A Study of Debio 025 (Alisporivir) Combined With Peg-IFNα2a and Ribavirin in Treatment naïve Chronic Hepatitis C Genotype 1 Patients

A Multicentre, Randomised, Double-blind, Placebo-controlled, Parallel-group Phase II Study on the Efficacy and Safety of Debio 025 Combined With Peg-IFNα2a and Ribavirin in Treatment naïve Chronic Hepatitis C Genotype 1 Patients

The purpose of this study is to compare several Debio 025 (alisporivir)/peg-IFNα2a/ribavirin triple therapies with the current standard of care (SOC) in treatment naïve chronic hepatitis C genotype 1 patients.

This is an international, multicentre, randomised, double-blind, placebo-controlled, 4-arm, parallel-group, multiple dose phase II study comparing 3 Debio 025 (alisporivir)/peg-IFNα2a/ribavirin regimens to SOC treatment in treatment naïve chronic HCV genotype 1 patients.

Patients are randomised into 1 of 4 arms receiving either Debio 025/peg-IFNα2a/ribavirin triple therapy for a fixed treatment duration of 48 weeks (Treatment A) or 24 weeks (Treatment B), Debio 025/peg-IFNα2a/ribavirin triple therapy for a response-based treatment duration of 24 or 48 weeks (Treatment C), or blinded SOC treatment for 48 weeks (Treatment D). Follow-up is 24 weeks in all treatment arms.

Inclusion Criteria:

• Males or females aged ≥ 18 and ≤ 65 years.

• Body mass index (BMI) ≥ 18 and ≤ 32 kg/m^2.

• Hepatitis B surface antigen (HbsAg) negative and HIV-1 negative.

• Serological diagnosis of chronic hepatitis C viral infection genotype 1 for > 6 months.

• Chronic liver disease consistent with chronic hepatitis C infection on a biopsy or FibroScan® obtained within the past 24 months (36 months for patients with incomplete/transition to cirrhosis).

• Previously untreated for hepatitis C virus (HCV) infection (approved or investigational drug).

• Plasma HCV RNA level lower limit ≥ 100 IU/ml assessed by quantitative polymerase chain reaction (qPCR) or equivalent; no upper limit.

• Neutrophil count ≥ 1500/µL; hemoglobin (Hb) ≥ 12g/dL for females and ≥ 13g/dL for males; platelets ≥ 90,000/µL.

• Patients with incomplete/transition to cirrhosis on biopsy or an elasticity score between 9.5 and 14 kPa on FibroScan must have an abdominal ultrasound (US), computed tomographic (CT) scan, or magnetic resonance imaging (MRI) scan without evidence of hepatocellular carcinoma (within 2 months prior to randomisation) and a serum alpha-foetoprotein (AFP) < 100 ng/mL.

• Aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) < 5 times the upper limit of normal.

• Normal or compensated liver function and absence of complicated portal hypertension as documented by the following:

  • No history of bleeding oesophageal varices;
  • Absence of ascites;
  • Absence of encephalopathy;
  • Albumin ≥ 35 g/L;
  • Total bilirubin ≤ 1.8 mg/dL (≤ 30 µmol/L);
  • Prothrombin (INR ≤ 1.5).

• Creatinine clearance > 50 mL/min.

• Thyroid stimulating hormone (TSH) within normal range;

• All patients should be informed about Debio 025 and ribavirin foetotoxicity:

  • Females may participate if they are surgically sterile or post-menopausal. Pre-menopausal females may participate if they use 2 reliable contraceptive methods (oral contraceptive + barrier method). The contraceptive regimen must be maintained during the treatment period and for 4 months after the last Debio 025 or ribavirin dose.
  • Male patients must be surgically sterile or use 2 reliable contraceptive methods (oral contraceptive + barrier method). The contraceptive regimen must be maintained during the treatment period and for 7 months after the last Debio 025 or ribavirin dose.

• Signed informed consent before any study procedures.

• Negative pregnancy test within one week of first investigational product administration for female patients of child bearing potential.

Exclusion Criteria:

• Treatment with any investigational drug within 6 months prior to the first dose of investigational product.
• HCV genotype different from genotype 1.
• Any previous HCV treatment (approved or investigational).
• Histologic evidence of complete hepatic cirrhosis (including compensated cirrhosis) based on a previous liver biopsy (if available).
• Ongoing or recent use of any other medication (including over the counter medication and herbal products) within 2 weeks before study start or within 5 drug half-lives of that medication (whichever is longer) that are known inhibitors/inducers of cytochrome P450 (CYP450) 3A, substrates of P-glycoprotein 1 (P-gP), or substrates/inhibitors of organic anion-transporting polypeptides (OATP), multidrug resistance-associated protein 2 (MRP2), or bile salt export pump (BSEP) and are mentioned in the list of unauthorised medications;
• Any medical contraindications to peg-IFNα2a and/or ribavirin treatment;
• Any other cause of relevant liver disease other than HCV including but not limited to hepatitis B virus (HBV), drug- or alcohol-related cirrhosis, autoimmune hepatitis, haemochromatosis, Wilson's disease, nonalcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), or primary biliary cirrhosis (PBC).
• Any other condition which, in the opinion of the Investigator, would make the patient unsuitable for enrollment or could interfere with the patient participating in and completing the study. Patients with risk factors (hypertension or diabetes) need to have an ophthalmologic investigation (including fundoscopy).
• History of moderate, severe, or uncontrolled psychiatric disease, especially depression, including a history of hospitalisation or prior suicidal attempt.
• Uncontrolled arterial hypertension, ie, patients with systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 100 mmHg.
• History of pancreatitis, uncontrolled diabetes mellitus, or retinopathy.
• Anti-nuclear antibody (ANA) titre > 1:640 at screening and/or evidence of autoimmune hepatitis on liver biopsy.
• Alcohol consumption > 20 g/day for females and > 30 g/day for males.
• History of major organ transplantation with an existing functional graft.
• Pregnancy or lactation.
• Haemoglobinopathies (thalassaemia major, sickle cell anaemia or drepanocytosis).
• Familial history of severe neonatal cholestasis or pregnancy cholestasis.
• Evidence of an active or suspected cancer, or a history of malignancy where the risk of recurrence is ≥ 20% within 2 years.