<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03833362</url>
  </required_header>
  <id_info>
    <org_study_id>CJ05013008</org_study_id>
    <nct_id>NCT03833362</nct_id>
  </id_info>
  <brief_title>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)</brief_title>
  <acronym>PIONEER</acronym>
  <official_title>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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>R-Pharm</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>R-Pharm</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study was to confirm that combination of narlaprevir (NVR) and ritonavir&#xD;
      (RTV) used as a metabolic inhibitor with pegylated interferon (PEG-INF) and ribavirin (RBV)&#xD;
      leads to a superior Sustained Virological Response (SVR) rate compared to treatment with&#xD;
      pegylated interferon and ribavirin in treatment-naïve and treatment failure patient&#xD;
      populations.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study included 3 time periods:&#xD;
&#xD;
        -  Screening period with duration up to 3 weeks during which study eligibility was&#xD;
           confirmed.&#xD;
&#xD;
        -  Double-blind treatment period: all eligible patients divided into Treatment naive and&#xD;
           Previous treatment failure subpopulations were randomized in one of the two parallel&#xD;
           treatment arms in 2:1 ratio:&#xD;
&#xD;
             1. Arm 1: All patients received the combination of NVR/RTV + PEG-INF/RBV for 12 weeks&#xD;
                that was followed by PEG-INF and RBV for 12 weeks (total treatment duration of 24&#xD;
                weeks).&#xD;
&#xD;
             2. Arm 2: Therapy with PEG-INF and RBV (standard of care) for 48 weeks with placebo&#xD;
                equivalent for NVR and RTV for the first 12 weeks.&#xD;
&#xD;
                Different types of pegylated interferon could be used for treatment. The assignment&#xD;
                to the pegylated interferon alfa-2a or pegylated interferon alfa-2b treatment will&#xD;
                be also performed using web system, in a 1:1 ratio.&#xD;
&#xD;
                Clinical efficacy of each arm were assessed 24 weeks after the end of treatment&#xD;
                with undetectable hepatitis C virus (HCV) RNA by lower limit of detection (LOD) 24&#xD;
                weeks following the end of treatment. In case of serum HCV-RNA levels were greater&#xD;
                than or equal to 100 IU/mL at Week 12 of treatment (Arm 1) or serum HCV RNA&#xD;
                declined from baseline less than 2 log after 12 weeks of treatment or serum HCV-RNA&#xD;
                levels ≥LOD at week 24 of treatment (Arm 2) patients were considered non-responders&#xD;
                and discontinued participation in the study. In case of satisfactory treatment&#xD;
                response all patients were additionally administered with PEG-INF/RBV for 12 weeks&#xD;
                (total of 24 weeks of treatment) in Arm 1, and for 36 weeks (total of 48 weeks of&#xD;
                treatment) in Arm 2.&#xD;
&#xD;
        -  Follow-up period during which patients do not receive any study medication. The duration&#xD;
           of the follow-up period after the end of study treatment will be 24 weeks.&#xD;
&#xD;
      Overall, each patient will participate in the study for approximately up to 75 weeks from the&#xD;
      time the patient signs the Informed Consent Form through the final visit&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 7, 2014</start_date>
  <completion_date type="Actual">February 21, 2017</completion_date>
  <primary_completion_date type="Actual">March 23, 2016</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of patients with Sustained Virologic Response (SVR24)</measure>
    <time_frame>Week 24 after the end of treatment</time_frame>
    <description>HCV RNA undetectable by Limit of detection (LOD)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients who achieve the Rapid Virological Response (RVR)</measure>
    <time_frame>Week 4 of treatment</time_frame>
    <description>HCV RNA &lt; LOD</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients who achieve the Early Virological Response (EVR)</measure>
    <time_frame>Week 12 of treatment</time_frame>
    <description>HCV RNA &lt;LOD</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients who achieve the End of Treatment Response (ETR)</measure>
    <time_frame>Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)</time_frame>
    <description>HCV RNA &lt;LOD</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients who achieve the SVR12</measure>
    <time_frame>Week 12 after the end of treatment</time_frame>
    <description>HCV RNA undetectable (by LOD)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients who develop viral breakthrough</measure>
