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Lessons Learned from a Clinical Trial Failure

Posted on March 14th, 2017 by in Chemistry


Revisiting failed clinical trials is important because these studies may generate new insights into drug research and development, leading to effective new treatments. Researchers in the recent IMPROVE-IT trial learned valuable lessons from the failure of the earlier ENHANCE study, which was focused on using ezetemibe and simvastatin to lower cholesterol levels.

For decades, researchers and clinicians had confidence in the cholesterol-diet-CHD hypothesis. They believed that high cholesterol levels help form the atherosclerotic plaques that clog coronary arteries in coronary heart disease (CHD). Treatment involved interventions and medications that could significantly reduce levels of cholesterol in the blood, thus preventing the eventual clinical effects of CHD, such as heart attack, stroke and unstable angina.

Recently, the way experts view the cholesterol-diet-CHD hypothesis, as well as the progression of CHD, has changed. Specifically, they are unsure whether a diet rich in cholesterol and saturated fats actually raises levels of cholesterol. Experts are also unsure whether lowering blood cholesterol levels alone in those at risk for heart disease helps prevent heart attacks and other conditions.

The new understanding — that lowering lipids results in only limited reduction of cardiac risk in most people — stems from clinical trial failures. For instance, participants in the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study who were patients with familial hypercholesterolemia,  a genetic disorder that results in extremely high levels of LDL-C did not benefit from large reductions in cholesterol levels in the blood.

The results of the ENHANCE study were reported in The New England Journal of Medicine in 2008. The study examined 720 participants with familial hypercholesterolemia. The study was double-blind, randomized and lasted 24 months. During the trial, all participants received 80 mg of simvastatin (a statin) and either a placebo or ezetemibe (Zetia), the drug being tested.

Ezetemibe is a cholesterol-absorption inhibitor that dramatically reduces levels of LDL-C and C-reactive protein. ENHANCE researchers were testing whether the addition of ezetemibe to statin therapy would proffer any additional benefit, compared to the administration of the statin alone. Using ultrasound, the researchers measured the intima-media thickness of the carotid artery during the trial to see whether the addition of ezetemibe mitigated wall thickening, a sign of CHD progression. They found no difference in carotid intima-medial thickness (CIMT) among ezetemibe and placebo groups, indicating no differences in signs or progression of CHD.

Statins do not merely lower LDL-C levels. Decreased cardiac risk experienced by those who take these medications is likely due to the fact that statins stabilize atherosclerotic plaques. Statins are also hypothesized to have other anti-inflammatory and endothelial effects.

The ENHANCE researchers conceded that simply lowering LDL-C, which is what ezetemibe does, may not mean much in a clinical sense. The researchers also suggested that the participants whom they examined were too “low risk” to demonstrate incremental changes in CIMT.

In a 2009 article published in Heart, Lung and Circulation, the co-authors suggested a possible reason that the trial failed: “The negative results of ENHANCE may have been the result of long-term previous statin therapy, which had normalised CIMT and may have rendered the arterial wall less responsive to further LDL-C lowering.” A recent ezetemibe study, the 2015 IMPROVE-IT trial, avoided this specific failure. Its results suggest that incremental lowering of LDL-C using statins and ezetemibe improved cardiovascular outcomes in patients who had been hospitalized for acute coronary syndrome.

Re-examining failed clinical trials can be productive if researchers can successfully identify the underlying flaws that led to the failures, so researchers can avoid these defects in future trials. The IMPROVE-IT trial shows that researchers can learn lessons from failed drug trials.



All opinions shared in this post are the author’s own.

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