Hepatitis C, Hepatocellular Carcinoma
Conditions
Keywords
Hepatitis, Chronic, hepatocellular carcinoma, HCC, transplant
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.
Interventions
DRUGSofosbuvir
Sofosbuvir 400 mg (2 x 200 mg tablets) administered orally once daily
DRUGRibavirin
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)
Sponsors
Gilead Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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) 5. HCV RNA \> 10\^4 IU/mL at screening 6. 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. 7. Child-Pugh Score (CPT) ≤ 7 8. Planned management of the subject to meet United Network for Organ Sharing (UNOS) criteria, with imaging studies made available for review if required. 9. 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 5. Current, uncontrolled ascites, variceal hemorrhage, hepatic encephalopathy, hepatorenal syndrome and hepatopulmonary syndrome, among other signs of decompensated cirrhosis. 6. Chronic liver disease of a non-HCV etiology (eg, hemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, cholangitis) 7. Infection with hepatitis B virus (HBV) or HIV 8. Contraindications to RBV therapy 9. Chronic use of systemically administered immunosuppressive agents (eg, prednisone equivalent \> 10 mg/day) in the pretransplant treatment period. 10. History of previous solid organ transplantation 11. Evidence of renal impairment (CLcr \< 60 mL/min) calculated by the Cockcroft-Gault equation. 12. 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) 13. Known hypersensitivity to RBV, the study investigational medicinal product, the metabolites, or formulation excipients 14. 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). 15. Treatment with Transcatheter arterial chemoembolization (TACE) or radio frequency ablation (RFA) within 30 days prior to the first dose. 16. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| Percentage of Participants Experiencing Any Adverse Event Leading to Permanent Discontinuation of Sofosbuvir Prior to Receiving Transplant | Up to 48 weeks prior to transplant | — |
| Percentage of Participants With Graft Loss Following Transplant | Up to 48 weeks following transplant | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48 | Up to 48 weeks prior to transplant | — |
| HCV RNA and Change From Baseline in HCV RNA Through Week 8 | Up to 8 weeks prior to transplant | — |
| 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) |
Countries
New Zealand, Spain, United States
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 details
92 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| SOF+RBV 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. | 61 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Consent Withdrawn | 7 |
| Overall Study | Death | 5 |
| Overall Study | Efficacy Failure | 10 |
| Overall Study | No Longer A Transplant Candidate | 3 |
Baseline characteristics
| Characteristic | SOF+RBV |
|---|---|
| Age, Continuous | 59 years STANDARD_DEVIATION 5.5 |
| Baseline Child-Pugh Turcotte (CPT) Score 5 | 26 participants |
| Baseline Child-Pugh Turcotte (CPT) Score 6 | 18 participants |
| Baseline Child-Pugh Turcotte (CPT) Score 7 | 14 participants |
| Baseline Child-Pugh Turcotte (CPT) Score 8 | 3 participants |
| Baseline HCV RNA | 6.14 log10 IU/mL STANDARD_DEVIATION 0.633 |
| Baseline HCV RNA Category ≥ 6 and < 7 log10 IU/mL | 38 participants |
| Baseline HCV RNA Category < 6 log10 IU/mL | 20 participants |
| Baseline HCV RNA Category ≥ 7 log10 IU/mL | 3 participants |
| Baseline Model For End-Stage Liver Disease (MELD) Score 10 | 6 participants |
| Baseline Model For End-Stage Liver Disease (MELD) Score 11 | 8 participants |
| Baseline Model For End-Stage Liver Disease (MELD) Score 13 | 2 participants |
| Baseline Model For End-Stage Liver Disease (MELD) Score 14 | 1 participants |
| Baseline Model For End-Stage Liver Disease (MELD) Score 6 | 5 participants |
| Baseline Model For End-Stage Liver Disease (MELD) Score 7 | 18 participants |
| Baseline Model For End-Stage Liver Disease (MELD) Score 8 | 12 participants |
| Baseline Model For End-Stage Liver Disease (MELD) Score 9 | 9 participants |
| Days on Transplant Waitlist | 266 days STANDARD_DEVIATION 488.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| HCV Genotype Genotype 1a | 24 participants |
| HCV Genotype Genotype 1b | 21 participants |
| HCV Genotype Genotype 2a | 1 participants |
| HCV Genotype Genotype 2b | 7 participants |
| HCV Genotype Genotype 3a | 7 participants |
| HCV Genotype Genotype 4a | 1 participants |
| IL28b Status CC | 13 participants |
| IL28b Status CT | 39 participants |
| IL28b Status Missing | 1 participants |
| IL28b Status TT | 8 participants |
| Prior Hepatitis C Virus (HCV) Treatment No | 15 participants |
| Prior Hepatitis C Virus (HCV) Treatment Yes | 46 participants |
| Race/Ethnicity, Customized Black or African American | 6 participants |
| Race/Ethnicity, Customized White | 55 participants |
| Region of Enrollment New Zealand | 1 participants |
| Region of Enrollment Spain | 5 participants |
| Region of Enrollment United States | 55 participants |
| Response to Last Prior HCV Treatment Regimen Had Not Received Prior Treatment | 15 participants |
| Response to Last Prior HCV Treatment Regimen Non-Responder: Null | 11 participants |
| Response to Last Prior HCV Treatment Regimen Non-Responder: Partial | 11 participants |
| Response to Last Prior HCV Treatment Regimen Responder: Breakthrough | 3 participants |
| Response to Last Prior HCV Treatment Regimen Responder: Relapser | 9 participants |
| Response to Last Prior HCV Treatment Regimen Unknown | 12 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 49 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 49 / 61 |
| serious Total, serious adverse events | 11 / 61 |
Outcome results
Primary
