HONOLULU – according to a study presented at the International Stroke Conference sponsored by the American Heart Association. However, the treatment does reduce the rate of angiographic vasospasm significantly and does not raise significant safety concerns.
Approximately 70% of patients with subarachnoid hemorrhage develop vasospasm, which can in turn cause delayed cerebral ischemia. The only evidence-based treatment for ischemia of the brain resulting from vasospasm is nimodipine, which has been the standard of care for more than a decade.
EG-1962 was developed to deliver higher amounts of nimodipine to the CNS and spastic vessels than oral nimodipine. The formulation contains 50-mcm particles of nimodipine combined with a biodegradable polymer. Pharmacokinetic studies indicate that EG-1962 successfully delivers higher amounts of nimodipine to the CNS than the oral formulation does.
A multisite, phase 3 trial
, William T. Gossett Endowed Chair of Neurology at the Henry Ford Health System in Detroit, presented the trial results. He and his colleagues conducted , a phase 3 trial to evaluate the safety and efficacy of a single 600-mg intraventricular dose of EG-1962 in patients with aneurysmal subarachnoid hemorrhage, compared with those of oral nimodipine. Eligible participants had a World Federation of Neurosurgeons Score (WFNS) of 2-4, Glasgow Coma Scale scores of 7-14, and an indication for placement of an external ventricular drain (such as hydrocephalus). All patients had their aneurysms clipped or coiled.
On the first day after the operation, the investigators randomized patients in equal groups to EG-1962 plus oral placebo or oral nimodipine plus placebo injection. Patients in the EG-1962 arm received a 600-mg injection of nimodipine into the ventricular system. The primary endpoint was the proportion of subjects with an extended Glasgow Outcome Scale (eGOS) score of 6-8 (that is, minimal or mild disability) at day 90. The main secondary endpoint was the proportion of subjects with a Montreal Cognitive Assessment (MOCA) score of 26 or greater (indicating no important cognitive disability) at day 90. Safety outcomes included cerebral infarction, hypotension, and ventriculitis.
Dr. Mayer and his colleagues conducted the study at 65 centers in 11 countries. They planned to enroll 374 patients and conduct an interim analysis after the first 210 participants had their 90-day follow-up. An independent data monitoring committee reviewed the safety data as it was collected. The investigators stopped the study for futility after the preplanned interim analysis was completed.
The challenge of identifying responders
The two study arms were well matched on age and gender. The proportion of patients with poor WFNS was 45% in the EG-1962 arm and 53% in the oral nimodipine arm.
The rate of any vasospasm (such as symptomatic or by imaging) was 56% in the intervention group and 70% in the oral nimodipine group, a statistically significant difference. Follow-up angiography showed vasospasm in 50% of the intervention group, compared with 63% of the oral nimodipine group, which was also statistically significant.
When the investigators examined the primary endpoint, they found that 46% of patients who received EG-1962 had a favorable outcome, compared with 43% of patients who received oral nimodipine, a nonsignificant difference. If the investigators had defined a favorable outcome as an eGOS score of 4 or greater, “there would have been a more favorable effect,” said Dr. Mayer. The investigators found no difference between groups in MOCA score at day 90.
Subgroup analyses produced “puzzling” results, said Dr. Mayer. For example, more patients with poor-grade WFNS had a favorable outcome at 3 months in the EG-1962 group than in the nimodipine group, but fewer patients with good-grade WFNS had a favorable outcome at 3 months in the EG-1962 group than in the nimodipine group. In addition, the treatment effect was more evident in the United States than abroad.
The safety analysis indicated a trend toward less rescue therapy – defined as hypertensive therapy or any interventional approach – in the EG-1962 group (27%), compared with the oral nimodipine group (35%). The rate of hypotension was slightly lower in the EG-1962 group. The rates of treatment-emergent serious adverse events and hydrocephalus were not significantly different between groups.
The results may encourage neurologists to treat “extremely sick patients with highly refractory vasospasms,” said Dr. Mayer. “We have a biologically active agent. The problem is, though, that it’s very hard ... to prove efficacy in trials, because we do not fully understand who the responders were going to be.”
Dr. Mayer reported receiving consulting fees from Edge Therapeutics, the company that developed EG-1962, in the past for activities unrelated to this study. Other investigators are employees of Edge Therapeutics.
SOURCE: Mayer SA et al. ISC 2019, Abstract LB15.