participants requiring planned induction therapy with biologics posttransplantation or with a posttransplantation immunosuppressive regimen not consistent with the following within the first 12 weeks posttransplant:

• Solumedrol/Prednisone (tapering over approximately 7 days)

• Tacrolimus (maintaining a serum level of 5 12 ng/mL)

• Mycophenolate mofetil (up to 2 g/day)

• Introduction of new maintenance immunosuppressants different from the above list is disallowed except in consultation during the first 12 weeks posttransplant

1. Current, uncontrolled ascites, variceal hemorrhage, hepatic encephalopathy, hepatorenal syndrome and hepatopulmonary syndrome, among other signs of decompensated cirrhosis.

2. Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, cholangitis)

3. Infection with hepatitis B virus (HBV) or HIV

4. Contraindications to RBV therapy

5. Chronic use of systemically administered immunosuppressive agents (eg, prednisone equivalent > 10 mg/day) in the pretransplant treatment period.

6. History of previous solid organ transplantation

7. Evidence of renal impairment (CLcr < 60 mL/min) calculated by the Cockcroft-Gault equation.

8. History or current evidence of psychiatric illness, immunologic disorder, hemoglobinopathy, pulmonary or cardiac disease, porphyria, or poorly controlled diabetes, cancer other than HCC, or a history of malignancy that in the opinion of the investigator makes the patient unsuitable for the study. Patients with clinical signs or symptoms of acute pancreatitis with elevated lipase (at Screening or during the screening period)

9. Known hypersensitivity to RBV, the study investigational medicinal product, the metabolites, or formulation excipients

10. History of having received any systemic antineoplastic (including sorafenib) or immunomodulatory treatment (including radiation) within 6 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study (excluding a local regional therapy such as TACE).

11. Treatment with Transcatheter arterial chemoembolization (TACE) or radio frequency ablation (RFA) within 30 days prior to the first dose.

12. Participation in a clinical study with an investigational drug, biologic, or device within 3 months prior to first dose administration at the baseline/Day 1 Visit.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA Medical Center-The Pfleger Liver Institute	Los Angeles	California	United States	90095
2	UC San Diego	San Diego	California	United States	92103
3	University of California, San Francisco	San Francisco	California	United States	94143-0124
4	University of Colorado	Aurora	Colorado	United States	80010
5	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
6	University of Miami	Miami	Florida	United States	33102-5405
7	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
8	Lahey Clinic Medical Center	Burlington	Massachusetts	United States	01805
9	Henry Ford Hospital	Detroit	Michigan	United States	48202
10	St. Louis University Hospital	St. Louis	Missouri	United States	63110-0250
11	Columbia University	New York	New York	United States	10032
12	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
13	Baylor Health Care System	Dallas	Texas	United States	75246
14	Auckland Clinical Studies	Auckland		New Zealand
15	Liver Unit Clinica University de Navara	Pamplona		Spain	31008

Sponsors and Collaborators

• Gilead Sciences

Investigators

• Study Director: Jill Denning, MA, Gilead Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT01559844
• Other Study ID Numbers: P7977-2025
• First Posted: Mar 21, 2012
• Last Update Posted: Jul 27, 2016
• Last Verified: Jun 1, 2016

• Keywords provided by Gilead Sciences: Hepatitis; Chronic; hepatocellular carcinoma; HCC; transplant
• Additional relevant MeSH terms: Hepatitis A; Hepatitis C; Carcinoma, Hepatocellular; Hepatitis; Recurrence; Ribavirin; Sofosbuvir

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at study sites in the United States, Spain, and New Zealand. The first participant was screened on 27 March 2012. The last study visit occurred on 20 October 2014.
Pre-assignment Detail	92 participants were screened.

