Sofosbuvir-Containing Regimens Without Interferon For Treatment of Acute Hepatitis C Virus (HCV) Infection
- Conditions
- HIV-1 InfectionHepatitis
- Interventions
- Registration Number
- NCT02128217
- Lead Sponsor
- Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
- Brief Summary
Early identification of acute HCV infection is essential to prevent chronic infections and the long-term liver disease complications that may occur. Early identification and treatment of HCV during the acute phase can result in significantly higher response rates with shorter durations of therapy.
Pegylated-interferon alfa (PEG-IFN) was the typical treatment for HCV infection. Participants subcutaneously inject PEG-IFN where the average duration of treatment was approximately 20 weeks. With the advancement of direct-acting antivirals (DAAs), it was possible to see if a new DAA might be non-inferior compared to (PEG-IFN).
The study was designed to see if a fixed-dose combination tablet can replace the old HCV treatments by being more effective, safer and better tolerated in HIV-infected participants with new HCV infection. The study was a Phase I, open-label, two cohort clinical trial, in which 44 acutely HCV-infected HIV-1 positive participants were enrolled. Participants in each cohort were evaluated in two steps: on treatment (Step 1) and follow-up after discontinuing study treatment (Step 2). The cohorts were enrolled sequentially. Participants in Cohort 1 were enrolled and administered oral Sofosbuvir (SOF) in combination with weight-based ribavirin (RBV). Participants in Cohort 2 were enrolled and administered an oral fixed dose combination of Ledipasvir/Sofosbuvir (LDV/SOF).
- Detailed Description
The first cohort opened with SOF/RBV treatment for 12 weeks and accrued 17 participants. All participants under Cohort 1 were to visit the clinical site at weeks 0, 1, 2, 4, 8, and 12 when on treatment (Step 1), then visit the clinical site again at 2, 4, 8, 12 and 24 weeks during follow-up after discontinuing study treatment (Step 2).
The second cohort opened for an 8-week treatment of LDV/SOF and included at least 27 subjects. All participants under Cohort 2 were to visit the clinical site at weeks 0, 1, 2, 4, and 8 when on treatment (Step 1), then visit the clinical site again at 2, 4, 8, 12 and 24 weeks during follow-up after discontinuing study treatment (Step 2).
Both cohorts were monitored for safety and HCV viral load response while the participants were on treatment.
The primary objective did not compare the cohorts together; instead, each study cohort was formally assessed for efficacy with sustained virologic response 12 weeks after treatment based on non-inferiority criteria compared to a historical SVR rate of 60% separately.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 44
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Cohort 2: LDV/SOF for 8 wks Ledipasvir/Sofosbuvir Participants in Cohort 2 were assigned Ledipasvir/Sofosbuvir for 8 weeks. Follow-up visits occurred through to 24 weeks after the end of treatment. Cohort 1: SOF+weight-based RBV for 12 wks Sofosbuvir Participants in Cohort 1 were assigned Sofosbuvir (SOF)+weight-based ribavirin (RBV) for 12 weeks. Follow-up visits occurred through to 24 weeks after the end of treatment. Cohort 1: SOF+weight-based RBV for 12 wks Ribavirin Participants in Cohort 1 were assigned Sofosbuvir (SOF)+weight-based ribavirin (RBV) for 12 weeks. Follow-up visits occurred through to 24 weeks after the end of treatment.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Sustained Virologic Response 12 (SVR12) At 12 weeks after date of last dose of study treatment. The duration of study treatment for Cohort 1 and Cohort 2 were 12 and 8 weeks, respectively. SVR12 was defined as HCV RNA undetectable less than the lower limit of quantification, Target Not Detected (\<LLOQ TND) of the assay at 12 weeks after date of last dose of study treatment.
For both Cohort 1 and Cohort 2, the 12 week measurement used for determining SVR12 was the measurement obtained closest to 84 days (i.e. 12\*7 days), within the window 79 to 112 days inclusive. If a participant did not have an HCV RNA measurement within this window, then the participant was considered as having detectable HCV RNA at 12 weeks unless the preceding and subsequent HCV RNA measurements were both undetectable (\<LLOQ TND).
