<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/NCT01725542</url>
  </required_header>
  <id_info>
    <org_study_id>ANRS HC30 QUADRIH</org_study_id>
    <secondary_id>2012-002589-11</secondary_id>
    <nct_id>NCT01725542</nct_id>
  </id_info>
  <brief_title>Pilot Study to Assess the Efficacy of and Tolerance to a QUadruple Therapy to Treat HIV-HCV Coinfected Patients Previously Null Responders</brief_title>
  <acronym>QUADRIH</acronym>
  <official_title>Pilot Study to Assess the Efficacy and Tolerance to a QUadruple Therapy With Asunaprevir , Daclatasvir, Ribavirin and Pegylated Interferon Alpha-2a, in HIV-HCV Genotype 1 or 4 Coinfected Patients Previously Null Responders to a Standard Pegylated Interferon -Ribavirin Regimen</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>ANRS, Emerging Infectious Diseases</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>ANRS, Emerging Infectious Diseases</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Evaluation of efficacy and tolerance to a QUadruple therapy with Asunaprevir , Daclatasvir,&#xD;
      Ribavirin and pegylated Interferon alpha-2a, in HIV-HCV genotype 1 or 4 coinfected patients&#xD;
      previously null responders to a standard Pegylated Interferon -Ribavirin regimen.&#xD;
&#xD;
      The proportion of patients presenting cirrhosis (defined by a METAVIR F4 score on liver&#xD;
      biopsy and/or with hepatic impulse elastometry ≥ 15 kPa) will be limited to 50% of all of the&#xD;
      patients included&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The clinical trial is multi-center, national, Phase 2, open-label, single-arm.&#xD;
&#xD;
      Primary objective is to estimate the Sustained Virological Response rate (SVR) 12 weeks after&#xD;
      24 weeks of treatment with quadruple therapy combining Asunaprevir, Daclatasvir, Ribavirin&#xD;
      and Pegylated Interferon alpha-2a in HIV-HCV genotype 1 or 4 coinfected patients previously&#xD;
      null responders to a Pegylated Interferon -Ribavirin standard regimen.&#xD;
&#xD;
      Estimated enrolment is 65 patients during the enrolment period (9 months). The first 12&#xD;
      patients included will be on Raltegravir, Emtricitabine and Tenofovir and will participate to&#xD;
      the pharmacological sub-study.&#xD;
&#xD;
      Schedule of assessments:&#xD;
&#xD;
      Evaluation of inclusion criteria: 4 to 8 weeks Anti-HCV treatment: 28 weeks (or shorter&#xD;
      according to futility rules) Follow up: 24 weeks following the end of the treatment&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2012</start_date>
  <completion_date type="Actual">June 2014</completion_date>
  <primary_completion_date type="Actual">April 2014</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>HCV Sustained virological response rate</measure>
    <time_frame>wk40</time_frame>
    <description>the undetectable HCV RNA at wk40 (ie 12 weeks after the end of the quadritherapy associating Asunaprevir, Daclatasvir, Pegylated interferon alpha-2a and Ribavirin in case of premature total or partial discontinuation of HCV treatment, the principal endpoint will also be assessed at wk40)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of participants with adverse events as a measure of safety and tolerability</measure>
    <time_frame>during throughout all the study</time_frame>
    <description>Clinical and biological Adverse Events&#xD;
Treatment premature discontinuations&#xD;
Perceived symptoms (ANRS AC24 Symptom Perception Scale)&#xD;
Adherence (ANRS observance scale and effective dispensation by the pharmacy)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Kinetics of HCV Virological response</measure>
    <time_frame>wk4, wk5, wk6, wk8, wk12, wk16, wk20, wk24, wk28, wk32, wk40 and wk52</time_frame>
    <description>Measurements of HCV RNA at wk4, wk5, wk6, wk8, wk12, wk16, wk20, wk24, wk28, wk32, wk40 and wk52 (ie 24 weeks after the end of the treatment), globally or according to the HCV genotype (1 or 4) and sub-type (1a or 1b, 4a or 4c/d)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunological and virological evolution of HIV infection</measure>
    <time_frame>wk0, wk4, wk8, wk12,wk16, wk24, wk28, wk40 et wk52</time_frame>
    <description>HIV RNA levels&#xD;
CD4 and CD8</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evolution of cirrhosis (for cirrhotic patients)</measure>
    <time_frame>wk12, wk28, wk40 and wk52</time_frame>
    <description>Child-Pugh and MELD scores&#xD;
end stage liver disease onset&#xD;
hepatocarcinoma onset</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants with HIV and non HIV related clinical events</measure>
