BOSTON -- The effectiveness of high-dose vitamin D supplements in multiple sclerosis remains unproven in the wake of disappointing results from two highly anticipated trials reported here, but researchers remain convinced that the treatment has genuine value.
Both trials, dubbed CHOLINE and SOLAR, missed key endpoints, according to platform presentations at the American Academy of Neurology's annual meeting. But they did show significant advantages in enough other outcomes that enthusiasm for vitamin D as a safe add-on to conventional treatment appeared to remain undiminished, and perhaps increased.
It wouldn't be the first time that negative results on primary endpoints failed to dampen excitement about a therapy -- drugs to increase high-density lipoprotein cholesterol come to mind -- and the "yes, but" responses from investigators have a similar ring.
Nonetheless, the CHOLINE and SOLAR results do parallel those found in a number of earlier studies, and increasingly it appears that vitamin D has a consistent favorable effect on MRI activity in MS, though less easily demonstrated in relapse rates.
, reported by William Camu, MD, PhD, of CHU Gui de Chauliac in Montpellier, France, tested 100,000 IU of vitamin D3 given every 2 weeks or placebo in combination with standard interferon-beta-1a in a 96-week trial. The disappointment was that it only showed a non-significant trend toward a lower annualized relapse rate among those assigned to vitamin D treatment in an intent-to-treat (ITT) analysis.
But restricting the analysis to patients completing the 96 weeks of assigned treatment did show a statistically significant, 60% reduction in annualized relapse rate with vitamin D (P=0.011), Camu said. The completer analysis also showed a significant reduction in MRI lesions.
He attributed the missed ITT endpoint to the fact that most of the study's dropouts were among patients in the placebo group who withdrew because of relapse. Also, he said, the annualized relapse rate was unexpectedly low with placebo plus interferon (0.34), leaving little room to demonstrate a benefit; and enrollment fell short of the planned 100 patients per group (less than 70 per group), thus limiting the trial's statistical power.
Following Camu to the podium was Joost Smolders, MD, PhD, of Maastricht University in the Netherlands, who presented 48-week results from the phase II, 229-patient . In this trial, enrolling patients with early MS (median time since diagnosis less than 1 year), all patients also received interferon-beta-1a and were randomized to either placebo or vitamin D3 at 14,007 IU/day.
Like CHOLINE, it too showed a non-significant trend favoring vitamin D in annualized relapse rate (0.28 versus 0.41, P=0.17), but did show a significant benefit in MRI activity. Specifically, there was a 32% reduction in cumulative unique activity lesions (P=0.0045).
Smolders also reported that the two arms showed no difference at all in what has become an important outcome measure: the proportion of patients meeting criteria for "no evidence of disease activity," or NEDA, which is based on lack of relapses and disability progression and quiescence in MRI lesions.
In a review following the presentations, discussant Kassandra Munger, ScD, of the Harvard T.H. Chan School of Public Health, regarded both trials as essentially wins for vitamin D despite the missed endpoints.
She suggested that there remains plenty of life left in vitamin D as an MS therapy, saying the field is "approaching a pivotal point." In addition to SOLAR and CHOLINE, Munger pointed out that five other randomized trials are underway, with enrollment topping 300 patients in one of these.
These answer criticisms of earlier studies that failed to find benefit: that they were too short (almost all no longer than 1 year) and too small (none with as many as 100 patients), Munger said.
But they won't answer all the questions about vitamin D as an add-on MS therapy, she noted. Even if a clear benefit is proved, more studies will be needed to determine optimal dosing, the role of baseline vitamin D levels, and whether vitamin D works better with some conventional MS therapies than with others.
Moreover, she said, the current vitamin D studies haven't begun to address long-term effects such as whether it can slow disability progression.