Chronic Hepatitis C
Conditions
Keywords
Hepatitis C relapse
Brief summary
This study will evaluate the safety, tolerability, and efficacy of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in adults with chronic hepatitis C infection who have failed to eradicate hepatitis C despite previous combination directly acting antiviral therapy.
Detailed description
The treatment of chronic Hepatitis C with combination directly acting antiviral agents (DAAs) represents a dramatic improvement over previous therapies in safety, tolerability and efficacy, but these therapies are not universally effective. Some patients fail to achieve sustained virologic response (SVR) following therapy with combination DAAs, yet the ideal retreatment strategy for these patients has not yet been determined. As DAA medications become more widely available outside clinical trial settings, it is important to evaluate retreatment strategies in patients who fail combination DAA therapy, regardless of whether they had virologic failure, post-treatment relapse, or discontinued treatment prematurely. The RESOLVE study will evaluate the safety, tolerability, and efficacy of treatment with a fixed dose combination of sofosbuvir (an approved NS5B inhibitor), velpatasvir (formerly GS-5816, a second generation NS5A inhibitor) and voxilaprevir (formerly GS-9857, an approved NS3/4A protease inhibitor) in HCV infected patients with early and advanced liver disease, including those with HIV or hepatitis B, who have failed previous combination DAA therapy. Patients with early stage and compensated cirrhosis will receive 12 weeks of therapy, and be followed for adverse events and SVR following completion of therapy. RESOLVE will aid our understanding of the determinants of response to re-treatment with combination DAA therapy * With and without cirrhosis * In patients with HCV GT1 subtypes a and b * In patients who previously failed DAA therapy * With and without HIV or hepatitis B RESOLVE will also examine factors associated with treatment response, including * the viral and pharmacokinetics of patients receiving the combination of SOF/VEL/VOX, in patients with and without cirrhosis * differential interferon sensitive gene responses * host genetic and proteomic factors * evolution of HCV quasispecies and resistance associated variants at baseline and in response to therapy * changes in host HCV-specific immunity in patients with and without advanced liver disease
Interventions
Sponsors
Unity Health Care, Inc.
Gilead Sciences
University of Maryland, Baltimore
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
* Available for clinical follow-up through Week 44 after enrollment. * Recurrent HCV GT-1 * Exposure to combination DAA therapy * Able and willing to complete the informed consent process. * Use of protocol specified methods of contraception * Hepatitis B coinfected participants must have evidence of chronic infection and controlled on treatment * HIV coinfected participants must have HIV status of one of the following: 1. HIV untreated for \>8 weeks prior to screening, CD4 \>500, no intention of initiating ARV therapy for the duration of the trial. 2. HIV suppressed on a stable, protocol-approved ARV regimen for \>4 weeks prior to screening.
Exclusion criteria
* Combination DAA therapy was completed or discontinued less than 8 weeks prior to enrollment. * Current or prior history of any clinically significant illness, organ transplantation, and/or concomitant medication that may interfere with the subject treatment, assessment of compliance with the protocol. * Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson's disease, alfa-1 antitrypsin deficiency, cholangitis) * Laboratory results outside acceptable ranges at screening. * Female who is pregnant, breast-feeding or planning to become pregnant during study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade 3 and 4 Adverse Events | up to 16 weeks | Number of participants with grade 3 and 4 adverse events during treatment with and/or within 30 of completion of SOF/VEL/VOX in HCV infected |
| Number of Participants Who Achieve Sustained Virologic Response (SVR) 12 Weeks After Completion of Therapy (SVR12) | Post-treatment week 12 | Intention to treat (ITT) analysis. Sustained Virologic Response as measure by an undetectable HCV RNA level 12 weeks after completion of therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieve End of Treatment Virologic Response (ETR) at Completion of Therapy. | Week 12 | Per protocol analysis. End of Treatment Virologic Response as measure by an undetectable HCV RNA level completion of therapy. |
| Number of Participants Who Achieve Sustained Virologic Response (SVR) 4 Weeks After Completion of Therapy. | Post-treatment week 4 | Per protocol analysis. Sustained Virologic Response as measure by an undetectable HCV RNA level 4 weeks after completion of therapy. |
| Number of Participants Who Achieve Sustained Virologic Response (SVR) 24 Weeks After Completion of Therapy. | Post-treatment week 24 | Per protocol analysis. Sustained Virologic Response as measure by an undetectable HCV RNA level 24 weeks after completion of therapy. |
Countries
United States
Participant flow
Recruitment details
Study enrollment opened 5-May-2016 and closed 24-Jan-2018. All study visits were done in an outpatient medical clinic in Baltimore or Washington DC.
Pre-assignment details
Participants infected with chronic hepatitis C (HCV), genotype 1, who previously were treated with unsuccessful combination DAA-based therapy were enrolled in the study. Subjects included HCV mono-infection, HCV/HIV co-infection or HCV/hepatitis B (HBV) co-infection or HCV/HIV/HBV triple-infected patients.
Participants by arm
| Arm | Count |
|---|---|
| SOF/VEL/VOX Fixed dose combination of SOF/VEL/VOX (Sofosbuvir 400mg/Velpatasvir 100mg/ Voxilaprevir 100mg) dosed once daily for 12 weeks in participants with chronic hepatitis c previously exposed to direct acting antivirals (DAA). | 77 |
| Total | 77 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 2 |
Baseline characteristics
| Characteristic | SOF/VEL/VOX |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 13 Participants |
| Age, Categorical Between 18 and 65 years | 64 Participants |
| Age, Continuous | 60 years STANDARD_DEVIATION 8 |
| Co-infected with HIV | 22 Participants |
| Coinfected with HIV and hepatitis B | 2 Participants |
| Compensated cirrhotic | 31 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 76 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 66 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 77 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 77 |
| other Total, other adverse events | 75 / 77 |
| serious Total, serious adverse events | 12 / 77 |
Outcome results
Primary
Number of Participants Who Achieve Sustained Virologic Response (SVR) 12 Weeks After Completion of Therapy (SVR12)
Intention to treat (ITT) analysis. Sustained Virologic Response as measure by an undetectable HCV RNA level 12 weeks after completion of therapy.
Time frame: Post-treatment week 12
Population: All participants who took at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOF/VEL/VOX | Number of Participants Who Achieve Sustained Virologic Response (SVR) 12 Weeks After Completion of Therapy (SVR12) | 70 Participants |
Primary
Number of Participants With Grade 3 and 4 Adverse Events
Number of participants with grade 3 and 4 adverse events during treatment with and/or within 30 of completion of SOF/VEL/VOX in HCV infected
Time frame: up to 16 weeks
Population: All participants who received at least one dose of treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOF/VEL/VOX | Number of Participants With Grade 3 and 4 Adverse Events | 12 Participants |
Secondary
Number of Participants Who Achieve End of Treatment Virologic Response (ETR) at Completion of Therapy.
Per protocol analysis. End of Treatment Virologic Response as measure by an undetectable HCV RNA level completion of therapy.
Time frame: Week 12
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOF/VEL/VOX | Number of Participants Who Achieve End of Treatment Virologic Response (ETR) at Completion of Therapy. | 71 Participants |
Secondary
Number of Participants Who Achieve Sustained Virologic Response (SVR) 24 Weeks After Completion of Therapy.
Per protocol analysis. Sustained Virologic Response as measure by an undetectable HCV RNA level 24 weeks after completion of therapy.
Time frame: Post-treatment week 24
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOF/VEL/VOX | Number of Participants Who Achieve Sustained Virologic Response (SVR) 24 Weeks After Completion of Therapy. | 70 Participants |
Secondary
Number of Participants Who Achieve Sustained Virologic Response (SVR) 4 Weeks After Completion of Therapy.
Per protocol analysis. Sustained Virologic Response as measure by an undetectable HCV RNA level 4 weeks after completion of therapy.
Time frame: Post-treatment week 4
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| SOF/VEL/VOX | Number of Participants Who Achieve Sustained Virologic Response (SVR) 4 Weeks After Completion of Therapy. | 70 Participants |