Schering Plough reported final results of the IDEAL study, the first large, randomised, clinical study comparing the leading therapies for chronic hepatitis C.
The IDEAL study compared combination therapy with Pegintron (peginterferon alfa-2b) and Rebetol (ribavirin, USP) vs. Pegasys (peginterferon alfa-2a) and Copegus (ribavirin, USP), as well as a lower dose of Pegintron in an investigational combination with Rebetol. The results showed that sustained virologic response (SVR).
The primary endpoint of the study was similar for all three treatment regimens. 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. Safety and tolerability were similar among the treatment arms.
"IDEAL provides important insights about the similarities and differences of the two leading combination therapies for hepatitis C, and how physicians can use these findings to help manage their patients," said Robert J. Spiegel, M.D., chief medical officer and senior vice president, Schering-Plough Research Institute.
In IDEAL (Individualized Dosing Efficacy vs. flat dosing to assess optimaL pegylated interferon therapy), 3,070 previously untreated US patients with HCV genotype 1, the most common form of the virus worldwide and most difficult to treat, were randomized and treated with one of three treatment regimens:
Patients received up to 48 weeks of combination therapy with 24 weeks of follow-up.
In IDEAL, the combination regimen of Pegasys and Copegus used the recommended doses in accordance with their approved US labeling, which includes a flat dose of Pegasys (180 mcg/week) for all patients regardless of body weight, and 1,000 or 1,200 mg/day of Copegus, adjusted for two weight categories. Pegintron was dosed either at 1.5 mcg/kg/week or an investigational combination dose of 1.0 mcg/kg/week with Rebetol at a dose of 800-1,400 mg/day, adjusted by four weight categories.
As a result, 51 per cent of patients in the study were assigned the same dose of ribavirin (either Rebetol or Copegus) based on their weight groups, 39 per cent of patients in the Pegasys arm were assigned a higher dose of ribavirin and 10 per cent of patients in the Pegintron arms were assigned a higher dose of ribavirin.
SVR, the primary endpoint of the study, was similar for the three treatment regimens (40 vs. 38 vs. 41 percent, respectively) overall, and among those patients who were assigned equivalent doses of ribavirin based on their weight group (40 vs. 38 vs. 38 per cent, respectively) (ITT).
Predictability of response at early treatment milestones was confirmed in a secondary analysis as an important assessment tool for physicians. More patients in the Pegintron combination arms who had undetectable virus (HCV-RNA) in plasma at treatment week 4 or treatment week 12 went on to achieve SVR (positive predictive value, PPV) than patients in the Pegasys combination arm (92 vs. 87 vs. 80 percent, and 81 vs. 83 vs. 74 per cent, respectively).
Relapse after the end of treatment was lower for patients in the Pegintron combination therapy arms compared to patients receiving Pegasys and Copegus (24 vs. 20 vs. 32 per cent, respectively). In a multivariate logistic regression analysis, among the factors significantly affecting relapse were: baseline viral load greater than 600,000 IU/mL vs. less than or equal to 600,000 IU/mL (p-value less than 0.001); age greater than 40 vs. less than or equal to 40 (p-value less than 0.001); fibrosis F3/4 vs. F0/1/2 (p-value equal to 0.001); Pegasys regimen vs. Pegintron 1.0 mcg regimen (p-value less than 0.001); glucose fasting greater than or equal to 5.6 vs. less than 5.6 (p-value equal to 0.002); steatosis 0 percent vs. greater than 0 percent (p-value equal to 0.002); ALT normal vs. elevated (p-value equal to 0.008); and Pegasys regimen vs. PEGINTRON 1.5 mcg regimen (p-value equal to 0.012).
One of the key questions of the study has been whether the protocol-assigned ribavirin dose regimen or the protocol-specified dose reduction schedule disadvantaged patients in any of the treatment arms, particularly in the Pegasys combination arm. However, the final results of IDEAL showed that the majority of patients in the Pegasys therapy arm received a higher ribavirin dose over the duration of the study, including patients with ribavirin dose reductions or discontinuations, based on the actual median ribavirin dose received (mg/kg/day), regardless of treatment outcome (SVR, relapsers and nonresponders) [p-value less than 0.001 for ribavirin dose received in the Pegintron 1.5 mcg arm vs. Pegasys arm and p-value less than or equal to 0.001 for ribavirin dose received in the Pegintron 1.0 arm vs. Pegasys arm.
Safety and tolerability were similar among the three treatment groups, with no new peginterferon or ribavirin related adverse events identified in this large study. Overall adverse events reported for the three treatment regimens were similar. As seen in other studies with these treatments, a range of "flu-like symptoms" were the most commonly reported adverse events for all three treatment regimens. Overall, the proportion of patients reporting serious adverse events was similar (9 vs. 9 vs. 12 per cent, respectively). Discontinuation rates due to adverse events were similar across the three treatment arms (13 vs. 10 vs. 13 per cent, respectively) as were discontinuations due to psychiatric adverse events (3 vs. 2 vs. 2 per cent, respectively).
The IDEAL study was undertaken by Schering-Plough as an important step in meeting the needs of the hepatitis C medical and patient communities to identify improved treatment strategies to optimize outcomes for patients. IDEAL, a Phase IIIb, randomized, parallel-group study, was conducted at 118 academic and community centres across the United States. The study treated 3,070 adult patients with chronic HCV genotype 1. Of these, 82 percent of patients had high viral load (greater than 600,000 IU/mL),(3) 11 percent had grade F3/4 fibrosis/cirrhosis, and 19 percent were African Americans. There were no significant differences in patient demographics or disease characteristics across the three treatment arms.
The comparison of the two Pegintron combination therapy doses (1.5 vs. 1.0 mcg/kg/week) was conducted as a post-approval commitment to the US Food and Drug Administration (FDA). The comparison of the Pegintron and Pegasys combination therapy regimens was added to the study because no randomised, controlled head-to-head study of the two available peginterferon regimens had been conducted to date. Cross-study comparisons and retrospective analyses of previous data are difficult to interpret because of differences in study designs, patient populations and assay limits.