AMSTERDAM, Netherlands, Jan. 13 /PRNewswire-FirstCall/ -- Schering-Plough announced today that it is initiating a large multinational clinical trial to evaluate the use of low-dose PEG-INTRON(R) (peginterferon alfa-2b) maintenance monotherapy in preventing or delaying hepatitis C disease progression and thus potentially reducing the occurrence of clinical events such as liver transplantation, liver cancer and death in cirrhotic patients with hepatitis C who are coinfected with HIV. Known as the ENDURE study, the trial is targeted to enroll 448 patients at approximately 80 sites worldwide, including centers in the United States, Europe and Canada.
Approximately one third of HIV patients, or about 10 million people worldwide, are coinfected with the hepatitis C virus (HCV) and HIV.(1) Liver disease caused by chronic hepatitis C is now a leading cause of morbidity and mortality among HIV-infected patients in the developed world.(2,3) Furthermore, studies have shown that HCV can aggravate the course of HIV infection.(4)
“The principal goal for treating patients infected with hepatitis C is viral eradication, with pegylated interferon and ribavirin combination therapy being the current standard of care. However, many coinfected patients fail to respond to this combination therapy and there currently is no approved treatment for such patients. Until more effective HCV agents such as protease and polymerase inhibitors are available, it is critically important to try to prevent or delay progression of liver disease in these patients,” said Mark S. Sulkowski, M.D., associate professor of medicine in the Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, USA, and co-lead investigator of the study.
“Another patient group that may benefit from low-dose PEG-INTRON maintenance monotherapy is cirrhotic patients with coinfection who are ineligible for combination therapy due to contraindications to ribavirin or who simply cannot tolerate full-dose combination therapy,” added co-lead investigator Massimo Puoti, M.D., associate professor in the Department of Infectious Diseases, University of Brescia, Italy, directed by professor G. Carosi. “The purpose of the ENDURE study is to address this question with a large, randomized, controlled clinical study.”
Study Design
ENDURE is a randomized, open-label, multicenter, Phase III, parallel-group clinical study evaluating the efficacy and safety of maintenance therapy with low-dose PEG-INTRON (0.5 mcg/kg once weekly) versus standard supportive care in patients with cirrhotic hepatitis C who are coinfected with HIV. The primary objective of the study is to compare efficacy for the two treatment groups at the end of the study, using the time to any of the following clinical events as primary endpoints: death, liver decompensation, liver transplant or liver cancer (hepatocellular carcinoma). All patients will be enrolled within the first 12 months of this 36-month study and treated until the end of the study or until a clinical event occurs. Written informed consent will be obtained and all other regulatory requirements adhered to for all patients participating in the study.
The ENDURE study is consistent with Schering-Plough’s research strategy to conduct and support clinical studies with weight-based PEG-INTRON therapy, particularly in hepatitis patients with difficult-to-treat forms of the disease.
“Although we have made great advances over the past decade in the effective treatment of chronic hepatitis C, one of the most common blood-borne infections in the world, improved treatment options are still needed,” said Robert J. Spiegel, M.D., chief medical officer and senior vice president of medical affairs, Schering-Plough Research Institute. “Schering-Plough is undertaking studies with our existing hepatitis C products to explore new approaches to treatment, including maintenance therapy with our ongoing EPIC3 study(5) in HCV patients and the new ENDURE study in coinfected patients, while at the same time developing new antiviral agents such as our investigational hepatitis C protease inhibitor.(6) These research efforts underscore our long-term commitment to this therapeutic area and the hepatitis community.”
About PEG-INTRON
PEG-INTRON is approved in the United States as monotherapy and for use in combination therapy with REBETOL(R) (ribavirin, USP) for the treatment of chronic hepatitis C in patients with compensated liver disease who are at least 18 years of age, and is not approved for treatment of patients who are coinfected with HCV and HIV.
PEG-INTRON, recombinant interferon alfa-2b linked to a 12,000 dalton polyethylene glycol (PEG) molecule, is a once-weekly therapy dosed according to patient body weight that is designed to achieve an effective balance between antiviral activity and elimination half-life.
Important Safety Information Regarding U.S. Labeling for PEG-INTRON and REBETOL
WARNING
Alpha interferons, including PEG-INTRON, 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 PEG-INTRON therapy.
