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) (PIONEER)

International, Multicenter, Randomized, Double Blind, Active-controlled, Parallel-group Phase III Study of Narlaprevir/Ritonavir and Pegylated Interferon/Ribavirin in 2 Patient Populations - naïve and Treatment Failure Patients With Genotype 1 Chronic Hepatitis C

The purpose of this study was to confirm that combination of narlaprevir (NVR) and ritonavir (RTV) used as a metabolic inhibitor with pegylated interferon (PEG-INF) and ribavirin (RBV) leads to a superior Sustained Virological Response (SVR) rate compared to treatment with pegylated interferon and ribavirin in treatment-naïve and treatment failure patient populations.

Study Overview

• Status: Completed
• Conditions: Hepatitis C
• Intervention / Treatment: Drug: Narlaprevir; Drug: Ritonavir; Drug: Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b; Drug: Ribavirin; Drug: Placebo Narlaprevir; Drug: Placebo Ritonavir

Detailed Description

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:

  1. 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).

  2. 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

• Study Type: Interventional
• Enrollment (Actual): 420
• Phase: Phase 3

Contacts and Locations

Study Locations

• Russian Federation
  • Chelyabinsk, Russian Federation
    • South-Ural State Medical University, Clinic of Medical Academy, Infectious Diseases Department
  • Kazan, Russian Federation
    • Kazan State Medical Academy, Republican Clinical Hospital of Infectious Diseases n.a. A.F. Agafonov
  • Moscow, Russian Federation
    • Federal Budget Science Institution Central Science and Research Institute of Epidemiology of RosPotrebNadzor
  • Moscow, Russian Federation
    • Federal State Budget Healthcare Institution Central Clinical Hospital of Russian Academy of Science
  • Moscow, Russian Federation
    • First Moscow State Medical University n.a. I.M. Sechenov, Clinic of Nephrology, Internal and Professional Diseases n.a. E.M. Tarleev
  • Moscow, Russian Federation
    • First Moscow State Medical University n.a. I.M. Sechenov, Propedeutics of Internal Diseases Department
  • Moscow, Russian Federation
    • Moscow State Medical Stomatological University n.a. A. I. Evdokimov, Clinical Infectious Hospital #1, Clinical Infections Department
  • Moscow, Russian Federation
    • Public Corporation "Clinical Hospital of Centrosouze"
  • Moscow, Russian Federation
    • Public Corporation "MedElitConsulting"
  • Moscow, Russian Federation
    • State Budget Healthcare Moscow Institution Clinical Scientific Center of Healthcare Department of Moscow
  • Moscow, Russian Federation
    • State Budgetary Healthcare Organization Clinical city hospital #24
  • Novosibirsk, Russian Federation
    • Novosibirsk State Medical University, Clinical city hospital #12, Therapeutic Department
  • Saint Petersburg, Russian Federation
    • Military Medical Academy of Ministry of Defense of Russian Federation n.a. S.M. Kirov, Infectious Diseases Department
  • Saint Petersburg, Russian Federation
    • Saint Petersburg State Budget Healthcare Institution Center of AIDS and Infectious Diseases Prevention and Control
  • Saint Petersburg, Russian Federation
    • Saint Petersburg State Budgetary Healthcare Institution Clinical Hospital of Infectious Diseases n.a. S.P. Botkin
  • Samara, Russian Federation
    • Clinic of Samara State Medical University, Department of Infectious Diseases
  • Samara, Russian Federation
    • Public corporation Medical company "Gepatolog"
  • Saratow, Russian Federation
    • Municipal Healthcare Institution Clinical city hospital #2 n.a. V.I. Razumovsky, Infectious Diseases Department
  • Stavropol', Russian Federation
    • Stavropolsky Krai Clinical Hospital, Gastroenterology Department related to Hospital Therapy Department
  • Stavropol', Russian Federation
    • Stavropolsky State Medical University, Clinic of Gastroenterology, Hepatology and Pancreatology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Body weight ≥ 40 and ≤ 125 kg;

• Documented infection with HCV genotype 1 (Mixed infections with other genotypes are not eligible):

  1. treatment naïve (to interferon and ribavirin); or
  2. 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:

