Clazosentan Does Not Meet Primary Endpoint in CONSCIOUS-2

February 11, 2011—According to a late-breaking study presented at the American Stroke Association's International Stroke Conference 2011 in Los Angeles, patients with aneurysmal subarachnoid hemorrhage (SAH) receiving the intravenous drug clazosentan (Actelion Pharmaceuticals US, Inc., South San Francisco, CA) were 17% less likely to reach a composite endpoint including stroke, neurological problems, and the necessity for rescue treatment related to uncontrolled blood vessel contractions, as well as death from any cause, compared to patients receiving placebo.

However, these results were not significantly different from placebo and could have been due to chance, the investigators noted. Clazosentan is an endothelin receptor antagonist, a class of drugs that decrease cellular calcium that in high levels can cause excessive muscular contractions.

“The composite primary outcome showed a trend in the right direction but was not statistically significant,” commented the study's lead author Robert Loch Macdonald, MD. “We need to do more analysis to explore why there was not a significant effect on the primary outcome.”


The investigators also noted that pulmonary complications, anemia, and hypotension were more common in clazosentan-treated patients, but these results were not analyzed for statistical significance. Cerebral vasospasm, a sudden blood vessel constriction in the brain, is a dangerous complication of aneurysmal SAH that affects approximately 30,000 Americans annually and comprises about 5% of all strokes, advised the American Stroke Association.


In CONSCIOUS-2 (Clazosentan to Overcome Neurological Ischemia and Infarct Occurring After Subarachnoid Hemorrhage), the investigators examined aneurysmal SAH, for which the death rate is approximately 45%, and long-term, serious disability is prevalent among survivors. A total of 764 aneurysmal SAH patients received clazosentan, and 383 patients received a placebo for up to 2 weeks. All patients had undergone surgery to clip the aneurysm to prevent further bleeding. The patient characteristics were: 68% were women, average age was 52 years, 71% were white, and 25% were Asian. The international study ran from December 2007 to July 2010 at 102 sites in 27 countries.

At 6 weeks after aneurysmal SAH, investigators assessed the incidence of serious complications related to blood vessel spasms, which they confirmed with special imaging techniques. The serious complications related to spasms occurred in 21% of patients on clazosentan compared to 25% of those on placebo. Follow-up continued for 12 weeks, at which time researchers also assessed overall functional outcome, which did not appear to be any better in the clazosentan-treated patients.

On the Glasgow Outcome Scale of functioning ability, 29% of patients who received the study drug performed poorly compared to 25% on placebo. Adverse events included lung complications in 34% of clazosentan patients versus 18% of placebo patients, anemia in 22% of treated patients versus 15% of placebo patients, and abnormally low blood pressure in 12% of treated patients versus 4% of placebo patients.

The trial's findings are surprising because they do not support those of the 2008 CONSCIOUS-1 study that found that clazosentan significantly reduced the incidence of blood vessel spasms after stroke, stated Dr. Macdonald, who was also lead author of the initial study. It is unclear why the latest study did not find a similar benefit for the complications related to spasms.

“We don't think it's due to sample size,” Dr. Macdonald said. “There's a fundamental problem with either the drug, its side effects, or the effect of the drug not translating into improving those parts of the outcome measured, even though the primary endpoint was selected to specifically respond to the known action of the drug.”

Actelion sponsored the CONSCIOUS trials. Actelion announced the initial results of the phase 3 CONSCIOUS-2 trial on September 27, 2010, noting that it failed to meet its primary endpoint by showing a nonsignificant relative risk reduction of 17% in favor of clazosentan (P = .1). Because of this, the company announced the termination of the CONSCIOUS-3 trial on October 21.