No sooner have we had a Worms trial, but a vitamin D trial is reported. My time capsules are coming home. Maybe my type writter got stuck.

N

This study reports the trial of vitamin D + beta interferon verses vitamin D and the vitamin D trial fails. In my time capsule, I had this one as a fail too, just as the WORMS study failed to meet its endpoint too.

You say I am saying this, after the event, which is true…but my time capsule for microbiome trials were planted about three years ago and they say the same thing.

Academics are showing themselves to be lemmings and they often follow dogma. So a trial in arthritis is followed by trials in diabetes, MS disease X and Y and vice versa. The charties feed the lemmings to fund the trials. However, people pay no attention to me, I have been arguing for combiation trials for neuroprotection and repair that deal with the inflammations as a base, so often my face has turned into the colour a Smurf. Mark my words, trials will be announced and they will be single chemical studies that don’t deal with the underlying infiltration.

Prof G may come back to give his opinion. After all he has an interest in vitamin D

We have loads of trials to wait for them to report, but I rather think if you have an effect you get a side-effect. No side-effect..No effect?. This does not mean vitamin D is not important, as the information suggests it may be involved in susceptibility, but the trials should not be in established MS, rather before MS occurs. This may mean treating pregnant mums. However it is importat that you are vitamin D replete to save bone health.

Randomized trial of daily high-dose vitamin D3 in patients with RRMS receiving subcutaneous interferon β-1a. Hupperts R, Smolders J, Vieth R, Holmøy T, Marhardt K, Schluep M, Killestein J, Barkhof F, Beelke M, Grimaldi LME; SOLAR Study Group. Neurology. 2019. pii: 10.1212/WNL.0000000000008445. 

OBJECTIVE: In the phase II, randomized, double-blind, placebo-controlled Supplementation of Vigantol Oil versus Placebo Add-on in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) Receiving Rebif Treatment (SOLAR) study (NCT01285401), we assessed the efficacy and safety of add-on vitamin D3 in patients with RRMS.

METHODS: Eligible patients with RRMS treated with SC interferon-β-1a (IFN-β-1a) 44 μg 3 times weekly and serum 25(OH)D levels <150 nmol/L were included. From February 15, 2011, to May 11, 2015, 229 patients were included and randomized 1:1 to receive SC IFN-β-1a plus placebo (n = 116) or SC IFN-β-1a plus oral high-dose vitamin D3 14,007 IU/d (n = 113). The revised primary outcome was the proportion of patients with no evidence of disease activity (NEDA-3) at week 48.

RESULTS:At 48 weeks, 36.3% of patients who received high-dose vitamin D3 had NEDA-3, without a statistically significant difference in NEDA-3 status between groups (placebo 35.3%; odds ratio 0.93; 95% confidence interval [CI] 0.53-1.63; p = 0.80). Compared with placebo, the high-dose vitamin D3 group had better MRI outcomes for combined unique active lesions (incidence rate ratio 0.68; 95% CI 0.52-0.89; p = 0.0045) and change from baseline in total volume of T2 lesions (difference in mean ranks: -0.074; p = 0.035).

CONCLUSIONS: SOLAR did not establish a benefit for high-dose vitamin D3 as add-on to IFN-β-1a, based on the primary outcome of NEDA-3, but findings from exploratory outcomes suggest protective effects on development of new MRI lesions in patients with RRMS.

CLINICALTRIALSGOV IDENTIFIER: NCT01285401.

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MouseDoctor

9 comments

  • Mouse,

    You are great at predicting after the event has occurred. A bit like me telling you on Sunday what I predicted Saturday’s lottery numbers to be. You also have a tendency to ‘predict’ failed trials with the usual “I knew this trial would fail after the trial result has been published”.

    The issue I have is that team G have a bucket load of failed trials – Charcot Project, your spasticity trial… Did you expect these to fail before the trial started?

    To test your real Mystic Meg skills here is a challenge:

    The remylination trial being undertaken in Cambridge – pass or fail?

    Think Hand trial – pass or fail?

    Stat 2 trial currently underway – pass or fail?

    At least we would have a record of your predictions so that we wouldn’t have to put up with “I knew this trial would fail” after results are published. Give that most trials seem to fail, I suspect you will predict fail for all three trials above. So predicting fail for an MS trial isn’t too difficult. I think I could match your predictions and I’m not a Professor / haven’t got a PhD. However, Professorships at Barts are like ar**holes – everyone’s got one (expect poor Welsh Mouse Doctor).

    PS apologise for the rant, but your stupid post title annoyed me + I’m sick of the constant negative trials pumped out by MS researchers. Surely you people can get something right sometimes!

    • 1. If you don’t try you can never succeed.
      2. I think if you look you may find that ProfGs name appears on quite a few positive studies.
      3. As for Professorships, these are awarded after rigourous assesment which includes international peer review. ProfBs application went through an internal review and was sent out to six different internationally recognised and independent reviewers, before being reviewed by an additional panel. ProfK has just finished his review and as a reviewer for a chair for another univeristy, I can say his CV was light-years better.
      4. Don’t shoot the messenger

      Now to address your rant….My original title was edited 🙂

      (a) Microbiome trials have yet to report and have yet to start in some cases So your accusations are not completely correct.

