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Peg-IFN Maintenance Therapy Study: interim analysis at 2 yrs shows positive results
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Reported by Jules Levin
--"Low dose maintenance PEG is superior to COLC in preventing clinical complications of cirrhosis over 2 years of treatment, particularly in patients with portal hypertension and hypoalbuminemia. Maintenance therapy with PEG may be an option in cirrhotic patients who fail interferon based therapies", study authors conclude.--
"COLCHICINE VERSUS PEG-INTRON LONG TERM (COPILOT) TRIAL: INTERIM ANALYSIS OF CLINICAL OUTCOMES AT YEAR 2'
Authors conclude Peg-IFN a2b should be considered as a maintenance therapy in patients with cirrhosis and portal hypertension who have failed eradication therapy.
You could consider use of colchicine in essence a placebo.
Interim results from CoPilot were reported by Nezam Afdhal at AASLD (October 2004). Co-Pilot is a study examining maintenance therapy (half-dose of PegIntron) as a therapy to prevent HCV disease progression in patients not able to achieve viral eradication with interferon+ribavirin.
Afdhal reported the results of the planned 2-year interim analysis of the primary clinical endpoints (death, liver failure with sustained CPT increase > 2 points, variceal bleeding, HCC or liver transplant) which was scheduled to occur once >50% of patients had been on treatment for 2 years or more.
Patients in Co-Pilot Study had failure of prior IFN based therapies. Study patients had no evidence of liver decompensation or HCV (liver cancer); Ishak Fibrosis stage 3 or more; HIV & HbeAg negative. IFN failures (interferon/ribavirin or Peg/ribavirin) were randomized to colchcine, which is essentially a placebo, or half-dose PegIFN a-2b .05 ug/kg/week. Baseline liver biopsy, ultrasound and endoscopy were performed. Clinical evaluation was performed at week 12, ultrasound at 24 weeks, and endoscopy & liver biopsy at 2 and 4 years.
Brief Summary of results:
KM survival analysis demonstrated efficacy for PEG versus COLC (log rank p = 0.003). Secondary stratification showed a benefit in favor of PEG for event free survival (all patients: cirrhosis & Non-cirrhosis) p=0.007, on-treatment liver-related endpoints (p=0.004)cirrhosis CPT 5-7, albumin < 3.5 g/dL (log rank p<0.04), platelets <100,000 (log rank p=0.05), and portal hypertension (log rank p<0.01). Annual events rate (ITT) favored PegIFN vs colchicines, see detailed breakdown below.
534 patients are enrolled in the study to date; COLC 264 and PEG 270. Both groups are well matched for age (mean 49years), gender 70% men, ethnicity (>70% Caucasian, 13% African-American), disease duration (mean 22 years), prior therapy, genotype (Geno 1 87%), cirrhosis (80%), CPT score (mean 5), portal hypertension (40%), bilirubin, albumin, AST, ALT and platelet count (mean 130,000). Mean ALB: 4.1, <3.5 g/dl: 18%; platelets (x103) Mean 134-148, ,100 27%-23%; ALT/AST: 100-107/90-99.
70% of the patients have reached 2 years of therapy or an endpoint. Primary statistical analysis was Kaplan-Meier survival curves for primary clinical events with dropouts censored at the time of withdrawal.
Overall 83 patients (14%) failed to comply with the study and are being followed off treatment or on alternative treatment. 38 patients (7%) discontinued for an adverse event (COLC 15; PEG 23). There were no unexpected or unusual SAE's in either group.
Mechanism of action may be mediated by effects on portal hypertension.
Effect of PegIFN as an antifibrotic and in prevention of HCC (liver cancer) will await further results from CO-PILOT, HALT-C, and EPIC.
Primary study endpoints:
Death
Liver transplant
Liver cancer
Variceal or portal hypertensive bleeding
Liver failure: increase in CPT by 2 points with ascites, jaundice or encephalopathy.
Secondary endpoints:
Histology
Quality of life
Serum fibrosis markers
Development of portal hypertension
All data presented as Intention To treat (ITT) for any patient receiving a single dose of treatment.
RESULTS
Colchicines (n=42); PegIFN a2b (n=26).
PRIMARY ENDPOINTS (ITT) | Death | OLT | HCC | CPT>2pt | Variceal Bleed | | Colchicine | 1 | 2 | 8 | 20 | 11 | | Peg-Intron | 3 | 0 | 9 | 13 | 1 |
Afdahl reported a highly statistically significant difference in event free survival (all patients: cirrhosis & non-cirrhotic) for Peg-Intron over Colchicine (p=0.007; 95% CI 1.18-3.08). Followup was 1440 days.
Primary Liver Endpoints On-Treatment Analysis:
Death: 0 for both arms; OLT: 2 for colchicines, 0 for PegIFN; variceal bleed: 11 for colch, 0 for PegIFN; CPT>2: 16 colch, 12 PegIFN; HCC: 8 colch, 6 PegIFN.
On Treatment Liver related Endpoints:
Statistically significant events free survival favoring PegIntron vs colchicines (p=0.0004); 1440 days followup.
ANNUAL EVENT RATE
| Colch | PegIFN | | All events,ITT | 8.5% | 5% | | Liver related on treatment | 7.5% | 3.5% | | Patients with PHTN | 13.5% | 5% | | HCC | 2% | 2% |
PORTAL HYPERTENSION: PegIfn highly effective maintenance for patients with portal hypertension (HTSN)
| No. PHTN | PHTN | | Colch | 134 | 126 | | Events | 8(6%) | 34(27%)* | | PegIFNa2b | 155 | 111 | | Events | 12(7%) | 14(11%)* |
*Fishers test, p<0.004: PegIFNa2b vs colchicine
SIDE EFFECTS n=42 | Colch(n=18) | Peg n=24 | | Intolerance | 12 | 14 | | Depression | 2 | 3 | | Thrombocytopenia | 1 | 4 | | ALT flare | 1 | 1 | | Other | 2 | 2 |
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