High-dose Pegylated Interferon-alfa-2a (Pegasys): A Safety Evaluation

By Marina Nunez, MD

In a poster presentation at the 56^th AASLD, researchers presented the safety data reported at an oral presentation from the REPEAT study, a randomized trial evaluating the usefulness of induction with double dose of pegylated interferon (pegIFN)-a -2a plus ribavirin for the treatment of patients not responding to prior peginterferon alfa-2b/ribavirin (RBV) combination therapy.

A total of 950 patients were randomized into 4 arms, two of high-dose induction (N=476) in which 360 mg/Kg of pegIFN-a-2a were given for the first 12 weeks of treatment, and two of standard dose (474) in which patients received 180 mg/Kg. The study is ongoing, and these results concern to the first 12 weeks of therapy.

Premature withdrawals:

A slightly higher proportion of patients receiving high-dose compared with standard-dose pegIFN-a-2a discontinued treatment prematurely (table 1).

Overall, a similar proportion of patients in the high-dose induction group and the standard-dose group discontinued because of adverse events (table 1). The proportion of patients with cirrhosis who withdrew from treatment because of adverse events was similar to that in the overall patient population (3% in the high-dose induction group, 2% in the standard-dose group).

Withdrawals due to non-safety reasons in the overall patient population were more common in the high-dose induction group than in the standard-dose group (table 1).

Dose reductions and discontinuations of study medication:

A greater proportion of patients in the high-dose induction group required dose reductions or discontinuation of pegIFN-a-2a due to adverse events and/or laboratory abnormalities (table 1). The frequency of dose reductions or discontinuation of pegIFN-a-2a due to neutropenia was slightly higher in the high-dose induction vs. the standard-dose group (11% vs. 8%).

Ribavirin dose modifications or discontinuations occurred in a similar proportion of patients receiving high-dose and standard-dose pegIFN-a-2a (18% vs. 14%) (table 1).

Adverse events, serious adverse events and deaths:

The overall frequency of adverse events was similar between the two groups (table 2)

Serious adverse events were uncommon (2% in the high-dose arm and 4% in the standard-dose arm), and occurred in similar proportions among cirrhotic and non-cirrhotic patients.

No deaths were reported.                                       

Changes in hematological parameters:

Mean platelet and neutrophil counts decreased in both groups. Only one patient in the standard-dose group discontinued treatment due to neutropenia (table 2).

In the standard-dose group 3% of patients, and in the high-dose group 6% of patients had a nadir platelet count of 20 to <50 x 10⁹ cells/L. No patient withdrew from treatment due to thrombocytopenia.

In conclusion, this interim analysis demonstrates that the safety profile of pegIFN-a-2a combined with RBV does not appear to be compromised in patients receiving a high fixed induction dose (360 mg/week), compared with the standard treatment regimen (180 mg/week), even in cirrhotic patients.

11/23/05

Reference
P Marcellin and others. Planned interim analysis of patients enrolled in the randomized, international REtreatment with PEgasys® in pATients not responding to prior peginterferon alfa-2b/ribavirin (RBV) combination therapy (REPEAT study). Abstract 1174. 56^th annual meeting of the American Association for the Study of Liver Diseases (56^th AASLD). November 11-15, 2005. San Francisco, CA.