WASHINGTON (FRONTLINE MEDICAL NEWS) As a potential add-on therapy to phenobarbital, bumetanide demonstrated acceptable safety and promising antiseizure activity in a phase 1/2 safety study presented at the annual meeting of the American Epilepsy Society .

“This is an early-phase trial, but it did associate bumetanide with an additional reduction in seizure burden relative to phenobarbital alone,” reported Janet S. Soul, MD , director of the fetal-neonatal neurology program at Boston Children’s Hospital. She added, “The adverse events observed were not substantially different in the group that received the experimental agent.”

This study is also “the first to use an ethical placebo control group” to study an experimental drug in neonatal seizures, according to Dr. Soul. In the study, all neonates received phenobarbital and were randomized to receive bumetanide, a loop diuretic currently licensed for treatment of heart failure, or placebo as an add-on.

Of the 111 neonates with documented seizures enrolled at four participating hospitals, 43 proceeded to randomization if their seizures proved to be refractory to standard doses of phenobarbital. After randomization, the next dose of phenobarbital was administered either with placebo or with 0.1, 0.2, or 0.3 mg/kg of bumetanide. Seizure burden was evaluated at 0-2, 2-4, and 0-4 hours after study-drug administration and compared with the burden during the 2 hours before treatment.

All three doses were active, reducing the seizure burden by a median of 41%-75% in a dose-dependent manner. Whether assessed in the first 2 hours or the first 4 hours, the efficacy of bumetanide was significantly greater in those with the greatest, relative to the least, baseline seizure burden (P = .01 for hours 0-2; P = .04 for hours 0-4). The median seizure burden during the baseline period was higher in the 27 children randomized to bumetanide (114 minutes) relative to those randomized to placebo (33 minutes), although researchers attributed this to random effects in a small study.

The evidence of antiseizure activity from bumetanide as an add-on to phenobarbital is consistent with its mechanism of action, which is blockading the chloride transporter NKCC1. In the immature neurons of neonates, NKCC1 is highly expressed, and there is basic scientific evidence that this impairs the efficacy of gamma-aminobutyric acid–receptor agonists like phenobarbital, according to Dr. Soul. The hypothesis driving the study of bumetanide is that blockading NKCC1 would improve the efficacy of phenobarbital while adding its own antiseizure effects, which together could potentially provide synergistic benefit.

The efficacy and the safety of this study are somewhat discordant with a previously published study evaluating bumetanide in 14 neonates with hypoxic-ischemic encephalopathy (HIE) seizures ( Lancet Neurol 2015;14:469-77 ). Even though there were seizure reductions in five children in this other series, which did not include a control arm, there were three cases of hearing loss considered potentially related to bumetanide. The authors of that study concluded that efficacy was not shown.

There were also three cases of hearing loss in the randomized trial presented by Dr. Soul, but one occurred in the placebo group. Although the potential for ototoxicity “still needs to be addressed” in the next set of studies, Dr. Soul noted that hearing loss in children with epilepsy is common and has numerous potential etiologies. Based on these data, she concluded, “All serious adverse events were related to severe HIE with multiorgan dysfunction and/or withdrawal of care for poor prognosis.”

Among nonserious adverse events, diuresis was the only one found significantly more common in the bumetanide group (P = .02).

Phenobarbital has been a standard in the treatment of neonatal seizures for several decades despite the substantial proportion of children who do not achieve an adequate response, according to Dr. Soul. She noted that bumetanide is one of several agents being evaluated as an adjunctive agent. For example, a phase 2 crossover trial with levetiracetam is now underway. She suggested that there is reason for optimism about gaining new treatments for neonates in an area in which she believes there are unmet needs.

“I think we may see a phase 2 trial with bumetanide within a year or 2,” Dr. Soul said. If bumetanide moves forward, she expects its role to be primarily for the treatment of acute seizures caused by HIE, stroke, or hemorrhage. She is less optimistic about its benefit for seizures caused by other etiologies, such as brain malformations.

SOURCE: Soul J Abstract 2.426


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