ARTICLE IN BRIEF
In a randomized, placebo-controlled trial, the synthetic vitamin D analogue alfacalcidol significantly improved fatigue and reduced relapse rates in multiple sclerosis patients.
PHILADELPHIA—The synthetic vitamin D analogue alfacalcidol significantly improved fatigue among multiple sclerosis (MS) patients, researchers from Israel reported here at the American Academy of Neurology Annual Meeting.
In a secondary finding, patients who received the drug also were significantly more likely to remain relapse-free compared with patients on a placebo, a finding that researchers attributed in part to vitamin D's effect of enhancing apoptosis of autoreactive T cells.
Fatigue related to MS can occur daily, often worsens as the day goes on, and is intensified by heat and humidity. It is not directly correlated with either depression or the degree of neurological disability.
Other drugs such as amantadine, an antiviral medication, and modafinil, a drug for improving wakefulness, have been studied for alleviating fatigue in MS but have not shown significant effects. No medications are approved specifically for fatigue caused by MS.
STUDY METHODOLOGY, RESULTS
In a trial sponsored by the drug-maker Teva Pharmaceuticals, Anat Achiron, MD, PhD, director of the Multiple Sclerosis Center at Sheba Medical Center in Israel, and colleagues randomized 80 MS patients — who had reported that fatigue impacts their lives and who had poor scores on scales that measure fatigue — to receive alfacalcidol, and 78 to receive a placebo over eight months.
The researchers considered a 30 percent reduction in scores on the Fatigue Impact Scale (FIS) — a 40-item questionnaire — as a cut-off point for improvement. Those receiving alfacalcidol improved by 41.6 percent, while those in the placebo group improved by 27.4 percent.
Patients in the alfacalcidol group also had a significantly lower number of relapses compared with the placebo group — eight relapses compared with 25. After six months, 89.5 percent of patients receiving alfacalcidol were relapse-free, compared with 67.1 percent of those in the placebo group, researchers said.
Previous findings about vitamin D's effects on T cells and demyelination might shed light on why this might have been found, Dr. Achiron said.
“This beneficial effect is not surprising, considering that vitamin D enhances apoptosis of autoreactive T cells, and high dietary doses of vitamin D3 reduce demyelination and attenuate microglia activation and macrophage infiltration into the CNS in a mouse model,” Dr. Achiron said.
Patients in the alfacalcidol group performed significantly better on the psychological and social portions of the modified Fatigue Impact Scale (p=.033 and .043, respectively).
There were no significant differences observed between the two groups in adverse events of any origin. In the alfacalcidol group, 12 patients — or 15 percent — suffered an adverse event, and 13 — or 17 percent — suffered an adverse event in the placebo group.
“Alfacalcidol is a safe and effective treatment strategy for treating fatigue in MS,” Dr. Achiron said.
Commenting on the study, John R. Corboy, MD, FAAN, professor of neurology at the University of Colorado and co-director of the Rocky Mountain MS Center at Anschutz Medical Campus, said the study was interesting, but noted that the placebo effect was “quite large” — with a decrease of 27 percent in FIS scores. The researchers didn't provide the number of patients in each group that improved by at least 30 percent on the FIS, he said, adding that only the average improvement was given.
Dr. Corboy also noted that no data were presented on the baseline vitamin D levels in the two groups. “This was a relatively large effect in a relatively small period of time,” he said. “Many studies with approved agents have barely been able to show an effect on relapses at 8 months, with much larger sample sizes, [and therefore those studies] needed a smaller effect size.”
But he noted that questions remain, especially given the dearth of available data on these and other issues: the number of relapses the year before in each group, the baseline number of enhancing lesions, the vitamin D levels before and after, and whether vitamin D levels predicted response.
“If this would be repeated, with the controls and analyses suggested, and a similar effect size noted, this would be an additional compelling argument to use vitamin D regularly in all relapsing MS patients,” Dr. Corboy said.
“There is no significant logic as to why this version of vitamin D may be better or more useful than other versions, although it should allow for bypass of the kidney during vitamin D metabolism, and this may be modestly beneficial,” he said. “This is rarely a concern. Thus, if this version of vitamin D is any more expensive than any generic vitamin D3 product, with the data presently available, it would be difficult to justify spending more on this product.”