    <time_frame>Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients who develop relapse</measure>
    <time_frame>Week 24 after the end of treatment</time_frame>
    <description>HCV RNA undetectable by LOD at end of treatment with subsequent detectable HCV RNA</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients who develop anemia</measure>
    <time_frame>Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)</time_frame>
    <description>Anemia is defined as as Hb &lt;10g/dL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients who develop neutropenia</measure>
    <time_frame>Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)</time_frame>
    <description>Neutropenia is defined as neutrophils &lt;0.75x109/L</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">420</enrollment>
  <condition>Hepatitis C</condition>
  <arm_group>
    <arm_group_label>NVR/RTV + PEG-INF/RBV (Treatment Naive)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Narlaprevir - 2 tablets once a day orally&#xD;
Ritonavir - 1 capsule once a day orally&#xD;
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.&#xD;
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</description>
  </arm_group>
  <arm_group>
    <arm_group_label>PEG-INF/RBV (Treatment Naive)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Placebo Narlaprevir - 2 tablets once a day orally&#xD;
Placebo Ritonavir - 1 capsule once a day orally&#xD;
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.&#xD;
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</description>
  </arm_group>
  <arm_group>
    <arm_group_label>NVR/RTV + PEG-INF/RBV (Treatment Failure)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Narlaprevir - 2 tablets once a day orally&#xD;
Ritonavir - 1 capsule once a day orally&#xD;
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.&#xD;
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</description>
  </arm_group>
  <arm_group>
    <arm_group_label>PEG-INF/RBV (Treatment Failure)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Placebo Narlaprevir - 2 tablets once a day orally&#xD;
Placebo Ritonavir - 1 capsule once a day orally&#xD;
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.&#xD;
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</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Narlaprevir</intervention_name>
    <description>yellow film-coated 100 mg. tablets</description>
    <arm_group_label>NVR/RTV + PEG-INF/RBV (Treatment Failure)</arm_group_label>
    <arm_group_label>NVR/RTV + PEG-INF/RBV (Treatment Naive)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ritonavir</intervention_name>
    <description>100 mg tablets encapsulates in gelatin capsules (for blinding purposes)</description>
    <arm_group_label>NVR/RTV + PEG-INF/RBV (Treatment Failure)</arm_group_label>
    <arm_group_label>NVR/RTV + PEG-INF/RBV (Treatment Naive)</arm_group_label>
    <other_name>Norvir</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Narlaprevir</intervention_name>
    <description>yellow film-coated 100 mg. tablets identical to Narlaprevir tablets</description>
    <arm_group_label>PEG-INF/RBV (Treatment Failure)</arm_group_label>
    <arm_group_label>PEG-INF/RBV (Treatment Naive)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Ritonavir</intervention_name>
    <description>100 mg lactose/ cellulose tablets encapsulated in gelatin capsules (for blinding purposes) identical to Ritonavir capsules</description>
    <arm_group_label>PEG-INF/RBV (Treatment Failure)</arm_group_label>
    <arm_group_label>PEG-INF/RBV (Treatment Naive)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b</intervention_name>
    <description>180µg for subcutaneous injections in 0.5 ml syrettes / 1.5 µg/kg for subcutaneous injections in 50µkg, 80µkg,100µkg, 120µkg, 150µkg in vials</description>
    <arm_group_label>NVR/RTV + PEG-INF/RBV (Treatment Failure)</arm_group_label>
    <arm_group_label>NVR/RTV + PEG-INF/RBV (Treatment Naive)</arm_group_label>
    <arm_group_label>PEG-INF/RBV (Treatment Failure)</arm_group_label>
    <arm_group_label>PEG-INF/RBV (Treatment Naive)</arm_group_label>
    <other_name>Pegasys</other_name>
    <other_name>PegIntron</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ribavirin</intervention_name>
    <description>hard gelatin, white 200mg. capsules&#xD;
Weight-based dose was 1000 mg/day (patient weight &lt;75 kg) or 1200 mg/day (patient weight ≥75 kg) with Peginterferon alfa-2a and 800 mg/day (patient weight &lt;65 kg) - 1400 (patient weight &gt;105 kg) mg/day with Peginterferon alfa-2b</description>
    <arm_group_label>NVR/RTV + PEG-INF/RBV (Treatment Failure)</arm_group_label>
    <arm_group_label>NVR/RTV + PEG-INF/RBV (Treatment Naive)</arm_group_label>
    <arm_group_label>PEG-INF/RBV (Treatment Failure)</arm_group_label>
    <arm_group_label>PEG-INF/RBV (Treatment Naive)</arm_group_label>
