EXtended Therapy in Hepatitis C Genotype 3 Infected Patients (EXACT-R(3))

September 27, 2011 updated by: University Health Network, Toronto

EXtended Therapy in Genotype 3 Infected Patients Who do Not AChieve a Treatment Response at Week 4 (RVR) But do Achieve a Complete Early Virologic Response (cEVR)

The purpose of this study is to evaluate the effect of 48 vs 24 weeks of treatment with Peginterferon alfa-2b plus weight-based ribavirin on Sustained Virologic Response (SVR) and relapse rates in patients infected with genotype 3 chronic hepatitis C (CHC) who do not achieve a Rapid Virologic Response (RVR) but attain a complete Early Virologic Response (cEVR).

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

This study plans to address the issue of whether increasing the duration of therapy from 24 weeks to 48 weeks with PegIFNα2b 1.5mg/kg/week and using weight-based ribavirin (15mg/kg) may reduce relapse rates and thereby increase SVR rates in patients infected with genotype 3 who fail to achieve an RVR but do achieve a complete cEVR defined as undetectable HCV RNA (ie. <50 or <15 IU/ml by 12 weeks). This study is necessary because although most patients with genotype 3 ultimately become HCV RNA undetectable during treatment, relapse after discontinuation of therapy remains a major cause of failure to achieve SVR. This is a very important issue given that to date none of the new small molecule drugs appear effective against genotype 3 meaning that at the present time patients with genotype 3 infection have no other options. Relapse is particularly common in patients with advanced liver disease but it has been shown that if SVR can be achieved in patients with advanced disease, the risk of liver failure is significantly reduced, as may be the risk of hepatocellular carcinoma (HCC). As a consequence the need for liver transplantation is diminished and survival is improved. Identifying strategies to reduce relapse and improve rates of SVR are therefore critical.

Certain individuals are at greater risk of infection with genotype 3. In the Western world, the main risk groups are current or former drug users (IDU) and immigrants raised in South Asia (India and Pakistan) where infection likely occurs early in childhood due to exposure to contaminated instruments, needles, etc.

A second potential benefit of achieving SVR is reduction in the rate of diabetes. Diabetes has been demonstrated to be more common in those infected with Hepatitis C than in the general population - this observation was made by examination of the NHANES population based database. The prelude to the development of Type 2 diabetes is insulin resistance. Insulin resistance (IR) is present in about one third of patients chronically infected with HCV - the rate being highest in those with cirrhosis and in those who are overweight or obese. Early data indicates that although the presence of insulin resistance impairs interferon responsiveness if SVR can be achieved, insulin resistance is lost. Studies of IR in individuals infected with genotype 3 HCV are lacking. Independent of HCV infection, being born South Asian is a risk factor for Type 2 diabetes.

The issue of insulin resistance and the effectiveness of antiviral therapy in chronic hepatitis C has been addressed exclusively in Caucasians infected with genotype 1. Recent data from Japan indicates that in patients with diabetes and hepatitis C successful eradication of HCV RNA may simultaneously prevent subsequent diabetes and presumably the systemic complications of this disease.

There is little data on the rate of RVR in the South Asian population as few therapeutic trials in patients with genotype 3 infections have been reported from Pakistan and India. Estimates can only be obtained from studies performed in Caucasians from Northern Europe and North America. In the trial by Shiffman the rate of RVR in those with genotype 3 infection was 62% and preliminary report from the trial of Albuferon in those with genotype 2 and 3 indicate RVR rates ranged from 44-60% in Asians -this figure included all Asians.

There are several reasons to specifically address ways to improve the outcome of antiviral therapy in patients infected with genotype 3 CHC. Firstly virtually all treatment studies report on a combined rate of SVR achieved in genotypes 2 and 3 even though the evidence has suggested that the response to therapy is different between these two genotypes. Within populations of patients with genotype 3 infection, there may be differences as well. South Asians are predominantly infected with genotype 3a, while injection drug users typically have genotype 3b infection. There are no formal trials published in the English literature of antiviral therapy in South Asians or comparing subtypes of genotype 3.

In patients infected with genotype 1 slow response to antiviral therapy i.e. lack of RVR, is associated with a significantly higher rate of relapse in those who go on to achieve undetectable HCV RNA at 12 weeks rather than at 4 weeks into treatment. Extending treatment for a further six months reduces this relapse rate considerably. By extending treatment in patients infected with genotype 3 who had previously relapsed following only 14 weeks of therapy to 24 weeks reduced relapse rates. Thus, it is anticipated that by extending treatment from 24 to 48 weeks in those who fail to achieve a RVR (i.e. slow responders) but who do achieve a complete EVR we hope to prevent relapse off treatment. A potential added benefit of achieving SVR in this patient population, many of whom are already at high risk of T2DM, is that it may reduce the virally mediated component of IR.

