Long Term Interferon for Patients Who Did Not Clear Hepatitis C Virus With Standard Treatment

Study Overview
=================
Brief Summary
-----------------
The HALT-C Trial is a National Institute of Diabetes and Digestive and Kidney Diseases sponsored, randomized clinical trial of long-term use of Peginterferon alfa-2a (pegylated interferon) in patients who failed to respond to prior interferon treatment. All patients who enter the trial will be treated for 6 months with Peginterferon alfa-2a and Ribavirin. Patients who respond to this 6 month treatment will continue to be treated for an additional 6 months. Patients who do not respond to this treatment will be eligible for the long-term maintenance phase of this study where patients will be randomly selected to be treated with Peginterferon alfa-2a or to discontinue treatment for 3.5 years. Patients in both arms of this study will be followed closely with quarterly study visits. The combination of peginterferon plus ribavirin has recently been approved by the FDA for treatment of chronic hepatitis C. Patients who remain HCV-RNA positive after being treated for at least 6 months with peginterferon and ribavirin outside of this study may be eligible to directly enter the randomized portion of the HALT-C Trial. The HALT-C study is designed to determine if continuing interferon long-term over several years will suppress Hepatitis C virus, prevent progression to cirrhosis, prevent liver cancer and reduce the need for liver transplantation.

Official Title
-----------------
Hepatitis C Antiviral Long-term Treatment Against Cirrhosis Trial (HALT-C)

Conditions
-----------------
Chronic Hepatitis c, Cirrhosis, Liver, Fibrosis, Liver, Hepatic Cirrhosis

Intervention / Treatment
-----------------
* Drug: Peginterferon alfa-2a + Ribavirin
* Drug: Peginterferon alfa-2a