    <other_name>Rebetol</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Body weight ≥ 40 and ≤ 125 kg;&#xD;
&#xD;
          -  Documented infection with HCV genotype 1 (Mixed infections with other genotypes are&#xD;
             not eligible):&#xD;
&#xD;
               1. treatment naïve (to interferon and ribavirin); or&#xD;
&#xD;
               2. treatment failure patients (patients must have received interferon/ribavirin at&#xD;
                  standard doses for a minimum of 12 weeks);&#xD;
&#xD;
          -  Minimum HCV-RNA level of ≥10,000 IU at baseline;&#xD;
&#xD;
          -  No evidence of cirrhosis; availability at Baseline of at least one of the following&#xD;
             tests negative results:&#xD;
&#xD;
               1. Liver biopsy showing no cirrhosis (not later than within 3 years prior to&#xD;
                  Baseline) or&#xD;
&#xD;
               2. FibroScan elasticity score &lt; 12.5 kPa 12 months prior to baseline or&#xD;
&#xD;
               3. FibroTest &lt; 0.75 12 months prior to baseline and aspartate aminotransferase&#xD;
                  (AST)/platelet ratio (APRI) of ≤ 1 during screening&#xD;
&#xD;
          -  Using acceptable contraception methods for both partners from enrollment into the&#xD;
             study until 6 months following the end of treatment;&#xD;
&#xD;
          -  Willingness to give written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous treatment with any HCV NS3-specific protease inhibitor and/ or other direct&#xD;
             antiviral agents (e.g. HCV polymerase inhibitors);&#xD;
&#xD;
          -  Treatment for HCV infection 30 days before the enrolment;&#xD;
&#xD;
          -  Use of prohibited medications within 2 weeks prior to start of study medications&#xD;
             (inducers or substrates of CYP3A4);&#xD;
&#xD;
          -  Findings suspicious for hepatocellular carcinoma (HCC);&#xD;
&#xD;
          -  Hepatic failure at present or in history;&#xD;
&#xD;
          -  Auto-immune hepatitis in history;&#xD;
&#xD;
          -  Anti-nuclear antibodies (ANA) titers &gt; 1:320;&#xD;
&#xD;
          -  Evidence of gallstones, choledocholithiasis and calcified gallbladder;&#xD;
&#xD;
          -  HBsAg positive;&#xD;
&#xD;
          -  HIV positive;&#xD;
&#xD;
          -  Serum hemoglobin of &lt;13g/dL for males and &lt;12g/dL for females;&#xD;
&#xD;
          -  Neutrophils &lt;1500/mm3 (&lt;1,5х109/L) at Screening;&#xD;
&#xD;
          -  Platelets &lt;150000/mm3 (&lt;150х109/L) at Screening (patients with a platelet count&#xD;
             &gt;100,000/mm3 (&gt;100х109/L) but less than 150,000/mm3 (150х109/L) can be included in the&#xD;
             study in case a Fibroscan or FibroTest or liver biopsy during the study screening&#xD;
             period shows no cirrhosis)&#xD;
&#xD;
          -  Total bilirubin &gt;1.6 mg/dL (&gt;27.36 µmol/L) unless history of Gilbert's disease. If&#xD;
             Gilbert's disease is the proposed etiology, this must be documented in the subject's&#xD;
             chart;&#xD;
&#xD;
          -  Direct bilirubin &gt;1.5 x upper limit of normal (ULN) of the laboratory reference range&#xD;
             at Screening;&#xD;
&#xD;
          -  Serum albumin &lt; lower limit of normal (LLN) of laboratory reference range at&#xD;
             Screening;&#xD;
&#xD;
          -  Serum creatinine &gt;ULN of the laboratory reference at Screening;&#xD;
&#xD;
          -  Serum aspartate aminotransferase (AST) / alanine aminotransferase (ALT) &gt;5 x ULN of&#xD;
             the laboratory reference range at Screening;&#xD;
&#xD;
          -  Thyroid stimulating hormone (TSH) &gt;1.2 ULN or &lt;0.8 LLN;&#xD;
&#xD;
          -  Contraindications to pegylated interferon, ribavirin and/or ritonavir treatment;&#xD;
&#xD;
          -  Hypersensitivity to any of the study drugs;&#xD;
&#xD;
          -  Active or suspected cancer;&#xD;
&#xD;
          -  Psychiatric disease (moderate or severe depression, schizophrenia, bipolar disorder et&#xD;
             al);&#xD;
&#xD;
          -  Previous suicide attempt or suicidal ideation;&#xD;
&#xD;
          -  Drug addiction;&#xD;
&#xD;
          -  Opiate agonist substitution therapy;&#xD;
&#xD;
          -  History of active gout within the past year;&#xD;
&#xD;
          -  Organ transplant (except of cornea and hair transplant);&#xD;
&#xD;
          -  Pregnant or nursing women;&#xD;
&#xD;
          -  Men whose female partners are pregnant or planning pregnancy;&#xD;
&#xD;
          -  Any medical condition that could interfere with the patient's participation and&#xD;
             completion of the study;&#xD;
&#xD;
          -  Use of other investigational drugs/ participation in other clinical trial within 30&#xD;
             days before the enrolment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mikhail Samsonov</last_name>
