<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/NCT01686789</url>
  </required_header>
  <id_info>
    <org_study_id>RC08-064</org_study_id>
    <nct_id>NCT01686789</nct_id>
  </id_info>
  <brief_title>Randomized Controlled Open Label Trial of Peg Alpha 2a Interferon and Adjusted-dose of Ribavirin vs. Standard Therapy in the Treatment of Naive Chronic Hepatitis C Patients Infected With Genotype 4</brief_title>
  <official_title>Randomized Controlled Open Label Trial of Peg Alpha 2a Interferon and Adjusted-dose of Ribavirin vs. Standard Therapy in the Treatment of Naive Chronic Hepatitis C Patients Infected With Genotype 4</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>King Abdulaziz Medical City</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>King Abdulaziz Medical City</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study aims to study the outcome of pharmacokinetics-adjusted dose ribavirin (plus pegIFN)&#xD;
      on the SVR in chronic HCV patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background: The introduction of Peg interferon and Ribavirin (an oral nucleoside analogue)&#xD;
      for chronic Hepatitis C has led to the concept that chronic hepatitis C (HCV) is a curable&#xD;
      disease. Improvement of treatment efficacy is still a major challenge. Optimal Ribavirin&#xD;
      doses are essential to achieve SVR (sustained virological response). A recent trial showed&#xD;
      significantly higher sustained virological response (SVR) in patients receiving 15.2&#xD;
      mg/kg/day of Ribavirin compared with 13.3 mg/kg/day. Ribavirin was given in combination with&#xD;
      Peg interferon alpha-2b (1). A small pilot study, in which 10 patients with Chronic Hepatitis&#xD;
      C genotype 1 were treated with Ribavirin dosage up to 3600 mg/day- mean of 2540 mg/day- plus&#xD;
      Peg-interferon alpha-2a, achieving a target concentration of Ribavirin &gt;15 micromol before W&#xD;
      12, led to 90% of SVR(2). All patients managed to complete the one year treatment period but&#xD;
      all needed EPO and two were transfused.&#xD;
&#xD;
      Patient's global exposure to Ribavirin as evaluated by the area under the curve (AUC) seems&#xD;
      more pertinent in terms of exposure-effect relationship than measuring Ribavirin level at any&#xD;
      single time point. A recent study showed in HCV patients infected with genotype 1 that&#xD;
      Ribavirin plasma exposure after the first dose (i.e., interdose AUC0-12h or abbreviated&#xD;
      AUC0-4h) was significantly and strongly linked with SVR, whereas AUCs determined at W12 and&#xD;
      W24 and trough concentrations at Day 0 and W12 were not (3).&#xD;
&#xD;
      Therefore, we propose a randomized controlled trial to investigate whether adjusted Ribavirin&#xD;
      doses based on AUC0-4h obtained at D-7 after 600mg dose of Ribavirin versus fixed standard&#xD;
      doses can improve outcome in treatment of chronic hepatitis C naïve patients infected with&#xD;
      genotype 4.&#xD;
&#xD;
      Methodology: After AUC0-4h has been determined at D-7 (7 days before randomization) for 190&#xD;
      genotype 4 patients recruited into the trial, the patients are randomized into two groups:&#xD;
      Group A: to receive standard dose of Ribavirin 1000-1200 mg/day) and Group B: to receive&#xD;
      adjusted-dose of Ribavirin according to AUC0-4h. The individual calculated dose should be&#xD;
      administered for each patient beginning on the first day of treatment. Both groups will&#xD;
      receive combination treatment with peginterferon alpha 2a 180 mcg/week for a total of 48&#xD;
      weeks.&#xD;
&#xD;
      Both treatment groups will receive Darbepoetin if subsequent Hb is &lt; 11 g/dl for males and&#xD;
      females. Our main inclusion criteria will be: patients 18-70 years old with serological&#xD;
      evidence of chronic hepatitis C and positive HCV RNA of genotype 4, with a liver biopsy&#xD;
      within 3 years prior to recruitment. Our main exclusion criteria will be: decompensated&#xD;
