Vitamin D effect in the pivotal fingolimod clinical trials

Chicken or egg? Causation or association (reverse causation)? Is vitamin D a DMT or not? Does this study muddy the waters or provide some clarity? 

J Neurol. 2017 Dec 14. doi: 10.1007/s00415-017-8697-3. [Epub ahead of print]

Efficacy and safety outcomes in vitamin D supplement users in the fingolimod phase 3 trials.

Hongell K, Silva DG, Ritter S, Meier DP, Soilu-Hänninen M.



Low serum levels of 25-hydroxyvitamin D have been associated with worse outcomes in multiple sclerosis (MS) patients treated with interferon-beta. Association of vitamin D nutrition on the outcomes of other MS therapies has been studied less.


Whether patients in the phase 3 fingolimod trials using vitamin D supplements have better clinical, MRI and safety outcomes than non-users.


Pooled data from phase 3 FREEDOMS trials was analyzed post hoc. Vitamin D use was defined as ‘non-users’ (n = 562), ‘casual users’ (n = 157) and ‘daily users’ (usage 100% time in the study, n = 110).


Expanded Disability Status Scale change from baseline to month 24, and annual relapse rate and proportion of patients with relapses were similar across the vitamin D user groups. Proportion of patients free of new/enlarging T2 lesions significantly favored vitamin D ‘daily users’ versus ‘non-users’. Mean number of lesions were lower and proportion of patients free of gadolinium-enhanced T1-lesions were higher in the ‘daily users’. At month 12, percent brain volume change was significantly lower in the ‘daily users’ versus ‘non-users’ and remained low at month 24 (non-significant). Incidence of depression was lower for vitamin D ‘daily users’ (non-significant).


We observed improved MRI outcomes on percent brain volume change and proportion of patients free of new/enlarging T2 lesions, and a trend of less depression in the ‘daily users’ of vitamin D supplement in patients in the FREEDOMS trials.

Figure: MRI outcomes by vitamin D use in FREEDOMS and FREEDOMS II.

Sometimes it’s difficult to see the wood for the trees. You must travel through the woods again and again, and with luck you may be able to avoid the wolf. Read on and you’ll understand my meaning.

In their introduction, Hongell et al. allude to an influence of vitamin D levels in the B interferon trials. Firstly, in the BEYOND trial (which compares high dose 500 ug IFN- β 1b to standard dose 250 ug), where high levels of vitamin D were associated with less disease activity on MRI, so much so that an increase of 50 nmol/L in blood levels resulted in a 31% lower rate of new lesion formation (Fitzgerald et al. JAMA Neurol 2015; 72: 1458-1465). Secondly, in the Benefit trial, where low blood levels of vitamin D was associated with worse clinical and MRI outcomes in PwMS (Ascherio et al JAMA Neurol 2014; 71(3): 306-314). They believe there to be a synergistic effect between vitamin D and the interferons and possibly even an influence on the therapeutic activity of interferon on relapses.

Armed with this knowledge, the authors (three of whom work for Novartis; the proprietor of fingolimod) have studied the effect of vitamin D use in the pivotal fingolimod Phase III clinical trials; FREEDOMS and FREEDOMS II. Just to be clear this was never a part of the original trial analysis and therefore would be considered post-hoc analyses or a data mining expedition.

They studied the effect of ‘daily’ vitamin D users with that of ‘non-users’ among those who were assigned to either receive fingolimod or placebo (dummy tablet).

What they found was that ‘daily’ users of vitamin D supplements had better MRI outcomes compared to the ‘non-users’. Although, there was no statistically significant difference in the mean numbers of new/newly enlarged T2 lesions, they did note that the proportion of PwMS free of new/newly enlarged T2 lesions significantly favoured the ‘daily’ users from month 0 – 12 and month 0 – 24 (see figure above). Surprisingly, even the percent brain volume change (or brain atrophy/volume loss) was significantly lower at month 12 in ‘daily’ users than ‘non-users’ and remained low at month 24 (although the latter was not statistically significant).

It therefore begs the question – what role did vitamin D play in the much reported favourable outcomes of fingolimod in the FREEDOMS and FREEDOMS II studies? Of course, the answer lies in the detail (or the trees metaphorically speaking) – on how much information was collected in the original data sets. The lack of blood vitamin D levels in the trials is a handicap, which makes these findings even more difficult to interpret.

About the author

Neuro Doc Gnanapavan


  • For 2 years since being diagnosed I have taken Vitamin D almost every day yet it fails to go beyond like 20 so I have given up. I can't really stop either otherwise my levels will fall to about 6. Any ideas?

    • Vitamin D from supermarket contains 400 units which is enough to stop you getting rickets but not enough to get you levels up.

      ProfG recommends 5000 a day so you have to get tablets from specialist pharmacy.

      To put in perspective, 15min full sun gives you10,000-15,000 units

    • I was in exactly the same situation and followed those rules:

      1) hedge your supply: have 2 different pills of 5,000 units every day (10,000 a day) produced by 2 different companies. That would cover you in case 1 is not as effective (which i suspect was the case with me).

