CONSCIOUS-2: No Benefit of Clazosentan on Vasospasm After SAH

Susan Jeffrey

February 18, 2011

February 18, 2011 (Los Angeles, California) — Results of a randomized, double-blind trial have shown no significant benefit of treatment with clazosentan, an investigational endothelin receptor antagonist, in reducing mortality or vasospasm-related morbidity in patients who underwent surgical clipping after subarachnoid hemorrhage (SAH).

There was a 17% reduction in events that did not reach significance, and no effect was seen on functional outcomes on the Glasgow Outcome Scale, a secondary endpoint. Adverse effects, including pulmonary complications and hypotension, were also increased with treatment.

Results of the second Clazosentan to Overcome Neurological Ischemia and Infarct Occurring after Subarachnoid Hemorrhage (CONSCIOUS-2) were presented here at the American Stroke Association's International Stroke Conference 2011. Topline results were released September 27, 2010.

Dr. Robert Loch MacDonald

Lead investigator Robert Loch MacDonald, MD, PhD, head of the division of neurosurgery at St. Michael's Hospital, University of Toronto, Ontario, Canada, said that on the basis of these findings, a second phase 3 trial, called CONSCIOUS-3, that includes SAH patients who underwent endovascular coiling rather than surgical clipping was stopped.

"Once we found out in October that CONSCIOUS-2 had not reached the primary endpoint, we stopped recruitment into CONSCIOUS-3, but the final follow-up is 3 months, so now the last patients are being followed up and by March or so we'll know the results of that," Dr. MacDonald told Medscape Medical News. "Then we'll have to make a decision with the company that funded it, Actelion, as to whether or not to pursue development of this in subgroups."

CONSCIOUS-2

Endothelin has been shown to have a role in generating angiographic vasospasm, and experimental studies have shown clazosentan, an endothelin receptor antagonist, can prevent vasospasm, Dr. MacDonald said.

Results of CONSCIOUS-1, a previously reported dose-finding study (Stroke. 2008), showed a dose-dependent reduction in the degree of vasospasm with increasing doses of clazosentan, he said, and that on a combined morbidity and mortality endpoint — the same endpoint used in CONSCIOUS-2 — there was a trend to reduction with increasing doses of drug.

On the basis of those findings, CONSCIOUS-2 was launched, a phase 3 trial comparing a 5-mg/hour dose of intravenous clazosentan vs placebo in 1147 patients admitted for aneurismal SAH, World Federation of Neurological Surgeons (WFNS) grades 1 to 4.

The primary endpoint, a composite of all-cause mortality, new cerebral infarction due to vasospasm, delayed neurological deterioration due to vasospasm, or the need for rescue therapy due to vasospasm, was assessed at 6 weeks. The main secondary endpoint was functional outcome on the extended Glasgow Outcome Scale (GOSE) at 12 weeks, dichotomized into good (score >4) or poor (<4) outcome.

Results of the combined primary endpoint showed a trend toward a reduction in death or vasospasm-related morbidity, a relative risk reduction of 17% that was not statistically significant.

Table 1. CONSCIOUS-2: Primary Endpoint

Endpoint Placebo Clazosentan Relative Risk Reduction (95% CI), % P Value
Death or vasospasm-related morbidity, % 25.3 21.1 17 (−4 to 33) .1037

CI = confidence interval

Each of the individual components showed no difference in death, but each of the other components were reduced with treatment, including new infarcts and delayed neurologic deterioration, and most of the difference was due to a reduction in rescue therapy from 16.4% to 10.5%.

There was no significant difference in the main secondary outcome, functional outcome on the GOSE, and in fact a trend to worse outcome in treated patients, Dr. MacDonald said.

Table 2. CONSCIOUS-2: Patients With Poor Outcome (GOSE Score <4) by Treatment

Endpoint Placebo Clazosentan Relative Risk Reduction (95% CI) P Value
GOSE score <4, % 24.8 29.3 -18 (-45 to 4) .1048

CI = confidence interval; GOSE = Glasgow Outcome Scale

Some subgroups appeared to have more benefit, including those with diffuse thick clot and those with poorer clinical WFNS grade.

In terms of treatment-emergent adverse events, pulmonary complications, anemia, and hypotension were increased with clazosentan vs placebo.

"Endothelin antagonists seem to be pretty good at reversing the constriction of arteries," Dr. MacDonald said. "The problem I think is none of these drugs, clazosentan, nimodipine, which is approved and used in a relatively low dose, none of them will dilate brain arteries without dilating arteries in the rest of the body and causing low blood pressure which counteracts the benefit."

They are now experimenting with delivering these drugs more locally during surgical clipping or endovascular coiling to see if they can reduce systemic complications, he said. Dr. MacDonald has launched a company, Edge Therapeutics, looking at using an US Food and Drug Administration–approved biodegradable polymer for local drug delivery.

"Preliminary results show we can achieve high concentrations inside the head, dilate arteries, and [it] does get absorbed into the body, but the concentration in the body is well below what would cause side effects," he said.

Await CONSCIOUS-3

Dr. Ralph Sacco

Ralph Sacco, MD, chairman of the Department of Neurology at the University of Miami's Miller School of Medicine in Florida and current president of the American Heart Association moderated a press conference here on this and other late-breaking trials. Asked for comment, Dr. Sacco pointed out that vasospasm is one of the "most feared complications" of SAH.

"Nimodipine has been around for many years and does help, but we hope we can find more effective drugs," Dr. Sacco told Medscape Medical News. "Unfortunately, in this study, in those who were clipped, there was no significant benefit in the reduction of vasospasm in the primary outcome of this trial.

"We still await CONSCIOUS-3, which is all coiled aneurysms, as opposed to clipped aneurysms in using this drug," he added. "My only concern in looking at the data myself is maybe we can dilate arteries, but some of the other adverse experiences that we're seeing in the trial with clazosentan, including pulmonary lung complications and anemia, could be working against preventing some of the delayed neurological deficits of subarachnoid hemorrhage."

He was also interested to hear about the plans for local delivery of the drug.

"Even if you just think about tPA [tissue plasminogen activator]: intravenous tPA can cause bleeding in other areas, while intra-arterial tPA delivers the drug right to the clot," he said. "So as we get more expertise in delivery of drugs right to their target, we can sometimes decrease complication risk."

The study was supported by Actelion Pharmaceuticals Ltd. Dr. MacDonald reports receiving research grants from Brain Aneurysm Foundation and Actelion and has served as a consultant/advisory board member for Actelion. He also has ownership interest in Edge Therapeutics. Disclosures for the coauthors appear in the abstract. Dr. Sacco has disclosed no relevant financial relationships.

International Stroke Conference (ISC) 2011: Abstract LB9. Presented February 11, 2011.

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