      cirrhotic patients, HBV/HIV co-infection, evidence of hepatocellular carcinoma (HCC),&#xD;
      significant evolutive cardiovascular, pulmonary, renal or psychiatric disease,&#xD;
      pregnancy/breast feeding or patients post liver transplantation and anemia.&#xD;
&#xD;
      Our primary outcome will be: HCV-RNA negativity 24 weeks after the end of treatment (SVR)&#xD;
      (input adjusted dose on SVR). Our secondary outcome will be: rapid virological response&#xD;
      (RVR), early virological response (EVR), partial early virological response (pEVR), end of&#xD;
      treatment response (ETR), relapse after (ETR), biochemical response and safety and&#xD;
      tolerability of high doses of Ribavirin.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2011</start_date>
  <completion_date type="Actual">August 2015</completion_date>
  <primary_completion_date type="Actual">August 2015</primary_completion_date>
  <phase>Phase 4</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Sustained virological response</measure>
    <time_frame>72 weeks</time_frame>
    <description>Detectability of HCV RNA after 24 weeks of treatment completion by a realTime PCR-based technique</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Requirement of blood-related products</measure>
    <time_frame>48 weeks</time_frame>
    <description>The development of anemia or requirement of blood-related products</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">181</enrollment>
  <condition>Chronic Hepatitis C Virus</condition>
  <arm_group>
    <arm_group_label>Pegylated interferon alpha-2a plus standard dose ribavirin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Pegylated interferon alpha-2a 180 mcg weekly plus standard dose ribavirin 100-1200 mg/day for 48 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Pegylated interferon alpha-2a 180 mcgs adjusted dose ribavirin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pegylated interferon alpha-2a 180 mcg weekly plus adjusted dose ribavirin for 48 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pegylated interferon alpha-2a</intervention_name>
    <arm_group_label>Pegylated interferon alpha-2a 180 mcgs adjusted dose ribavirin</arm_group_label>
    <arm_group_label>Pegylated interferon alpha-2a plus standard dose ribavirin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. 18-70 years of age&#xD;
&#xD;
          2. Chronic hepatitis C documented by a detectable HCV RNA level by a PCR performed within&#xD;
             3 months -A liver biopsy performed within 3 years or fibro test/fibroscan within 1&#xD;
             year of inclusion.&#xD;
&#xD;
          3. Naive patients&#xD;
&#xD;
          4. Genotype 4&#xD;
&#xD;
          5. Compensated cirrhosis hepatitis C liver disease (Child-Pugh ≤ 6)&#xD;
&#xD;
          6. Patient needing, according to the physician, the initiation of a combined therapy of&#xD;
             pegylated interferon alfa plus Ribavirin&#xD;
&#xD;
          7. Negative HBsAg test and HIV-Elisa test&#xD;
&#xD;
          8. Negative pregnancy test at baseline in women in age of procreation&#xD;
&#xD;
          9. Efficient contraception all along the treatment period, and for 6 months after&#xD;
             discontinuation of the treatment for women and men&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Decompensated Cirrhotic patients&#xD;
&#xD;
          2. HBV or HIV co-infection&#xD;
&#xD;
          3. Evidence of hepatocellular carcinoma&#xD;
&#xD;
          4. Significant and evolutive cardiovascular, pulmonary, severe psychiatric disorder or&#xD;
             renal dysfunction (calculated creatinine CL &lt; 50 ml/min) *. Patients who met the trial&#xD;
             criteria if subsequent calculated creatinine CL &lt; 50 ml/min may need ribavirin dose&#xD;
             reduction.&#xD;
&#xD;
          5. Non compensated thyroid dysfunction&#xD;
&#xD;
          6. Recent history of epilepsy (less than 6 months)&#xD;
&#xD;
          7. Absolute contraindications to one of the drug of combination therapy&#xD;
&#xD;
          8. Any non-compensated cardiac disease including ischemic heart disease Chronic cardiac&#xD;
             failure (grade III or IV - NYHA classification)&#xD;
&#xD;
          9. Uncontrolled high blood pressure (SBP &gt; 180 mmHg during inclusion in spite of&#xD;
             hypertension treatment)&#xD;
&#xD;
         10. Pregnancy or breast feeding.&#xD;
&#xD;
         11. Post liver transplantation patient with HCV&#xD;
&#xD;
         12. Alcohol or drug induced liver disease.&#xD;
&#xD;
         13. Metabolic or autoimmune liver disease.&#xD;
&#xD;
         14. Hemoglobinopathies or anemia; hemoglobin &lt;12 gm /dl for females and &lt;12.5 for males&#xD;
             not corrected by erythropoietin&#xD;
&#xD;
         15. Neutropenia (&lt;1500/mm³)&#xD;
&#xD;
         16. Thrombocytopenia (&lt;90,000/mm3), thrombocytosis (&gt; 500,000/mm3)&#xD;
&#xD;
         17. Patients with evolutive diabetic or hypertensive retinopathy. Patients who are stable&#xD;
             can be included but should be regularly followed during treatment.&#xD;
&#xD;
         18. Hypersensitivity to epoetin beta or one of its excipients&#xD;
&#xD;
         19. Previous history or increased risk of venous thrombosis&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>King Faisal Specialist Hospital &amp; Research Centre</name>
      <address>
        <city>Riyadh</city>
        <zip>11159</zip>
        <country>Saudi Arabia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>King Abdulaziz Medical City</name>
      <address>
        <city>Riyadh</city>
        <zip>11462</zip>
        <country>Saudi Arabia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>King Khaled University Hospital</name>
      <address>
        <city>Riyadh</city>
        <country>Saudi Arabia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Saudi Arabia</country>
  </location_countries>
  <verification_date>February 2016</verification_date>
  <study_first_submitted>September 13, 2012</study_first_submitted>
  <study_first_submitted_qc>September 13, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 18, 2012</study_first_posted>
  <last_update_submitted>February 23, 2016</last_update_submitted>
  <last_update_submitted_qc>February 23, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 24, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>King Abdulaziz Medical City</investigator_affiliation>
    <investigator_full_name>Faisal M Sanai</investigator_full_name>
    <investigator_title>Consultant Hepatologist &amp; Liver Transplant Physician</investigator_title>
  </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>
    <mesh_term>Hepatitis, Chronic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Interferons</mesh_term>
    <mesh_term>Interferon-alpha</mesh_term>
    <mesh_term>Interferon alpha-2</mesh_term>
    <mesh_term>Peginterferon alfa-2a</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/NCT01686789
org study id: RC08-064
nct id: NCT01686789
lead sponsor: 
has dmc: Yes
The study aims to study the outcome of pharmacokinetics-adjusted dose ribavirin (plus pegIFN)
      on the SVR in chronic HCV patients.
Background: The introduction of Peg interferon and Ribavirin (an oral nucleoside analogue)
      for chronic Hepatitis C has led to the concept that chronic hepatitis C (HCV) is a curable
      disease. Improvement of treatment efficacy is still a major challenge. Optimal Ribavirin
      doses are essential to achieve SVR (sustained virological response). A recent trial showed
      significantly higher sustained virological response (SVR) in patients receiving 15.2
      mg/kg/day of Ribavirin compared with 13.3 mg/kg/day. Ribavirin was given in combination with
      Peg interferon alpha-2b (1). A small pilot study, in which 10 patients with Chronic Hepatitis
      C genotype 1 were treated with Ribavirin dosage up to 3600 mg/day- mean of 2540 mg/day- plus
      Peg-interferon alpha-2a, achieving a target concentration of Ribavirin >15 micromol before W
      12, led to 90% of SVR(2). All patients managed to complete the one year treatment period but
      all needed EPO and two were transfused.

