Efficacy and Safety of Narlaprevir Used in Combination With Ritonavir in Treatment-Naïve and Failed Prior Treatment With Pegylated Interferon/Ribavirin Patients With Chronic Hepatitis C Genotype 1 (PIONEER - Study)

The study included 3 time periods:

• Screening period with duration up to 3 weeks during which study eligibility was confirmed.
• Double-blind treatment period: all eligible patients divided into Treatment naive and Previous treatment failure subpopulations were randomized in one of the two parallel treatment arms in 2:1 ratio:

• Arm 1: All patients received the combination of NVR/RTV + PEG-INF/RBV for 12 weeks that was followed by PEG-INF and RBV for 12 weeks (total treatment duration of 24 weeks).
• Arm 2: Therapy with PEG-INF and RBV (standard of care) for 48 weeks with placebo equivalent for NVR and RTV for the first 12 weeks.

Different types of pegylated interferon could be used for treatment. The assignment to the pegylated interferon alfa-2a or pegylated interferon alfa-2b treatment will be also performed using web system, in a 1:1 ratio.

Clinical efficacy of each arm were assessed 24 weeks after the end of treatment with undetectable hepatitis C virus (HCV) RNA by lower limit of detection (LOD) 24 weeks following the end of treatment. In case of serum HCV-RNA levels were greater than or equal to 100 IU/mL at Week 12 of treatment (Arm 1) or serum HCV RNA declined from baseline less than 2 log after 12 weeks of treatment or serum HCV-RNA levels ≥LOD at week 24 of treatment (Arm 2) patients were considered non-responders and discontinued participation in the study. In case of satisfactory treatment response all patients were additionally administered with PEG-INF/RBV for 12 weeks (total of 24 weeks of treatment) in Arm 1, and for 36 weeks (total of 48 weeks of treatment) in Arm 2.

• Follow-up period during which patients do not receive any study medication. The duration of the follow-up period after the end of study treatment will be 24 weeks.

Overall, each patient will participate in the study for approximately up to 75 weeks from the time the patient signs the Informed Consent Form through the final visit

Inclusion criteria

• Body weight ≥ 40 and ≤ 125 kg;
• Documented infection with HCV genotype 1 (Mixed infections with other genotypes are not eligible):

• treatment naïve (to interferon and ribavirin); or
• treatment failure patients (patients must have received interferon/ribavirin at standard doses for a minimum of 12 weeks);
• Minimum HCV-RNA level of ≥10,000 IU at baseline;
• No evidence of cirrhosis; availability at Baseline of at least one of the following tests negative results:

• Liver biopsy showing no cirrhosis (not later than within 3 years prior to Baseline) or
• FibroScan elasticity score < 12.5 kPa 12 months prior to baseline or
• FibroTest < 0.75 12 months prior to baseline and aspartate aminotransferase (AST)/platelet ratio (APRI) of ≤ 1 during screening
• Using acceptable contraception methods for both partners from enrollment into the study until 6 months following the end of treatment;
• Willingness to give written informed consent.

Exclusion criteria

• Previous treatment with any HCV NS3-specific protease inhibitor and/ or other direct antiviral agents (e.g. HCV polymerase inhibitors);
• Treatment for HCV infection 30 days before the enrolment;
• Use of prohibited medications within 2 weeks prior to start of study medications (inducers or substrates of CYP3A4);
• Findings suspicious for hepatocellular carcinoma (HCC);
• Hepatic failure at present or in history;
• Auto-immune hepatitis in history;
• Anti-nuclear antibodies (ANA) titers > 1:320;
• Evidence of gallstones, choledocholithiasis and calcified gallbladder;
• HBsAg positive;
• HIV positive;
• Serum hemoglobin of <13g/dL for males and <12g/dL for females;
• Neutrophils <1500/mm3 (<1,5х109/L) at Screening;
• Platelets <150000/mm3 (<150х109/L) at Screening (patients with a platelet count >100,000/mm3 (>100х109/L) but less than 150,000/mm3 (150х109/L) can be included in the study in case a Fibroscan or FibroTest or liver biopsy during the study screening period shows no cirrhosis)
• Total bilirubin >1.6 mg/dL (>27.36 µmol/L) unless history of Gilbert's disease. If Gilbert's disease is the proposed etiology, this must be documented in the subject's chart;
• Direct bilirubin >1.5 x upper limit of normal (ULN) of the laboratory reference range at Screening;
• Serum albumin < lower limit of normal (LLN) of laboratory reference range at Screening;
• Serum creatinine >ULN of the laboratory reference at Screening;
• Serum aspartate aminotransferase (AST) / alanine aminotransferase (ALT) >5 x ULN of the laboratory reference range at Screening;
• Thyroid stimulating hormone (TSH) >1.2 ULN or <0.8 LLN;
• Contraindications to pegylated interferon, ribavirin and/or ritonavir treatment;
• Hypersensitivity to any of the study drugs;
• Active or suspected cancer;
• Psychiatric disease (moderate or severe depression, schizophrenia, bipolar disorder et al);
• Previous suicide attempt or suicidal ideation;
• Drug addiction;
• Opiate agonist substitution therapy;
• History of active gout within the past year;
• Organ transplant (except of cornea and hair transplant);
• Pregnant or nursing women;
• Men whose female partners are pregnant or planning pregnancy;
• Any medical condition that could interfere with the patient's participation and completion of the study;
• Use of other investigational drugs/ participation in other clinical trial within 30 days before the enrolment.