      2) Always have you pills after a solid meal

      I have managed to raise and my level from 30ish to 150 following these 2 rules.

      I hope this helps – otherwise consider subcutaneous injections.

      Tony Fonda

    • Make sure you are taking vitamin d3 and not d2. That makes a difference if you want to significantly increase the serum levels.

    • It was shown by two independent studies that the IoM in the USA got the maths wrong in its calculation of the RDA for vitamin d. The IoM have now agreed they got it wrong although the document is written in such a way as to hide the admission . They say it would not have affected their recommendation but it is hard to see how you can admit the maths mistake and then not accept the consequences of that mistake. I guess it may be because they do not wish to be subject to a class action for negligence. 5,000IU to 10,000IU a day looks to be correct unless you have an underlying medical condition that affects blood calcium levels.

  • Hello,
    Thank you for posting about this paper. From the quote above:

    "They believe there to be a synergistic effect between vitamin D and the interferons and possibly even an influence on the therapeutic activity of interferon on relapses"

    Do you know if there are there any systematic and/or meta-analyses of clinical trials that measured vitamin D levels and detected any sort of trend with DMT's?
    Is there a possibility that use of vitamin D was a confounding factor not accounted for in any number of DMT trials and not just in FREEDOMs and FREEDOMS II studies? Thanks, David

    • I’m not aware of a meta-analysis on this but there have been prospective studies around this and even natalizumab is not immune to the effects of add on vitamin D!

    • Well, that is interesting…if one could go back to these trials and retrospectively factor in vitamin D levels (if values are known of course), would the positive trials be nearly as statistically significant? Thanks, David

    • Glad you asked that, their are sample repositories from Phase III studies banked away and it would be useful to go back to them and perform the analysis. I for one will be interested in doing this!!

    • Definitely a good idea! If it does indicate any sort of trend, then that could possibly put a few question marks over the current DMT's (and may make future trials include vitamin D in their analyses at the protocol stage, which would make the statistical analysis more robust than post analysis.)
      Thanks, David

  • Vitamin d is being looked at the wrong way round. It is assumed that deficiency is normal and correcting Vitamin d levels is modifying the immune system. This is incorrect. It is the lack of vitamin d that is modifying the immune system. A lack of vitamin d allows something to happen that will not happen if the person has enough vitamin d. Do I know for certain what that thing is, well no, but my money is on it affecting the ability of lymph nodes to trap and neutralise Epstein Barr virus infected B cells. This opinion comes from my experience with Hodgkin's lymphoma not MS.

    • A review showed there was no link between vitamin d intake and kidney stones, so long as you did not get into the toxic range, when you overload the body's ability to store vitamin d. This is some where in the range of 40,000IU a day for about 6 months. It is probably higher if calcium intake is restricted. It is likely that between replete and toxicity there is no real effect as the body stores the vitamin d in a stable inert form only using what it requires. I will try and find a link to the paper that is open access.

    • I was the pwMS who got kidney stones, I cut my 2,500 IU a day vit D tablet intake and the kidney stones stopped.
      I think there are some people perhaps who are more vulnerable to kidney stones.
      I was not in the toxicity range but I still got the kidney stones.

    • Anonymous Wednesday, December 20, 2017 8:41:00 am It may be worth getting your blood calcium levels checked, a quick test would rule out parathyroid problems or sarcoidosis. The form of vitamin d in supplements is inert, it is the conversion to the active form 1,25(OH)D that affects blood calcium. This conversion is normally carefully controlled by the body, which is why people can tolerate large variations in vitamin d intake. Sarcoidosis and some lymphomas leak active vitamin d in to the blood causes high blood and urine calcium levels.

  • I only know that I will do 04 years of diagnosis and use of Vitamin D3 (10.400 IU every day) plus Copaxone and only had the releapse that made me discover the disease, I didn't have any new lesion or relapse.
    Of the group of patients that I participate I am the only one who associates Vitamin D (I use D3, cholecalciferol) with a DMT (even if it is of low efficacy), and I'm the only one who did not relapse during this period.
    Virtually all other participants in the group already use Fingolimode.

    Is MS in me, only MS or Vit D plus DMT?
    One day maybe we'll come to this answer…

  • I very easily exceeded the toxicity levels (100) with 4000iu and was told to stop taking for a while. How is it possible to not exceed with the 10.000iu daily??

    • What you refer to is one action of vitamin d, used to control blood calcium levels. It has other uses related to the function of the immune system.

      The basic problem is there is more that one chemical called vitamin d. There is vitamin d2 (Ergocalciferol) and vitamin d3 (Cholecalciferol) that is vitamin d in supplements. There is both D2 and D3 forms of the type stored in the blood (Calcidiol, 25(OH)D2 & 25(OH)D3) and there is the active hormone Calcitriol (1,25(OH)2D, which also has D2 & D3 forms).



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