    <role>Study Director</role>
    <affiliation>R-Pharm</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>South-Ural State Medical University, Clinic of Medical Academy, Infectious Diseases Department</name>
      <address>
        <city>Chelyabinsk</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kazan State Medical Academy, Republican Clinical Hospital of Infectious Diseases n.a. A.F. Agafonov</name>
      <address>
        <city>Kazan</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Federal Budget Science Institution Central Science and Research Institute of Epidemiology of RosPotrebNadzor</name>
      <address>
        <city>Moscow</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Federal State Budget Healthcare Institution Central Clinical Hospital of Russian Academy of Science</name>
      <address>
        <city>Moscow</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>First Moscow State Medical University n.a. I.M. Sechenov, Clinic of Nephrology, Internal and Professional Diseases n.a. E.M. Tarleev</name>
      <address>
        <city>Moscow</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>First Moscow State Medical University n.a. I.M. Sechenov, Propedeutics of Internal Diseases Department</name>
      <address>
        <city>Moscow</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Moscow State Medical Stomatological University n.a. A. I. Evdokimov, Clinical Infectious Hospital #1, Clinical Infections Department</name>
      <address>
        <city>Moscow</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Public Corporation &quot;Clinical Hospital of Centrosouze&quot;</name>
      <address>
        <city>Moscow</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Public Corporation &quot;MedElitConsulting&quot;</name>
      <address>
        <city>Moscow</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>State Budget Healthcare Moscow Institution Clinical Scientific Center of Healthcare Department of Moscow</name>
      <address>
        <city>Moscow</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>State Budgetary Healthcare Organization Clinical city hospital #24</name>
      <address>
        <city>Moscow</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novosibirsk State Medical University, Clinical city hospital #12, Therapeutic Department</name>
      <address>
        <city>Novosibirsk</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Military Medical Academy of Ministry of Defense of Russian Federation n.a. S.M. Kirov, Infectious Diseases Department</name>
      <address>
        <city>Saint Petersburg</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Petersburg State Budget Healthcare Institution Center of AIDS and Infectious Diseases Prevention and Control</name>
      <address>
        <city>Saint Petersburg</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Saint Petersburg State Budgetary Healthcare Institution Clinical Hospital of Infectious Diseases n.a. S.P. Botkin</name>
      <address>
        <city>Saint Petersburg</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinic of Samara State Medical University, Department of Infectious Diseases</name>
      <address>
        <city>Samara</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Public corporation Medical company &quot;Gepatolog&quot;</name>
      <address>
        <city>Samara</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Municipal Healthcare Institution Clinical city hospital #2 n.a. V.I. Razumovsky, Infectious Diseases Department</name>
      <address>
        <city>Saratow</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stavropolsky Krai Clinical Hospital, Gastroenterology Department related to Hospital Therapy Department</name>
      <address>
        <city>Stavropol'</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stavropolsky State Medical University, Clinic of Gastroenterology, Hepatology and Pancreatology</name>
      <address>
        <city>Stavropol'</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Russian Federation</country>
  </location_countries>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>February 5, 2019</study_first_submitted>
  <study_first_submitted_qc>February 5, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 7, 2019</study_first_posted>
  <last_update_submitted>February 5, 2019</last_update_submitted>
  <last_update_submitted_qc>February 5, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 7, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis A</mesh_term>
    <mesh_term>Hepatitis C</mesh_term>
    <mesh_term>Hepatitis C, Chronic</mesh_term>
    <mesh_term>Hepatitis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Interferons</mesh_term>
    <mesh_term>Ritonavir</mesh_term>
    <mesh_term>Ribavirin</mesh_term>
    <mesh_term>Interferon-alpha</mesh_term>
