A pivotal phase 3 clinical trial demonstrated that dichlorphenamide (Keveyis) significantly reduced the rate and severity of hypokalemic episodes in patients with periodic paralysis, a rare muscle disease affecting children and young adults. In addition, a parallel phase 3 clinical trial with dichlorphenamide showed a similar treatment effect in patients with hyperkalemic periodic paralysis but failed to demonstrate significance because of recruitment issues.
“According to pivotal phase 3 data, hypokalemic subjects demonstrated improved attack frequency, severity, and quality of life. Dichlorphenamide was also well tolerated, with few safety-related withdrawals,” said James Burge, MD, Consultant in Clinical Neurophysiology, King's College Hospital NHS Foundation Trust, London, England, at the 2016 American Academy of Neurology annual meeting.
“Treatment effects on attack rates appeared consistent in both trials, but, partly due to small sample size, were inconclusive for hyperkalemic patients,” Dr Burge added.
A rare disease affecting an estimated 1 in 100,000 individuals, periodic paralysis is defined as a muscle channelopathy marked by sudden episodes of muscle weakness and long-term progressive weakness. Hypokalemic paralysis is caused by decreased levels of potassium in the blood and can persist from 2 to 72 hours. Conversely, hyperkalemic paralysis is caused by increased potassium levels in the blood, and is characterized by more transient episodes of weakness, enduring a few minutes to up to 1 hour.
Although hypokalemic episodes are typically triggered by carbohydrate-rich meals, which lower potassium levels in the blood, hyperkalemic episodes are usually related to exercise.
“For kids experiencing their first episode, it can be very frightening. They're unable to move because of arm and leg paralysis, and they often end up in the emergency room,” said Dr Burge.
In addition to dichlorphenamide, treatment options for patients with periodic paralysis include off-label use of acetazolamide (Diamox), diuretics, and avoiding potassium-rich foods.
Although the 2 clinical trials were initially designed to compare the safety and efficacy of dichlorphenamide with that of acetazolamide and placebo, patients who had formerly been taking dichlorphenamide were reluctant to switch to acetazolamide, because it proved to be less effective than dichlorphenamide.
The 2 multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trials—one including 44 patients with hypokalemic periodic paralysis and the other including 21 patients with hyperkalemic periodic paralysis—used identical protocols comparing dichlorphenamide with placebo and lasting 9 weeks. Each study was subsequently followed by a 1-year, open-label extension period in which all patients received dichlorphenamide.
The median weekly attack rate in the double-blind phase of the study was significantly lower in the dichlorphenamide group compared with the placebo group (0.3 vs 2.4, respectively).
Dichlorphenamide also had a significant treatment effect on several secondary end points, including attack duration, severity, and quality of life. In addition, the physical component score on the Short Form-36 was improved in patients who received dichlorphenamide.
The benefit of dichlorphenamide on the attack rates was maintained in the open-label extension period, and patients who switched from placebo to dichlorphenamide also saw a marked reduction in the frequency and severity of attacks.
The most common adverse events with dichlorphenamide were paresthesia (47%) and confusion (19%). Although 3 patients (2 patients with hyperkalemic paralysis and 1 with hypokalemic paralysis) who received dichlorphenamide withdrew from the double-blind phase because of adverse events, “the majority of patients tolerated side effects very well,” Dr Burge said.
Because of the small number of patients who were recruited to participate, the study results were not significant; however, dichlorphenamide is a safe and effective treatment option for both forms of periodic paralysis, Dr Burge emphasized.
In August 2015, dichlorphenamide became the first FDA-approved treatment option for patients with primary hypokalemic or hyperkalemic periodic paralysis.