A two-sided 90% confidence interval was calculated for this percentage using the Blyth-Still-Casella method.Percentage of Participants With an Occurrence of a Grade ≥ 2 Adverse Event, Serious AE According to ICH Criteria, or Treatment-limiting AE. From initiation of study treatment to 28 days after last dose of study treatment. The duration for study treatment for Cohort 1 and Cohort 2 were 12 and 8 weeks, respectively. Any adverse event occurring after initiation of study treatment through to 28 days after the date of last dose of study treatment was included (except that an event that was ongoing at the same grade from before start of study treatment was excluded). Adverse events consisted of Grade ≥ 2 primary diagnosis, primary sign/symptoms, and primary laboratory abnormality. It also included any serious adverse event according to ICH criteria and any treatment-limiting AE (ie, an AE reported as the reason for permanent discontinuation of study treatment).
A two-sided 90% confidence interval was calculated for the percentage using the Blyth-Still-Casella method.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With HCV RNA Undetectable During Study Treatment 1, 2, 4, 8 and, for the 12-week regimen, 12 weeks after starting study treatment. HCV RNA undetectable was defined as an HCV RNA measurement \<LLOQ, TND. If there was no measurement at a scheduled time, then the participant was considered as having detectable HCV RNA at that time, unless both the preceding and succeeding measurements were undetectable.
A two-sided 90% confidence interval was calculated for each proportion using the Blyth-Still-Casella method.Percentage of Participants With HCV RNA Undetectable After End of Study Treatment 2, 4, 8 and 24 weeks after last dose of study treatment. The duration of study treatment for Cohort 1 and Cohort 2 were 12 and 8 weeks, respectively. HCV RNA undetectable is defined as an HCV RNA measurement \<LLOQ, TND. If there was no measurement at a scheduled time, then the participant was considered as having detectable HCV RNA at that time, unless both the preceding and succeeding measurements were undetectable. This outcome measure was referred to as SVR2, SVR4, SVR8 and SVR24 where SVR means sustained virologic response.
A two-sided 90% confidence interval was calculated for the percentage using the Blyth-Still-Casella method.Percentage of HCV Virologic Failure Participants That Developed SOF- or LDV-Associated Resistance Mutations At time of HCV virologic failure; any time from start of study treatment to 24 weeks after end of study treatment. Duration of study treatment for Cohort 1 and 2 were 12 and 8 weeks, respectively. Percentage of participants who developed SOF- or LDV-associated resistance mutation found within HCV Virologic Failure participants. HCV virologic failure was defined as HCV RNA undetectable at end-of-treatment but HCV RNA quantifiable during follow-up with subsequent confirmation as quantifiable.
Count of Participants With HIV-1 RNA <50 Copies/mL 4 and 12 weeks after start of study treatment for Cohort 1. 4 and 8 weeks after start of study treatment for the 8-week regimen used in Cohort 2) Because all except one participant had HIV-1 RNA \< 50 copies/mL, participants were categorized according to whether or not their HIV-1 RNA was \<5 copies/mL at each follow-up evaluation.
Adherence as Measured by RBV Pill Count 12 weeks after starting study treatment. The count and percentage of participants who had a pill count consistent with 100% of RBV doses taken. This outcome measure was evaluated in Cohort 1 only.
Self-reported Adherence to LDV/SOF 1, 2, 4, and 8 weeks after starting study treatment. Count and percentage of participants who reported having taken all doses of LDV/SOF. This outcome measure was evaluated in Cohort 2 only.
Count and Percentage of Participants With an Adverse Event by Type. Any time from start of treatment to 28 days after date of last dose of study treatment. The duration of study treatment for Cohort 1 and Cohort 2 were 12 and 8 weeks, respectively. The adverse events considered were Grade 2 or higher adverse events (primary diagnosis, primary sign and symptom, or a primary lab), SAE according to ICH criteria, or treatment-limiting adverse events. Participants may experience more than one type of adverse event.
