Cirrhosis, Hepatitis C, Portal Hypertension, With or Without Liver Decompensation
Conditions
Brief summary
This study will evaluate the antiviral efficacy of combination therapy with sofosbuvir (SOF) plus ribavirin (RBV) for 48 weeks in adults with compensated and decompensated chronic hepatitis C virus (HCV) infection. Approximately 50 adults will be randomized (1:1) to receive study drug for 48 weeks or take part in an untreated observational arm for the first 24 weeks followed by study drug for another 48 weeks.
Interventions
DRUGSOF
SOF 400 mg tablet administered orally once daily
DRUGRBV
RBV tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (\< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Chronic infection with Hepatitis C with HCV RNA \> 1000 IU/mL * Individuals with cirrhosis with Child-Pugh score \< 10 * Esophageal or gastric varices on endoscopy within 6 months prior to or at screening * Hepatic Venous Pressure Gradient (HVPG) \> 6 mmHg * Body mass index (BMI) ≥ 18 kg/m\^2 * Naïve to all nucleotides/nucleoside treatments for chronic HCV infection
Exclusion criteria
* Have any serious or active medical or psychiatric illness which, in the opinion of the investigator, would interfere with subject treatment, assessment, or compliance * HIV or chronic hepatitis B virus (HBV) infection (HBsAg positive) * Alpha-fetoprotein (AFP) \> 50 unless negative imaging for hepatic masses within the last 6 months or during screening * Refractory ascites as defined by requiring paracentesis \> twice within 1 month prior to screening * Active variceal bleeding within 6 months of screening * Expected survival of \< 1 year * History of hepatorenal, or hepatopulmonary syndrome. * Evidence of renal impairment (CrCl \< 50 mL/min) * History of major organ transplantation, including liver transplant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | Posttreatment Week 12 (SOF+RBV) and up to 24 weeks (Observation) | SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ; ie, 25 IU/mL) at 12 weeks after stopping study treatment. For the Observation/SOF+RBV group, SVR12 during the observational period was defined as HCV RNA \< LLOQ for 12 consecutive weeks, any time during the observational period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing On-Treatment Virologic Failure | Up to 48 weeks | On-treatment virologic failure was defined as: * Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ while on treatment), or * Rebound (confirmed \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or * Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment) |
| Percentage of Participants Experiencing Viral Relapse | Up to Posttreatment Week 24 | Viral relapse was defined as HCV RNA ≥ LLOQ during the post-treatment period having achieved HCV RNA \< LLOQ at end of treatment, confirmed with 2 consecutive values or last available post-treatment measurement. |
| Percentage of Participants With SVR at 4, 24, and 48 Weeks After Discontinuation of Therapy (SVR4, SVR24, and SVR48) | Posttreatment Weeks 4, 24, and 48 | SVR4, SVR24, and SVR48 were defined as HCV RNA \< LLOQ at 4, 24, and 48 weeks after stopping study treatment, respectively. |
| Change From Baseline in Child-Pugh-Turcotte (CPT) Score | Baseline; Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV) | CPT scores, widely used to grade the severity of cirrhosis and to determine the need for liver transplantation, are calculated based on a combination of laboratory values and clinical features. CPT scores can range from 5 to 15, with higher scores indicating a greater severity of disease. Data are presented as improvement, no change, or worsening in CPT scores at Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV groups). Improvement in CPT score was defined as having a decrease in CPT score from baseline, no change in CPT score was defined as having no change in CPT score from baseline, and worsening in CPT score was defined as having an increase in CPT score from baseline. Baseline values were the last available values on or prior to first dose date of any study drug. |
| Change From Baseline in Model for End Stage Liver Disease (MELD) Scores | Baseline; Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV) | MELD scores, used to assess prognosis and suitability for transplant, are calculated based on laboratory values only and can range from 6 to 40, with higher scores indicating greater disease severity. Data are presented as improvement, no change, or worsening in MELD scores at Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV groups). Improvement in MELD score was defined as having a baseline MELD score of 11-15 or 16-20 that changed to 0-10, or a baseline MELD score of 16-20 that changed to 11-15; no change in MELD score was defined as having no change in score group (0-10, 11-15, or 16-20) from baseline; and worsening in MELD score was defined as having a baseline MELD score of 0-10 that changed to 11-15 or 16-20, or a baseline MELD score of 11-15 that changed to 16-20. Baseline values were the last available values on or prior to first dose date of any study drug. |
| Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) at End of Treatment | Baseline; Week 24 (Observation) and Week 48 (SOF+RBV) | HVPG closely reflects the degree of portal hypertension in patients with cirrhosis. The end of treatment for the Observation group was defined as the end of the observation period. The treatment period for Group 2 was defined as the end of the observation period to the end of the treatment. Baseline values were the last available values on or prior to first dose date of any study drug. |
Countries
Australia, France, New Zealand, Spain, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States, Europe, Australia, and New Zealand. The first participant was screened on 27 November 2012. The last study visit occurred on 06 October 2015.