Arm/Group Title	SOF+RBV
Arm/Group Description	Sofosbuvir (SOF) 400 mg tablet once daily + ribavirin (RBV) tablets (1000-1200 mg daily based on weight) for up to 48 weeks or until time of transplant, whichever occured first.
Period Title: Overall Study
STARTED	61
COMPLETED	36
NOT COMPLETED	25

Baseline Characteristics

Arm/Group Title	SOF+RBV
Arm/Group Description	SOF 400 mg tablet once daily + RBV tablets (1000-1200 mg daily based on weight) for up to 48 weeks or until time of transplant, whichever occured first.
Overall Participants	61
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59 (5.5)
Sex: Female, Male (Count of Participants)
Female	12 19.7%
Male	49 80.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	12 19.7%
Not Hispanic or Latino	49 80.3%
Unknown or Not Reported	0 0%
Race/Ethnicity, Customized (participants) [Number]
White	55 90.2%
Black or African American	6 9.8%
Region of Enrollment (participants) [Number]
United States	55 90.2%
Spain	5 8.2%
New Zealand	1 1.6%
Prior Hepatitis C Virus (HCV) Treatment (participants) [Number]
Yes	46 75.4%
No	15 24.6%
Response to Last Prior HCV Treatment Regimen (participants) [Number]
Non-Responder: Null	11 18%
Non-Responder: Partial	11 18%
Responder: Breakthrough	3 4.9%
Responder: Relapser	9 14.8%
Unknown	12 19.7%
Had Not Received Prior Treatment	15 24.6%
Days on Transplant Waitlist (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	266 (488.8)
Baseline HCV RNA (log10 IU/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [log10 IU/mL]	6.14 (0.633)
Baseline HCV RNA Category (participants) [Number]
< 6 log10 IU/mL	20 32.8%
≥ 6 and < 7 log10 IU/mL	38 62.3%
≥ 7 log10 IU/mL	3 4.9%
HCV Genotype (participants) [Number]
Genotype 1a	24 39.3%
Genotype 1b	21 34.4%
Genotype 2a	1 1.6%
Genotype 2b	7 11.5%
Genotype 3a	7 11.5%
Genotype 4a	1 1.6%
IL28b Status (participants) [Number]
CC	13 21.3%
CT	39 63.9%
TT	8 13.1%
Missing	1 1.6%
Baseline Child-Pugh Turcotte (CPT) Score (participants) [Number]
5	26 42.6%
6	18 29.5%
7	14 23%
8	3 4.9%
Baseline Model For End-Stage Liver Disease (MELD) Score (participants) [Number]
6	5 8.2%
7	18 29.5%
8	12 19.7%
9	9 14.8%
10	6 9.8%
11	8 13.1%
13	2 3.3%
14	1 1.6%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Posttransplant Virologic Response (pTVR) at Posttransplant Week 12
Description	pTVR was defined as HCV RNA < the lower limit of quantification (LLOQ, ie, 25 mL/IU) at Week 12 after transplant.
Time Frame	Posttransplant Week 12

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set (enrolled and received at least 1 dose of study drug) who underwent liver transplantation, and who had HCV RNA < LLOQ at last measurement prior to transplant were analyzed.

Arm/Group Title	SOF+RBV
Arm/Group Description	SOF 400 mg tablet once daily + RBV tablets (1000-1200 mg daily based on weight) for up to 48 weeks or until time of transplant, whichever occured first.
Measure Participants	43
Transplant after ≥ 12 weeks of treatment (N=32)	75.0 123%
Transplant after any duration of treatment (N=43)	69.8 114.4%

2. Primary Outcome

Title	Percentage of Participants Experiencing Any Adverse Event Leading to Permanent Discontinuation of Sofosbuvir Prior to Receiving Transplant
Time Frame	Up to 48 weeks prior to transplant

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	SOF+RBV
Arm/Group Description	SOF 400 mg tablet once daily + RBV tablets (1000-1200 mg daily based on weight) for up to 48 weeks or until time of transplant, whichever occured first.
Measure Participants	61
Number [percentage of participants]	3.3 5.4%

3. Primary Outcome

Title	Percentage of Participants With Graft Loss Following Transplant
Time Frame	Up to 48 weeks following transplant

Outcome Measure Data

Analysis Population Description

Participants in the Safety Analysis Set who underwent liver transplantation were analyzed.