Change in CD4+ Cell Count Baseline to 12 weeks after end of study treatment. Duration of study treatment for Cohort 1 and Cohort 2 were 12 and 8 weeks, respectively. The change in CD4+ cell count from baseline to 12 weeks after the end of study treatment.
Self-reported Adherence to SOF 1, 2, 4, 8 and 12 weeks after starting study treatment. Count and percentage of participants who reported having taken all doses of SOF. This outcome measure was evaluated in Cohort 1 only.
Adherence as Measured by SOF Pill Count 12 weeks after starting study treatment. The count and percentage of participants who had a pill count consistent with 100% of SOF doses taken. This outcome measure was evaluated in Cohort 1 only.
Self-reported Adherence to RBV 1, 2, 4, 8 and 12 weeks after starting study treatment. Count and percentage of participants who reported having taken all doses of RBV. This outcome measure was evaluated in Cohort 1 only.
Adherence as Measured by LDV/SOF Pill Count 8 weeks after starting study treatment. The count and percentage of participants who had a pill count consistent with 100% of LDV/SOF doses taken.. This outcome measure was evaluated in Cohort 2 only.
Ribavirin Concentration in Plasma 4, 8, and 12 weeks after starting study treatment. Ribavirin concentration in plasma. This outcome was evaluated in Cohort 1 only.
Number of Participants Who Had HCV Virologic Relapse From end of study treatment through to 24 weeks after end of study treatment. The duration of study treatment for Cohort 1 and Cohort 2 were 12 and 8 weeks, respectively. HCV virologic relapse was defined as HCV RNA undetectable at end-of-treatment but HCV RNA quantifiable during follow-up with subsequent confirmation as quantifiable.
Cellular Concentration of Tenofovir Diphosphate (TFV-DP) Baseline (before HCV study treatment), EOT (end of trial dosing), 12 weeks after end of HCV study treatment. The duration of HCV study treatment for Cohort 1 and Cohort 2 were 12 and 8 weeks, respectively. Cellular concentration of tenofovir diphosphate (TFV-DP) from dried blood spot samples.
Concentration of Tenofovir Diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cells (PBMCs) Baseline (before SOF + RBV dosing), EOT (end of study treatment), 12 weeks after end of HCV study treatment. Concentration of tenofovir diphosphate (TFV-DP) in peripheral blood mononuclear cells (PBMCs). This outcome is measured in Cohort 1 only.
Concentration of Tenofovir (TFV) in Plasma Baseline (before HCV study treatment), EOT (end of trial dosing), 12 weeks after end of HCV study treatment. The duration of HCV study treatment for Cohort 1 and Cohort 2 were 12 and 8 weeks, respectively. Concentration of tenofovir (TFV) in plasma among participants who took TFV for treatment of HIV infection.
Trial Locations
- Locations (12)
7804 Weill Cornell Chelsea CRS
🇺🇸New York, New York, United States
2701 Northwestern University CRS
🇺🇸Chicago, Illinois, United States
Rush Univ. Med. Ctr. ACTG CRS (2702)
🇺🇸Chicago, Illinois, United States
7803 Weill Cornell Upton CRS
🇺🇸New York, New York, United States
2401 Cincinnati CRS
🇺🇸Cincinnati, Ohio, United States
31443 Trinity Health and Wellness Center CRS
🇺🇸Dallas, Texas, United States
6201 Penn Therapeutics CRS
🇺🇸Philadelphia, Pennsylvania, United States
31473 Houston AIDS Research Team (HART) CRS
🇺🇸Houston, Texas, United States
Whitman Walker Health CRS (31791)
🇺🇸Washington, District of Columbia, United States
101 Massachusetts General Hospital (MGH) CRS
🇺🇸Boston, Massachusetts, United States
701 University of California, San Diego AntiViral Research Center CRS
🇺🇸San Diego, California, United States
801 University of California, San Francisco HIV/AIDS CRS
🇺🇸San Francisco, California, United States