Pre-assignment details
63 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| SOF+RBV (Group 1) SOF 400 mg tablet once daily + RBV tablets (1000 or 1200 mg daily based on weight) for up to 48 weeks | 25 |
| SOF+RBV (Group 2; Received Treatment) This reporting group includes participants who completed observation and received SOF 400 mg tablet once daily + RBV tablets (1000 or 1200 mg daily based on weight) for up to 48 weeks. | 21 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
| Overall Study | Efficacy Failure | 6 | 0 | 5 |
| Overall Study | Investigator's Discretion | 0 | 3 | 0 |
| Overall Study | Subject Withdrew Consent | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Total | SOF+RBV (Group 1) | SOF+RBV (Group 2; Received Treatment) |
|---|---|---|---|
| Age, Continuous | 55 years STANDARD_DEVIATION 7 | 55 years STANDARD_DEVIATION 7.2 | 56 years STANDARD_DEVIATION 7 |
| Child-Pugh-Turcotte (CPT) Score Category CPT A (5-6) | 18 participants | 8 participants | 10 participants |
| Child-Pugh-Turcotte (CPT) Score Category CPT B (7-10) | 28 participants | 17 participants | 11 participants |
| HCV Genotype Genotype 1a | 18 participants | 10 participants | 8 participants |
| HCV Genotype Genotype 1b | 14 participants | 9 participants | 5 participants |
| HCV Genotype Genotype 2a/2c | 1 participants | 1 participants | 0 participants |
| HCV Genotype Genotype 2b | 2 participants | 1 participants | 1 participants |
| HCV Genotype Genotype 3a | 8 participants | 2 participants | 6 participants |
| HCV Genotype Genotype 4 | 2 participants | 1 participants | 1 participants |
| HCV Genotype Genotype 4h | 1 participants | 1 participants | 0 participants |
| HCV RNA | 6.1 log10 IU/mL STANDARD_DEVIATION 0.64 | 6.1 log10 IU/mL STANDARD_DEVIATION 0.49 | 6.2 log10 IU/mL STANDARD_DEVIATION 0.79 |
| HCV RNA Category < 800,000 IU/mL | 15 participants | 10 participants | 5 participants |
| HCV RNA Category ≥ 800,000 IU/mL | 31 participants | 15 participants | 16 participants |
| Hepatic Venous Pressure Gradient (HVPG) | 17.0 mmHg STANDARD_DEVIATION 4.85 | 17.4 mmHg STANDARD_DEVIATION 4.7 | 16.4 mmHg STANDARD_DEVIATION 4.88 |
| IL28b Status CC | 9 participants | 3 participants | 6 participants |
| IL28b Status CT | 24 participants | 14 participants | 10 participants |
| IL28b Status TT | 13 participants | 8 participants | 5 participants |
| Model for End-Stage Liver Disease (MELD) Score 10 | 9 participants | 5 participants | 4 participants |
| Model for End-Stage Liver Disease (MELD) Score 11 | 4 participants | 0 participants | 4 participants |
| Model for End-Stage Liver Disease (MELD) Score 12 | 5 participants | 4 participants | 1 participants |
| Model for End-Stage Liver Disease (MELD) Score 13 | 3 participants | 2 participants | 1 participants |
| Model for End-Stage Liver Disease (MELD) Score 15 | 6 participants | 3 participants | 3 participants |
| Model for End-Stage Liver Disease (MELD) Score 16 | 2 participants | 2 participants | 0 participants |
| Model for End-Stage Liver Disease (MELD) Score 6 | 3 participants | 1 participants | 2 participants |
| Model for End-Stage Liver Disease (MELD) Score 7 | 3 participants | 0 participants | 3 participants |
| Model for End-Stage Liver Disease (MELD) Score 8 | 7 participants | 5 participants | 2 participants |
| Model for End-Stage Liver Disease (MELD) Score 9 | 4 participants | 3 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Other | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized White | 42 participants | 22 participants | 20 participants |
| Region of Enrollment Australia | 5 participants | 3 participants | 2 participants |
| Region of Enrollment France | 6 participants | 2 participants | 4 participants |
| Region of Enrollment New Zealand | 6 participants | 2 participants | 4 participants |
| Region of Enrollment Spain | 11 participants | 8 participants | 3 participants |
| Region of Enrollment United States | 22 participants | 10 participants | 12 participants |
| Sex: Female, Male Female | 12 Participants | 7 Participants | 5 Participants |
| Sex: Female, Male Male | 34 Participants | 18 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 25 | 10 / 25 | 20 / 21 |
