ACHIEVE Stopped: IMT Study With Niacin/Laropiprant Halted by Merck & Co

May 23, 2008

May 23, 2008 — The Assessment of Coronary Health Using an Intima-Media Thickness (IMT) Endpoint for Vascular Effects (ACHIEVE) trial, a two-year study of familial hypercholesterolemia (FH) patients treated with a novel compound designed to raise HDL-cholesterol levels, is no longer. The sponsor, Merck & Co, halted the trial after the advisory committee recommended ending the carotid IMT study of cholesterol drug MK-524A, two months after the committee urged that the enrollment of more patients be put on hold.

ACHIEVE was an investigation of a novel combination tablet, once known as Cordaptive, and before that as MK-524A, that was designed to help patients tolerate the long-term use of the HDL-cholesterol-raising treatment. The combination tablet contains extended-release niacin and laropiprant, a specific blocker of prostaglandin D2 to prevent flushing.

Stopping the trial, however, won't come as too much of a surprise. Just a few weeks ago, the US Food and Drug Administration issued a "not-approvable" letter to Merck with regard to the drug. The agency even rejected the US trade name of Cordaptive for the product, so the combination tablet is again known as MK-524A.

ENHANCE Circus and Now ACHIEVE

In a press release issued by Merck, the company said that ACHIEVE was not stopped because of the FDA rejection, but rather because of the patient population being studied. Merck also said they are continuing to work to bring the drug to market. According to company officials and the steering committee, recent IMT studies, including the Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial, have suggested that an FH patient population is not ideal for testing the ability of the drug to halt the progression of atherosclerosis.

"It was clear from the steering committee's review of pooled data from recently completed [carotid] IMT studies of other medicines that the patient population being studied in ACHIEVE was no longer the correct population to test the primary study hypothesis of IMT progression," Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands), chair of the study's steering committee, is quoted as saying in Merck's statement.

ACHIEVE included a patient population similar to the one in the recently presented and published ENHANCE trial, a study that also used carotid IMT measurements as the primary outcome.

ENHANCE investigators found that the ezetimibe/simvastatin combination did not result in a significant difference in changes in IMT, compared with simvastatin alone, despite significantly greater reductions in LDL cholesterol and C-reactive protein. This led some to speculate that because these patients had been treated with high-dose statin therapy from an early age, the intensive therapy attenuated the progression of IMT to such a degree that the benefits of the additional drug were moot.

Looking Across the Landscape Not Good Enough, Says One Expert

Dr Steven Nissen (Cleveland Clinic, OH), nonetheless, is particularly critical of the fact that ACHIEVE was stopped before completion, telling heartwire that there are obligations--to patients, clinicians, and the research community--that set a very high bar for stopping a clinical trial before its completion.

"To stop a study because there is evidence of harm is easy," said Nissen. "But once you start and are well underway, to stop a study because it appears you're going to lose is simply not a good enough reason."

Nissen said that trials are sometimes stopped because of futility. This occurs after a within-trial analysis reveals there is no possible way one drug is going to be shown superior to another. However, "looking across the landscape" to other clinical trials, such as ENHANCE, and stopping a study because these studies failed is uncommon and unjustifiable. Today's climate, said Nissen, especially in light of recent regulatory upheavals and the way Schering-Plough suffered with their handling of the ENHANCE study, makes many companies risk adverse. Still, he would have liked to have seen the trial completed.

"The purpose of a clinical trial is not to succeed," he added. "The purpose is to determine if a drug works. Choosing only to complete studies where you know you're going to show a benefit in selected patient populations, this is a very slippery slope."

A clinical trial testing whether extended-release niacin and laropiprant prevents MI, stroke, or revascularization procedures in 20 000 patients with existing vascular disease is still underway at the Clinical Trial Service Unit (CTSU) of Oxford University. That study, known as the Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), remains unaffected by the decision to stop ACHIEVE and results are expected in about four years.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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