Study of Long-term Peg Intron vs. Colchicine in Non-responders. (COPILOT)

Phase IV Study of Long Term Peg-Intron for Patients Who Have Failed to Respond to Rebetron/Interferon With Advanced Fibrosis and Cirrhosis Secondary to Hepatitis C- The Copilot Trial

In this study Peg-Intron will be tested to see if it will give better results than Colchicine. At this time, there is currently no recommended maintenance treatment for patients who have failed to respond to Interferon/Rebetron/Peg Intron and have advanced fibrosis. The purpose of this study is to compare two treatments to slow down the progression of liver disease and to prevent liver failure and liver cancer. The treatment will not cure Hepatitis C, but is being evaluated to see if it can slow down disease progression.

Study Overview

• Status: Completed
• Conditions: Cirrhosis; Hepatitis C Virus; Advanced Fibrosis
• Intervention / Treatment: Drug: PEG -Intron; Drug: Colchicine

Detailed Description

We are proposing a randomized trial of Peg-Intron 0.5mcg per kg weekly versus colchicine 0.6mg bid in prior non-responders to Interferon, Rebetron, PegIntron, or PegIntron & Ribavirin or any third agent such as Pegasys, CellCept, Amantadine with advanced fibrosis/cirrhosis. The specific aims of this proposal are to evaluate the role of long term Peg-Intron therapy on the natural history of patients with advanced chronic HCV infection with a primary focus on prevention of hepatic decompensation, progression of fibrosis and hepatoma development.

The study design will focus on 3 monthly clinical evaluation for decompensation of liver function, rigorous clinical screening for development of hepatocellular cancer and liver biopsies for determination of progression of liver fibrosis every second year.

• Study Type: Interventional
• Enrollment (Actual): 549
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Birmingham Gastroenterology Associates
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • UAMS Medical Center
  • California
    • Bakersfield, California, United States, 93301-1645
      • 34th Street Community Health Center
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center
    • Sacramento, California, United States, 95825
      • Kaiser Permanende-GI Department
    • San Diego, California, United States, 92115
      • Gastroenterology Associates
  • Colorado
    • Denver, Colorado, United States, 80220
      • University of Colorado Health Sciences Center
  • Connecticut
    • Danbury, Connecticut, United States, 06810
      • Danbury Hospital
    • Manchester, Connecticut, United States, 06040
      • Bruce Stein, MD
    • New Haven, Connecticut, United States, 06510
      • Connecticut Gastroenterology Consultants
  • District of Columbia
    • Washington, D.C., District of Columbia, United States, 20307-5001
      • Walter Reed Army Medical Center
    • Washington, D.C., District of Columbia, United States, 20007-2197
      • Georgetown University Medical Center
  • Florida
    • Bradenton, Florida, United States, 34205
      • Bach and Godofsky Infectious Disease
    • Hollywood, Florida, United States, 33021
      • Southern Clinical Research Consultants
    • South Miami, Florida, United States, 33143
      • Gastroenterology Associates of South Florida
  • Illinois
    • Downers Grove, Illinois, United States, 60515
      • Digestive Health Services
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • Digestive Disease Associates
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Burlington, Massachusetts, United States, 01805
      • Lahey Clinic
    • Florence, Massachusetts, United States, 01062
      • Hampshire Gastroenterology
    • Worcester, Massachusetts, United States, 01608
      • Fallon Clinic
  • Michigan
    • Detroit, Michigan, United States, 48601
      • Wayne State University/Haper Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55417
      • Gastroenterology Division Veterans Affairs Medical Center
    • Plymouth, Minnesota, United States, 55446
      • Minnesota Gastroenterology
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Kansas City, Missouri, United States, 64131
      • Gastroenterology Associates
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • New Jersey
    • East Orange, New Jersey, United States, 07018
      • VA New Jersey Healthcare System
    • Egg Harbor, New Jersey, United States, 08234
      • Atlantic Gastroenterology
    • Florham Park, New Jersey, United States, 07932
      • Florham Park Endoscopy Center
  • New Mexico
    • Santa Fe, New Mexico, United States, 87505
      • Northern New Mexico Gastroenterology
  • New York
    • Forest Hills, New York, United States, 11375
      • Dr. Sam Moskowitz, MD, PC
    • New York, New York, United States, 10032
      • Columbia University
    • New York, New York, United States, 10003
      • Liberty Medical, LLP
    • New York, New York, United States, 10011
      • Metro Medical
    • Poughkeepsie, New York, United States, 12601
      • Peter Varunok, MD
    • Syracuse, New York, United States, 13210
      • Upstate Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Medical Center
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Sayre, Pennsylvania, United States, 18840
      • Guthrie Research Foundation
  • Rhode Island
    • Providence, Rhode Island, United States, 02908
      • Roger Williams Medical Center
    • Providence, Rhode Island, United States, 02905
      • University Gastroenterologists
  • Tennessee
    • Nashville, Tennessee, United States, 37211
      • Nashville Gastroenterology Specialists Incorporated
  • Texas
    • Austin, Texas, United States, 78745
      • Austin Gastroenterology
    • Granbury, Texas, United States, 76048
      • G.I. and Liver Associates
    • San Antonio, Texas, United States, 78229
      • Texas Transplant Institute
    • San Antonio, Texas, United States, 78205
      • Digestive Disease Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Health Science Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical Center of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• *Adult male or female, age 18 to 75 years

