Healthcare Industry News: Biostat
News Release - November 19, 2007
Merck/Schering-Plough Pharmaceuticals Provides Update on ENHANCE TrialWHITEHOUSE STATION, N.J. & KENILWORTH, N.J.--(HSMN NewsFeed)--Merck/Schering-Plough Pharmaceuticals today announced that an independent panel of clinical and Biostatistics experts was convened on Friday, November 16, 2007 to offer advice about the prospective analysis of the ENHANCE trial. ENHANCE is a multinational, randomized, double-blind, trial that examines the effects of the highest approved dose of VYTORIN/INEGY (10 mg ezetimibe + 80 mg simvastatin) versus the highest approved dose of simvastatin 80 mg alone in patients with Heterozygous Familial Hypercholesterolemia (HeFH). Patients with this uncommon genetic condition usually have very high cholesterol levels. HeFH occurs in approximately 0.2 percent of the population.
The independent panel recommended focusing the primary endpoint to the common carotid artery to expedite the reporting of the study findings. Merck/Schering-Plough now anticipates that these results of the ENHANCE study will be presented at the American College of Cardiology meeting in March 2008.
While the clinical portion of the ENHANCE study is complete, the study remains blinded and the data are now being analyzed. The rigorous study design and analytical process specified in the study protocol require examination of more than 40,000 scans of the arterial intima-media thickness (IMT) of the carotid and femoral arteries collected in eighteen multi-national study sites. This has been time consuming and taken longer than originally anticipated because during the analysis, observations of variability in some of the data were detected as part of the validation/data review procedures. Such potentially confounding observations are not unusual in studies of this kind.
The primary objective of the ENHANCE trial is to measure the change in the intima media thickness at three points of the carotid artery (the internal carotid, carotid bulb and the common carotid), at the beginning of the study and at two years. The ENHANCE trial employs a novel non-invasive methodology to assess the intima-media thickness using digital single-frame ultrasound imagery of the arteries. This technique was pioneered by Professor John Kastelein, the lead investigator of the ENHANCE study.
“It is critically important for researchers to take the appropriate time and rigor to conduct clinical trials, analyze data and report study results. The ENHANCE trial is complex and is being conducted with great care,” said John Kastelein, M.D., Ph.D., professor of medicine and chairman, Department of Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands. “We view the experts panel's recommendation to narrow the primary endpoint to the common carotid artery as helpful, and we will continue to expedite the completion of ENHANCE and reporting of its results, while ensuring the integrity of the data." Kastelein added, “We anticipate that results of the ENHANCE study will be presented at the American College of Cardiology meeting in 2008, dependent upon successful completion of the data analysis.”
The ENHANCE study was initiated in 2002, and involves over 700 HeFH patients. HeFH is characterized by markedly elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol (LDL-C), typically well above the 95th percentile for age and sex.1 Images from HeFH patients in this study are analyzed from the right and left carotid arteries at numerous time points (baseline, 6, 12, 18 and 24 months). Images of the femoral arteries are also analyzed at numerous time points in the ENHANCE trial, a surrogate endpoint study.
In addition, Merck/Schering-Plough Pharmaceuticals is conducting a robust clinical outcomes studies program to evaluate the effects of VYTORIN/INEGY, which includes more than 20,000 high-risk patients enrolled in three outcomes studies: SHARP, SEAS and IMPROVE-IT.
Important information about VYTORIN®
VYTORIN contains simvastatin and ezetimibe. VYTORIN is indicated as adjunctive therapy to diet for the reduction of elevated total cholesterol, LDL cholesterol, Apo B2, triglycerides and non-HDL cholesterol and to increase HDL cholesterol in patients with primary (heterozygous familial and non-familial) hypercholesterolemia or mixed hyperlipidemia.
VYTORIN is also indicated for the reduction of elevated total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia, as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if such treatments are unavailable.
VYTORIN is a prescription medicine and should not be taken by people who are hypersensitive to any of its components. VYTORIN should not be taken by anyone with active liver disease or unexplained persistent elevations of serum transaminases. Women who are of childbearing age (unless highly unlikely to conceive), are nursing or who are pregnant should not take VYTORIN.
Selected cautionary information for VYTORIN
Muscle pain, tenderness or weakness in people taking VYTORIN should be reported to a doctor promptly because these could be signs of a serious side effect. VYTORIN should be discontinued if myopathy is diagnosed or suspected. To help avoid serious side effects, patients should talk to their doctor about medicine or food they should avoid while taking VYTORIN.