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age at entry at least 18 years. Positive for Hepatitis C. Previous treatment with any interferon or interferon and ribavirin for at least 3 months. Documented non-response to treatment with interferon. A liver biopsy demonstrating significant liver scarring. Exclusion Criteria: No other liver disease. No unstable major medical diseases or conditions. No major complications of cirrhosis. No recent abuse of alcohol or illicit drugs.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Peg-interferon alfa-2a 90 mcg/week | Drug: Peginterferon alfa-2a + Ribavirin<br>* Peginterferon alfa-2a 180 mcg/week injection, for 24 weeks, plus 1000-1200 mg Ribavirin oral (prescribed according to weight <75 kg, >75 kg) daily in two divided doses for 24 weeks<br>* Other names: Copegus (Hoffman-La Roche);Drug: Peginterferon alfa-2a<br>* 90 mcg/week injection, for 3.5 years<br>* Other names: Pegasys (Hoffman-La Roche);|
| Active Comparator: 2<br>Standard of care followup | Drug: Peginterferon alfa-2a + Ribavirin<br>* Peginterferon alfa-2a 180 mcg/week injection, for 24 weeks, plus 1000-1200 mg Ribavirin oral (prescribed according to weight <75 kg, >75 kg) daily in two divided doses for 24 weeks<br>* Other names: Copegus (Hoffman-La Roche);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression of Liver Disease as Indicated by Death, Hepatic Decompensation, Hepatocellular Carcinoma, or for Patients With Noncirrhotic Fibrosis at Baseline, an Increase in the Ishak Hepatic Fibrosis Score of 2 or More Points | Progression of liver disease within 1400 days as indicated by death, hepatic decompensation (variceal hemorrhage; ascites; spontaneous bacterial peritonitis; hepatic encephalopathy), hepatocellular carcinoma, a Child-Turcotte-Pugh (CTP) score of 7 or more on two consecutive study visits (score range 5-15, higher score indicates greater decompensation), or for patients with noncirrhotic fibrosis at baseline, an increase in Ishak hepatic fibrosis score (range 0-6, higher score indicates greater fibrosis) of at least 2 points by assessment of a liver-biopsy specimen obtained during the study | 1400 days (3.85 years) post randomization | 
| Increase in Ishak Fibrosis Score by 2 Points or More at 2 or 4 Year Biopsies | For patients with noncirrhotic fibrosis at baseline, an increase in Ishak hepatic fibrosis score (range 0-6, higher score indicates greater fibrosis) of at least 2 points by assessment of a liver-biopsy specimen obtained during the study (collected at Year 2 and Year 4 biopsies, 1.5 and 3.5 years after randomization) | 1400 days (3.85 years) post randomization | 
| Death From Any Cause |  | 1400 days (3.85 years) post randomization | 
| Development of Hepatocellular Carcinoma (HCC) | A diagnosis of development of hepatocellular carcinoma (HCC) was based on either Histology showing HCC (from a biopsy, surgery, or autopsy) or A new hepatic defect on imaging with an alpha-fetoproteion (AFP) level rising to > 1,000 ng/ml. | 1400 days (3.85 years) post randomization | 
| Child-Turcotte-Pugh (CTP) Score of 7 or Higher at Two Consecutive Study Visits | Child-Turcotte-Pugh (CTP) score of 7 or more on two consecutive study visits (score range 5-15, higher score indicates greater hepatic decompensation) | 1400 days (3.85 years) post randomization | 
| Variceal Hemorrhage | A gastrointestinal hemorrhage which is believed by the investigator to be due to bleeding esophageal or gastric varices. In general, an endoscopy will have been performed and will have revealed either direct evidence of variceal bleeding (bleeding varix, red wale sign) or historical evidence for significant upper gastro-intestinal bleeding plus upper endoscopy revealing moderate varices and no other site of bleeding is identified | 1400 days (3.85 years) post randomization | 
| Ascites | Any abdominal fluid which is: Mild, moderate or marked on ultrasound; or Progressive on serial physical examinations; or Requires diuretic therapy. To meet the definition of ascites, abdominal fluid that is mild (barely detectable) on physical examination requires ultrasound confirmation that is mild, moderate or marked ascites. Ultrasound reports of minimal fluid around the liver do not meet the definition. | 1400 days (3.85 years) post randomization | 
| Spontaneous Bacterial Peritonitis | Any episode of spontaneous ascitic infection diagnosed on the basis of elevated neutrophil count (> 250/ml) in paracentesis fluid or positive bacterial cultures and clinical diagnosis in the absence of white blood cell (WBC) availability. | 1400 days (3.85 years) post randomization | 
| Hepatic Encephalopathy | Any mental status alteration which is deemed by the investigator to be due to portosystemic encephalopathy, whether occurring during a provoked episode (GI bleeding, diuretics, usual sedative doses), or spontaneously (without apparent cause). | 1400 days (3.85 years) post randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious Adverse Events | A serious adverse event (SAE) is an untoward medical occurrence that results in any of the following: Death Is life threatening (risk of death at the time of the event) Requires in-patient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability/incapacity Congenital abnormality or birth defect Trial outcomes (except death) were not considered serious adverse events. | 1400 days (3.85 years) post randomization | 
| Changes in Fibrosis From Baseline at Year 2 or Year 4 Biopsy. | Change in Ishak hepatic fibrosis score (range 0-6, higher score indicates greater fibrosis) by assessment of a liver-biopsy specimen obtained during the study (collected at baseline, Year 2 and Year 4 biopsies, 1.5 and 3.5 years after randomization) | 1400 days (3.85 years) post randomization | 
| Presumed Hepatocellular Carcinoma (HCC) | Presumed HCC was considered when histology was not available and alpha-fetoprotein (AFP) is <1000 ng/ml, if: A new hepatic lesion was shown on ultrasound and 1 additional imaging showed a hepatic lesion with characteristics of HCC. AFP> upper limit of normal (ULN) and 2 imaging studies showed a hepatic lesion with characteristics of HCC. A progressively enlarging hepatic lesion starting as a new defect resulting in patient death. A new hepatic defect with at least 1 characteristic scan and: Increase in size over time or Increasing AFP rising to a level of >200 ng/ml | 1400 days (3.85 years) post randomization | 
| SF-36 Vitality Summary Score | Change from baseline to years 0.5, 1.5, 2.5, and 3.5 in Short Form Health Survey (SF-36) Vitality summary score. The SF-36 Vitality summary score is the sum of 4 individual scores. It is scaled from 0 to 100 with a score of 0 equivalent to maximum disability and a score of 100 equivalent to no disability. A negative value indicates a decrease in quality of life from baseline. | 0.5, 1.5, 2.5, and 3.5 years after randomization | 
| SF-36 Physical Function Summary Score | Change from baseline to years 0.5, 1.5, 2.5, and 3.5 in Short Form Health Survey (SF-36) Physical Function summary score. The SF-36 Physical Function summary score is the sum of 10 individual scores. It is scaled from 0 to 100 with a score of 0 equivalent to maximum disability and a score of 100 equivalent to no disability. A negative value indicates a decrease in quality of life from baseline. | 0.5, 1.5, 2.5, and 3.5 years after randomization | 
| SF-36 Mental Health Summary Score | Change from baseline to years 0.5, 1.5, 2.5, and 3.5 in Short Form Health Survey (SF-36) Mental Health summary score. The SF-36 Mental Health summary score is the sum of 5 individual scores. It is scaled from 0 to 100 with a score of 0 equivalent to maximum disability and a score of 100 equivalent to no disability. A negative value indicates a decrease in quality of life from baseline. | 0.5, 1.5, 2.5, and 3.5 years after randomization | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
liver disease, hepatitis c virus, antiviral agent, cirrhosis