Hepatitis C
Conditions
Brief summary
The aim of the study is to determine if treatment for recently acquired hepatitis C infection (with or without HIV coinfection) can be shortened when treating with the interferon-free therapy sofosbuvir/velpatasvir (SOF/VEL). SOF/VEL is a new treatment for hepatitis C called direct acting antiviral which targets the hepatitis C virus replication cycle and has been shown in phase II studies in chronic HCV to be highly effective (SVR12 \>95%) when given for 12 weeks. Data has shown that treatment can be shortened when treating recently acquired HCV with interferon containing treatments. It is not known whether treatment with SOF/VEL can be shortened. This study aims to find out if treatment for 6 weeks with open-label SOF/VEL is equivalent to treatment for 12 weeks with SOF/VEL in participants with recently acquired hepatitis C infection. The project is a randomised study where both participants and investigators would not find out the treatment duration of the participants until week 6 of treatment.
Detailed description
Globally, 3-4 million new HCV infections are estimated to occur annually. People who inject drugs (PWID) represent one of the groups at highest risk of transmitting and acquiring infection with the majority of new (60%) and existing (80%) infections in developed countries occur in this population with HCV antibody prevalence estimated at 67% (60-80%). HIV-positive men-who-have-sex-with-men (MSM) are another high risk group for HCV acquisition. Direct acting antivirals (DAA) has changed the treatment landscape for individuals with chronic HCV infection with interferon-free therapy offering high effectiveness and tolerability, even in difficult-to-treat populations. Given the burden of HCV-related disease among PWID and HIV-positive MSM, strategies to enhance HCV assessment, treatment and prevention in these groups are urgently needed. Much of what is known about the timing of treatment initiation, regimen choice and duration of therapy in acute HCV infection comes from small observational studies and randomized controlled (randomly assigned into one or other of the different treatment groups)trials in selected populations with limited data on treatment in PWID and HIV co-infection. With recent rapid advances in HCV treatments, management strategies for acute HCV will evolve rapidly over the next few years. The REACT study will compare the efficacy and safety of open-label SOF/VEL administered for 6 or 12 weeks in individuals with recent HCV infection. Participants will be randomised into receiving 6 weeks or 12 weeks treatment. Both investigators and participants will be blinded to the treatment duration until week 6 of treatment. The role and activity of DAA regimens in acute HCV infection requires evaluation, with the potential to be given as highly effective, short course interferon-sparing regimens, maximising acceptability to patients, encouraging uptake of treatment, limiting further transmission and preventing progression to chronic liver disease.
Interventions
DRUGSOF/VEL for 6 weeks
Open-label SOF/VEL 400mg/100mg once daily to be given to participants randomised to Arm A (6 weeks short treatment duration).
DRUGSOF/VEL for 12 weeks
Open-label SOF/VEL 400mg/100mg once daily to be given to participants randomised to Arm B (12 weeks standard treatment duration).
Sponsors
Kirby Institute
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must meet all of the following inclusion criteria to be eligible to participate in this study: 1. Participants have voluntarily signed the informed consent form. 2. 18 years of age or older. 3. Detectable HCV RNA at screening (\>10,000 IU/ml), and in the opinion of the investigator is unlikely to demonstrate spontaneous viral clearance 4. HCV genotypes 1-6. 5. HBsAg negative 6. Compensated liver disease (Child-Pugh A) 7. Negative pregnancy test at baseline (females of childbearing potential only). 8. Medically stable on the basis of physical examination, medical history and vital signs 9. Adequate English to provide reliable responses to the study questionnaires 10. All fertile males and females must be using effective contraception during treatment and during the 30 days after treatment end. 11. Recently acquired HCV infection (estimated duration of infection ≤12 months)\* Recently acquired HCV infection as defined by: A) i) First anti-HCV Ab or HCV RNA positive within the previous 3 months and ii) Documented anti-HCV Ab negative within the 12 months prior to anti-HCV antibody positive result OR B) i) First anti-HCV Ab or HCV RNA positive within the previous 3 months and ii) Acute clinical hepatitis \[jaundice or alanine aminotransferase (ALT)\] \> 10 X ULN) within the previous 6 months prior to first positive HCV antibody or HCV RNA, with no other cause of acute hepatitis identifiable OR C) For cases of recent HCV reinfection the following criteria are required: Documented prior HCV antibody positive with HCV RNA negative on at least 2 occasions 6 months apart AND new HCV RNA positive within the previous 6 months \*Estimated duration of infection based on midpoint between last antibody negative or HCV RNA and first antibody positive or HCV RNA in the case of seroconversion and 6 weeks prior to date of maximum ALT in the case of acute hepatitis. If co-infection with HIV is documented, the subject must meet the following criteria: 1. Antiretroviral (ARV) untreated for \>8 weeks preceding screening visit with cluster of differentiation 4 (CD4) T cell count \>500 cells/mm3 OR 2. On a stable ARV regimen for \>8 weeks prior to screening visit, with CD4 T cell count \>200 cells/mm3 and an undetectable plasma HIV RNA level. * Suitable ARV include: * Tenofovir (TDF) and tenofovir alafenamide (TAF) * Emtricitabine (FTC) * Rilpivirine * Dolutegravir * Elvitegravir/cobicistat * Contraindicated ARV include: * Efavirenz 50% reduction in velpatasvir (GS-5816) exposure * Didanosine * Zidovudine * Tipranavir Other ARV agents may be permissible at the time of study commencement pending further drug-drug interaction studies; please discuss with Study Principal Investigator.