      Patient's global exposure to Ribavirin as evaluated by the area under the curve (AUC) seems
      more pertinent in terms of exposure-effect relationship than measuring Ribavirin level at any
      single time point. A recent study showed in HCV patients infected with genotype 1 that
      Ribavirin plasma exposure after the first dose (i.e., interdose AUC0-12h or abbreviated
      AUC0-4h) was significantly and strongly linked with SVR, whereas AUCs determined at W12 and
      W24 and trough concentrations at Day 0 and W12 were not (3).

      Therefore, we propose a randomized controlled trial to investigate whether adjusted Ribavirin
      doses based on AUC0-4h obtained at D-7 after 600mg dose of Ribavirin versus fixed standard
      doses can improve outcome in treatment of chronic hepatitis C naïve patients infected with
      genotype 4.

      Methodology: After AUC0-4h has been determined at D-7 (7 days before randomization) for 190
      genotype 4 patients recruited into the trial, the patients are randomized into two groups:
      Group A: to receive standard dose of Ribavirin 1000-1200 mg/day) and Group B: to receive
      adjusted-dose of Ribavirin according to AUC0-4h. The individual calculated dose should be
      administered for each patient beginning on the first day of treatment. Both groups will
      receive combination treatment with peginterferon alpha 2a 180 mcg/week for a total of 48
      weeks.

      Both treatment groups will receive Darbepoetin if subsequent Hb is < 11 g/dl for males and
      females. Our main inclusion criteria will be: patients 18-70 years old with serological
      evidence of chronic hepatitis C and positive HCV RNA of genotype 4, with a liver biopsy
      within 3 years prior to recruitment. Our main exclusion criteria will be: decompensated
      cirrhotic patients, HBV/HIV co-infection, evidence of hepatocellular carcinoma (HCC),
      significant evolutive cardiovascular, pulmonary, renal or psychiatric disease,
      pregnancy/breast feeding or patients post liver transplantation and anemia.

      Our primary outcome will be: HCV-RNA negativity 24 weeks after the end of treatment (SVR)
      (input adjusted dose on SVR). Our secondary outcome will be: rapid virological response
      (RVR), early virological response (EVR), partial early virological response (pEVR), end of
      treatment response (ETR), relapse after (ETR), biochemical response and safety and
      tolerability of high doses of Ribavirin.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Sustained virological response
time frame: 72 weeks
description: Detectability of HCV RNA after 24 weeks of treatment completion by a realTime PCR-based technique
measure: Requirement of blood-related products
time frame: 48 weeks
description: The development of anemia or requirement of blood-related products
arm group label: Pegylated interferon alpha-2a plus standard dose ribavirin
arm group type: Active Comparator
description: Pegylated interferon alpha-2a 180 mcg weekly plus standard dose ribavirin 100-1200 mg/day for 48 weeks
arm group label: Pegylated interferon alpha-2a 180 mcgs adjusted dose ribavirin
arm group type: Experimental
description: Pegylated interferon alpha-2a 180 mcg weekly plus adjusted dose ribavirin for 48 weeks
intervention type: Drug
intervention name: Pegylated interferon alpha-2a
arm group label: Pegylated interferon alpha-2a 180 mcgs adjusted dose ribavirin
arm group label: Pegylated interferon alpha-2a plus standard dose ribavirin
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
facility: 
facility: 
facility: 
country: Saudi Arabia
responsible party type: Principal Investigator
investigator affiliation: King Abdulaziz Medical City
investigator full name: Faisal M Sanai
investigator title: Consultant Hepatologist & Liver Transplant Physician
mesh term: Hepatitis A
mesh term: Hepatitis C
mesh term: Hepatitis C, Chronic
mesh term: Hepatitis
mesh term: Hepatitis, Chronic
mesh term: Interferons
mesh term: Interferon-alpha
mesh term: Interferon alpha-2
mesh term: Peginterferon alfa-2a