      (b) Charcot trial. There was anecdote, but they used an anti-integrase (stops intergration of virus into the genome) to stop a virus (HERV) that had already integrated, I think one of the readers was questioning this all along the study, if you check out the comments before the trial reported. You can see my view. The original idea of ProfG down under was to use HAART treatment, but Merck Sharp Dome offered to pay for a trial with a single agent. With the anecdote they took a risk and it wasn’t successful…..as I predicted. However, the Charcot idea is not dead if they can get a HAART study. I can sow a time capsule then.

      (c) Spasticity trial…sadly we may have got the wrong dose and the PK was not good enough :-(. VSN16S (S enantiomer of VSN16) should probably have been developed rather than VSN16R (a side chain points in a different dirrention to the S version). But when you are cash limited you can’t develop two agents. Better luck with the new candidates.

      (d) There are agents I thought could work like amiloride in MS SMART again with the proviso that the studies were not done on top of DMT. The failure im MS-SMART led me to question the trial design, but now there a question mark about whether amiloride gets in the brain and if true the trial was perhaps doomed before started. Indeed without a DMT in the mix it is harder to show. Was the trial design fit for purpose?

      (e) I do not normally comment on studies that are recruiting, because I do not want to influence people in their willingness to participate. If a comment makes anyone not participate because I don’t think it will work, maybe then it doesn’t recruit and therefore it will fail for all the wrong reasons. Therefore, you contribute to the reasons why you think I am being an a-hole. However, many people won’t read comments and it is just an opinion and only that. You think I am an A-hole, others may disagree…I said others may disagree:-). At least my mum likes me.

      If you know the answer it would not be an experiment. Therefore you do an experiment hoping it will succeed, but with the knowledge that it may fail.

      Cambridge trial….Fail. I am willing to accept that it could be a pass. However the pre-clinical work only showed it influences a lesion that will repair anyway. No remyelination study has shown that these agents can repair pre-existing chronic demyelination in any models. Increasing risk of failure in trial. Next, I think remyelination trials are in their infancy and trial design is key. Therefore you learn from your failures. The history of experience with immune modulators showed us this. Until beta interferon, a string of failures before, now you can get a positive trial in 6 months. Not sure how well bexarotine will be tolerated in the long run and it will have off-target effects. The outcome I think is MTR and I am not sure how well that represents myelination and there is no DMT at the base. I thought the trial was supposed to have finished in 2016, we are now really 2020 and nothing has surfaced, it does not bode well for a startling result, even if positive as it must have finished by now. If the new work from Cambridge is right then the implications are it should be combined with metformin.

      Oratorio hand…Positive. If the placebo arm doesn’t do well to make finding a postive impossible and there is worsening in the placebo arm then it should be positive. The Oratorio study showed a 45% slowing of progression so I am hopeful on this one and it should repeat.The trial should be loaded with people with active lesions.

      MS-STAT2 fails in its trial design because there should have been a dose-response in the study as the 80mg dose is not inert and is not tolerated by some people. If it is positive, we ask the question what happens now? If there is activity one will ask the question would the lower (say 20mg) dose work as it will be safer? . The phase II effects were modest but there was an effect on EDSS. This is a phase III that is massive in scale and so they may recruit people where it is harder to see an effect as they need to recruit over 1,000 people, so I would expect to see same effect or slightly worse. If slightly worse will that make it a negative? I don’t know. Based on the idea of how the instigater of the approach thought it works I would say no chance (remember MD2 and I did that original work), but given that the cholesterol pathway is one of the most dysregulated pathways in progressive EAE, progressive MS and even Alzheimers disease then I think it may influence disease in a different way. Again study is not done with a DMT and if you get worsening because of disease activity the trial will get messed up. Hopefully recruiting will finish before Siponimoid gets approved, so please sign up and get it over the line.

      • Mouse,

        I didn’t say you were an a-hole. I was merely pointing out that everyone at Barts seems to be a Professor (Professorships at Barts are like a-holes – everyone has one).

        I think the Cambridge re-myelination trial is to report in Oct / Nov.

        Have a nice weekend.

        PS my prediction for Monday is 3-0 (England v Bulgaria).

  • Given that these people have other sources of vitamin d that are not controlled why didn’t they compare blood 25(OH)D at the end of the trial with outcome? That make much more sense. There is no such thing as a random controlled trial with vitamin d, you are not controlling the dose as it is affected by things like midday sun exposure.

    These doses are still within what the body can control so it will not be acting as a drug, just a food. You would need to go above 40,000iu a day to see drug effects.

    That said the evidence is that consistently non deficient levels of vitamin d avoids MS not cures it.

    Also why are they not using better drugs than beta interferon, this is people lives they are playing with.

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