MILAN, Italy, April 26 /PRNewswire-FirstCall/ -- Final results of the IDEAL study, the first large, randomized, clinical study comparing the leading therapies for chronic hepatitis C, were presented today at the 43rd Annual Meeting of the European Association for the Study of the Liver (EASL), providing important insights that may help guide clinical practice for physicians worldwide treating this serious and potentially life-threatening disease.
The IDEAL study compared combination therapy with PEGINTRON(TM) (peginterferon alfa-2b) and REBETOL(R) (ribavirin, USP) vs. Pegasys (peginterferon alfa-2a) and Copegus (ribavirin, USP),(1) as well as a lower dose of PEGINTRON in an investigational combination with REBETOL. The results showed that sustained virologic response (SVR),(2) 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 U.S. 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:
(1) PEGINTRON 1.5 mcg/kg/week and REBETOL 800-1,400 mg/day; (2) PEGINTRON 1.0 mcg/kg/week and REBETOL 800-1,400 mg/day; and (3) Pegasys 180 mcg/week and Copegus 1,000-1,200 mg/day
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 U.S. 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 percent of patients in the study were assigned the same dose of ribavirin (either REBETOL or Copegus) based on their weight groups, 39 percent of patients in the Pegasys arm were assigned a higher dose of ribavirin and 10 percent of patients in the PEGINTRON arms were assigned a higher dose of ribavirin.
Key Findings from IDEAL
(For the PEGINTRON 1.5 mcg, PEGINTRON 1.0 mcg, and Pegasys combination arms, respectively.)
-- 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 percent, respectively) (ITT).(3,4)
-- 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 percent, respectively).(5)
-- 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 percent, 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).
-- End of treatment response was higher in the Pegasys combination arm (53 vs. 49 vs. 64 percent, respectively).
-- Ribavirin dose: 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 percent, respectively). Discontinuation rates due to adverse events were similar across the three treatment arms (13 vs. 10 vs. 13 percent, respectively) as were discontinuations due to psychiatric adverse events (3 vs. 2 vs. 2 percent, respectively).
The complete results of the IDEAL study will be submitted for peer-reviewed publication, as well as to health authorities worldwide.
About IDEAL
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 centers 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 U.S. Food and Drug Administration (FDA). The comparison of the PEGINTRON and Pegasys combination therapy regimens was added to the study because no randomized, 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.
Mark Sulkowski, M.D., and John McHutchison, M.D., are the co-principal investigators of the IDEAL study. They also are co-chairmen of the IDEAL Publication Committee, which also includes three independent expert members not associated with the study to provide an unbiased evaluation of the data. The Publication Committee was responsible for the preparation of the prespecified data analysis plan for the statistical analysis conducted for the primary publication of the study results.
About PEGINTRON
In the United States, PEGINTRON is indicated for use alone or with ribavirin for the treatment of chronic hepatitis C in patients with compensated liver disease who have not been previously treated with interferon alpha and who are at least 18 years of age.
Important Safety Information Regarding U.S. Labeling for PEGINTRON and REBETOL
Alpha interferons, including PEGINTRON and INTRON(R) A, may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening signs or symptoms of these conditions should be withdrawn from therapy. In many, but not all cases, these disorders resolve after stopping PEGINTRON and/or INTRON A therapy.
Use with Ribavirin: Ribavirin may cause birth defects and/or death of the unborn child. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with REBETOL therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen.
Contraindications
PEGINTRON is contraindicated in patients with hypersensitivity to PEGINTRON or any other component of the product, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6 [class B and C]) in cirrhotic CHC patients before or during treatment. INTRON A (Interferon alfa-2b, recombinant) for Injection is contraindicated in patients with hypersensitivity to INTRON A or any component of the product, autoimmune hepatitis, and decompensated liver disease. PEGINTRON or INTRON A in combination with REBETOL therapy is additionally contraindicated in patients with hypersensitivity to ribavirin or any other component of the product, women who are pregnant, men whose female partners are pregnant, patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia), and patients with creatinine clearance less than 50 mL/min.
Avoid Pregnancy
REBETOL therapy should not be started until a report of a negative pregnancy test has been obtained immediately prior to planned initiation of therapy. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients during therapy and 6 months post-treatment. Patients should use at least two effective forms of contraception and have monthly pregnancy tests during therapy and for 6 months after completion of therapy. A Ribavirin Pregnancy Registry has been established to monitor maternal-fetal outcomes of pregnancies in female patients and female partners of male patients exposed to ribavirin during treatment, and for 6 months following cessation of treatment. Physicians and patients are encouraged to report such cases by calling 1-800-593-2214.
Incidence of Adverse Events
There are no new adverse events specific to PEGINTRON as compared to INTRON A; however, the incidence of some (e.g., injection site reactions, fever, rigors, nausea) were higher. The most common adverse events associated with PEGINTRON were "flu-like" symptoms, occurring in approximately 50% of patients, which may decrease in severity as treatment continues. Application site disorders were common (47%), but all were mild (44%) or moderate (4%) and no patient discontinued, and included injection site inflammation and reaction (i.e., bruise, itchiness, irritation). Injection site pain was reported in 2% of patients receiving PEGINTRON. Alopecia (thinning of the hair) is also often associated with alpha interferons including PEGINTRON.
