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Pseudobulbar Affect Drug Combo Has No Safety Concerns


 

Major Finding: No serious cardiovascular adverse events or clinically meaningful changes in QT interval were recorded.

Data Source: The STAR trial, a 12-week randomized, placebo-controlled trial of 326 patients with pseudobulbar affect, followed by a 12-week open-label extension phase.

Disclosures: The study was supported by Avanir Pharmaceuticals. Dr. Pioro has received personal compensation for serving as a consultant and scientific advisory board member for Avanir. Dr. Kaye is the chief medical officer of Avanir.

TORONTO — The combination of dextromethorphan and quinidine to treat pseudobulbar affect does not appear to cause serious cardiovascular adverse events or clinically meaningful changes in QT interval, according to a 12-week, randomized, placebo-controlled trial.

The analysis was undertaken to address safety concerns expressed in October 2006 by the Food and Drug Administration in an approvable letter that the agency sent to Avanir Pharmaceuticals Inc., the company seeking to bring the combination medication (Zenvia) to market.

At a press conference at the annual meeting of the American Academy of Neurology, Dr. Erik P. Pioro, director of the section of ALS and Related Disorders at the Cleveland Clinic, explained that one of the FDA's concerns was the potential for quinidine to have a proarrhythmic effect, even though the dose used for pseudobulbar affect (PBA) is lower than that recommended to treat dysrhythmias. This might be particularly problematic for patients taking higher quinidine doses or those having pre-existing conditions such as torsades de pointes.

“We found no red flags at all that were clinically significant [and] no indication of cardiovascular problems,” Dr. Pioro said.

PBA refers to a syndrome of disinhibition of emotional expression. Patients with neurologic conditions such as multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson's disease sometimes display uncontrollable episodes of laughing, crying, or other emotions that have no apparent cause. Patients who have PBA can have more than 30 or more episodes per week.

No drugs are currently approved for the treatment of PBA in the United States. Dr. Pioro said antidepressants are commonly used off-label, with variable efficacy and a high side-effect profile.

Previous work has shown that dextromethorphan, an N-methyl-D-aspartate-receptor antagonist and sigma-1-receptor agonist, in combination with quinidine, can reduce the frequency and severity of PBA episodes (Neurology 2004;63:1364–70; Ann. Neurol. 2006;59:780–7). Quinidine is used to increase the bioavailability of dextromethorphan.

In the STAR trial, the investigators randomized 326 patients to receive 30 mg of dextromethorphan plus 10 mg of quinidine (DMq-30), 20 mg of dextromethorphan plus 10 mg of quinidine (DMq-20), or placebo for 12 weeks. During the first week of the study, patients ingested a single capsule of study drug in the morning, but this increased to twice-daily dosing during weeks 2 through 12. Twelve-lead electrocardiograms were performed at baseline and on days 15, 29, 57, and 84.

Almost 87% of patients completed the trial. Approximately 60% of the patients had ALS, and 40% had multiple sclerosis. Effectiveness was assessed using the Center for Neurologic Study Lability Scale; a minimum score of 13 was needed to enroll in the trial.

Changes in QT interval were considered small and not clinically meaningful, with a mean change of 6.6 msec and 8.3 msec for the DMq-20 and DMq-30 groups, respectively.

Corrected mean changes in QT interval showed changes of less than 5 msec from baseline. No subjects had QT or corrected QT intervals of more than 500 msec at day 84, according to Dr. Randall Kaye, who presented the results at the meeting.

There were few cardiac or vascular adverse events, and none were considered serious. “QT prolonged” was reported in 2 subjects, including one in the placebo group. Neither event was assessed as serious or clinically meaningful.

Eight reports of cardiac adverse events were noted in the treated groups, including sinus bradycardia (two), palpitations (one), AV block first degree (two), tachycardia (one), sinus tachycardia (one), and atrial fibrillation (one).

Dr. Pioro also reported safety and tolerability results of a 12-week open-label extension of the STAR trial that enrolled 253 of the 283 patients who completed the double-blind trial; all of these patients received the DMq-30 combination.

During this open-label extension, no treatment-related or cardiovascular serious adverse events were reported. A total of 74% of patients reported one or more adverse events, with similar rates reported no matter which group they had been in during the controlled trial.

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