| serious Total, serious adverse events | 4 / 25 | 3 / 25 | 6 / 21 |
Outcome results
Primary
Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12)
SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ; ie, 25 IU/mL) at 12 weeks after stopping study treatment. For the Observation/SOF+RBV group, SVR12 during the observational period was defined as HCV RNA \< LLOQ for 12 consecutive weeks, any time during the observational period.
Time frame: Posttreatment Week 12 (SOF+RBV) and up to 24 weeks (Observation)
Population: Participants who were randomized to the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV (Group 1) | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 72.0 percentage of participants |
| Observation Period (Group 2) | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 0 percentage of participants |
| SOF+RBV (Group 2) | Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) | 71.4 percentage of participants |
Secondary
Change From Baseline in Child-Pugh-Turcotte (CPT) Score
CPT scores, widely used to grade the severity of cirrhosis and to determine the need for liver transplantation, are calculated based on a combination of laboratory values and clinical features. CPT scores can range from 5 to 15, with higher scores indicating a greater severity of disease. Data are presented as improvement, no change, or worsening in CPT scores at Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV groups). Improvement in CPT score was defined as having a decrease in CPT score from baseline, no change in CPT score was defined as having no change in CPT score from baseline, and worsening in CPT score was defined as having an increase in CPT score from baseline. Baseline values were the last available values on or prior to first dose date of any study drug.
Time frame: Baseline; Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV)
Population: Participants who were randomized to the study with available data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SOF+RBV (Group 1) | Change From Baseline in Child-Pugh-Turcotte (CPT) Score | Improvement in CPT Score | 65.2 percentage of participants |
| SOF+RBV (Group 1) | Change From Baseline in Child-Pugh-Turcotte (CPT) Score | Worsening in CPT Score | 8.7 percentage of participants |
| SOF+RBV (Group 1) | Change From Baseline in Child-Pugh-Turcotte (CPT) Score | No Change in CPT Score | 26.1 percentage of participants |
| Observation Period (Group 2) | Change From Baseline in Child-Pugh-Turcotte (CPT) Score | Improvement in CPT Score | 10.0 percentage of participants |
| Observation Period (Group 2) | Change From Baseline in Child-Pugh-Turcotte (CPT) Score | Worsening in CPT Score | 15.0 percentage of participants |
| Observation Period (Group 2) | Change From Baseline in Child-Pugh-Turcotte (CPT) Score | No Change in CPT Score | 75.0 percentage of participants |
| SOF+RBV (Group 2) | Change From Baseline in Child-Pugh-Turcotte (CPT) Score | No Change in CPT Score | 50.0 percentage of participants |
| SOF+RBV (Group 2) | Change From Baseline in Child-Pugh-Turcotte (CPT) Score | Improvement in CPT Score | 38.9 percentage of participants |
| SOF+RBV (Group 2) | Change From Baseline in Child-Pugh-Turcotte (CPT) Score | Worsening in CPT Score | 11.1 percentage of participants |
| All SOF+RBV (Groups 1 and 2) | Change From Baseline in Child-Pugh-Turcotte (CPT) Score | Improvement in CPT Score | 53.7 percentage of participants |
| All SOF+RBV (Groups 1 and 2) | Change From Baseline in Child-Pugh-Turcotte (CPT) Score | Worsening in CPT Score | 9.8 percentage of participants |
| All SOF+RBV (Groups 1 and 2) | Change From Baseline in Child-Pugh-Turcotte (CPT) Score | No Change in CPT Score | 36.6 percentage of participants |
Secondary
Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) at End of Treatment
HVPG closely reflects the degree of portal hypertension in patients with cirrhosis. The end of treatment for the Observation group was defined as the end of the observation period. The treatment period for Group 2 was defined as the end of the observation period to the end of the treatment. Baseline values were the last available values on or prior to first dose date of any study drug.
