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)

NCT03833362 | Completed Phase 3

• 1 other identifier: CJ05013008
• Study Type: interventional
• Target: 420
• Locations: 1 country
• Sites: 20

Brief Summary

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.

Conditions

Hepatitis C

Outcome Measures

Primary Outcomes (1)

• Number of patients with Sustained Virologic Response (SVR24)

  HCV RNA undetectable by Limit of detection (LOD)

  Week 24 after the end of treatment

Secondary Outcomes (8)

• Number of patients who achieve the Rapid Virological Response (RVR)

  Week 4 of treatment

• Number of patients who achieve the Early Virological Response (EVR)

  Week 12 of treatment

• Number of patients who achieve the End of Treatment Response (ETR)

  Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)

• Number of patients who achieve the SVR12

  Week 12 after the end of treatment

• Number of patients who develop viral breakthrough

  Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)

Study Arms (4)

NVR/RTV + PEG-INF/RBV (Treatment Naive)

EXPERIMENTAL

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; Drug: Ritonavir; Drug: Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b; Drug: Ribavirin

PEG-INF/RBV (Treatment Naive)

ACTIVE COMPARATOR

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: Placebo Narlaprevir; Drug: Placebo Ritonavir; Drug: Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b; Drug: Ribavirin

NVR/RTV + PEG-INF/RBV (Treatment Failure)

EXPERIMENTAL

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; Drug: Ritonavir; Drug: Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b; Drug: Ribavirin

PEG-INF/RBV (Treatment Failure)

ACTIVE COMPARATOR

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: Placebo Narlaprevir; Drug: Placebo Ritonavir; Drug: Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b; Drug: Ribavirin

Interventions

Narlaprevir DRUG

yellow film-coated 100 mg. tablets

NVR/RTV + PEG-INF/RBV (Treatment Failure); NVR/RTV + PEG-INF/RBV (Treatment Naive)

Ritonavir DRUG

100 mg tablets encapsulates in gelatin capsules (for blinding purposes)

Also known as: Norvir

NVR/RTV + PEG-INF/RBV (Treatment Failure); NVR/RTV + PEG-INF/RBV (Treatment Naive)

Placebo Narlaprevir DRUG

yellow film-coated 100 mg. tablets identical to Narlaprevir tablets

PEG-INF/RBV (Treatment Failure); PEG-INF/RBV (Treatment Naive)

Placebo Ritonavir DRUG

100 mg lactose/ cellulose tablets encapsulated in gelatin capsules (for blinding purposes) identical to Ritonavir capsules

PEG-INF/RBV (Treatment Failure); PEG-INF/RBV (Treatment Naive)

Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b DRUG

180µg for subcutaneous injections in 0.5 ml syrettes / 1.5 µg/kg for subcutaneous injections in 50µkg, 80µkg,100µkg, 120µkg, 150µkg in vials

Also known as: Pegasys, PegIntron

NVR/RTV + PEG-INF/RBV (Treatment Failure); NVR/RTV + PEG-INF/RBV (Treatment Naive); PEG-INF/RBV (Treatment Failure); PEG-INF/RBV (Treatment Naive)

Ribavirin DRUG

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

Also known as: Rebetol

NVR/RTV + PEG-INF/RBV (Treatment Failure); NVR/RTV + PEG-INF/RBV (Treatment Naive); PEG-INF/RBV (Treatment Failure); PEG-INF/RBV (Treatment Naive)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;

Sponsors & Collaborators

• R-Pharm: lead

Study Sites (20)

South-Ural State Medical University, Clinic of Medical Academy, Infectious Diseases Department

Chelyabinsk, Russia

Location

Kazan State Medical Academy, Republican Clinical Hospital of Infectious Diseases n.a. A.F. Agafonov

Kazan', Russia

Location

Federal Budget Science Institution Central Science and Research Institute of Epidemiology of RosPotrebNadzor

Moscow, Russia

Location

Federal State Budget Healthcare Institution Central Clinical Hospital of Russian Academy of Science

Moscow, Russia

Location

First Moscow State Medical University n.a. I.M. Sechenov, Clinic of Nephrology, Internal and Professional Diseases n.a. E.M. Tarleev

Moscow, Russia

Location

First Moscow State Medical University n.a. I.M. Sechenov, Propedeutics of Internal Diseases Department

Moscow, Russia

Location

Moscow State Medical Stomatological University n.a. A. I. Evdokimov, Clinical Infectious Hospital #1, Clinical Infections Department

Moscow, Russia

Location

Public Corporation "Clinical Hospital of Centrosouze"

Moscow, Russia

Location

Public Corporation "MedElitConsulting"

Moscow, Russia

Location

State Budget Healthcare Moscow Institution Clinical Scientific Center of Healthcare Department of Moscow

Moscow, Russia

Location

State Budgetary Healthcare Organization Clinical city hospital #24

Moscow, Russia

Location

Novosibirsk State Medical University, Clinical city hospital #12, Therapeutic Department

Novosibirsk, Russia

Location

Military Medical Academy of Ministry of Defense of Russian Federation n.a. S.M. Kirov, Infectious Diseases Department

Saint Petersburg, Russia

Location

Saint Petersburg State Budget Healthcare Institution Center of AIDS and Infectious Diseases Prevention and Control

Saint Petersburg, Russia

Location

Saint Petersburg State Budgetary Healthcare Institution Clinical Hospital of Infectious Diseases n.a. S.P. Botkin

Saint Petersburg, Russia

Location

Clinic of Samara State Medical University, Department of Infectious Diseases

Samara, Russia

Location

Public corporation Medical company "Gepatolog"

Samara, Russia

Location

Municipal Healthcare Institution Clinical city hospital #2 n.a. V.I. Razumovsky, Infectious Diseases Department

Saratov, Russia

Location

Stavropolsky Krai Clinical Hospital, Gastroenterology Department related to Hospital Therapy Department

Stavropol, Russia

Location

Stavropolsky State Medical University, Clinic of Gastroenterology, Hepatology and Pancreatology

Stavropol, Russia

Location

MeSH Terms

Conditions

Hepatitis C

Interventions

narlaprevir; Ritonavir; peginterferon alfa-2a; peginterferon alfa-2b; Ribavirin

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Ribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Mikhail Samsonov

  R-Pharm

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 5, 2019
• First Posted: February 7, 2019
• Study Start: May 7, 2014
• Primary Completion: March 23, 2016
• Study Completion: February 21, 2017
• Last Updated: February 7, 2019

Record last verified: 2019-02

Locations

RU (20)