Number of Participants Who Died
* 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
Population: Safety Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SOF+RBV | Number of Participants Who Died | All Deaths | 5 participants |
| SOF+RBV | Number of Participants Who Died | Treatment-Emergent Death (N = 61) | 1 participants |
| SOF+RBV | Number of Participants Who Died | Death Following Transplant (N = 46) | 3 participants |
| SOF+RBV | Number of Participants Who Died | Death Not Meeting Either Criteria (N = 61) | 1 participants |
Primary
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
Population: Safety Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV | Percentage of Participants Experiencing Any Adverse Event Leading to Permanent Discontinuation of Sofosbuvir Prior to Receiving Transplant | 3.3 percentage of participants |
Primary
Percentage of Participants With Graft Loss Following Transplant
Time frame: Up to 48 weeks following transplant
Population: Participants in the Safety Analysis Set who underwent liver transplantation were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV | Percentage of Participants With Graft Loss Following Transplant | 6.5 percentage of participants |
Primary
Percentage of Participants With Posttransplant Virologic Response (pTVR) at Posttransplant Week 12
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SOF+RBV | Percentage of Participants With Posttransplant Virologic Response (pTVR) at Posttransplant Week 12 | Transplant after ≥ 12 weeks of treatment (N=32) | 75.0 percentage of participants |
| SOF+RBV | Percentage of Participants With Posttransplant Virologic Response (pTVR) at Posttransplant Week 12 | Transplant after any duration of treatment (N=43) | 69.8 percentage of participants |
Secondary
HCV RNA and Change From Baseline in HCV RNA Through Week 8
Time frame: Up to 8 weeks prior to transplant
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SOF+RBV | HCV RNA and Change From Baseline in HCV RNA Through Week 8 | Week 1 (N = 59) | -3.87 log10 IU/mL | Standard Deviation 0.7 |
| SOF+RBV | HCV RNA and Change From Baseline in HCV RNA Through Week 8 | Week 2 (N = 61) | -4.43 log10 IU/mL | Standard Deviation 0.771 |
| SOF+RBV | HCV RNA and Change From Baseline in HCV RNA Through Week 8 | Week 3 (N = 60) | -4.64 log10 IU/mL | Standard Deviation 0.67 |
| SOF+RBV | HCV RNA and Change From Baseline in HCV RNA Through Week 8 | Week 4 (N = 58) | -4.69 log10 IU/mL | Standard Deviation 0.686 |
| SOF+RBV | HCV RNA and Change From Baseline in HCV RNA Through Week 8 | Week 8 (N = 53) | -4.66 log10 IU/mL | Standard Deviation 0.708 |
Secondary
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
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SOF+RBV | Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48 | Week 1 (N = 61) | 13.1 percentage of participants |
| SOF+RBV | Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48 | Week 2 (N = 61) | 57.4 percentage of participants |
| SOF+RBV | Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48 | Week 3 (N = 60) | 81.7 percentage of participants |
| SOF+RBV | Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48 | Week 4 (N = 58) | 93.1 percentage of participants |
| SOF+RBV | Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48 | Week 8 (N = 54) | 90.7 percentage of participants |
| SOF+RBV | Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48 | Week 12 (N = 48) | 93.8 percentage of participants |
| SOF+RBV | Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48 | Week 24 (N = 30) | 100.0 percentage of participants |
| SOF+RBV | Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48 | Week 36 (N = 9) | 100.0 percentage of participants |
| SOF+RBV | Percentage of Participants With HCV RNA < LLOQ (ie, 25 mL/IU) During Treatment Through Week 48 | Week 48 (N = 8) | 100.0 percentage of participants |
Secondary
Percentage of Participants With Posttransplant Virologic Response (pTVR) Through Posttransplant Week 48
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
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SOF+RBV | Percentage of Participants With Posttransplant Virologic Response (pTVR) Through Posttransplant Week 48 | Posttransplant Week 8 (N = 32) | 75.0 percentage of participants |
| SOF+RBV | Percentage of Participants With Posttransplant Virologic Response (pTVR) Through Posttransplant Week 48 | Posttransplant Week 1 (N = 32) | 87.5 percentage of participants |
| SOF+RBV | Percentage of Participants With Posttransplant Virologic Response (pTVR) Through Posttransplant Week 48 | Posttransplant Week 2 (N = 32) | 81.3 percentage of participants |
| SOF+RBV | Percentage of Participants With Posttransplant Virologic Response (pTVR) Through Posttransplant Week 48 | Posttransplant Week 4 (N = 32) | 75.0 percentage of participants |
| SOF+RBV | Percentage of Participants With Posttransplant Virologic Response (pTVR) Through Posttransplant Week 48 | Posttransplant Week 24 (N = 32) | 75.0 percentage of participants |
| SOF+RBV | Percentage of Participants With Posttransplant Virologic Response (pTVR) Through Posttransplant Week 48 | Posttransplant Week 48 (N = 30) | 66.7 percentage of participants |
Secondary
Proportion of Participants With Virologic Failure 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)
Time frame: Up to 48 weeks prior to transplant
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SOF+RBV | Proportion of Participants With Virologic Failure Prior to Transplant | On-treatment VF (N = 61) | 8.2 percentage of participants |
| SOF+RBV | Proportion of Participants With Virologic Failure Prior to Transplant | Posttreatment/Pretransplant VF - 24 Weeks (N = 15) | 73.3 percentage of participants |
| SOF+RBV | Proportion of Participants With Virologic Failure Prior to Transplant | Posttreatment/Pretransplant VF - 48 Weeks (N = 8) | 37.5 percentage of participants |