SAN DIEGO – The midpoint results of the CLEAR III trial that is investigating the safety and benefit of using recombinant tissue plasminogen activator to lyse intraventricular clots formed after intracerebral hemorrhage didn’t set off any safety alarms.
"The mortality, bleeding, and infection rates are lower than expected, indicating that the study protocol is safe for patients with severe intraventricular hemorrhage," said Dr. Wendy Ziai, chair of the trial’s safety event committee and the principal investigator of the trial at Johns Hopkins University, Baltimore, which is one of 70 sites involved in the trial.
There are currently very few treatments available for the treatment of intraventricular hemorrhage (IVH) and intracerebral hemorrhage (ICH). Clot lysis with recombinant tissue plasminogen activator (TPA) is one treatment option that has reached phase III, and it could have practice-changing implications, depending on the final results.
But for now, "we still don’t have enough information to change patient care," said Dr. Darin Zahuranec of the department of neurology at the University of Michigan, Ann Arbor. "These findings mean that we need to eagerly await the final results," said Dr. Zahuranec, who was not involved in the study.
The double-blind, randomized placebo-controlled CLEAR III trial (Clot Lysis: Evaluation of Accelerated Resolution of Interventricular Hemorrhage Phase III) is evaluating the benefit, safety, and best protocol for extraventricular drainage use plus 1-mg recombinant TPA (Alteplase) every 8 hours, in patients with IVH. The control group had extraventricular drainage in place, but received placebo.
The midpoint results, which included 250 patients in 61 centers, also showed that prophylactic heparin during and immediately after dosing may be associated with a higher risk of intracranial bleeding. Thrombotic events, however, may be more frequent in patients who were not receiving prophylaxis, said Dr. Ziai, who presented her findings at the International Stroke Conference, sponsored by the American Heart Association.
The CLEAR III trial monitored three prespecified safety endpoint thresholds: symptomatic hemorrhage within 72 hours of the agent, brain infections within 30 days of randomization, and 30-day mortality.
The results for all patients showed that there were 36 hemorrhages at 72 hours after the last dose of the study agent, 3 (1.2%) of which were symptomatic. Also, 22 (61%) of the hemorrhages occurred in the setting of prophylactic heparin.
Within 30 days of randomization, there were 60 brain hemorrhages in 44 patients at a rate of 17.5% (10% were symptomatic and 90% were asymptomatic). Mortality was 12.4%, bacterial ventriculitis was 2%, and nonbacterial ventriculitis was 5.2%.
"These are well below the [Data Safety Monitoring Board’s] safety thresholds," Dr. Ziai said.
Of 215 patients not on antiplatelet therapy prior to diagnosis, 15% had a bleeding event 72 hours after randomization, compared with 11% of the 35 patients who were on antiplatelet therapy. The association was not significant.
Also, of the 116 patients not on prophylactic heparin, 12% had a hemorrhagic event, compared with 16% of the 134 patients who were receiving the therapy, showing no significant association.
Meanwhile, 23% of the patients who were not on prophylactic heparin had a thrombotic event by day 30, while 9% of those on heparin had such an event ( P = .005).
There were 259 severe adverse events within 1-year follow-up, 19 (7%) of which were possibly related to the study agent. Ventriculoperitoneal shunts were placed in 53 patients.
"It should be remembered that intraventricular rTPA is not currently the standard of care , and it’s hoped that CLEAR III trial will demonstrate the benefit and safety of this therapy," Dr. Ziai said. "The safety, however, cannot be achieved without strict protocols for stabilizing hemorrhages, concurrent drug use, and careful tracking of adverse events through an adjudication process."
Dr. Ziai and Dr. Zahuranec said they had no relevant financial disclosures. The study is funded by the National Institute of Neurological Disorders and Stroke.
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