Psychiatric adverse events, which include insomnia, were common (57%) with PEGINTRON but similar to INTRON A (58%). Depression was most common at 29%. Suicidal behavior including ideation, suicidal attempts, and completed suicides occurred in 1% of patients during or shortly after completing treatment with PEGINTRON.
The following serious or clinically significant adverse events have been reported at a frequency less than 1% with PEGINTRON or interferon alpha: Severe decreases in neutrophil or platelet counts, hypothyroidism, hyperglycemia, hypotension, arrhythmia, ulcerative and hemorrhagic colitis, development or exacerbation of autoimmune disorders including thyroiditis, RA, systemic lupus erythematosus, psoriasis, pulmonary disorders (dyspnea, pulmonary infiltrates, pneumonitis and pneumonia, some resulting in patient deaths), urticaria, angioedema, bronchoconstriction, anaphylaxis, retinal hemorrhages, and cotton wool spots.
In the PEGINTRON/REBETOL combination trial, the incidence of serious adverse events was 17% in the PEGINTRON/REBETOL groups compared to 14% in the INTRON A/ REBETOL group. The incidence of severe adverse events in the PEGINTRON/REBETOL combination therapy trial was 23% in the INTRON A/REBETOL group and 31-34% in the PEGINTRON/REBETOL groups. Dose reductions due to adverse reactions occurred in 42% of patients receiving PEGINTRON (1.5 mcg/kg)/REBETOL and in 34% of those receiving INTRON A/REBETOL.
In a study with weight-based ribavirin, there was a higher rate of anemia among patients in the weight-based dosing group (29%) compared to the flat-dosing group (19%). The majority of these cases were mild and responded to dose reductions. Serious adverse events were similar between the two groups (12%), and discontinuations for adverse events (15% in weight-based dosing and 14% in flat dosing) were also similar. Dose modifications due to adverse events occurred more frequently in the weight-based dosing group (29%) compared to the flat-dosing (23%) group.
Additional Safety Information
Relapse of drug addiction/overdose has occurred in patients on PEGINTRON therapy. Aggressive behavior sometimes directed towards others has occurred in patients with and without a previous psychiatric disorder during PEGINTRON and/or INTRON A treatment and follow-up. If patients develop psychiatric problems, including clinical depression, it is recommended that patients be carefully monitored during treatment and in the 6-month follow-up period. If psychiatric symptoms persist or worsen, or suicidal ideation or aggressive behavior towards others is identified, it is recommended that treatment with PEGINTRON and/or INTRON A be discontinued, and the patient be carefully followed with psychiatric intervention, as appropriate. Cases of encephalopathy have been observed in some patients, usually elderly, treated with higher doses of PEGINTRON and/or INTRON A. Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alpha therapies, including PEGINTRON and INTRON A. Dental and periodontal disorders have been reported in patients receiving PEGINTRON or INTRON A in combination with REBETOL therapy.
Please see important full U.S. prescribing information and the Medication Guide for PEGINTRON at http://www.schering-plough.com/.
About Schering-Plough
Schering-Plough is an innovation-driven, science-centered global health care company. Through its own biopharmaceutical research and collaborations with partners, Schering-Plough creates therapies that help save and improve lives around the world. The company applies its research-and-development platform to human prescription and consumer products as well as to animal health products. Schering-Plough's vision is to "Earn Trust, Every Day" with the doctors, patients, customers and other stakeholders served by its colleagues around the world. The company is based in Kenilworth, N.J., and its Web site is http://www.schering-plough.com/.
SCHERING-PLOUGH DISCLOSURE NOTICE: The information in this press release includes certain "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements relating to the IDEAL study and the potential market for PEGINTRON and REBETOL. Forward-looking statements relate to expectations or forecasts of future events. Schering-Plough does not assume the obligation to update any forward-looking statement. Many factors could cause actual results to differ materially from Schering-Plough's forward-looking statements, including market forces, economic factors, product availability, patent and other intellectual property protection, current and future branded, generic or over-the-counter competition, the regulatory process, and any developments following regulatory approval, among other uncertainties. For further details about these and other factors that may impact the forward-looking statements, see Schering-Plough's Securities and Exchange Commission filings, including Part I, Item 1A. "Risk Factors" in Schering-Plough's 2007 10-K/A.
Endnotes: 1 Pegasys and Copegus are registered trademarks of Hoffmann-La Roche Inc. Please see the Pegasys and Copegus product inserts for information on these products. 2 SVR, the protocol specified primary efficacy endpoint, is defined as achievement of undetectable HCV-RNA in plasma at 24 weeks after the end of treatment. Per protocol, if a patient did not have a 24-week post- treatment assessment, the patient's 12-week post-treatment assessment was utilized. 3 Roche Cobas Taqman 1.0 assay; lower limit of quantitation (LLQ) is 27 IU/mL. 4 Intention-To-Treat (ITT) analysis includes any patient who has taken at least one dose of any study drug. 5 Sensitivity Analysis: Patients with missing data at follow-up week 24 are included in the analysis if treatment week 4 and treatment week 24 undetectable (HCV-RNA): PPVs at treatment week 4 were 94 vs. 91 vs. 89 percent for the PEGINTRON 1.5 mcg arm, PEGINTRON 1.0 mcg arm and Pegasys arm, respectively.