Exclusion criteria
Subjects who meet any of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Undetectable HCV RNA at 12 Weeks Post End of Treatment (SVR12) Following SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Intention-to-treat (ITT) Population | 12 weeks post treatment | To evaluate the proportion of participants with HCV RNA below the level of quantification at 12 weeks post treatment following SOF/VEL for 6 weeks as compared with 12 weeks in people with recent HCV infection- among intention-to-treat (ITT) population The ITT population included all randomized participants, with loss to follow-up deemed treatment failure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Undetectable HCV RNA at 12 Weeks Post End of Treatment (SVR12) Following SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Modified Intention-to-treat (ITT) Population | 12 Weeks Post End of Treatment | To evaluate the proportion of participants with HCV RNA below the level of quantification at 12 weeks post treatment following SOF/VEL for 6 weeks as compared with 12 weeks in people with recent HCV infection- among modified intention-to-treat (ITT) population The modified ITT population included participants in the ITT population, but excluded those with non-virological reasons for treatment failure (including death and loss to follow-up) and reinfection. |
| Number of Participants With Undetectable HCV RNA at End of Treatment (ETR) of SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Intention-to-treat (ITT) Population | End of treatment - week 6 of the shortened treatment duration arm, and week 12 of the standard treatment duration arm | To evaluate the proportion of participants with HCV RNA below the level of quantification at end of treatment of SOF/VEL for 6 Weeks as compared With 12 Weeks in People With Recent HCV Infection The ITT population included all randomized participants, with loss to follow-up deemed treatment failure. |
| Number of Participants With Undetectable HCV RNA at 12 Weeks Post End of Treatment (SVR12) Following SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Per Protocol (PP) Population | 12 weeks post treatment | To evaluate the proportion of participants with HCV RNA below the level of quantification at 12 weeks post treatment following SOF/VEL for 6 weeks as compared with 12 weeks in people with recent HCV infection- among Per Protocol (PP) population The per protocol population included participants who received \>90% of scheduled treatment for \>90% of the scheduled treatment period with follow-up virologic data at SVR12 (excluding reinfection and retreatments) |
Countries
Australia, Canada, Germany, Netherlands, New Zealand, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Total 277 participants screened for protocol eligibility. Of 277 participants, 55 participants did not meet the protocol eligibility and excluded. Hence, a total 222 participants were enrolled into the study.
Pre-assignment details
Of 277 participants screened for eligibility,55 were excluded \[not meeting inclusion criteria (n=38),consent withdrawn/refusal (n=7),lost to follow-up (n=4), other (n=6)\] and 26 commenced treatment but not randomized were excluded \[between baseline (BSL) and wk 6 at Data Safety & Monitoring Board (DSMB) advice (n=9),in screening at DSMB advice (n=12),lost to follow-up before wk 6 (n=5)\]. 196 were randomized with 8 (4 in each arm) excluded following DSMB advice,hence a final population of 188.
Participants by arm
| Arm | Count |
|---|---|
| Drug: Sofosbuvir/Velpatasvir (SOF/VEL) for 6 Weeks Open-label sofosbuvir/velpatasvir (SOF/VEL) 400mg/100mg co-formulated tablet once daily will be given to participants who are randomised into the short treatment duration arm (A) for 6 weeks.