Ribavirin causes hemolytic anemia. Anemia associated with REBETOL therapy may exacerbate cardiac disease that has led to fatal and nonfatal myocardial infarctions. Patients with a history of significant or unstable cardiac disease should not be treated with REBETOL. It is advised that complete blood counts (CBC) be obtained at baseline and at weeks 2 and 4 of therapy or more frequently if clinically indicated.
REBETOL and combination REBETOL/PEG-INTRON therapy must not be used by women, or male partners of women, who are or may become pregnant during therapy and during the 6 months after stopping therapy. REBETOL and combination REBETOL/PEG-INTRON therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Women of childbearing potential and men must use effective contraception (at least two reliable forms) during treatment and during the 6-month post-treatment follow-up period. Significant teratogenic and/or embryocidal effects have been demonstrated for ribavirin in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as one twentieth of the recommended human dose of REBETOL. If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment stops, physicians are encouraged to report such cases by calling (800) 727-7064.
PEG-INTRON
There are no new adverse events specific to PEG-INTRON as compared to INTRON(R) A (interferon alfa-2b, recombinant) for Injection, however, the incidence of some (e.g., injection site reactions, fever, rigors, nausea) were higher. The most common adverse events associated with PEG-INTRON 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 PEG-INTRON. Alopecia (thinning of the hair) is also often associated with alpha interferons including PEG-INTRON.
Psychiatric adverse events, which include insomnia, were common (57%) with PEG-INTRON, 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 PEG-INTRON.
PEG-INTRON/REBETOL is contraindicated in patients with autoimmune hepatitis, decompensated liver disease, and in patients with hemoglobinopathies (e.g., thalassemia major, sickle-cell anemia).
The following serious or clinically significant adverse events have been reported at a frequency less than or equal to 1% with PEG-INTRON 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 PEG-INTRON/REBETOL combination trial the incidence of serious adverse events was 17% in the PEG-INTRON/REBETOL groups compared to 14% in the INTRON A/REBETOL group. The incidence of severe adverse events in the PEG-INTRON/REBETOL combination therapy trial was 23% in the INTRON A/REBETOL group and 31-34% in the PEG-INTRON/REBETOL groups. Dose reductions due to adverse reactions occurred in 42% of patients receiving PEG-INTRON (1.5 mcg/kg)/ REBETOL and in 34% of those receiving INTRON A/REBETOL.
REBETOL should not be used in patients with creatinine clearance less than 50 mL/min.
Schering-Plough Corporation is a global science-based health care company with leading prescription, consumer and animal health products. Through internal research and collaborations with partners, Schering-Plough discovers, develops, manufactures and markets advanced drug therapies to meet important medical needs. Schering-Plough’s vision is to earn the trust of the physicians, patients and customers served by its more than 30,000 people around the world. The company is based in Kenilworth, N.J., USA, 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 Securities Litigation Reform Act of 1995, including statements relating to PEG-INTRON and the potential market for drugs that treat hepatitis. 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, current and future branded, generic or over-the-counter competition and the regulatory process, 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 the company’s third quarter 2005 10-Q.
References 1. Rockstroh J, Mocroft A, Soriano V, et al. Influence of hepatitis C coinfection on HIV disease progression within the EuroSIDA cohort for the EuroSIDA study group. 9th European AIDS Conference (EACS), Warsaw, 2003; F12/4. 2. Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunode.ciency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338:853-860. 3. Sulkowski M, Thomas D. Hepatitis C in the HIV-infected person. Ann Intern Med 2003; 138:197-207. 4. Fischer HP, Willsch E, Bierhoff E, Pfeifer U. Histopathologic findings in chronic hepatitis C. J Hepatol. 1996; 24 (2 suppl) 35-42. 5. EPIC3 (Evaluation of PEG-INTRON in Control of Hepatitis C Cirrhosis), a large multicenter, multi-part treatment and maintenance therapy clinical study involving nearly 4,000 patients at approximately 140 sites worldwide. Schering-Plough Research Institute. 6. SCH-503034, an investigational oral HCV NS3 protease inhibitor, Schering-Plough Research Institute.
Schering-Plough Corporation
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