Study Type

Interventional

Enrollment (Actual)

2

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Alberta
      • Calgary, Alberta, Canada, T2N 4Z6
        • Calgary Heart Centre
      • Edmonton, Alberta, Canada, T2N 4Z6
        • Hys Med Centre
    • British Columbia
      • Vancouver, British Columbia, Canada, V5Z 1H2
        • Liver and Intestinal Research Centre
      • Vancouver, British Columbia, Canada, V6A 4B6
        • Dr. John D Farley Medical Office
      • Vancouver, British Columbia, Canada, V6Z 2K5
        • Pacific Gastroenterology Assoc
    • Ontario
      • Kingston, Ontario, Canada, K7L 5G2
        • Hotel Dieu Hospital
      • London, Ontario, Canada, N6A 5A5
        • London Health Sciences Centre
      • Mississauga, Ontario, Canada, L5B 2V2
        • Dr. Dalia El-Ashry clinic
      • Mississauga, Ontario, Canada, L5M2V8
        • Credit Valley Med Arts Centre
      • Toronto, Ontario, Canada, M5G 2C4
        • Toronto General Hospital - Dr. M. Sherman
      • Toronto, Ontario, Canada, M5T 2S8
        • Toronto Western Hospital - Liver Clinic
    • Quebec
      • Montreal, Quebec, Canada, H3T 1E2
        • SMBD Jewish Gen Hosp

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Infected with only genotype 3, hepatitis C
  • Treatment naïve before current course of therapy
  • A positive HCV RNA test result at Week 4 (no RVR)
  • A negative HCV RNA test result at Week 12 (cEVR)
  • A recent liver biopsy (within 3 years prior to study entry) is required. If the patient has either liver biopsy proven cirrhosis in the past or has splenomegaly with features of cirrhosis on ultrasound and/or thrombocytopenia (<150x109/ml) at any time in the past or has a Fibroscan reading of 10 or above or has a Fibrotest score of 0.75 or above (equivalent to F3 on the METAVIR scale), a biopsy will not be required. A copy of the latest report must be available.

Exclusion Criteria:

  • Under age 18
  • Co-infection with HIV or Hepatitis B or any other HCV genotype in addition to genotype 3
  • Prior treatment for Hepatitis C aside from herbal remedies
  • Evidence of decompensated liver disease, such as ascites, bleeding varices, hepatic encephalopathy or jaundice (conjugated hyperbilirubinemia)
  • INR > 1.3 at baseline
  • Platelet count <70 X 109/μl at baseline
  • Those subjects with diabetes and/or systemic hypertension will need to have ocular examinations (as per standard of care [SOC]) prior to treatment and will be excluded if they are found to have a diabetic retinopathy, optic nerve disorders, retinal hemorrhage or any other clinically significant abnormality

  • Pre-existing psychiatric conditions including:

    • Current moderate or severe depression despite appropriate therapy.
    • Active suicidal ideation or previous attempt at suicide
    • Patients with a history of severe psychiatric disorder (may be included if so desired by the investigator but pretreatment psychiatric evaluation is required (SOC)).
    • Clinical diagnosis of current substance abuse: Alcohol (>40g/d), injection drugs, inhalational drugs (not including marijuana), psychotropics, narcotics, cocaine use, prescription or over the counter drugs within one year of the screening visit.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: Standard of care treatment
Participants will be randomized to receive only the standard 24 weeks of therapy (Peginterferon alfa-2b plus ribavirin).
Active Comparator: Extended therapy
Participants will be randomized to receive 24 weeks of therapy (Peginterferon alfa-2b plus ribavirin) in addition to their standard of care therapy.
Drug: Peginterferon alfa-2b (Pegetron) plus ribavirin (Rebetol)
Dosage Form: Pegetron - powder for solution; Rebetol - capsules Strength: Pegetron Redipen - 120 mcg per pen; Rebetol - 200 mg Route of Administration: Pegetron - subcutaneous; Rebetol - oral
Other Names:
  • Rebetol
  • Pegetron

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
End of treatment response
Time Frame: 24 weeks following end of therapy
Undetectable hepatitis C virus (HCV) RNA at 24 weeks following end of therapy
24 weeks following end of therapy

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Relapse rate
Time Frame: 24 weeks following end of therapy
Undetectable HCV RNA at end of treatment but detectable HCV RNA at 24 weeks following end of therapy
24 weeks following end of therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Health Network, Toronto

Collaborators

Schering-Plough

Investigators

  • Principal Investigator: E. Jenny Heathcote, MB,BS,MD,FRCP,FRCP(C), University Health Network - Toronto Western Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2010

Primary Completion (Actual)

June 1, 2011

Study Completion (Actual)

June 1, 2011

Study Registration Dates

First Submitted

March 26, 2010

First Submitted That Met QC Criteria

March 29, 2010

First Posted (Estimate)

March 30, 2010

Study Record Updates

Last Update Posted (Estimate)

September 29, 2011

Last Update Submitted That Met QC Criteria

September 27, 2011

Last Verified

March 1, 2010

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EXACT-R(3)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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