Arm/Group Title	SOF+RBV
Arm/Group Description	SOF 400 mg tablet once daily + RBV tablets (1000-1200 mg daily based on weight) for up to 48 weeks or until time of transplant, whichever occured first.
Measure Participants	46
Number [percentage of participants]	6.5 10.7%

4. Secondary Outcome

Title	Percentage of Participants With Posttransplant Virologic Response (pTVR) Through Posttransplant Week 48
Description	pTVR was defined as HCV RNA < the lower limit of quantification (LLOQ, ie, 25 mL/IU) at the relevant time point after transplant.
Time Frame	Up to 48 weeks following transplant

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set who underwent liver transplantation and who had ≥ 12 weeks treatment and HCV RNA < LLOQ at last measurement prior to transplant were analyzed.

Arm/Group Title	SOF+RBV
Arm/Group Description	SOF 400 mg tablet once daily + RBV tablets (1000-1200 mg daily based on weight) for up to 48 weeks or until time of transplant, whichever occured first.
Measure Participants	32
Posttransplant Week 1 (N = 32)	87.5 143.4%
Posttransplant Week 2 (N = 32)	81.3 133.3%
Posttransplant Week 4 (N = 32)	75.0 123%
Posttransplant Week 8 (N = 32)	75.0 123%
Posttransplant Week 24 (N = 32)	75.0 123%
Posttransplant Week 48 (N = 30)	66.7 109.3%

5. Secondary Outcome

Title	Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48
Time Frame	Up to 48 weeks prior to transplant

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with available data were analyzed.

Arm/Group Title	SOF+RBV
Arm/Group Description	SOF 400 mg tablet once daily + RBV tablets (1000-1200 mg daily based on weight) for up to 48 weeks or until time of transplant, whichever occured first.
Measure Participants	61
Week 1 (N = 61)	13.1 21.5%
Week 2 (N = 61)	57.4 94.1%
Week 3 (N = 60)	81.7 133.9%
Week 4 (N = 58)	93.1 152.6%
Week 8 (N = 54)	90.7 148.7%
Week 12 (N = 48)	93.8 153.8%
Week 24 (N = 30)	100.0 163.9%
Week 36 (N = 9)	100.0 163.9%
Week 48 (N = 8)	100.0 163.9%

6. Secondary Outcome

Title	HCV RNA and Change From Baseline in HCV RNA Through Week 8
Time Frame	Up to 8 weeks prior to transplant

Outcome Measure Data

Analysis Population Description

Participants in the Full Analysis Set with available data were analyzed.

Arm/Group Title	SOF+RBV
Arm/Group Description	SOF 400 mg tablet once daily + RBV tablets (1000-1200 mg daily based on weight) for up to 48 weeks or until time of transplant, whichever occured first.
Measure Participants	61
Week 1 (N = 59)	-3.87 (0.700)
Week 2 (N = 61)	-4.43 (0.771)
Week 3 (N = 60)	-4.64 (0.670)
Week 4 (N = 58)	-4.69 (0.686)
Week 8 (N = 53)	-4.66 (0.708)

7. Secondary Outcome

Title	Proportion of Participants With Virologic Failure Prior to Transplant
Description	Virologic failure (VF) in the pretransplant phase was defined by: Breakthrough (HCV RNA ≥ 25 IU/ml after having previously had HCV RNA < 25 IU/ml, while on treatment) Rebound (breakthrough or > 1 log10 IU/ml increase in HCV RNA from nadir while on treatment) Non-response (HCV RNA ≥ 25 IU/ml through 8 weeks of treatment) Pre-transplant relapse (HCV RNA ≥ 25 IU/ml during the Pre-Transplant off-treatment follow-up period after having achieved HCV RNA < 25 IU/ml at last observed HCV RNA on treatment)
Time Frame	Up to 48 weeks prior to transplant

Outcome Measure Data

Analysis Population Description

On-treatment VF: Full Analysis Set. Posttreatment/Pretransplant VF - 24 Weeks or 48 Weeks: Participants who completed 24 or 48 weeks of treatment and had an observed or imputed Week 4 posttreatment follow-up HCV RNA value relapsed during posttreatment follow-up were analyzed.