SOF/VEL for 6 weeks: Open-label SOF/VEL 400mg/100mg once daily to be given to participants randomised to Arm A (6 weeks short treatment duration). | 93 |
| Drug: Sofosbuvir/Velpatasvir (SOF/VEL) for 12 Weeks Open-label sofosbuvir/velpatasvir (SOF/VEL) 400mg/100mg co-formulated tablet once daily will be given to participants who are randomised into the standard treatment duration arm (B) for 12 weeks.
SOF/VEL for 12 weeks: Open-label SOF/VEL 400mg/100mg once daily to be given to participants randomised to Arm B (12 weeks standard treatment duration). | 95 |
| Total | 188 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 0 |
| Overall Study | Lack of Efficacy | 9 | 2 |
| Overall Study | Lost to Follow-up | 3 | 5 |
| Overall Study | Reinfection | 3 | 2 |
Baseline characteristics
| Characteristic | Drug: Sofosbuvir/Velpatasvir (SOF/VEL) for 12 Weeks | Total | Drug: Sofosbuvir/Velpatasvir (SOF/VEL) for 6 Weeks |
|---|---|---|---|
| Age, Continuous | 43.4 years STANDARD_DEVIATION 10.2 | 43.8 years STANDARD_DEVIATION 10.2 | 44.2 years STANDARD_DEVIATION 10.3 |
| Baseline ALT | 128 International units per liter (IU/L) | 126 International units per liter (IU/L) | 114 International units per liter (IU/L) |
| Baseline HCV ribonucleic acid (RNA) | 5.4 log10 IU/ml | 5.6 log10 IU/ml | 5.6 log10 IU/ml |
| Estimated duration of infection to baseline | 25.0 weeks | 25.8 weeks | 26.1 weeks |
| HCV genotype 1a | 57 Participants | 115 Participants | 58 Participants |
| HCV genotype 1b | 2 Participants | 6 Participants | 4 Participants |
| HCV genotype 1 unknown subtype | 0 Participants | 1 Participants | 1 Participants |
| HCV genotype 2 | 4 Participants | 4 Participants | 0 Participants |
| HCV genotype 3 | 17 Participants | 32 Participants | 15 Participants |
| HCV genotype 4 | 15 Participants | 30 Participants | 15 Participants |
| Human Immunodeficiency Virus (HIV) positive | 65 Participants | 130 Participants | 65 Participants |
| Max alanine aminotransferase (ALT) | 360 International units per liter (IU/L) | 362 International units per liter (IU/L) | 364 International units per liter (IU/L) |
| Mode of HCV exposure Injecting drug use | 22 Participants | 40 Participants | 18 Participants |
| Mode of HCV exposure Occupational (needle stick or other exposure) | 1 Participants | 1 Participants | 0 Participants |
| Mode of HCV exposure Other | 2 Participants | 4 Participants | 2 Participants |
| Mode of HCV exposure Sexual exposure with person(s) of opposite sex | 4 Participants | 7 Participants | 3 Participants |
| Mode of HCV exposure Sexual exposure with person(s) of same sex | 66 Participants | 135 Participants | 69 Participants |
| Mode of HCV exposure Use of non-injectable recreational drugs | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 8 Participants | 4 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Caucasian/White | 78 Participants | 157 Participants | 79 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 8 Participants | 11 Participants | 3 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 87 Participants | 176 Participants | 89 Participants |
| Race/Ethnicity, Customized Other | 8 Participants | 17 Participants | 9 Participants |
| Race/Ethnicity, Customized Unknown or not reported | 0 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 2 Participants |
| Sex: Female, Male Male | 91 Participants | 182 Participants | 91 Participants |
| Symptomatic presentation | 14 Participants | 30 Participants | 16 Participants |
| Type of hepatitis C virus (HCV) infection Primary infection | 60 Participants | 119 Participants | 59 Participants |
| Type of hepatitis C virus (HCV) infection Reinfection | 35 Participants | 69 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 93 | 0 / 95 |
| other Total, other adverse events | 34 / 93 | 48 / 95 |
| serious Total, serious adverse events | 1 / 93 | 5 / 95 |
Outcome results
Primary
Number of Participants With Undetectable HCV RNA at 12 Weeks Post End of Treatment (SVR12) Following SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Intention-to-treat (ITT) Population
To evaluate the proportion of participants with HCV RNA below the level of quantification at 12 weeks post treatment following SOF/VEL for 6 weeks as compared with 12 weeks in people with recent HCV infection- among intention-to-treat (ITT) population The ITT population included all randomized participants, with loss to follow-up deemed treatment failure.
