“There was a very high placebo effect, which was somewhat surprising,” said Dr. Pioro. Nevertheless, he added, “Whatever effect placebo had, this combination was significantly better.”
Open-Label Efficacy
Of the 283 patients who completed the double-blind trial, 253 (89%) entered the open-label extension: 94 from the trial’s dextromethorphan 30-mg group, 76 from its dextromethorphan 20-mg group, and 83 from its placebo group. Some of these patients began the extension immediately after completing the double-blind trial, but about half chose to delay up to two weeks between completing the double-blind trial and enrolling in the extension.
In the extension, all patients received dextromethorphan 30 mg and quinidine 10 mg twice daily for 12 weeks. The researchers obtained the patients’ data at baseline and weeks two, six, and 12.
The patients’ mean CNS–LS score decreased from 13.8 at the extension’s baseline to 11.2 at week 12—a decrease that Dr. Pioro called “highly significant.” He also noted that patients who had received placebo during the double-blind phase showed the most improvement during the open-label phase: The mean CNS–LS score reductions were approximately 2.6 in patients originally from the dextromethorphan 30-mg group, 2.4 in those originally from the dextromethorphan 20-mg group, and 3.1 in those originally from the placebo group.
Safety and Tolerability
Asked how the trial and extension would alleviate the FDA’s concerns about cardiovascular safety, Dr. Pioro said, “There were no cardiovascular serious adverse events at all, in either the double-blind or the open-label phase.”
During the trial, the patients showed small changes from baseline to week 12 in mean QT interval (QTcF) with a Fridericia correction (a formula for adjusting QT intervals for heart rate). Those changes were 4.8 msec in the dextromethorphan 30-mg group, 1.0 msec in the dextromethorphan 20-mg group, and 1.0 msec in the placebo group. No patients in the treatment groups had QTcF interval increases greater than 60 msec or absolute QTcF interval greater than 480 msec, however. The researchers concluded from the double-blind phase that the treatment has low pro-arrhythmic potential.
During the open-label extension, 73.5% of patients—72.3% of those previously treated with dextromethorphan 30 mg, 75% of those previously treated with dextromethorphan 20 mg, and 73.5% of those previously treated with placebo—reported adverse events. However, 5.5% of patients—6.4%, 6.6%, and 3.6% from the previous dextromethorphan 30-mg, previous dextromethorphan 20-mg, and previous placebo groups, respectively—reported serious adverse events.
The rates of adverse event-related discontinuations during the open-label extension were 5.5% overall and 6.4%, 3.9%, and 2.4% for patients previously treated with dextromethorphan 30 mg, dextromethorphan 20 mg, and placebo, respectively. Dr. Pioro noted that some patients “didn’t complete because of death … which occurred in the ALS patient population, as one might expect. Other individuals were unable to either tolerate the medication because of adverse events—most commonly, mild to moderate dizziness, nausea, [and] diarrhea. Overall, however, both formulations of the drug combination were found to be safe and well-tolerated.”
—Jack Baney