By Liz Highleyman

Since about half of all patients with chronic hepatitis do not achieve sustained response to standard therapy with pegylated interferon plus ribavirin - especially if they have hard-to-treat HCV genotype 1 -- researchers have explored alternative treatment regimens.

In a late-breaker session at the 43rd annual meeting of the European Association for the Study of the Liver (EASL) last week in Milan, researchers presented final results from the IDEAL study (Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy), which compared the 2 marketed brands of pegylated interferon alfa: 2a (Pegasys, produced by Roche) and 2b (PegIntron, produced by Schering-Plough).

The IDEAL trial -- described by sponsor Schering-Plough as "the first large, randomized clinical study comparing the leading therapies for chronic hepatitis C" - included 3070 treatment-naive participants at 118 U.S. sites with genotype 1 HCV. A majority (60%) were men, 71% were Caucasian, 19% were Black, and the mean age was about 48 years. Most (82%) had a baseline HCV RNA level of 600,000 IU/mL or higher and 11% had advanced (stage F3-F4) liver fibrosis or cirrhosis.

Participants were randomly assigned to receive one of the following regimens:

• Standard dose of Pegasys (180 mcg/week) plus Roche's Copegus brand of ribavirin (1000-1200 mg/day ribavirin, depending on weight);

• Standard dose of PegIntron (1.5 mcg/kg/week) plus Schering's Rebetol brand of ribavirin (800-1400 mg/day ribavirin, depending on weight);

• A lower dose of PegIntron (1.0 mcg/kg/week) plus the same dose of Rebetol.

Treatment continued for up to 48 weeks. Participants who experienced virological failure at week 12 or 24 were withdrawn from the study, since this is a strong predictor of failure to achieve sustained virological response (SVR), or continued undetectable HCV RNA 24 weeks after completion of therapy.

Pegasys and Copegus were dosed in accordance with their approved label instructions. This has caused some commentators to suggest that the trial did not really compare the 2 brands of pegylated interferon in a true head-to-head manner, since the dose of ribavirin in the PegIntron arms was more closely tailored to patient weight and the top dose was higher. As it turned out, the initial ribavirin dose was the same in the Pegasys and PegIntron arms for 51% of participants, greater in the Pegasys arm for 39%, and greater in the PegIntron arm for 10%.

Results

• At 48 weeks, the end-of-treatment response rate was higher in the Pegasys arm:

• Standard-dose PegIntron/ribavirin: 53%
• Low-dose PegIntron/ribavirin: 49%;
• Standard-dose Pegasys/ribavirin: 64%%.

• However, the relapse rate was lower in the PegIntron arms:

• Standard-dose PegIntron/ribavirin: 24%;
• Low-dose PegIntron/ribavirin: 20%;
• Standard-dose Pegasys/ribavirin: 32%.

• Thus, the primary endpoint of sustained virological response, in an intent-to-treat analysis, was statistically similar across all 3 treatment arms:

• Standard-dose PegIntron/ribavirin: 40%;
• Low-dose PegIntron/ribavirin: 38%;
• Standard-dose Pegasys/ribavirin: 41%.

• Other than treatment regimen, factors associated with a higher risk of relapse were baseline viral load above 600,000 IU/mL, age greater than 40 years, advanced fibrosis, elevated blood glucose (reduced insulin sensitivity), more extensive steatosis, and normal ALT.

• Adverse event (AE) profiles were similar in all 3 treatment groups.

• Serious AEs: 9% standard-dose PegIntron, 9% low-dose PegIntron, 12% Pegasys;
• Discontinuations due to AEs: 13%, 10%, and 13%, respectively;
• Psychiatric serious AEs: 2%, 1%, and 1%, respectively;
• Psychiatric discontinuations: 3%, 2%, and 2%, respectively;
• Anemia (<10g/dL): 31%, 25%, and 30%, respectively;
• Neutropenia (< 750 cells/mm3): 22%, 15%, and 27%, respectively.
• Use of epoetin to boost red blood cells was similar across all arms (16%-17%).

Conclusion

Based on these findings, the investigators concluded that, "SVR rates were not significantly different between all three treatment regimens. Safety/tolerability was similar. While EOT responses were higher with [Pegasys], relapse was less frequent with [PegIntron]."

In an April 26 press release announcing the findings, Schering-Plough stated that, "The study also showed in secondary analyses that PegIntron combination therapy provided greater predictability of response at important treatment milestones and significantly lower relapse rates after the end of treatment than Pegasys and Copegus combination therapy, despite patients in the Pegasys arm overall receiving a significantly higher median ribavirin dose over the duration of the study."

While the overall efficacy of Pegasys and PegIntron combination therapy appear comparable, the equivalence between the standard and lower doses of PegIntron suggests that patients may be able to lower the cost of treatment, and perhaps slightly reduce the risk of hematological side effects, without sacrificing much benefit.

Johns Hopkins University School of Medicine, Baltimore, MD; Alamo Medical Research, San Antonio, TX; Virginia Commonwealth University Medical Center, Richmond, VA; Duke University, Durham, NC; 5 Kelsey Research Foundation, Houston, TX; McCone Endoscopy Center, Alexandria, VA; Southern California Permanente Medical Group, San Diego, CA; University of Texas Southwestern Medical Center, Dallas, TX; The Liver Institute at Methodist Dallas, Dallas, TX; University Of Miami Center for Liver Diseases, Miami, FL; Saint Louis University, St. Loius, MO; Schering-Plough Research Institute.

For further information:

Schering-Plough press release announcing final IDEAL results. (April 26, 2008).

IDEAL investigators John McHutchison and Mark Sulkowski discuss the design and rationale of the trial in a forthcoming issue of the Journal of Viral Hepatitis.

HIV and Hepatitis.com report on the preliminary IDEAL results, including media statements from Schering-Plough and Roche

Hepatology expert Douglas Dieterich discusses the preliminary findings in the January-March 2008 issue of Liver Health Today.

How Ideal is the IDEAL Study? Two HCV activists discuss the IDEAL trial design prior to the study's launch.

5/02/08

Reference

M Sulkowski, E Lawitz, ML Shiffman, and others. Final results of the IDEAL (Individualized Dosing Efficacy Versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) Phase IIIb study. 43rd Annual Meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.

Additional Sources

Schering-Plough. Final Results of Ideal Study Presented at Annual Meeting of the European Association for the Study of the Liver (EASL). Press release. April 26, 2008.

J McHutchison and M Sulkowski. Scientific rationale and study design of the individualized dosing efficacy vs flat dosing to assess optimal pegylated interferon therapy (IDEAL) trial: determining optimal dosing in patients with genotype 1 chronic hepatitis C. Journal of Viral Hepatitis. March 24, 2008.