Time frame: 12 weeks post treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Drug: SOF/VEL for 6 Weeks | Number of Participants With Undetectable HCV RNA at 12 Weeks Post End of Treatment (SVR12) Following SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Intention-to-treat (ITT) Population | 76 Participants |
| Drug: SOF/VEL for 12 Weeks | Number of Participants With Undetectable HCV RNA at 12 Weeks Post End of Treatment (SVR12) Following SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Intention-to-treat (ITT) Population | 86 Participants |
Secondary
Number of Participants With Undetectable HCV RNA at 12 Weeks Post End of Treatment (SVR12) Following SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Modified Intention-to-treat (ITT) Population
To evaluate the proportion of participants with HCV RNA below the level of quantification at 12 weeks post treatment following SOF/VEL for 6 weeks as compared with 12 weeks in people with recent HCV infection- among modified intention-to-treat (ITT) population The modified ITT population included participants in the ITT population, but excluded those with non-virological reasons for treatment failure (including death and loss to follow-up) and reinfection.
Time frame: 12 Weeks Post End of Treatment
Population: The modified ITT population included participants in the ITT population, but excluded those with non-virological reasons for treatment failure (including death and loss to follow-up) and reinfection. 8 out of 93 individuals in short arm (3 reinfections, 2 deaths and 3 lost to follow ups) and 7 out of 95 individuals in standard arm (2 reinfections and 5 lost to follow ups) were excluded. Therefore the final number for analysis population were 85 and 88 in short and standard arm, respectively.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Drug: SOF/VEL for 6 Weeks | Number of Participants With Undetectable HCV RNA at 12 Weeks Post End of Treatment (SVR12) Following SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Modified Intention-to-treat (ITT) Population | 76 Participants |
| Drug: SOF/VEL for 12 Weeks | Number of Participants With Undetectable HCV RNA at 12 Weeks Post End of Treatment (SVR12) Following SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Modified Intention-to-treat (ITT) Population | 86 Participants |
Secondary
Number of Participants With Undetectable HCV RNA at 12 Weeks Post End of Treatment (SVR12) Following SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Per Protocol (PP) Population
To evaluate the proportion of participants with HCV RNA below the level of quantification at 12 weeks post treatment following SOF/VEL for 6 weeks as compared with 12 weeks in people with recent HCV infection- among Per Protocol (PP) population The per protocol population included participants who received \>90% of scheduled treatment for \>90% of the scheduled treatment period with follow-up virologic data at SVR12 (excluding reinfection and retreatments)
Time frame: 12 weeks post treatment
Population: The per protocol population included participants who received \>90% of scheduled treatment for \>90% of the scheduled treatment period with follow-up virologic data at SVR12 (excluding reinfection and retreatments) which was 74 and 77 for short and standard arm, respectively.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Drug: SOF/VEL for 6 Weeks | Number of Participants With Undetectable HCV RNA at 12 Weeks Post End of Treatment (SVR12) Following SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Per Protocol (PP) Population | 69 Participants |
| Drug: SOF/VEL for 12 Weeks | Number of Participants With Undetectable HCV RNA at 12 Weeks Post End of Treatment (SVR12) Following SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Per Protocol (PP) Population | 77 Participants |
Secondary
Number of Participants With Undetectable HCV RNA at End of Treatment (ETR) of SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Intention-to-treat (ITT) Population
To evaluate the proportion of participants with HCV RNA below the level of quantification at end of treatment of SOF/VEL for 6 Weeks as compared With 12 Weeks in People With Recent HCV Infection The ITT population included all randomized participants, with loss to follow-up deemed treatment failure.
Time frame: End of treatment - week 6 of the shortened treatment duration arm, and week 12 of the standard treatment duration arm
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Drug: SOF/VEL for 6 Weeks | Number of Participants With Undetectable HCV RNA at End of Treatment (ETR) of SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Intention-to-treat (ITT) Population | 85 Participants |
| Drug: SOF/VEL for 12 Weeks | Number of Participants With Undetectable HCV RNA at End of Treatment (ETR) of SOF/VEL for 6 Weeks as Compared With 12 Weeks in People With Recent HCV Infection- Among Intention-to-treat (ITT) Population | 87 Participants |