Higher doses of Cerestat produced benefits in ischemic strokepatients participating in a Cambridge NeuroScience Inc. Phase IIstudy, an investigator reported Thursday.
With the results from the study and two other Phase II trials,Cambridge NeuroScience and its Cerestat partner, BoehringerIngelheim GmbH, have planned pivotal studies encompassing 900patients and 100 sites. They may begin around mid-year, said ElkanGamzu, president and CEO of the Cambridge, Mass., company.
Cerestat is an N-Methyl-D-Aspartate ion channel blocker thatprevents nerve cell death and brain damage following head injury orstroke by preventing excessive entry of calcium into nerve cells.
The primary endpoint of improvement at 30 days was not reached inthe 132-patient Phase II trial, although neurological impairment wasimproved. However, there was statistical significance reached at day90 as measured by the National Institutes of Health Stroke Scale,which measures levels of impairment on a 42-point scale.
The double-blind, randomized study involved a placebo group andthree drug arms _ 30, 70 or 110 micrograms/kg of Cerestat by bolusand infusion over four hours. All patients were treated within sixhours of stroke.
At day 90 patients in the 110 microgram group improved on average6.3 points compared to control patients' 4.7-point improvement. Atday 90, 32 to 40 percent of those entering with severe impairmentand receiving the highest dose had minor or no disabilities, whileonly 19 percent of severely impaired placebo patients showed thatimprovement. Those responses were measured on the Rankin andBarthel scales.
Gamzu said the five-point Rankin Scale measured at 90 days will bethe primary endpoint in the pivotal study. The Rankin Scale resultswould have been significant had there been more patients in thePhase II study, he said.
"If we are able to replicate those findings it would be a veryimportant result for the company, and more importantly, the patientsand medical community," Gamzu said.
In the pivotal study patients will be given placebo or one of two drugdoses, both of which are higher than those used in the 132-patientPhase II trial. One group will get a bolus followed by drug every hourfor 12 hours, with total drug being about 190 micrograms/kg. Theother drug group will get a smaller bolus and less drug per hour, orabout 120 micrograms/kg total.
A previously reported Phase II study showed the larger dose was safeand well tolerated.
Keith Edwards, a neurologist at the Southwestern Vermont MedicalCenter and an investigator in the Cerestat study, presented the resultsThursday at the American Academy of Neurology meeting in SanFrancisco.
He said strokes suffered by those in the placebo group, as it turnedout, were not as severe as those in the treated groups. Gamzu saidthat makes the data even stronger.
Edwards said, "My impression, before the blind was broken, was thatsome patients had a course of recovery that was much better than Iwould have expected without treatment, and that impression has beenconfirmed by subsequent analysis. I am extremely encouraged by thestrong indication of activity that these results provide, particularly inlight of the absence of alternative therapies for stroke."
The pivotal stroke study will be conducted primarily in the U.S.,Gamzu said, with sites also in Australia and South Africa. He saidsome 80 patients a month should be enrolled, meaning the studycould take one year plus the 90-day follow-up period.
Boehringer Ingelheim, of Ingelheim, Germany, is funding at least 75percent of Cerestat development in the U.S. and Europe, and alldevelopment in Japan. Cambridge NeuroScience has co-promotionrights in the U.S.
The companies recently initiated a 700-patient Phase III study ofCerestat in traumatic brain injury patients. (See BioWorld Today,March 7, 1996, p.1.)
Cambridge NeuroScience's stock (NASDAQ:CNSI) fell $1.50Thursday to close at $12.50. n
-- Jim Shrine
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