Clinical trial NCT00179413: Study of Long-term Peg Intron vs. Colchicine in Non-responders.
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hepatitis C Virus
Advanced Fibrosis
Cirrhosis
Keywords: hepatitis C
cirrhosis
interferon
colchicine
Lead sponsor: Beth Israel Deaconess Medical Center
Sponsor class: OTHER
Collaborators: name: Schering-Plough
First posted: 2005-09-16
Enrollment: 549
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Determination of the Effect of PEG-Intron 0.5mg Per kg Weekly sc Versus Colchicine 0.6mg Bid Daily on:
timeFrame: 4 years
Secondary outcomes:
measure: Evaluation of Safety and Tolerability of Long Term Maintenance PEG-Intron in Patients With Cirrhosis
timeFrame: 4 years
measure: Development of Portal Hypertension
timeFrame: 4 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Birmingham Gastroenterology Associates
state: Alabama
city: Little Rock
country: United States
facility: UAMS Medical Center
state: Arkansas
city: Bakersfield
country: United States
facility: 34th Street Community Health Center
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Sacramento
country: United States
facility: Kaiser Permanende-GI Department
state: California
city: San Diego
country: United States
facility: Gastroenterology Associates
state: California
city: Denver
country: United States
facility: University of Colorado Health Sciences Center
state: Colorado
city: Danbury
country: United States
facility: Danbury Hospital
state: Connecticut
city: Manchester
country: United States
facility: Bruce Stein, MD
state: Connecticut
city: New Haven
country: United States
facility: Connecticut Gastroenterology Consultants
state: Connecticut
city: Washington, D.C.
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Washington, D.C.
country: United States
facility: Walter Reed Army Medical Center
state: District of Columbia
city: Bradenton
country: United States
facility: Bach and Godofsky Infectious Disease
state: Florida
city: Hollywood
country: United States
facility: Southern Clinical Research Consultants
state: Florida
city: South Miami
country: United States
facility: Gastroenterology Associates of South Florida
state: Florida
city: Downers Grove
country: United States
facility: Digestive Health Services
state: Illinois
city: Baltimore
country: United States
facility: Digestive Disease Associates
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Clinic
state: Massachusetts
city: Florence
country: United States
facility: Hampshire Gastroenterology
state: Massachusetts
city: Worcester
country: United States
facility: Fallon Clinic
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University/Haper Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Gastroenterology Division Veterans Affairs Medical Center
state: Minnesota
city: Plymouth
country: United States
facility: Minnesota Gastroenterology
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Kansas City
country: United States
facility: Gastroenterology Associates
state: Missouri
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: East Orange
country: United States
facility: VA New Jersey Healthcare System
state: New Jersey
city: Egg Harbor
country: United States
facility: Atlantic Gastroenterology
state: New Jersey
city: Florham Park
country: United States
facility: Florham Park Endoscopy Center
state: New Jersey
city: Santa Fe
country: United States
facility: Northern New Mexico Gastroenterology
state: New Mexico
city: Forest Hills
country: United States
facility: Dr. Sam Moskowitz, MD, PC
state: New York
city: New York
country: United States
facility: Liberty Medical, LLP
state: New York
city: New York
country: United States
facility: Metro Medical
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Poughkeepsie
country: United States
facility: Peter Varunok, MD
state: New York
city: Syracuse
country: United States
facility: Upstate Medical Center
state: New York
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Albert Einstein Medical Center
state: Pennsylvania
city: Sayre
country: United States
facility: Guthrie Research Foundation
state: Pennsylvania
city: Providence
country: United States
facility: University Gastroenterologists
state: Rhode Island
city: Providence
country: United States
facility: Roger Williams Medical Center
state: Rhode Island
city: Nashville
country: United States
facility: Nashville Gastroenterology Specialists Incorporated
state: Tennessee
city: Austin
country: United States
facility: Austin Gastroenterology
state: Texas
city: Granbury
country: United States
facility: G.I. and Liver Associates
state: Texas
city: San Antonio
country: United States
facility: Digestive Disease Center
state: Texas
city: San Antonio
country: United States
facility: Texas Transplant Institute
state: Texas
city: Salt Lake City
country: United States
facility: Health Science Center
state: Utah
city: Milwaukee
country: United States
facility: Medical Center of Wisconsin
state: Wisconsin
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Nezam H Afdhal, MD
role: PRINCIPAL_INVESTIGATOR
References: