Lancet: CRESCENDO halted after diet pill linked to suicides
Rimonabant (Acomplia, Sanofi-Aventis), a cannabinoid-1 receptor antagonist, was developed as a weight loss drug to diminish waist circumference and body weight; however, while researchers were studying the efficacy of the drug to also reduce vascular events, they found that it increased the incidence rates of neuropsychiatric effects, including suicide.

While use of endocannabinoid receptors have been known to reduce obesity and improve metabolic risk factors, little research was done to study the effectiveness of these drugs to reduce the risk of cardiovascular death, MI or stroke in patients with a prior diagnosis of CV disease or risk of atherosclerotic vascular disorders.

Eric J. Topol, MD, of the Scripps Translational Science Institute, in La Jolla, Calif., and colleagues set out to evaluate whether administration of rimonabant improved major vascular event-free survival during the Cardiovascular Endpoints and Outcomes (CRESCENDO) trial between Dec. 22, 2005, and July 29, 2008.

Rimonabant has been available in Europe since 2006; however, was never approved by FDA for usage in the U.S.

On Nov. 6, 2008, 13.8 months into what was expected to be a 33-month follow-up, the CRESCENDO trial was discontinued after health authorities in Ireland, Germany and France requested that all clinical research be halted after findings had shown the drug produced serious neuropsychiatric effects.

In the double-blind, placebo-controlled trial, Topol et al identified 18,695 patients at 974 sites in 42 countries. The patients were randomly assigned to receive either a 20 mg dose of rimonabant (9,381 patients) or placebo (9,314 patients).

Patients enrolled in the study had abdominal obesity—a waist circumference greater than 88 cm in women and 102 cm in men—were aged 55 or older. Also, the patients had either coronary heart, cerebrovascular or peripheral artery disease within the past three years or at least two major cardiovascular risk factors.

During the trial, researchers screened patients for neurological and psychiatric symptoms at baseline, at one month, three months and every three months for the duration of the trial. A neurological exam was performed at baseline and worsening symptoms were recorded as adverse events.

As researchers learned additional safety information about rimonabant, Topol and colleagues revised the neurological/psychiatric questions beginning Feb. 28, 2008. The neurological exams assessed patients’ mental status, visual acuity, eye movements, hearing, coordination and muscle tone, among others.

Depending on the symptoms, patients were sent to a neurologist or mental healthcare specialist. The drug was discontinued Feb. 28, 2008, in patients with a medical history of suicide attempt or psychiatric illness at baseline.

In October 2008, the European Medicines Agency withdrew the marketing and authorization for rimonabrant due to its potential to produce psychiatric side-effects; the CRESCENDO trial was eventually terminated in November 2008.

After the 13.8 months, trial results showed that the hazard ratio (HR) for the primary efficacy endpoint was 0.97—375 events occurred in the control arm compared to 364 in the rimonabant arm. These numbers were less than half of the anticipated 1,600 events the researchers expected.

Results showed that the HR for patients with overt vascular disease administered rimonabant was 0.95. Patients without overt vascular disease saw lower event rates and an HR of 1.89.

Additionally, patients administered rimonabant saw an 8.9 percent decrease in all-cause mortality. For patients without vascular disease, the rates of all-cause mortality increased by 15.7 percent. “Despite the opposing findings, there was no significant interaction of treatment by subgroup for all-cause mortality,” the authors wrote.

When looking at adverse events, researchers found that gastrointestinal side-effects (nausea and diarrhea) occurred at a higher frequency in patients administered rimonabrant than in the control group, 33 percent versus 22 percent.

Additionally, serious psychiatric side-effects differed between the control arm and the rimonabant arm, 1.3 percent and 2.5 percent, respectively.

Suicide occurred in four patients administered rimonabrant and one patient in the placebo group and nine patients attempted suicide in the rimonabrant arm compared to five in the placebo arm.

“The findings did not provide evidence of efficacy for rimonabant’s prevention of adverse cardiovascular outcomes, but further substantiated its effect of inducing serious neuropsychiatric side-effects,” the authors wrote.

“The absence of any reduction of CV endpoints, despite the anticipated benefit in metabolic parameters, is disappointing,” the authors wrote.

“Although patients receiving rimonabant had many other side-effects, almost all these would be expected to be resolved from discontinuation of the drug. The crucial issue about a favorable trade-off of improved CV outcomes overriding serious side-effects might never be resolved, since clinical development for endocannabinoid-1blockers from other manufactures has also been discontinued,” the authors wrote.

“[T]he predicament with rimonabant is not an isolated scenario. The new precedent here is the capacity for such regulatory agencies to stop an ongoing clinical research project. Hopefully, the experience and data from this clinical trial will prove useful in planning further drug development,” the authors concluded.

The study was funded by Sanofi-Aventis.

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