Study of Long-Term Peg Intron Vs. Colchicine in Non-Responders.

Cirrhosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00179413
• Other study ID #: 2001-P-000002
• Status: Active, not recruiting
• Phase: Phase 4
• First received: September 10, 2005
• Last updated: June 23, 2006
• Start date: January 2001
• Est. completion date: December 2009

Study information

• Verified date: September 2005
• Source: Beth Israel Deaconess Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 800
• Est. completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Advanced Fibrosis
• Cirrhosis
• Fibrosis
• Hepatitis
• Hepatitis C
• Hepatitis C Virus
• Liver Cirrhosis

Intervention

Drug:
• PEG interferon Alfa-2b; Colchicine

Locations

Country	Name	City	State
United States	Austin Gastroenterology	Austin	Texas
United States	34th Street Community Health Center	Bakersfield	California
United States	Digestive Disease Associates	Baltimore	Maryland
United States	Birmingham Gastroenterology Associates	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Bach and Godofsky Infectious Disease	Bradenton	Florida
United States	Lahey Clinic	Burlington	Massachusetts
United States	Danbury Hospital	Danbury	Connecticut
United States	University of Colorado Health Sciences Center	Denver	Colorado
United States	Wayne State University/Haper Hospital	Detroit	Michigan
United States	Digestive Health Services	Downers Grove	Illinois
United States	VA New Jersey Healthcare System	East Orange	New Jersey
United States	Atlantic Gastroenterology	Egg Harbor	New Jersey
United States	Hampshire Gastroenterology	Florence	Massachusetts
United States	Florham Park Endoscopy Center	Florham Park	New Jersey
United States	Dr. Sam Moskowitz, MD, PC	Forest Hills	New York
United States	G.I. and Liver Associates	Granbury	Texas
United States	Southern Clinical Research Consultants	Hollywood	Florida
United States	Gastroenterology Associates	Kansas City	Missouri
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	UAMS Medical Center	Little Rock	Arkansas
United States	Bruce Stein, MD	Manchester	Connecticut
United States	Medical Center of Wisconsin	Milwaukee	Wisconsin
United States	Gastroenterology Division Veterans Affairs Medical Center	Minneapolis	Minnesota
United States	Nashville Gastroenterology Specialists Incorporated	Nashville	Tennessee
United States	Connecticut Gastroenterology Consultants	New Haven	Connecticut
United States	Columbia University	New York	New York
United States	Liberty Medical, LLP	New York	New York
United States	Metro Medical	New York	New York
United States	Albert Einstein Medical Center	Philadelphia	Pennsylvania
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Minnesota Gastroenterology	Plymouth	Minnesota
United States	Peter Varunok, MD	Poughkeepsie	New York
United States	Roger Williams Medical Center	Providence	Rhode Island
United States	University Gastroenterologists	Providence	Rhode Island
United States	Mayo Clinic	Rochester	Minnesota
United States	Gastroenterology Associates of South Florida	S. Miami	Florida
United States	Kaiser Permanende-GI Department	Sacramento	California
United States	UC Davis Medical Center	Sacramento	California
United States	Health Science Center	Salt Lake City	Utah
United States	Digestive Disease Center	San Antonio	Texas
United States	Texas Transplant Institute	San Antonio	Texas
United States	Gastroenterology Associates	San Diego	California
United States	Northern New Mexico Gastroenterology	Santa Fe	New Mexico
United States	Guthrie Research Foundation	Sayre	Pennsylvania
United States	Upstate Medical Center	Syracuse	New York
United States	Georgetown University Medical Center	Washington	District of Columbia
United States	Walter Reed Army Medical Center	Washington	District of Columbia
United States	Fallon Clinic	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Beth Israel Deaconess Medical Center	Schering-Plough

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Determination of the effect of PEG-Intron 0.5mg per kg weekly sc versus colchicine 0.6mg bid daily on:
Primary	4 year survival or hepatic transplantation
Primary	Variceal or portal hypertensive bleeding
Primary	Development of jaundice, ascites or encephalopathy with an increase in CPT of > 2 points
Primary	Development of hepatoma
Secondary	Evaluation of safety and tolerability of long term maintenance PEG-Intron in patients with cirrhosis
Secondary	Evaluation of the effect of long term maintenance PEG-Intron on quality of life
Secondary	Evaluation of surrogate markers of fibrosis in determining effect of long term maintenance PEG-Intron on prevention of progression of fibrosis and correlation of fibrosis markers with pathology.
Secondary	Development of portal hypertension
Secondary	Progression of histological fibrosis