  • HCV RNA positive by PCR

  • Previous treatment with at least three months of interferon or interferon / Ribavirin. Patients should have had no interferon for at least 2 months prior to enrollment.

    1. Non-responders are identified by failure to clear virus by PCR after a minimum 3-month course of treatment and who have been off treatment for at least 2 months with a positive PCR for HCV prior to entry into the current study, 2) Partial responders have a reduction of 1 long in HCV RNA, but the virus is still detectable, 3) Breakthrough patients have been negative on treatment, but virus appeared while still on treatment, 4) Relapsers are defined as negative PCR at some point during treatment, but virus reoccurred or was detectable by HCV PCR when treatment stopped.

Patients should have had a liver biopsy showing at least Stage 3 disease prior to being considered for this study. A baseline liver biopsy is necessary for inclusion in the study. Baseline liver biopsies can be performed within six months of entering the study.

In patients with cirrhosis and endoscopic evidence of portal hypertension, a biopsy within the last 2 years is acceptable as the baseline biopsy. For patients with established cirrhosis on liver biopsy and no portal hypertension, a biopsy within 12 months can be used as the baseline biopsy if it is available for evaluation by the Pathology core. All these patients will still require liver biopsy at 2 years and 4 years. The decision to biopsy at 2 and 4 years is also a clinical decision and in the presence of clinical progression or coagulopathy, or where there may be a risk from liver biopsy, the Investigator should call the PI, Dr. Afdhal for a waiver of biopsy. Patients with Ishak Stage 3 and 4 require a biopsy within 6 months of randomization.

• Hemoglobin >= 11 g/dl in males and 10 g/dl in females
• Neutrophil count > 1,500/mm3
• Platelets > 50, 000/mm3

Platelet count: For standard dose of PEG-Intron 0.5mcg/kg platelet count must be greater than 70,000. Patients with platelet count 50 - 70,000 can start at 0.25mcg/kg for weeks 0 - 4. If platelets fall to less than 30,000, stop treatment. If platelets remain > 50,000 at week 4, PEG-Intron can be increased to 0.5mcg/kg. Patients randomized to Colchicine with platelets 50,000 - 70,000 can be started at standard dose 0.6mg bid po with standard dose reduction.

• Prothrombin time <= 3secs prolonged compared to control or an equivalent INR < 1.5
• Total bilirubin < 3gm/dL
• Fasting blood sugar <= 115 mg/dl or within 20% of the upper limit of normal for non-diabetic patients
• Albumin (> 2.8mg/dl)
• Serum creatinine < 1.4 mg/dL
• TSH within the normal range (Patients with thyroid disease who are well controlled are eligible if the remainder of the inclusion/exclusion criteria are met)

• HIV negative.

  • HBsAg negative
  • Childs Pugh score of less than or equal to 7
  • Serum positive for anti-hepatitis C antibodies or HCV RNA.
  • Alpha-fetoprotein < 100ng/ml with ultrasound negative for focal mass or HCC. For any patient with an Alpha-fetoprotein >100 ng/ml either a triple phase contrast CT scan or MRI with gadolinium must show no focal mass or evidence of HCC
  • Ultrasound with no evidence of focal mass suggestive of hepatoma (within 6 months of informed consent).
  • Documentation that sexually active female patients of childbearing potential are practicing adequate contraception during the treatment period. A urine pregnancy test obtained at entry prior to the initiation of treatment must be negative. Female patients must not be breast-feeding. Documentation that sexually active male patients are practicing acceptable methods of contraception during the treatment period.
  • Written informed consent specific for this protocol has been obtained prior to entry.

