High Dose Versus Standard Dose of Ribavirin in Patients With Chronic Hepatitis C, Genotype 3 (DARGEN-3)

Effect of High Dose vs. Standard Dose of Ribavirin in Patients With Chronic Hepatitis C, Genotype 3, High Viral Load Without Rapid Virological Response

The rate of sustained virological response (SVR) in patients with chronic hepatitis C, genotype 3, high viral load and without rapid virological response (RNA-HCV negative at week 4) is low. Standard of care of these patients include treatment with weekly peginterferon plus 800 mg/day of ribavirin (RBV). Extended treatment to 48 weeks does not provide more clinical benefit than the standard duration. The main hypothesis is that higher dose of ribavirin may be better in terms of SVR than the standard dose.

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis C
• Intervention / Treatment: Drug: Peginterferon alfa 2 A; Drug: ribavirin; Drug: ribavirin; Drug: ribavirin; Drug: Peginterferon alfa 2 A, ribavirin + Epo Beta; Drug: Peginterferon alfa 2

Detailed Description

Aims:

1. Efficacy 1.1) Rate of RNA-HCV negative at week 4 and 24 in each arm. 1.2) Rate of SVR in each arm.
2. Safety 2.1) Rate of adverse effects in each arm.

Design: Randomized controlled trial.

Patients will be randomly allocated into three arms:

Arm A : Peginterferon α-2a (180 μg/week)SC. plus Ribavirin (800 mg/day) p.o. over 24 weeks.

Arm B: Peginterferon α-2a (180 μg/week) plus Ribavirin (1600 mg/day) with support of Epoetin β (450 IU/kg/week) SC over 4 weeks:

B1.- If RNA-HCV undetectable at week 4, standard of care will be continued (Peginterferon α-2a, 180 μg/wee plus Ribavirin (800 mg/day) over 20 additional weeks).

B2.- If RNA-HCV were detectable at week 4, treatment will be continued with peginterferon α-2a (180 μg/week) plus RBV(1,600 mg/day) plus Epoetin β (450 UI/kg/week) over 20 additional weeks.

Sample size: 111 patients. To increase the SVR from 50% to 75%. Beta: 0.1; alfa: 0.05; Loss: 15%.

Randomization will be 1:2, 37 patients in Group A and 74 patients in group B.

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 4

Contacts and Locations

Study Locations

• Spain
  • Barcelona, Spain, 08003
    • Hospital Del Mar
  • Barcelona, Spain, 08036
    • Hospital Clínic i Provincial de Barcelona
  • Córdoba, Spain, 14004
    • Hospital Universitario Reina Sofia
  • Granada, Spain
    • Hospital San Cecilio
  • Granada, Spain, 18004
    • Hospital Universitario Virgen de Las Nieves
  • León, Spain, 24071
    • Hospital de Leon
  • Madrid, Spain, 28034
    • Hospital Ramón y Cajal
  • Madrid, Spain, 28007
    • Hospital Gregorio Marañón
  • Madrid, Spain, 28006
    • Hospital La Princesa
  • Madrid, Spain, 28021
    • Hospital 12 de Octubre
  • Málaga, Spain, 29010
    • Hospital Clinico Universitario Virgen de la Victoria
  • Oviedo, Spain, 33006
    • Hospital Central de Asturias
  • Salamanca, Spain, 37007
    • Hospital Clinico Universitario de Salamanca
  • Santander, Spain, 39008
    • Hospital Marques de Valdecilla
  • Sevilla, Spain, 41014
    • Hospital De Valme
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
  • Valladolid, Spain, 47005
    • Hospital Clínico Universitario de Valladolid
  • Vitoria, Spain, 01004
    • Hospital Santiago Apostol
  • Zaragoza, Spain, 50009
    • Hospital Miguel Servet
  • Zaragoza, Spain, 50009
    • Hospital Clínico de Zaragoza
  • Barcelona
    • Badalona, Barcelona, Spain, 08916
      • Hospital Germans Trias i Pujol
    • L´Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Hospital de Bellvitge
    • Sabadell, Barcelona, Spain, 08208
      • Hospital Parc Tauli
  • Guipuzcoa
    • San Sebastian, Guipuzcoa, Spain, 20014
      • Hospital de Donostia
  • Madrid
    • Alcorcón, Madrid, Spain, 28922
      • Hospital Fundación Alcorcón
    • Getafe, Madrid, Spain, 28901
      • Hospital de Getafe
    • Majadahonda, Madrid, Spain, 28222
      • Hospital Puerta de Hierro
  • Málaga
    • Marbella, Málaga, Spain, 29603
      • Hospital Costa del Sol

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:

• HCV Genotype 3
• RNA-HCV > > 600.000 IU/ml.
• Compromise to use contraceptive measures on treatment until 6 months after the end of treatment.

Exclusion Criteria:

• Pregnant or breastfeeding females.
• Concurrent treatment with antineoplastic or immunomodulatory agents, including corticosteroids or radiation therapy over the last 6 months before starting the trial
• Treatment with investigational drugs < 6 weeks before starting the trial
• Chronic liver disease other than hepatitis C.
• Evidence of hepatocellular carcinoma.
• Evidence of carcinoma hepatocellular
• Decompensated liver disease
• Baseline Neutrophil count < 1500/cc; or Platelet count < 90,000/cc
• Baseline Hemoglobin <12 g/dL in females o <13 g/dL in males.
• Increased risk of anemia(Eg, thalassemia, spherocytosis..).
• Ischemic heart disease or cerebrovascular disease.
• Serum creatinine >1.5 times upper limit of normality.
• History of severe psychiatric conditions (Major antidepressives or neuroleptic drugs required for major depression or psychosis), suicide attempts or psychiatric disability .
• History of convulsive disorders.
• Immunological conditions.
• Chronic Obstructive Lung Disease with limited functionality
• Severe heart disease or congestive cardiac insufficiency cardiopathy grave.
• Advanced atherosclerosis
• Solid organ or bone marrow transplant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A; Patients in this arm will receive standard of care (Peginterferon alfa 2A 180 mcg/weeks SC plus ribavirin 800 mg/day for 24 weeks).	Drug: Peginterferon alfa 2 A; Peginterferon alfa 2 A 180 mcg/week SC plus Ribavirin 800 mg/day po (Control Group) Peginterferon alfa 2 A 180 mcg/week SC plus Ribavirin 1,600 mg/day po plus Epoetin β (450 IU/kg/week) SC over 4 weeks (Arm B1) Peginterferon alfa 2 A 180 mcg/week SC plus Ribavirin 1,600 mg/day po plus Epo beta 450 UI over four weeks (Arm B1) If RNA-HCV positive at week 4, Peginterferon alfa 2 A 180 mcg/week SC plus Ribavirin 1,600 mg/day plus Epo beta 450 UI to keep Hb>12 g/dL if required over 20 additional weeks (Arm B2); Other Names: Pegasys; Drug: ribavirin; RBV 1600 mg/day 24 weeks; Other Names: peginterferon alfa 2 a; Epoetin beta; Drug: ribavirin; ribavirin 800 mg/day for 24 weeks; Other Names: Pegasys; Drug: ribavirin; RBV 1600 mg/day 4 weeks and then ribavirin 800 mg/day 20 weeks; Other Names: Pegasys
Experimental: B1; After a period of 4 weeks with peginterferon alfa 2 a 180 mcg/week plus RBV 1600 mg/day (Induction phase), these patients will be allocated according to negativity or positivity of RNA-HCV at week 4. If RNA-HCV negative, treatment with peginterferon alfa 2 a 180 mcg/week plus RBV 800 mg/day (SOC) will be continued over 20 additional weeks (Arm B1). Epo β (450 IU/kg/week) will be administered as required to maintain hemoglobin > 12g/dL.	Drug: Peginterferon alfa 2 A; Peginterferon alfa 2 A 180 mcg/week SC plus Ribavirin 800 mg/day po (Control Group) Peginterferon alfa 2 A 180 mcg/week SC plus Ribavirin 1,600 mg/day po plus Epoetin β (450 IU/kg/week) SC over 4 weeks (Arm B1) Peginterferon alfa 2 A 180 mcg/week SC plus Ribavirin 1,600 mg/day po plus Epo beta 450 UI over four weeks (Arm B1) If RNA-HCV positive at week 4, Peginterferon alfa 2 A 180 mcg/week SC plus Ribavirin 1,600 mg/day plus Epo beta 450 UI to keep Hb>12 g/dL if required over 20 additional weeks (Arm B2); Other Names: Pegasys; Drug: ribavirin; RBV 1600 mg/day 24 weeks; Other Names: peginterferon alfa 2 a; Epoetin beta; Drug: ribavirin; ribavirin 800 mg/day for 24 weeks; Other Names: Pegasys; Drug: ribavirin; RBV 1600 mg/day 4 weeks and then ribavirin 800 mg/day 20 weeks; Other Names: Pegasys; Drug: Peginterferon alfa 2 A, ribavirin + Epo Beta; Ribavirin 1,600 mg/day plus peginterferon alfa 2A 180 mcg/week plus Epo beta 450 IU/Kg/day to maintain Hb>12g/dl over 4 or 24 weeks; Other Names: Pegasys; Drug: Peginterferon alfa 2; Peginterferon alfa 2 a 180 mcg/week for 4 weeks and then peginterferon alfa 2A for 20 weeks; Other Names: Pegasys
Experimental: B2; If RNA-HCV at week 4 remains positive after the induction phase, then peginterferon alfa 2 a 180 mcg/week plus RBV 1600 mg/day will be continued for 20 additional weeks (Arm B2). Epo β (450 IU/kg/week) will be administered as required to maintain hemoglobin > 12g/dL.	Drug: Peginterferon alfa 2 A; Peginterferon alfa 2 A 180 mcg/week SC plus Ribavirin 800 mg/day po (Control Group) Peginterferon alfa 2 A 180 mcg/week SC plus Ribavirin 1,600 mg/day po plus Epoetin β (450 IU/kg/week) SC over 4 weeks (Arm B1) Peginterferon alfa 2 A 180 mcg/week SC plus Ribavirin 1,600 mg/day po plus Epo beta 450 UI over four weeks (Arm B1) If RNA-HCV positive at week 4, Peginterferon alfa 2 A 180 mcg/week SC plus Ribavirin 1,600 mg/day plus Epo beta 450 UI to keep Hb>12 g/dL if required over 20 additional weeks (Arm B2); Other Names: Pegasys; Drug: ribavirin; RBV 1600 mg/day 24 weeks; Other Names: peginterferon alfa 2 a; Epoetin beta; Drug: ribavirin; ribavirin 800 mg/day for 24 weeks; Other Names: Pegasys; Drug: ribavirin; RBV 1600 mg/day 4 weeks and then ribavirin 800 mg/day 20 weeks; Other Names: Pegasys; Drug: Peginterferon alfa 2 A, ribavirin + Epo Beta; Ribavirin 1,600 mg/day plus peginterferon alfa 2A 180 mcg/week plus Epo beta 450 IU/Kg/day to maintain Hb>12g/dl over 4 or 24 weeks; Other Names: Pegasys