Time frame: Baseline; Week 24 (Observation) and Week 48 (SOF+RBV)
Population: Participants who were randomized to the study with available data at baseline and end of observation or end of treatment were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SOF+RBV (Group 1) | Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) at End of Treatment | -1.6 mmHg | Standard Deviation 4.9 |
| Observation Period (Group 2) | Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) at End of Treatment | 0.5 mmHg | Standard Deviation 2.52 |
| SOF+RBV (Group 2) | Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) at End of Treatment | -0.4 mmHg | Standard Deviation 2.69 |
| All SOF+RBV (Groups 1 and 2) | Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) at End of Treatment | -1.0 mmHg | Standard Deviation 3.97 |
Secondary
Change From Baseline in Model for End Stage Liver Disease (MELD) Scores
MELD scores, used to assess prognosis and suitability for transplant, are calculated based on laboratory values only and can range from 6 to 40, with higher scores indicating greater disease severity. Data are presented as improvement, no change, or worsening in MELD scores at Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV groups). Improvement in MELD score was defined as having a baseline MELD score of 11-15 or 16-20 that changed to 0-10, or a baseline MELD score of 16-20 that changed to 11-15; no change in MELD score was defined as having no change in score group (0-10, 11-15, or 16-20) from baseline; and worsening in MELD score was defined as having a baseline MELD score of 0-10 that changed to 11-15 or 16-20, or a baseline MELD score of 11-15 that changed to 16-20. Baseline values were the last available values on or prior to first dose date of any study drug.
Time frame: Baseline; Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV)
Population: Participants who were randomized to the study with available data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SOF+RBV (Group 1) | Change From Baseline in Model for End Stage Liver Disease (MELD) Scores | Improvement in MELD Score | 33.3 percentage of participants |
| SOF+RBV (Group 1) | Change From Baseline in Model for End Stage Liver Disease (MELD) Scores | Worsening in MELD Score | 12.5 percentage of participants |
| SOF+RBV (Group 1) | Change From Baseline in Model for End Stage Liver Disease (MELD) Scores | No Change in MELD Score | 54.2 percentage of participants |
| Observation Period (Group 2) | Change From Baseline in Model for End Stage Liver Disease (MELD) Scores | Improvement in MELD Score | 20.0 percentage of participants |
| Observation Period (Group 2) | Change From Baseline in Model for End Stage Liver Disease (MELD) Scores | Worsening in MELD Score | 5.0 percentage of participants |
| Observation Period (Group 2) | Change From Baseline in Model for End Stage Liver Disease (MELD) Scores | No Change in MELD Score | 75.0 percentage of participants |
| SOF+RBV (Group 2) | Change From Baseline in Model for End Stage Liver Disease (MELD) Scores | No Change in MELD Score | 88.2 percentage of participants |
| SOF+RBV (Group 2) | Change From Baseline in Model for End Stage Liver Disease (MELD) Scores | Improvement in MELD Score | 5.9 percentage of participants |
| SOF+RBV (Group 2) | Change From Baseline in Model for End Stage Liver Disease (MELD) Scores | Worsening in MELD Score | 5.9 percentage of participants |
| All SOF+RBV (Groups 1 and 2) | Change From Baseline in Model for End Stage Liver Disease (MELD) Scores | Improvement in MELD Score | 22.0 percentage of participants |
