Clinical trial NCT01949168: A Pilot Study of Boceprevir for the Treatment of Genotype 6 HCV
Official title: Phase 2a Study of Boceprevir for the Treatment of Genotype 6 Hepatitis C
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Chronic Hepatitis C
Lead sponsor: St Vincent's Hospital Melbourne
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2013-09-24
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the antiviral efficacy of Boceprevir-based therapy for the treatment of genotype 6 chronic hepatitis C infection.

Boceprevir has recently been approved for the treatment of genotype 1 chronic hepatitis C infection. Recent in vitro studies suggest similar efficacy against genotype 6 chronic hepatitis C infection.

The investigators therefore hypothesise that:

i) Boceprevir is a potent inhibitor of genotype 6 hepatitis C replication in vivo.

ii) Boceprevir in combination with pegylated interferon-alpha and ribavirin for 24 weeks will cure a high proportion of patients chronically infected with genotype 6 chronic hepatitis C infection.

Detailed description: Genotype 6 HCV (HCV-6) is common in parts of South-East Asia, in particular Vietnam. There is a small but growing population of immigrant patients with chronic HCV-6 in Australia. The current standard-of-care treatment (SOC) for chronic HCV-6 infection is peg-interferon-α (PEG-IFN) and ribavirin (RBV) therapy for 48 weeks. The available data evaluating treatment outcome suggests that SVR rates are intermediate between those of HCV-1 and HCV-2/3. There is a medical need for novel therapies that might increase SVR rates and/or allow shortened treatment duration.

Boceprevir is a novel HCV NS3 protease inhibitor, and boceprevir-based triple therapy has recently been approved for the treatment of HCV-1. Boceprevir also appears to have some antiviral effect against HCV-2 and HCV-3 in vivo. Boceprevir has not been used to treat patients with chronic HCV-6 infection. Recent in vitro data have demonstrated that boceprevir has an antiviral effect against HCV-6.

The investigators are therefore undertaking an investigator-initiated proof-of-concept pilot study of boceprevir-based therapy for the treatment of patients chronically infected with HCV-6.

The study population will consist of a representative group of 30 adult patients who are chronically infected with genotype 6 HCV. All patients will be of Asian background, will be non-cirrhotic, and will carry a "good response" IL28B genotype (C/C for rs12979860). The patients will be recruited from the outpatient clinics of 4 Hepatology units in Melbourne, Australia, represented by the principal and associate investigators.

Eligibility criteria: Inclusion Criteria:

* Male or female, at least 18 years of age
* Asian background
* HCV treatment-naïve.
* Chronic HCV infection is defined as one of the following:
* Positive for anti-HCV antibody (Ab) or HCV RNA at least 6 months before Screening, and positive for HCV RNA and anti-HCVAb at the time of Screening; or
* Positive for anti-HCV Ab and HCV RNA at the time of Screening with a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed prior to enrollment with evidence of chronic hepatitis C disease).
* Screening laboratory result indicating HCV genotype 6-infection (HCV-6).
* Plasma HCV RNA level \> 10,000 IU/mL at Screening.
* IL28B C/C genotype (rs12979860)
* Per local standard practice, documented results of one of the following:
* A liver biopsy within 24 months prior to or during screening demonstrating the absence of cirrhosis, e.g., a METAVIR Score of 3 or less, Ishak score of 4 or less; or
* A screening FibroTest score of ≤ 0.72 and Aspartate Aminotransferase to Platelet Ratio Index (APRI) ≤ 2; or
* A screening FibroScan result of \< 9.6 kPa.
* Subjects with a non-qualifying Fibrotest/APRI or Fibroscan result may only be enrolled if they have a qualifying liver biopsy preformed within 24 months prior to or during screening.
* Candidate for PEG/RBV therapy
* Body mass index (BMI) between 18 and 36 kg/m2
* Agree to use two highly effective methods of avoiding contraception for the duration of the study and for 7 months after the last dose study medication. Females of childbearing potential must have negative pregnancy test at Screening and Baseline
* Provide written informed consent to participate in the study.
* Subjects must have the following laboratory parameters at Screening:
* ALT ≤ 10 × the upper limit of normal (ULN)
* AST ≤ 10 × ULN
* Hemoglobin ≥ 12 g/dL
* White blood cell count ≥ 2,500 cells/μL
* Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3
* Platelets ≥ 90,000/mm3
* Prothrombin time ≤ 1.5 × ULN
* Albumin \> 3 g/dL
* Direct (conjugated) bilirubin \< ULN
* Thyroid stimulating hormone (TSH) ≤ ULN
* Creatinine clearance (CLcr) ≥ 50 mL/min, as calculated by the Cockcroft-Gault equation

Exclusion Criteria:

* Non-genotype 6 HCV infection, or evidence of mixed genotype HCV infection
* IL28B C/T or T/T polymorphism (rs12979860)
* Any current or past clinical evidence of cirrhosis such as ascites or esophageal varices, or prior biopsy showing cirrhosis, e.g., a Metavir Score of \>3 or Ishak score of \> 4.
* Exceed defined thresholds for key laboratory parameters at Screening.
* Females who are pregnant or plan to become pregnant, or breastfeeding, or males whose partners are pregnant or planning to become pregnant within 7 months (or per local RBV label) after their last dose of study drug.
* Positive test result for Hepatitis B surface antigen (HBsAg) or anti-Human immunodeficiency virus antibody (HIV Ab).
* Diagnosis of autoimmune disease, decompensated liver, disease, poorly controlled diabetes mellitus, significant psychiatric illness, severe chronic obstructive pulmonary disease (COPD), hepatocellular carcinoma or other malignancy (with exception of certain skin cancers), hemoglobinopathy, retinal disease, or are immunosuppressed
* Subjects with current use of amphetamines, cocaine, opiates (e.g., morphine, heroin), or ongoing alcohol abuse are excluded. Subjects on stable methadone maintenance treatment for at least 6 months prior to Screening may be included into the study.
* Use of prohibited concomitant medications two weeks prior to baseline through the end of treatment, as defined by the product label.

Primary outcomes:
measure: Early viral kinetics
timeFrame: Day 5
Secondary outcomes:
measure: Rates of virological response
timeFrame: Day 3, 5, week 2, week 4, week 12 and end of treatment (week 24 or week 48)
measure: Number of patients eligible for Response Guided Therapy
timeFrame: Week 4 and week 20
measure: Rates of virological breakthrough
timeFrame: Week 4, week 20, week 24, week 48, week 60
measure: Rates of SVR12 and relapse
timeFrame: Week 48 and Week 60
measure: Rates of anaemia on treatment
timeFrame: Day 0, 1, 2, 3, 4, 5, then monthly up to week 48 of treatment
Other outcomes:
Locations:
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Fitzroy
country: Australia
facility: St Vincent's Hospital
state: Victoria
city: Footscray
country: Australia
facility: Western Hospital
state: Victoria
Study officials:
affiliation: St Vincent's Hospital Melbourne
name: Alexander Thompson, MBBS
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Bathgate A. Boceprevir for previously treated chronic hepatitis C virus genotype 1 infection. J R Coll Physicians Edinb. 2011 Jun;41(2):122-3. doi: 10.4997/JRCPE.2011.222. No abstract available.
citation: Silva MO, Treitel M, Graham DJ, Curry S, Frontera MJ, McMonagle P, Gupta S, Hughes E, Chase R, Lahser F, Barnard RJ, Howe AY, Howe JA. Antiviral activity of boceprevir monotherapy in treatment-naive subjects with chronic hepatitis C genotype 2/3. J Hepatol. 2013 Jul;59(1):31-7. doi: 10.1016/j.jhep.2013.02.018. Epub 2013 Feb 27.
citation: Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009 Sep 17;461(7262):399-401. doi: 10.1038/nature08309. Epub 2009 Aug 16.