  1. Liver biopsy showing no cirrhosis (not later than within 3 years prior to Baseline) or
  2. FibroScan elasticity score < 12.5 kPa 12 months prior to baseline or
  3. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NVR/RTV + PEG-INF/RBV (Treatment Naive); Narlaprevir - 2 tablets once a day orally Ritonavir - 1 capsule once a day orally Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b - subcutaneous injection once weekly. Patients will be instructed by the investigator on how to self-administer the drug and will be given at each dispensing visit the quantity of PEG-INF alfa-2a and PEG-INF alfa-2b needed between visits. Ribavirin - twice daily orally. In the case of co-administration with PEG-INF alfa-2a: 5 RBV capsules (2 in the morning + 3 in the evening) or 6 RBV capsules (3 in the morning + 3 in the evening) - weight based. In the case of co-administration with PEG-INF alfa-2b: 4 RBV capsules (2 in the morning + 2 in the evening) - minimal dose or 7 (3 in the morning + 4 in the evening) - maximal dose	Drug: Narlaprevir; yellow film-coated 100 mg. tablets; Drug: Ritonavir; 100 mg tablets encapsulates in gelatin capsules (for blinding purposes); Other Names: Norvir; Drug: Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b; 180µg for subcutaneous injections in 0.5 ml syrettes / 1.5 µg/kg for subcutaneous injections in 50µkg, 80µkg,100µkg, 120µkg, 150µkg in vials; Other Names: Pegasys; PegIntron; Drug: Ribavirin; hard gelatin, white 200mg. capsules Weight-based dose was 1000 mg/day (patient weight <75 kg) or 1200 mg/day (patient weight ≥75 kg) with Peginterferon alfa-2a and 800 mg/day (patient weight <65 kg) - 1400 (patient weight >105 kg) mg/day with Peginterferon alfa-2b; Other Names: Rebetol
Active Comparator: PEG-INF/RBV (Treatment Naive); Placebo Narlaprevir - 2 tablets once a day orally Placebo Ritonavir - 1 capsule once a day orally Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b - subcutaneous injection once weekly. Patients will be instructed by the investigator on how to self-administer the drug and will be given at each dispensing visit the quantity of PEG-INF alfa-2a and PEG-INF alfa-2b needed between visits. Ribavirin - twice daily orally. In the case of co-administration with PEG-INF alfa-2a: 5 RBV capsules (2 in the morning + 3 in the evening) or 6 RBV capsules (3 in the morning + 3 in the evening) - weight based. In the case of co-administration with PEG-INF alfa-2b: 4 RBV capsules (2 in the morning + 2 in the evening) - minimal dose or 7 (3 in the morning + 4 in the evening) - maximal dose	Drug: Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b; 180µg for subcutaneous injections in 0.5 ml syrettes / 1.5 µg/kg for subcutaneous injections in 50µkg, 80µkg,100µkg, 120µkg, 150µkg in vials; Other Names: Pegasys; PegIntron; Drug: Ribavirin; hard gelatin, white 200mg. capsules Weight-based dose was 1000 mg/day (patient weight <75 kg) or 1200 mg/day (patient weight ≥75 kg) with Peginterferon alfa-2a and 800 mg/day (patient weight <65 kg) - 1400 (patient weight >105 kg) mg/day with Peginterferon alfa-2b; Other Names: Rebetol; Drug: Placebo Narlaprevir; yellow film-coated 100 mg. tablets identical to Narlaprevir tablets; Drug: Placebo Ritonavir; 100 mg lactose/ cellulose tablets encapsulated in gelatin capsules (for blinding purposes) identical to Ritonavir capsules
Experimental: NVR/RTV + PEG-INF/RBV (Treatment Failure); Narlaprevir - 2 tablets once a day orally Ritonavir - 1 capsule once a day orally Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b - subcutaneous injection once weekly. Patients will be instructed by the investigator on how to self-administer the drug and will be given at each dispensing visit the quantity of PEG-INF alfa-2a and PEG-INF alfa-2b needed between visits. Ribavirin - twice daily orally. In the case of co-administration with PEG-INF alfa-2a: 5 RBV capsules (2 in the morning + 3 in the evening) or 6 RBV capsules (3 in the morning + 3 in the evening) - weight based. In the case of co-administration with PEG-INF alfa-2b: 4 RBV capsules (2 in the morning + 2 in the evening) - minimal dose or 7 (3 in the morning + 4 in the evening) - maximal dose	Drug: Narlaprevir; yellow film-coated 100 mg. tablets; Drug: Ritonavir; 100 mg tablets encapsulates in gelatin capsules (for blinding purposes); Other Names: Norvir; Drug: Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b; 180µg for subcutaneous injections in 0.5 ml syrettes / 1.5 µg/kg for subcutaneous injections in 50µkg, 80µkg,100µkg, 120µkg, 150µkg in vials; Other Names: Pegasys; PegIntron; Drug: Ribavirin; hard gelatin, white 200mg. capsules Weight-based dose was 1000 mg/day (patient weight <75 kg) or 1200 mg/day (patient weight ≥75 kg) with Peginterferon alfa-2a and 800 mg/day (patient weight <65 kg) - 1400 (patient weight >105 kg) mg/day with Peginterferon alfa-2b; Other Names: Rebetol
Active Comparator: PEG-INF/RBV (Treatment Failure); Placebo Narlaprevir - 2 tablets once a day orally Placebo Ritonavir - 1 capsule once a day orally Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b - subcutaneous injection once weekly. Patients will be instructed by the investigator on how to self-administer the drug and will be given at each dispensing visit the quantity of PEG-INF alfa-2a and PEG-INF alfa-2b needed between visits. Ribavirin - twice daily orally. In the case of co-administration with PEG alfa-2a: 5 RBV capsules (2 in the morning + 3 in the evening) or 6 RBV capsules (3 in the morning + 3 in the evening) - weight based. In the case of co-administration with PEG alfa-2b: 4 RBV capsules (2 in the morning + 2 in the evening) - minimal dose or 7 (3 in the morning + 4 in the evening) - maximal dose	Drug: Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b; 180µg for subcutaneous injections in 0.5 ml syrettes / 1.5 µg/kg for subcutaneous injections in 50µkg, 80µkg,100µkg, 120µkg, 150µkg in vials; Other Names: Pegasys; PegIntron; Drug: Ribavirin; hard gelatin, white 200mg. capsules Weight-based dose was 1000 mg/day (patient weight <75 kg) or 1200 mg/day (patient weight ≥75 kg) with Peginterferon alfa-2a and 800 mg/day (patient weight <65 kg) - 1400 (patient weight >105 kg) mg/day with Peginterferon alfa-2b; Other Names: Rebetol; Drug: Placebo Narlaprevir; yellow film-coated 100 mg. tablets identical to Narlaprevir tablets; Drug: Placebo Ritonavir; 100 mg lactose/ cellulose tablets encapsulated in gelatin capsules (for blinding purposes) identical to Ritonavir capsules

