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

Sponsor

University Health Network, Toronto (Other)

Overall Status

Terminated

CT.gov ID

NCT01095445

Collaborator

Schering-Plough (Industry)

Enrollment

Locations

Arms

15.9

Duration (Months)

0.2

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Chronic Hepatitis C	Drug: Peginterferon alfa-2b (Pegetron) plus ribavirin (Rebetol)	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

2 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Study Start Date :

Feb 1, 2010

Actual Primary Completion Date :

Jun 1, 2011

Actual Study Completion Date :

Jun 1, 2011

Arms and Interventions

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: Pegetron Rebetol

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:

Pegetron

Rebetol

Outcome Measures

Primary Outcome Measures

End of treatment response [24 weeks following end of therapy]
Undetectable hepatitis C virus (HCV) RNA at 24 weeks following end of therapy

Secondary Outcome Measures

Relapse rate [24 weeks following end of therapy]
Undetectable HCV RNA at end of treatment but detectable HCV RNA at 24 weeks following end of therapy

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

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