In three placebo-controlled, 12-week trials, the incidence of consecutive elevations (greater than or equal to 3 X ULN) in serum transaminases were 1.7 percent overall for patients treated with VYTORIN and 2.6 percent for patients treated with VYTORIN 10/80 mg. In controlled long-term (48-week) extensions, which included both newly-treated and previously-treated patients, the incidence of consecutive elevations (greater than or equal to 3 X ULN) in serum transaminases was 1.8 percent overall and 3.6 percent for patients treated with VYTORIN 10/80 mg. These elevations in transaminases were generally asymptomatic, not associated with cholestasis and returned to baseline after discontinuation of therapy or with continued treatment. Doctors should perform blood tests before, and periodically during treatment with VYTORIN when clinically indicated to check for liver problems. People taking VYTORIN 10/80 mg should receive an additional liver function test prior to and three months after titration and periodically during the first year.
Due to the unknown effects of increased exposure to ezetimibe (an ingredient in VYTORIN) in patients with moderate or severe hepatic insufficiency, VYTORIN is not recommended in these patients. The safety and effectiveness of VYTORIN with fibrates have not been established; therefore, co-administration with fibrates is not recommended. Caution should be exercised when initiating VYTORIN in patients treated with cyclosporine and in patients with severe renal insufficiency.
VYTORIN has been evaluated for safety in more than 3,800 patients in clinical trials and was generally well tolerated at all doses (10/10 mg, 10/20 mg, 10/40 mg, 10/80 mg). In clinical trials, the most commonly reported side effects, regardless of cause, included headache (6.8 percent), upper respiratory tract infection (3.9 percent), myalgia (3.5 percent), influenza (2.6 percent) and extremity pain (2.3 percent).
Important information about ZETIA®
ZETIA is a prescription medication and should not be taken by people who are allergic to any of its ingredients. When ZETIA is prescribed with a statin, it should not be taken by women who are nursing or pregnant or who may become pregnant, or by anyone with active liver disease. Statins should not be taken by anyone with these conditions. If you have ever had liver problems or are pregnant or nursing, your doctor will decide if ZETIA is right for you. Your doctor may do blood tests to check your liver before you start taking ZETIA with a statin and during treatment.
Due to the unknown effects of increased exposure to ZETIA in patients with moderate or severe hepatic insufficiency, ZETIA is not recommended in these patients. In clinical trials, there was no increased incidence of myopathy (muscle pain) or rhabdomyolysis (muscle breakdown) associated with ZETIA; however myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs. There are no adequate and well-controlled studies of ZETIA in pregnant women. ZETIA should not be used in pregnant or nursing women unless the benefit outweighs the potential risks.
When ZETIA was co-administered with a statin, consecutive elevations in liver enzymes, more than three times the upper limit of normal, were slightly higher than those with the statin alone (1.3 percent vs. 0.4 percent). These elevations were generally asymptomatic and returned to baseline after discontinuation of therapy or with continued treatment. When ZETIA was co-administered with fenofibrate, consecutive elevations in liver enzymes more than three times the upper limit of normal, were 2.7 percent, and 4.5 percent in patients treated with fenofibrate alone. Caution should be exercised when initiating ZETIA in patients treated with cyclosporine, particularly in patients with severe renal insufficiency, due to increased blood levels of ZETIA.
In clinical trials, most frequent side effects for ZETIA alone vs. placebo included: back pain (4.1 percent vs. 3.9 percent), arthralgia (3.8 percent vs. 3.4 percent), and fatigue (2.2 percent vs. 1.8 percent); for ZETIA plus statin vs. statin or placebo alone: back pain (4.3 percent vs. 3.7 percent vs. 3.5 percent), abdominal pain (3.5 percent vs. 3.1 percent vs. 2.3 percent), and fatigue (2.8 percent vs. 1.4 percent vs. 1.9 percent).
About Merck/Schering-Plough Pharmaceuticals
Merck/Schering-Plough Pharmaceuticals is a joint venture between Merck & Co., Inc. and Schering-Plough Corporation formed to develop and market in the United States new prescription medicines in cholesterol management. The collaboration includes worldwide markets (excluding Japan). VYTORIN is also marketed as INEGY outside the U.S.
Merck forward-looking statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.
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 potential market for VYTORIN and ZETIA. 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 II, Item 1A. "Risk Factors" in the Schering-Plough's third quarter 2007 10-Q.
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