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients with Sustained Virologic Response (SVR24)	HCV RNA undetectable by Limit of detection (LOD)	Week 24 after the end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of patients who achieve the Rapid Virological Response (RVR)	HCV RNA < LOD	Week 4 of treatment
Number of patients who achieve the Early Virological Response (EVR)	HCV RNA <LOD	Week 12 of treatment
Number of patients who achieve the End of Treatment Response (ETR)	HCV RNA <LOD	Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)
Number of patients who achieve the SVR12	HCV RNA undetectable (by LOD)	Week 12 after the end of treatment
Number of patients who develop viral breakthrough	Greater than or equal to 1 log10 increase in HCV-RNA above nadir, or detectable HCV-RNA, while on treatment after an initial drop below detection	Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)
Number of patients who develop relapse	HCV RNA undetectable by LOD at end of treatment with subsequent detectable HCV RNA	Week 24 after the end of treatment
Number of patients who develop anemia	Anemia is defined as as Hb <10g/dL	Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)
Number of patients who develop neutropenia	Neutropenia is defined as neutrophils <0.75x109/L	Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)

Collaborators and Investigators

• Sponsor: R-Pharm

Study record dates

Study Major Dates

• Study Start (Actual): May 7, 2014
• Primary Completion (Actual): March 23, 2016
• Study Completion (Actual): February 21, 2017

Study Registration Dates

• First Submitted: February 5, 2019
• First Submitted That Met QC Criteria: February 5, 2019
• First Posted (Actual): February 7, 2019

Study Record Updates

• Last Update Posted (Actual): February 7, 2019
• Last Update Submitted That Met QC Criteria: February 5, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Antineoplastic Agents; Immunologic Factors; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Interferons; Interferon-alpha; Ribavirin; Peginterferon alfa-2a; Interferon alpha-2; Ritonavir; Peginterferon alfa-2b
• Other Study ID Numbers: CJ05013008

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No