| All SOF+RBV (Groups 1 and 2) | Change From Baseline in Model for End Stage Liver Disease (MELD) Scores | Worsening in MELD Score | 9.8 percentage of participants |
| All SOF+RBV (Groups 1 and 2) | Change From Baseline in Model for End Stage Liver Disease (MELD) Scores | No Change in MELD Score | 68.3 percentage of participants |
Secondary
Percentage of Participants Experiencing On-Treatment Virologic Failure
On-treatment virologic failure was defined as: * Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ while on treatment), or * Rebound (confirmed \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or * Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment)
Time frame: Up to 48 weeks
Population: Participants who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV (Group 1) | Percentage of Participants Experiencing On-Treatment Virologic Failure | 8.0 percentage of participants |
| Observation Period (Group 2) | Percentage of Participants Experiencing On-Treatment Virologic Failure | 0 percentage of participants |
Secondary
Percentage of Participants Experiencing Viral Relapse
Viral relapse was defined as HCV RNA ≥ LLOQ during the post-treatment period having achieved HCV RNA \< LLOQ at end of treatment, confirmed with 2 consecutive values or last available post-treatment measurement.
Time frame: Up to Posttreatment Week 24
Population: Participants who were randomized and received at least 1 dose of study drug with available data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV (Group 1) | Percentage of Participants Experiencing Viral Relapse | 17.4 percentage of participants |
| Observation Period (Group 2) | Percentage of Participants Experiencing Viral Relapse | 23.8 percentage of participants |
Secondary
Percentage of Participants With SVR at 4, 24, and 48 Weeks After Discontinuation of Therapy (SVR4, SVR24, and SVR48)
SVR4, SVR24, and SVR48 were defined as HCV RNA \< LLOQ at 4, 24, and 48 weeks after stopping study treatment, respectively.
Time frame: Posttreatment Weeks 4, 24, and 48
Population: Participants who were randomized and received at least 1 dose of study drug with available data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SOF+RBV (Group 1) | Percentage of Participants With SVR at 4, 24, and 48 Weeks After Discontinuation of Therapy (SVR4, SVR24, and SVR48) | SVR4 (Group 1: N = 25; Group 2: N = 21) | 72.0 percentage of participants |
| SOF+RBV (Group 1) | Percentage of Participants With SVR at 4, 24, and 48 Weeks After Discontinuation of Therapy (SVR4, SVR24, and SVR48) | SVR24 (Group 1: N = 25; Group 2: N = 21) | 68.0 percentage of participants |
| SOF+RBV (Group 1) | Percentage of Participants With SVR at 4, 24, and 48 Weeks After Discontinuation of Therapy (SVR4, SVR24, and SVR48) | SVR48 (Group 1: N = 17; Group 2: N = 13) | 94.1 percentage of participants |
| Observation Period (Group 2) | Percentage of Participants With SVR at 4, 24, and 48 Weeks After Discontinuation of Therapy (SVR4, SVR24, and SVR48) | SVR4 (Group 1: N = 25; Group 2: N = 21) | 76.2 percentage of participants |
| Observation Period (Group 2) | Percentage of Participants With SVR at 4, 24, and 48 Weeks After Discontinuation of Therapy (SVR4, SVR24, and SVR48) | SVR24 (Group 1: N = 25; Group 2: N = 21) | 71.4 percentage of participants |
| Observation Period (Group 2) | Percentage of Participants With SVR at 4, 24, and 48 Weeks After Discontinuation of Therapy (SVR4, SVR24, and SVR48) | SVR48 (Group 1: N = 17; Group 2: N = 13) | 100.0 percentage of participants |