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Rate of patients with RNA-HCV negative in each arm at week 24 after the end of treatment.	1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Rate of patients with undetectable RNA-HCV in each arm at week 4 and 24 of treatment. Rate of adverse effects in each arm.	1 year

Collaborators and Investigators

• Sponsor: Dr. Conrado Fernandez
• Investigators: Study Director: Conrado M Fernandez-Rodriguez, Hospital Universitario Fundacion Alcorcon; University Rey Juan Carlos.

Publications and helpful links

General Publications

• Fernandez-Rodriguez CM, Morillas RM, Masnou H, Navarro JM, Barcena R, Gonzalez JM, Martin-Martin L, Poyato A, Miquel-Planas M, Jorquera F, Casanovas T, Salmeron J, Calleja JL, Sola R, Alonso S, Planas R, Romero-Gomez M. Randomized clinical trial comparing high versus standard dose of ribavirin plus peginterferon alfa-2a in hepatitis C genotype 3 and high viral load. Dargen-3 study. Gastroenterol Hepatol. 2014 Jan;37(1):1-8. doi: 10.1016/j.gastrohep.2013.10.005. Epub 2013 Dec 17.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: January 27, 2009
• First Submitted That Met QC Criteria: January 27, 2009
• First Posted (Estimate): January 28, 2009

Study Record Updates

• Last Update Posted (Estimate): March 13, 2012
• Last Update Submitted That Met QC Criteria: March 12, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: Chronic Hepatitis C; Genotype 3; High viral load
• 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; Hepatitis A; Hepatitis C; Hepatitis, Chronic; Hepatitis C, Chronic; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Immunologic Factors; Interferon-alpha; Ribavirin; Peginterferon alfa-2a
• Other Study ID Numbers: ROCHE FARMA S.A.