    <mesh_term>Interferon alpha-2</mesh_term>
    <mesh_term>Peginterferon alfa-2a</mesh_term>
    <mesh_term>Peginterferon alfa-2b</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03833362
org study id: CJ05013008
nct id: NCT03833362
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
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
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Number of patients with Sustained Virologic Response (SVR24)
time frame: Week 24 after the end of treatment
description: HCV RNA undetectable by Limit of detection (LOD)
measure: Number of patients who achieve the Rapid Virological Response (RVR)
time frame: Week 4 of treatment
description: HCV RNA < LOD
measure: Number of patients who achieve the Early Virological Response (EVR)
time frame: Week 12 of treatment
description: HCV RNA <LOD
measure: Number of patients who achieve the End of Treatment Response (ETR)
time frame: Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)
description: HCV RNA <LOD
measure: Number of patients who achieve the SVR12
time frame: Week 12 after the end of treatment
description: HCV RNA undetectable (by LOD)
measure: Number of patients who develop viral breakthrough
time frame: Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)
description: 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
measure: Number of patients who develop relapse
time frame: Week 24 after the end of treatment
description: HCV RNA undetectable by LOD at end of treatment with subsequent detectable HCV RNA
measure: Number of patients who develop anemia
time frame: Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)
description: Anemia is defined as as Hb <10g/dL
measure: Number of patients who develop neutropenia
time frame: Week 24 of treatment (Arm 1), Week 48 of treatment (Arm 2)
description: Neutropenia is defined as neutrophils <0.75x109/L
arm group label: NVR/RTV + PEG-INF/RBV (Treatment Naive)
arm group type: Experimental
description: 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
arm group label: PEG-INF/RBV (Treatment Naive)
arm group type: Active Comparator
description: 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
arm group label: NVR/RTV + PEG-INF/RBV (Treatment Failure)
arm group type: Experimental
description: 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
arm group label: PEG-INF/RBV (Treatment Failure)
arm group type: Active Comparator
description: 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
intervention type: Drug
intervention name: Narlaprevir
description: yellow film-coated 100 mg. tablets
arm group label: NVR/RTV + PEG-INF/RBV (Treatment Failure)
arm group label: NVR/RTV + PEG-INF/RBV (Treatment Naive)
intervention type: Drug
intervention name: Ritonavir
description: 100 mg tablets encapsulates in gelatin capsules (for blinding purposes)
arm group label: NVR/RTV + PEG-INF/RBV (Treatment Failure)
arm group label: NVR/RTV + PEG-INF/RBV (Treatment Naive)
other name: Norvir
intervention type: Drug
intervention name: Placebo Narlaprevir
description: yellow film-coated 100 mg. tablets identical to Narlaprevir tablets
arm group label: PEG-INF/RBV (Treatment Failure)
arm group label: PEG-INF/RBV (Treatment Naive)
intervention type: Drug
intervention name: Placebo Ritonavir
description: 100 mg lactose/ cellulose tablets encapsulated in gelatin capsules (for blinding purposes) identical to Ritonavir capsules
arm group label: PEG-INF/RBV (Treatment Failure)
arm group label: PEG-INF/RBV (Treatment Naive)
intervention type: Drug
intervention name: Pegylated interferon alfa-2a/ Pegylated interferon alfa-2b
description: 180µg for subcutaneous injections in 0.5 ml syrettes / 1.5 µg/kg for subcutaneous injections in 50µkg, 80µkg,100µkg, 120µkg, 150µkg in vials
arm group label: NVR/RTV + PEG-INF/RBV (Treatment Failure)
arm group label: NVR/RTV + PEG-INF/RBV (Treatment Naive)
arm group label: PEG-INF/RBV (Treatment Failure)
arm group label: PEG-INF/RBV (Treatment Naive)
other name: Pegasys
other name: PegIntron
intervention type: Drug
intervention name: Ribavirin
description: 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
arm group label: NVR/RTV + PEG-INF/RBV (Treatment Failure)
arm group label: NVR/RTV + PEG-INF/RBV (Treatment Naive)
arm group label: PEG-INF/RBV (Treatment Failure)
arm group label: PEG-INF/RBV (Treatment Naive)
other name: Rebetol
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Mikhail Samsonov
role: Study Director
affiliation: R-Pharm
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country: Russian Federation
responsible party type: Sponsor
mesh term: Hepatitis A
mesh term: Hepatitis C
mesh term: Hepatitis C, Chronic
mesh term: Hepatitis
mesh term: Interferons
mesh term: Ritonavir
mesh term: Ribavirin
mesh term: Interferon-alpha
mesh term: Interferon alpha-2
mesh term: Peginterferon alfa-2a
mesh term: Peginterferon alfa-2b