The primary objective is to evaluate the proportion of patients with HCV RNA below the level of quantitation (target not detected [TND] or target detected, not quantifiable [TDnq]) at 12 weeks post end of treatment (SVR12) following sofosbuvir/…
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Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the proportion of participants with HCV RNA below the
level of quantitation (target not detected [TND] or target detected, not
quantifiable [TDnq]) at 12 weeks post end of treatment (SVR12)
Secondary outcome
Secondary virological endpoints:
1) The proportion of participants with:
- ETR defined as HCV RNA below the level of quantitation at end of therapy
- SVR 4 defined as HCV RNA below the level of quantitation 4 weeks post therapy
- SVR 24 defined as HCV RNA below the level of quantitation 24 weeks post
therapy
- HCV RNA below the level of quantitation through 2 years post treatment
Results will be stratified by HCV genotype and HIV-coinfection.
2) 80/80 adherence: Defined as the receipt of >80% of scheduled doses for >80%
of the scheduled treatment period.
3) 90/90 adherence: Defined as the receipt of >90% of scheduled doses for >90%
of the scheduled treatment period.
4) 100/100 adherence: Defined as the receipt of 100% of scheduled doses for
100% of the scheduled treatment period.
5) On-treatment adherence: Calculated by subtracting the number of missed doses
from the total number of doses of scheduled treatment and dividing by the total
intended therapy duration. This measures the proportion of doses received from
the time that treatment was initiated until treatment was discontinued or
completed.
6) Toxicity: Proportion of participants with at least one severe or potentially
life threatening (grade 3 or 4) adverse event.
7) Early treatment discontinuation: Discontinuation of therapy prior to the
per-protocol planned end of treatment (6 or 12 weeks depending on study arm).
8) Resistance associated variants (RAVs): The proportion of treated subjects
with development of RAVs following virological relapse or breakthrough.
9) Reinfection rate: Rates of HCV reinfection will be calculated using
person-time of observation during and up to 48 months following end of
treatment.
10) Baseline characteristics, on-treatment adherence, risk behaviours and
toxicity will be evaluated among subjects withdrawing prior to randomisation.
Background summary
Globally, 3-4 million new hepatitis C virus (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.
The advent of DAAs has changed the therapeutic landscape for individuals with
chronic HCV infection with IFN-free therapy offering high efficacy and
tolerability, even in *difficult-to-treat* populations. Multiple agents in
different classes have been approved in Australia by the Therapeutic Goods
Administration (TGA), the European Union by the European Medicines Agency (EMA)
and the US by the Food and Drug Administration (FDA).
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 trials in selected
populations with limited data on treatment in PWID and HIV co-infection. With
recent rapid advances in HCV therapeutics, management strategies for acute HCV
will evolve rapidly over the next few years.
The REACT study will compare the efficacy and safety of sofosbuvir
(SOF)/velpatasvir (VEL) administered for 6 or 12 weeks in individuals with
recent HCV infection. The role and activity of potent DAA regimens in acute
HCV infection requires evaluation, with the potential to be given as highly
efficacious, short course IFN-sparing regimens, maximising acceptability to
patients, encouraging uptake of treatment, limiting further transmission and
preventing progression to chronic liver disease.
Study objective
The primary objective is to evaluate the proportion of patients with HCV RNA
below the level of quantitation (target not detected [TND] or target detected,
not quantifiable [TDnq]) at 12 weeks post end of treatment (SVR12) following
sofosbuvir/velpatasvir therapy for 6 weeks (short treatment duration) as
compared with 12 weeks (standard treatment duration) in people with recent HCV
infection (duration of infection <=12 months).
The secondary objectives are as follows:
1 To evaluate the proportion of participants with HCV RNA below the level of
quantitation (TND or TDnq) at the end of treatment (ETR), 4 weeks after
treatment completion (SVR4) and 24 weeks after treatment completion (SVR24);
2 To evaluate the proportion of participants with undetectable HCV RNA through
2 years post treatment;
3 To evaluate the levels of adherence, factors associated with suboptimal
adherence including HIV status, and the impact of suboptimal adherence on
therapeutic response;
4 To evaluate the impact of treatment on illicit drug use, injecting behaviour
and sexual risk taking behaviour (behavioural survey) during treatment;
5 To evaluate safety and tolerability
6 To evaluate the change in HIV RNA and CD4 (on-treatment and end of treatment);
7 To evaluate the rate and risk factors for reinfection during and up to 2
years following treatment;
8 To evaluate the immunological factors associated with treatment induced
clearance and reinfection
Study design
This study will be conducted as a phase III randomised, open-label,
non-inferiority multicentre international trial. A total of 250 people with
recently acquired hepatitis C will be enrolled.
The study consists of a screening phase (-12 to -4 weeks), treatment
commencement from baseline, randomisation between week 5 and 6, treatment for
another 6 weeks for those randomised to standard therapy (12 weeks of
treatment) or end of treatment for those randomised to shortened treatment (6
weeks of treatment). All participants will then enter the follow-up phase (96
weeks) to evaluate treatment response and reinfection.
Participants will receive six or twelve 12 weeks of open-label
sofosbuvir/velpatasvir (400mg/100mg daily) in an oral once-daily fixed dose
combination. Dose modifications are prohibited.
Intervention
Participants will receive six or twelve 12 weeks of open-label
sofosbuvir/velpatasvir (400mg/100mg daily) in an oral once-daily fixed dose
combination. Dose modifications are prohibited.
Study burden and risks
There are potential risks associated with this study. Participants may
experience drug toxicity associated with the use of study medications. The most
common adverse events were fatigue, headache, nausea, diarrhoea and insomnia.
These symptoms are generally mild and can be managed in a simple standardised
fashion and generally resolve on completion of therapy. In clinical trials
using the study medications to date, no subject discontinued the study
medications due to treatment related side effects.
Participants who receive a shortened duration of study treatment (6 weeks) may
potentially have a higher risk of virological relapse. A Data Safety and
Monitoring Board (DSMB) will be established in this study to monitor the safety
and efficacy data and virological relapse rate. Specifically, a pre-specified
high rate of relapse (>20%) in the shortened arm will trigger consideration of
terminating the short duration arm. Virological relapse can happen during
treatment or up to 6 months after treatment finishes. Participants who
experienced virological relapse after an initial response will have the option
of receiving re-treatment with current standard of care therapy for chronic HCV
infection.
Venepuncture may cause local pain, bruising, occasional light-headedness,
fainting, and very rarely, infection at the site of the blood draw. All study
staff are experienced in venepuncture to minimise the risk of infection and
pain.
There are 15 to 18 study visits (depending on the treatment duration a
participant receives). Each visit will take about 30 to 90 minutes depending
on the type of visit. A screening visit which involves more study assessments
will take about 90 minutes but a treatment follow-up visit may only take about
30 minutes.
Potential benefits arising from this proposed study include the possibility of
effective cure of HCV infection at an early stage of infection. Advantages to
participants treated at this stage may include a simpler regimen and a shorter
treatment duration than that routinely used in the treatment of chronic HCV
without loss of efficacy. Shortening duration may result in fewer adverse
events, better quality of life, less frequent dose reductions, and increasing
the likelihood of optimal adherence.
The Kirby Institute, The University of New South Wales Australia Wallace Wurth Building
Sydney, New South Wales 2052
AU
The Kirby Institute, The University of New South Wales Australia Wallace Wurth Building
Sydney, New South Wales 2052
AU
Listed location countries
Age
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 Negative pregnancy test at baseline (females of childbearing potential only).
7 Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception
8 Medically stable on the basis of physical examination, medical history and vital signs
9 Adequate literacy 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 6 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 6 months
and
ii) Acute clinical hepatitis (jaundice or 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 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:
o Nucleos(t)ide reverse transcriptase inhibitors: Tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), emtricitabine (FTC)Non-nucleoside reverse transcriptase inhibitors: Rilpivirine
o Protease inhibitors: Atazanavir, darunavir, lopinavir, ritonavir
o Integrase inhibitors: Dolutegravir, raltegravir, elvitegravir/cobicistat
• Contraindicated ARV include:
o Efavirenz
* - 50% reduction in velpatasvir (GS-5816) exposure
o Didanosine
o Zidovudine
o Tipranavir
Other ARV agents may be permissible at the time of study commencement pending further drug-drug interaction studies; please discuss with the Medical Monitor.
Exclusion criteria
Subjects who meet any of the exclusion criteria are not to be enrolled in this study.;1 History of any of the following:
a. Clinically significant illness (other than HCV) or any other major medical disorder that may interfere with the participant treatment, assessment or compliance with the protocol; participants currently under evaluation for a potentially clinically significant illness (other than HCV) are also excluded.
b. History of chronic pulmonary disease associated with functional limitation, severe cardiac disease, major organ transplantation or other evidence of severe illness, malignancy, or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study
c. Solid organ transplant
d. Malignancy within 5 years prior to screening, with exception of specific cancers that may have been cured by surgical resection (basal cell skin cancer, etc.). Subjects under evaluation for possible malignancy are also excluded.
e. Significant drug allergy (such as anaphylaxis or hepatotoxicity)
2. Subject has a known or documented prior history of cirrhosis
3 Subject shows evidence of significant liver disease in addition to hepatitis C, which may include but is not limited to drug- or alcohol-related cirrhosis, autoimmune hepatitis, hemochromatosis, Wilson*s disease, non-alcoholic steatohepatitis (NASH), or primary biliary cirrhosis
4 Any of the following lab parameters at screening:
a. Direct bilirubin > 1.5 x ULN
b. Platelets < 50,000/µL
c. Creatinine clearance (CLcr) < 50 mL/min
d. Haemoglobin < 10 g/dL
e. Albumin < 30g/L
f. International Normalised Ratio (INR) >1.5 (unless subject is on a stable anticoagulant regimen or has known coagulopathy)
5 Pregnant or nursing female
6 Use of prohibited concomitant medications as described in the study protocol
7 Chronic use of systemically administered immunosuppressive agents (e.g. prednisone equivalent > 10 mg/day)
8 Known hypersensitivity to velpatasvir, sofosbuvir or formulation excipients.
9 Therapy with any anti-neoplastic or immunomodulatory treatment (including supraphysiologic doses of steroids and radiation) <=6 months prior to the first dose of study drug.
10 Any investigational drug <=6 weeks prior to the first dose of study drug.
11 Previous failure of therapy with sofosbuvir or an NS5A inhibitor prior to the first dose of study drug.
12 Ongoing severe psychiatric disease as judged by the treating physician.
13 Frequent injecting drug use that is judged by the treating physician to compromise treatment safety.
14 Inability or unwillingness to provide informed consent or abide by the requirements of the study.
15. Prior enrolment within this study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-004243-39-NL |
| ClinicalTrials.gov | NCT02625909 |
| CCMO | NL55674.018.16 |