Clinical trial NCT02625909: Randomised Study of Interferon-free Treatment for Recently Acquired Hepatitis C in PWID and People With HIV Coinfection.
Official title: A Randomised Study of Interferon-free Treatment for Recently Acquired Hepatitis C in People Who Inject Drugs and People With HIV Coinfection.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hepatitis C
Lead sponsor: Kirby Institute
Sponsor class: OTHER_GOV
First posted: 2015-12-09
Enrollment: 222
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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 exclusion criteria are not to be enrolled in this study.

1. History of any of the following:

   1. 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.
   2. 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
   3. Solid organ transplant
   4. 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.
   5. Significant drug allergy (such as anaphylaxis or hepatotoxicity).
2. 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
3. Subject has known cirrhosis
4. Any of the following lab parameters at screening:

   1. Direct bilirubin \> 1.5 x ULN
   2. Platelets \< 50,000/μL
   3. Creatinine clearance (CLcr) \< 60 mL/min
   4. Haemoglobin \< 11 g/dL for females ; \< 12 g/dL for males
   5. Albumin \< 30g/L
5. Pregnant or nursing female.
6. Use of prohibited concomitant medications as described in section 5.2 in the 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 non-structural protein 5A (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.

Primary outcomes:
measure: 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
timeFrame: 12 weeks post treatment
Secondary outcomes:
measure: 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
timeFrame: 12 Weeks Post End of Treatment
measure: 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
timeFrame: End of treatment - week 6 of the shortened treatment duration arm, and week 12 of the standard treatment duration arm
measure: 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
timeFrame: 12 weeks post treatment
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Sydney
country: Australia
facility: Kirketon Road Centre
state: New South Wales
city: Sydney
country: Australia
facility: St. Vincent's Hospital
state: New South Wales
city: Sydney
country: Australia
facility: The Kirby Institute, University of New South Wales Australia
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Vancouver
country: Canada
facility: St Paul's Hospital
state: British Columbia
city: Victoria
country: Canada
facility: Cool Aid Community Health Centre
state: British Columbia
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Montreal
country: Canada
facility: Centre Hospitalier de l' Universite de Montreal
state: Quebec
city: Berlin
country: Germany
facility: Praxis Dr Cordes
city: Berlin
country: Germany
facility: Zentrum für Infektiologie Berlin-Prenzlauer Berg
city: Bonn
country: Germany
facility: University Hospital of Bonn
city: Frankfurt
country: Germany
facility: Infektio-Research GmbH
city: Amsterdam
country: Netherlands
facility: Academic Medical Centre, University of Amsterdam
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Zürich
country: Switzerland
facility: University Hospital Zurich
state: Zurich
city: Bern
country: Switzerland
facility: Bern University Hospital
city: Lugano
country: Switzerland
facility: Fondazione Epatocentro Ticino
city: Brighton
country: United Kingdom
facility: Brighton & Sussex University Hospitals NHS Trust
state: Brigton And Hove
city: Manchester
country: United Kingdom
facility: Pennine Acute Hospitals NHS Trust
state: Lancashire
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: Chelsea & Westminster Hospital
Study officials:
affiliation: The Kirby Institute, University of New South Wales Australia, Sydney, New South Wales, Australia, NSW 2052
name: Gail V Matthews, MbChB, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Matthews GV, Bhagani S, Van der Valk M, Rockstroh J, Feld JJ, Rauch A, Thurnheer C, Bruneau J, Kim A, Hellard M, Shaw D, Gane E, Nelson M, Ingiliz P, Applegate TL, Grebely J, Marks P, Martinello M, Petoumenos K, Dore GJ; REACT study group; Protocol Steering Committee; Coordinating Centre; Site Principal Investigators. Sofosbuvir/velpatasvir for 12 vs. 6 weeks for the treatment of recently acquired hepatitis C infection. J Hepatol. 2021 Oct;75(4):829-839. doi: 10.1016/j.jhep.2021.04.056. Epub 2021 May 21.