The anticonvulsant sultiame was associated with improved symptoms among patients with obstructive sleep apnea (OSA), a phase 2 trial showed.

In the largest published clinical trial of sultiame for the treatment of OSA, researchers found that compared with patients receiving placebo, those receiving the drug had a 35% decrease in breathing disturbances at 15 weeks.

Sultiame at 200 mg and 300 mg had clinically relevant improvements. However, given that adverse events (AEs) increased dose-dependently, investigators said the 200 mg dose offered the most favorable balance of benefits and side-effects.

“I think with these results, there would have to be a really hard argument if you should not go on with development because to me it’s very, very encouraging. Many drugs have been tested over the years, and I would say this is more repetitive, positive effects looking at this class of drugs,” principal investigator Jan Hedner, MD, senior researcher in the Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Gothenburg, Sweden, told Medscape Medical News.

The findings were published online on October 9 in The Lancet.

New Treatments Needed

OSA affects an estimated 15% of men and 7% of women globally, with risk factors including obesity and older age. The current gold standard treatment is continuous positive airway pressure (CPAP), which keeps the airways open during sleep.

However, this treatment is limited by low long-term patient adherence which can reduce its efficacy, highlighting the need for new therapies, the investigators noted.

Although widely used in Europe as an anticonvulsant, sultiame is not approved by the FDA for use in the US. In an earlier study, the researchers found that sultiame was safe and effective for OSA, but the most appropriate dosage was unclear.

For this randomized, double-blind, placebo-controlled trial, investigators included 298 patients (74% men; mean age, 56 years) with OSA from 28 hospitals and community-based sites across five European countries.

Participants were randomized (1:1:1:1 ratio) and assigned to a placebo or sultiame at dosages of 100 mg, 200 mg, or 300 mg. Three tablets were taken orally every night within an hour of going to sleep for 15 weeks.

A polysomnography was administered at baseline on two consecutive nights at week 4 and at the end of treatment.

The primary outcome was the relative change of the Apnea-Hypopnea Index (AHI)3a from baseline to week 15. Secondary outcomes included the absolute change of this index, oxygen saturation, and sleep fragmentation.

Participants were asked to rank their sleepiness using the Epworth Sleepiness Scale (ESS) questionnaire. Other included surveys focused on quality of life and health status (Sleep Apnea Quality of Life Index, the Patient Global Impressions scale, and the Clinical Global Impressions scale).

Improvements in Sleep and Breathing Disturbances

At week 15, the AHI3a adjusted means change for sultiame was -16.4% in the 100 mg group (P = .032), -30.2% in the 200 mg group (P < .0001), and -34.6% in the 300 mg group (P < .0001).

Compared with placebo, sleep fragmentation was significantly improved with sultiame, with reductions of 5.7 events per hour with 200 mg (P = .0002) and 6.7 events per hour with 300 mg (P < .0001).

For the 200 mg group, patient sleepiness also improved based on the ESS score (P = .031). There were no significant differences between groups in health status and quality of life, and sultiame did not affect heart rate.

The incidence of AEs increased dose-dependently, with AEs reported in 61% of the placebo group, 73% of the 100 mg group, 84% of the 200 mg group, and 91% of the 300 mg group. The most common AE was paresthesia.

Adverse effects were the main reason for drug discontinuations, and the 200 mg group had the largest discontinuation rate (24%).

“This study demonstrates that treatment of OSA with sultiame once per day might be a viable and convenient treatment option for those who reject or do not tolerate treatment with a continuous CPAP device,” the researchers wrote.

“The promising results and the available clinical data support a further development regarding the effect of sultiame in different phenotypes of patients and subgroups,” they added.

Further Development Needed

Commenting on the findings for Medscape Medical News, Vishesh Kapur, MD, MPH, professor of medicine and director of Sleep Medicine for the Division of Pulmonary, Critical Care, and Sleep Medicine at the University of Washington in Seattle, and a spokesperson for the American Academy of Sleep Medicine, said the findings are interesting, but more information is needed.

“Based on this trial, sultiame should not be prescribed off label for OSA. This was a phase 2 dose-finding study, designed to assess efficacy and safety, not to prove it as a definitive treatment,” said Kapur, who was not part of the study.

Study limitations included the low ethnic diversity and a lower-than-expected proportion of female participants, which prevented a sex-specific analysis. In addition, the 15-week duration was likely too short to demonstrate effects on comorbidities such as hypertension, Kapur said.

“This trial significantly progresses current knowledge by providing the largest and most robust evidence to date for sultiame as a pharmacologic therapy for OSA,” said Kapur. However, he added that the dose-dependent nature of AEs does warrant attention as it was the main factor for drug discontinuation.

Although the magnitude of effects suggests that sultiame may not be as effective as other therapies like CPAP, the drug might provide benefit for some patients who aren’t adequately treated by current options, Kapur said.

Investigators said that the next step is to conduct a phase 3 trial.

Future studies would be welcome and should seek to identify which patients are more likely to respond to treatment, as well as patient-reported cardiometabolic and neurocognitive outcomes while taking sultiame, Christopher Schmickl, MD, PhD, MPH, and Atul Malhotra, MD, University of California, San Diego, wrote in an accompanying editorial.

“The latter outcome is especially important given the widespread role of carbonic anhydrase in human physiology, raising concerns about off-target effects (eg, cognition), which might partly underlie reports of fatigue or asthenia and the smaller reduction in sleepiness observed with 300 mg vs 200 mg,” Schmickl wrote.

Although the overall effects of the drug were modest, the findings are “an important milestone in developing pharmacotherapies for the many patients with OSA with intolerance to current treatments,” he noted.

“Future OSA management will likely involve a personalized, mechanism-based approach, and often combine interventions targeting multiple pathways — as in hypertension or diabetes — with carbonic anhydrase inhibitors like sultiame expected to play a key role,” Schmickl added.

This study was funded by Desitin Arzneimittel, the manufacturer involved in early development of sultiame. Kapur reported no relevant disclosures. Hedner reported lecturing activities for Somnomed and Desitin; being a member of the advisory board for Somnomed; and being a shareholder of a company with a licensed patent on pharmacological treatment of OSA with sultiame.