Advanced Fibrosis, Cirrhosis, Hepatitis C Virus
Conditions
Keywords
hepatitis C, cirrhosis, interferon, colchicine
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.
Interventions
DRUGPEG -Intron
DRUGColchicine
0.6mg twice a day
Sponsors
Schering-Plough
Beth Israel Deaconess Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determination of the Effect of PEG-Intron 0.5mg Per kg Weekly sc Versus Colchicine 0.6mg Bid Daily on: | 4 years | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Safety and Tolerability of Long Term Maintenance PEG-Intron in Patients With Cirrhosis | 4 years | Defined as the number of patients who discontinued therapy due to an adverse event side |
| Development of Portal Hypertension | 4 years | Number of patients who develop endoscopic evidence of varices over 4 year period |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PEG-Intron PEG-Intron 0.5mcg/kg once a week SC
PEG -Intron | 282 |
| Colchicine 0.6mg twice a day
Colchicine: 0.6mg twice a day | 267 |
| Total | 549 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 38 | 20 |
| Overall Study | Withdrawal by Subject | 87 | 95 |
Baseline characteristics
| Characteristic | PEG-Intron | Total | Colchicine |
|---|---|---|---|
| Age, Continuous | 50 years STANDARD_DEVIATION 8.4 | 50.2 years STANDARD_DEVIATION 7.7 | 50.4 years STANDARD_DEVIATION 7.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 6 Participants | 9 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 36 Participants | 72 Participants | 36 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 240 Participants | 467 Participants | 227 Participants |
| Region of Enrollment United States | 282 participants | 549 participants | 267 participants |
| Sex: Female, Male Female | 90 Participants | 167 Participants | 77 Participants |
| Sex: Female, Male Male | 192 Participants | 382 Participants | 190 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 257 / 282 | 44 / 267 |
| serious Total, serious adverse events | 90 / 282 | 79 / 267 |
Outcome results
Primary
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
Time frame: 4 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PEG-Intron | Determination of the Effect of PEG-Intron 0.5mg Per kg Weekly sc Versus Colchicine 0.6mg Bid Daily on: | 53 Participants |
| Colchicine | Determination of the Effect of PEG-Intron 0.5mg Per kg Weekly sc Versus Colchicine 0.6mg Bid Daily on: | 59 Participants |
Secondary
Development of Portal Hypertension
Number of patients who develop endoscopic evidence of varices over 4 year period
Time frame: 4 years
Population: The number of patients at risk include only those patients who at the baseline endoscopy had no evidence of portal hypertension or varices
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PEG-Intron | Development of Portal Hypertension | 12 Participants |
| Colchicine | Development of Portal Hypertension | 24 Participants |
Secondary
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
Time frame: 4 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PEG-Intron | Evaluation of Safety and Tolerability of Long Term Maintenance PEG-Intron in Patients With Cirrhosis | 38 Participants |
| Colchicine | Evaluation of Safety and Tolerability of Long Term Maintenance PEG-Intron in Patients With Cirrhosis | 20 Participants |