    <time_frame>through the study</time_frame>
    <description>AIDS classifying clinical events&#xD;
Severe non-AIDS clinical events.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimum Plasma Concentration (Cmin) of ribavirin</measure>
    <time_frame>wk4 and wk8</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Antiretroviral drugs</measure>
    <time_frame>wk0 and wk8</time_frame>
    <description>sub-group study ((focusing on patients on Raltegravir, Emtricitabine and Tenofovir)&#xD;
plasma drugs concentrations from H0 to H10&#xD;
Cmin (Minimum Plasma Concentration), Cmax (Maximum Plasma Concentration) and AUC (Area Under the Plasma Concentration)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of Asunaprevir and Daclatasvir</measure>
    <time_frame>wk8</time_frame>
    <description>sub-group study (focusing on patients on Raltegravir, Emtricitabine, Tenofovir)&#xD;
plasma Asunaprevir and Daclatasvir concentrations from H0 to H10&#xD;
Cmin, Cmax and AUC</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">75</enrollment>
  <condition>HCV-HIV Co-Infection</condition>
  <arm_group>
    <arm_group_label>Asunaprevir, Daclatasvir, Ribavirin and Peginterferon alfa-2a</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Lead-in&quot; Phase: day 0 to week 4 PegInterferon alpha-2a + Ribavirin&#xD;
Quadruple therapy: week 4 to week 28 Asunaprevir + Daclatasvir + PegInterferon alpha-2a + Ribavirin</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Asunaprevir, Daclatasvir, Ribavirin and Peginterferon alfa-2a</intervention_name>
    <arm_group_label>Asunaprevir, Daclatasvir, Ribavirin and Peginterferon alfa-2a</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult ≥18 years with confirmed HIV-1 or 2 infection&#xD;
&#xD;
          -  Infection with HCV genotype 1 or 4 only, confirmed and with detectable HCV-RNA ≥ 1000&#xD;
             IU/mL at screening.&#xD;
&#xD;
          -  Null responders to a previous treatment with Peginterferon and Ribavirin, defined by a&#xD;
             fall of less than 2 log10 IU/ml HCV-RNA from baseline to week 12.&#xD;
&#xD;
          -  Stable antiretroviral treatment for &gt; 1 month at screening containing any of the&#xD;
             following drugs: Raltegravir, Enfuvirtide, Tenofovir-Emtricitabine,&#xD;
             Abacavir-Lamivudine.&#xD;
&#xD;
          -  CD4 &gt; 200 /mm3 and &gt; 15% at screening&#xD;
&#xD;
          -  HIV-RNA &lt; 400 copies/mL from ≥ 3 months at screening&#xD;
&#xD;
          -  Any liver fibrosis stage,&#xD;
&#xD;
          -  with the assessment of the presence or not of cirrhosis at screening:&#xD;
&#xD;
               -  previous liver biopsy exhibiting cirrhosis lesions (METAVIR F4), and/or&#xD;
&#xD;
               -  significant liver biopsy (cumulative length ≥ 15 mm and ≥ 6 portal spaces),&#xD;
                  within 18 months and after the end of last HCV treatment, and/or&#xD;
&#xD;
               -  significant and reliable liver stiffness assessment (Fibroscan®) within 6 months&#xD;
                  (at least 10 measures with IQR less then 25% of the mean value and a success rate&#xD;
                  of at least 80%)&#xD;
&#xD;
          -  cirrhosis being defined as a METAVIR score F4 on liver biopsy and/or liver elastometry&#xD;
             ≥ 15 kPa&#xD;
&#xD;
          -  the proportion of patients with cirrhosis (METAVIR F4) is limited to 50% of all&#xD;
             patients.&#xD;
&#xD;
          -  Body weight ≥ 40 kg and ≤125 kg&#xD;
&#xD;
          -  Male patients, female patients with child-bearing potential and their heterosexual&#xD;
             partners must use adequate contraception from 1 month before initiation of treatment&#xD;
             to 7 months following the end of treatment for men and to 4 months following the end&#xD;
             of treatment for women.&#xD;
&#xD;
          -  Informed and signed consent&#xD;
&#xD;
          -  For participating patients, informed and signed consent for the pharmacokinetic&#xD;
             sub-study&#xD;
&#xD;
          -  Patients affiliated to the National Health Insurance or covered by Universal Medical&#xD;
             Coverage&#xD;
&#xD;
          -  For the first 12 patients included (who will participate to the pharmacological&#xD;
             substudy): stable antiretroviral treatment for &gt; 1 month at screening, with&#xD;
             Raltegravir+ Emtricitabine+ Tenofovir&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  CHILD B and C cirrhosis, past history of decompensated cirrhosis. Patients with CHILD&#xD;
             A cirrhosis must demonstrate the absence of significant oesophageal varices (Stages&#xD;
             2-3) on an upper gastrointestinal endoscopy ≤ 12 months&#xD;
&#xD;
          -  Positive HBs antigenemia with HBV DNA &gt; 1000 IU/ml((if positive AgHBs with HBV DNA ≤&#xD;
             1000 IU/mL, patient will be included provided it is treated with Ténofovir)&#xD;
&#xD;
          -  Pregnant women, breast-feeding women&#xD;
&#xD;
          -  Refusal of adequate contraception&#xD;
&#xD;
          -  Contra-indication to Ribavirin, including hypersensitivity reaction to Ribavirin&#xD;
&#xD;
          -  Contra-indication to Peginterferon, including psychiatric contra-indications. Patients&#xD;
             with significant psychiatric past history, notably severe depression requiring&#xD;
             hospitalization or suicide attempt, cannot be included unless they undergo a&#xD;
             psychiatric evaluation and obtain a specific authorization for the use of interferon.&#xD;
&#xD;
          -  Premature discontinuation (during the first six months) of a previous HCV treatment&#xD;
             for toxicity. Patients who have stopped a previous treatment for severe anaemia or&#xD;
             neutropenia can enter the study if erythropoietin or granulocyte growth factor had not&#xD;
             been used during the previous treatment&#xD;
&#xD;
          -  Previous HCV therapy including HCV NS3 protease inhibitor&#xD;
&#xD;
          -  Severe pre-existing cardiac or pulmonary disease&#xD;
&#xD;
          -  History of organ transplant&#xD;
&#xD;
          -  Acute CDC stage C opportunistic infection occurring within the previouW6 months&#xD;
&#xD;
          -  Any active malignant disease including hepatocellular carcinoma for which a specific&#xD;
             assessment is required at screening&#xD;
&#xD;
          -  Alcohol intake that may represent an obstacle for the participation of the subject in&#xD;
             the study&#xD;
&#xD;
          -  Substance abuse that may represent an obstacle for the participation of the subject in&#xD;
             the study. Stabilized patients included in a substitution program can participate in&#xD;
             the study&#xD;
&#xD;
          -  Patients with previous observance problem unable to observe the study procedures&#xD;
&#xD;
          -  Participation in another clinical trial within the previous 30 days&#xD;
&#xD;
          -  Haemoglobin &lt; 90 g/L&#xD;
&#xD;
          -  Platelets &lt; 50 000 /mm3&#xD;
&#xD;
          -  Neutrophil count &lt; 750 /mm3&#xD;
&#xD;
          -  Renal insufficiency defined by an estimated Glomerular Filtration Rate &lt; 50 mL/mn&#xD;
             (MDRD equation)&#xD;
&#xD;
          -  Absence of antiretroviral treatment or antiretroviral treatment different from the&#xD;
             authorized combinations&#xD;
&#xD;
          -  Associated medication likely to interfere with any of the study drugs such as CPY3A4&#xD;
             inducers (rifampin, Millepertuis)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lionel Piroth, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>CHU Dijon</affiliation>
  </overall_official>
  <location>
    <facility>
      <address>
        <city>All the Regions of the Country (33 Centers)</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <link>
    <url>http://www.anrs.fr</url>
    <description>Related Info</description>
  </link>
  <verification_date>March 2014</verification_date>
  <study_first_submitted>October 22, 2012</study_first_submitted>
  <study_first_submitted_qc>November 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 14, 2012</study_first_posted>
  <last_update_submitted>September 5, 2014</last_update_submitted>
  <last_update_submitted_qc>September 5, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 8, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>HCV-HIV Co-Infection</keyword>
  <keyword>Quadruple therapy</keyword>
  <keyword>null responder to a standard Pegylated interferon/Ribavirin regimen</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Coinfection</mesh_term>
    <mesh_term>HIV Infections</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ribavirin</mesh_term>
    <mesh_term>Peginterferon alfa-2a</mesh_term>
    <mesh_term>Asunaprevir</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/NCT01725542
org study id: ANRS HC30 QUADRIH
secondary id: 2012-002589-11
nct id: NCT01725542
lead sponsor: 
collaborator: 
has dmc: Yes
Evaluation of efficacy and tolerance to a QUadruple therapy with Asunaprevir , Daclatasvir,
      Ribavirin and pegylated Interferon alpha-2a, in HIV-HCV genotype 1 or 4 coinfected patients
      previously null responders to a standard Pegylated Interferon -Ribavirin regimen.

      The proportion of patients presenting cirrhosis (defined by a METAVIR F4 score on liver
      biopsy and/or with hepatic impulse elastometry ≥ 15 kPa) will be limited to 50% of all of the
      patients included
The clinical trial is multi-center, national, Phase 2, open-label, single-arm.

      Primary objective is to estimate the Sustained Virological Response rate (SVR) 12 weeks after
      24 weeks of treatment with quadruple therapy combining Asunaprevir, Daclatasvir, Ribavirin
      and Pegylated Interferon alpha-2a in HIV-HCV genotype 1 or 4 coinfected patients previously
      null responders to a Pegylated Interferon -Ribavirin standard regimen.

      Estimated enrolment is 65 patients during the enrolment period (9 months). The first 12
      patients included will be on Raltegravir, Emtricitabine and Tenofovir and will participate to
      the pharmacological sub-study.

      Schedule of assessments:

      Evaluation of inclusion criteria: 4 to 8 weeks Anti-HCV treatment: 28 weeks (or shorter
      according to futility rules) Follow up: 24 weeks following the end of the treatment
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: HCV Sustained virological response rate
time frame: wk40
description: the undetectable HCV RNA at wk40 (ie 12 weeks after the end of the quadritherapy associating Asunaprevir, Daclatasvir, Pegylated interferon alpha-2a and Ribavirin in case of premature total or partial discontinuation of HCV treatment, the principal endpoint will also be assessed at wk40)
measure: Number of participants with adverse events as a measure of safety and tolerability
time frame: during throughout all the study
description: Clinical and biological Adverse Events
Treatment premature discontinuations
Perceived symptoms (ANRS AC24 Symptom Perception Scale)
Adherence (ANRS observance scale and effective dispensation by the pharmacy)
measure: Kinetics of HCV Virological response
time frame: wk4, wk5, wk6, wk8, wk12, wk16, wk20, wk24, wk28, wk32, wk40 and wk52
description: Measurements of HCV RNA at wk4, wk5, wk6, wk8, wk12, wk16, wk20, wk24, wk28, wk32, wk40 and wk52 (ie 24 weeks after the end of the treatment), globally or according to the HCV genotype (1 or 4) and sub-type (1a or 1b, 4a or 4c/d)
measure: Immunological and virological evolution of HIV infection
time frame: wk0, wk4, wk8, wk12,wk16, wk24, wk28, wk40 et wk52
description: HIV RNA levels
CD4 and CD8
measure: Evolution of cirrhosis (for cirrhotic patients)
time frame: wk12, wk28, wk40 and wk52
description: Child-Pugh and MELD scores
end stage liver disease onset
hepatocarcinoma onset
measure: Number of Participants with HIV and non HIV related clinical events
time frame: through the study
description: AIDS classifying clinical events
Severe non-AIDS clinical events.
measure: Minimum Plasma Concentration (Cmin) of ribavirin
time frame: wk4 and wk8
measure: Pharmacokinetics of Antiretroviral drugs
time frame: wk0 and wk8
description: sub-group study ((focusing on patients on Raltegravir, Emtricitabine and Tenofovir)
plasma drugs concentrations from H0 to H10
Cmin (Minimum Plasma Concentration), Cmax (Maximum Plasma Concentration) and AUC (Area Under the Plasma Concentration)
measure: Pharmacokinetics of Asunaprevir and Daclatasvir
time frame: wk8
description: sub-group study (focusing on patients on Raltegravir, Emtricitabine, Tenofovir)
plasma Asunaprevir and Daclatasvir concentrations from H0 to H10
Cmin, Cmax and AUC
arm group label: Asunaprevir, Daclatasvir, Ribavirin and Peginterferon alfa-2a
arm group type: Experimental
description: Lead-in" Phase: day 0 to week 4 PegInterferon alpha-2a + Ribavirin
Quadruple therapy: week 4 to week 28 Asunaprevir + Daclatasvir + PegInterferon alpha-2a + Ribavirin
intervention type: Drug
intervention name: Asunaprevir, Daclatasvir, Ribavirin and Peginterferon alfa-2a
arm group label: Asunaprevir, Daclatasvir, Ribavirin and Peginterferon alfa-2a
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lionel Piroth, MD PhD
role: Principal Investigator
affiliation: CHU Dijon
facility: 
country: France
url: http://www.anrs.fr
description: Related Info
responsible party type: Sponsor
mesh term: Coinfection
mesh term: HIV Infections
mesh term: Ribavirin
mesh term: Peginterferon alfa-2a
mesh term: Asunaprevir