Arm/Group Title	SOF+RBV
Arm/Group Description	SOF 400 mg tablet once daily + RBV tablets (1000-1200 mg daily based on weight) for up to 48 weeks or until time of transplant, whichever occured first.
Measure Participants	61
On-treatment VF (N = 61)	8.2 13.4%
Posttreatment/Pretransplant VF - 24 Weeks (N = 15)	73.3 120.2%
Posttreatment/Pretransplant VF - 48 Weeks (N = 8)	37.5 61.5%

8. Primary Outcome

Title	Number of Participants Who Died
Description	Treatment-emergent deaths were those that occurred while taking study drug or to the minimum of 1) date of transplantation, 2) retreatment 1st dose date, or 3) last dose date + 30 days. Only those participants who underwent liver transplantation were analyzed for death post-transplantation.
Time Frame	Up to 48 weeks following transplant

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	SOF+RBV
Arm/Group Description	SOF 400 mg tablet once daily + RBV tablets (1000-1200 mg daily based on weight) for up to 48 weeks or until time of transplant, whichever occured first.
Measure Participants	61
All Deaths	5 8.2%
Treatment-Emergent Death (N = 61)	1 1.6%
Death Following Transplant (N = 46)	3 4.9%
Death Not Meeting Either Criteria (N = 61)	1 1.6%

Adverse Events

Time Frame	Up to 48 weeks plus 30 days
Adverse Event Reporting Description	Safety Analysis Set
Arm/Group Title	SOF+RBV
Arm/Group Description	SOF 400 mg tablet once daily + RBV tablets (1000-1200 mg daily based on weight) for up to 48 weeks or until time of transplant, whichever occured first.
All Cause Mortality
	SOF+RBV
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	SOF+RBV
	Affected / at Risk (%)	# Events
Total	11/61 (18%)
Cardiac disorders
Atrial fibrillation	1/61 (1.6%)
Gastrointestinal disorders
Abdominal pain	1/61 (1.6%)
Abdominal strangulated hernia	1/61 (1.6%)
Mesenteric artery thrombosis	1/61 (1.6%)
Nausea	1/61 (1.6%)
Umbilical hernia, obstructive	2/61 (3.3%)
Vomiting	1/61 (1.6%)
General disorders
Pyrexia	2/61 (3.3%)
Infections and infestations
Cellulitis	1/61 (1.6%)
Infectious pleural effusion	1/61 (1.6%)
Peritonitis bacterial	1/61 (1.6%)
Sepsis	1/61 (1.6%)
Metabolism and nutrition disorders
Hyponatraemia	1/61 (1.6%)
Musculoskeletal and connective tissue disorders
Intervertebral disc degeneration	1/61 (1.6%)
Osteoarthritis	1/61 (1.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma	2/61 (3.3%)
Prostate cancer	1/61 (1.6%)
Tumour thrombosis	1/61 (1.6%)
Nervous system disorders
Hepatic encephalopathy	1/61 (1.6%)
Psychiatric disorders
Confusional state	1/61 (1.6%)
Renal and urinary disorders
Renal failure acute	1/61 (1.6%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	1/61 (1.6%)
Other (Not Including Serious) Adverse Events
	SOF+RBV
	Affected / at Risk (%)	# Events
Total	49/61 (80.3%)
Blood and lymphatic system disorders
Anaemia	13/61 (21.3%)
Gastrointestinal disorders
Constipation	6/61 (9.8%)
Diarrhoea	4/61 (6.6%)
Nausea	10/61 (16.4%)
General disorders
Fatigue	23/61 (37.7%)
Oedema peripheral	4/61 (6.6%)
Infections and infestations
Urinary tract infection	4/61 (6.6%)
Metabolism and nutrition disorders
Decreased appetite	4/61 (6.6%)
Nervous system disorders
Dizziness	4/61 (6.6%)
Headache	14/61 (23%)
Psychiatric disorders
Insomnia	7/61 (11.5%)
Respiratory, thoracic and mediastinal disorders
Cough	7/61 (11.5%)
Dyspnoea	7/61 (11.5%)
Skin and subcutaneous tissue disorders
Alopecia	4/61 (6.6%)
Pruritus	6/61 (9.8%)
Rash	9/61 (14.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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