Exclusion Criteria:

• Any cause of liver disease based on patient history and biopsy (where applicable) other than chronic hepatitis C including but not limited to:

  • Co-infection with hepatitis B or HIV
  • Hemochromatosis (confirmed by genetic testing)
  • Alpha-1 antitrypsin deficiency
  • Wilson's disease
  • Renal or liver transplant patients
  • Autoimmune hepatitis
  • Alcoholic liver disease
  • Obesity induced liver disease
  • Drug related liver disease

In addition:

• Evidence of decompensated liver disease such as a history or presence of ascites, and spontaneous encephalopathy. Patients with past bleeding esophageal varices that have not bled for more than 1 year can be included.
• Hypersensitivity to alpha interferon
• Drug related liver disease
• Hemoglobinopathies (e.g. Thalassaemia, sickle cell disease).
• Patients with clinically significant retinal abnormalities.
• Substance abuse, such as alcohol (·> 80 gm/day), I.V. drugs and inhaled drugs. If the patient has a history of substance abuse, to be considered for inclusion into the protocol, the patient must have abstained from using the abused substance for at least 6 months. Patients on methadone will be allowed in the study with no restrictions as is now standard of care in HCV therapy.
• Patients with a history of organ transplantation will be excluded.

Preexisting psychiatric conditions, especially depression, or a history of severe psychiatric disorder, such as major psychoses, suicidal ideation and/or suicidal attempt are excluded. Patients with a history of mild depression may enter the protocol if they meet the following eligibility criterion and are monitored more intensively.

Mild depression: to include either situational depression of a limited period or depressive symptoms, which do not significantly interfere with the patient's work or daily functions.

Any patient with an active manic element to his/her previous symptom complex will be excluded.

Any known pre-existing medical condition that could interfere with the patient's participation in and completion of the study such as:

• Pre-existing psychiatric condition, especially severe depression, or a history of severe psychiatric disorder
• CNS trauma or seizure disorder requiring therapy
• Significant cardiac dysfunction in the previous 6 months e.g. angina, CCF, hypertension or arrhythmia Patients on treatment are eligible as long as they have been symptom free for the previous 6 months.
• Poorly controlled diabetes mellitus
• Chronic pulmonary disease (e.g. COAD)
• Immunologically mediated diseases (e.g. inflammatory bowel disease, SLE, ITP, autoimmune hemolytic anemia, scleroderma, rheumatoid arthritis, severe psoriasis)
• Clinical gout
• Patients with clinically significant retinal abnormalities
• Patients with organ transplants

Any other condition, which in the view of the investigator, would make the patient unsuitable for enrolment, or could interfere with the patient participating in and completing the protocol are included as well.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: PEG-Intron; PEG-Intron 0.5mcg/kg once a week SC	Drug: PEG -Intron; Other Names: PEG interferon Alfa-2b 0.5mcg/kg weekly
Active Comparator: Colchicine; 0.6mg twice a day	Drug: Colchicine; 0.6mg twice a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of the Effect of PEG-Intron 0.5mg Per kg Weekly sc Versus Colchicine 0.6mg Bid Daily on:	number of patients with a liver related outcomes including: mortality, liver transplant, variceal or portal hypertensive bleeding,Development of jaundice, ascites or encephalopathy with an increase in CPT of > 2 points and development of hepatoma	4 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of Safety and Tolerability of Long Term Maintenance PEG-Intron in Patients With Cirrhosis	Defined as the number of patients who discontinued therapy due to an adverse event side	4 years
Development of Portal Hypertension	Number of patients who develop endoscopic evidence of varices over 4 year period	4 years

Collaborators and Investigators

• Sponsor: Beth Israel Deaconess Medical Center
• Collaborators: Schering-Plough
• Investigators: Principal Investigator: Nezam H Afdhal, MD, Beth Israel Deaconess Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2000
• Primary Completion (Actual): December 31, 2009
• Study Completion (Actual): March 3, 2010

Study Registration Dates

• First Submitted: September 10, 2005
• First Submitted That Met QC Criteria: September 10, 2005
• First Posted (Estimate): September 16, 2005

Study Record Updates

• Last Update Posted (Actual): July 11, 2017
• Last Update Submitted That Met QC Criteria: June 11, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: interferon; cirrhosis; hepatitis C; colchicine
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Fibrosis; Hepatitis; Hepatitis A; Hepatitis C; Liver Cirrhosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Gout Suppressants; Interferons; Interferon-alpha; Interferon alpha-2; Colchicine; Peginterferon alfa-2b
• Other Study ID Numbers: 2001P000002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO