March 30, 2016

Director's Letter

Carole Baggerly

Director, GrassrootsHealth

A group within Kaiser Permanente is recommending sun! Shout out to the world! I was ecstatic to see their latest news called for the need for sunshine for everyone. Barriers are coming down. Their title - "Find Some Sun and Let it Shine - On You!" They equate the need for sun on people with that of plants - varying degrees depending on the type of plant (skin type). We could not have written a better piece ourselves. The article explains the connection of vitamin D with disease prevention; indicates that the message to avoid the sun altogether may be misguided, and, indicates that a levels of 40 ng/ml to 75 ng/ml are recommended by experts. It even talks about the importance of vitamin D during pregnancy and early childhood. This is a big step for moving science into practice! Unfortunately, this news was written by a small branch, the Positive Choice Integrative Wellness Center in San Diego. So, while it is not the view of Kaiser Permanente as a whole, it is a step in the right direction.

This week, GrassrootsHealth and researchers from around the world are attending the 19th Vitamin D workshop in Boston, MA. GrassrootsHealth will have a poster presentation on our latest research - Serum 25-Hydroxyvitamin D Concentrations ≥40 ng/ml are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study. We will tell you more about this research and have a summary of the conference next week. Stay tuned.

Onwards!

Carole Baggerly

Director, GrassrootsHealth

A Public Health Promotion & Research Organization

Moving Research into Practice NOW!

New MS and Vitamin D RCT in Data Analysis Stage

Review of SOLAR study

This study is well known as "SOLAR" which stands for Supplementation of VigantOL® oil versus placebo as Add-on in patients with relapsing-remitting multiple sclerosis receiving Rebif® treatment. It is funded by Merck who makes both Rebif, an interferon drug used to treat MS, and Vigantol, vitamin D3 drops.

Why vitamin D?

SOLAR will evaluate the efficacy of vitamin D3 as add-on therapy to subcutaneous interferon beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS). The authors believe in studying vitamin D with MS both because of the evidence that vitamin D deficiency (latitude) may cause MS and because prior studies showed a correlation between higher 25(OH)D and lower relapse risk, specifically, that for every 10 nmol/L (4 ng/ml) increase in 25(OH)D resulted in a reduction in the risk of relapse of up to 12%.

First large double-blind study of higher dose vitamin D and MS

There have been RCTs on MS and vitamin D - but many have had very small sample sizes with fewer than 50 participants. The goal of this study, one of the first large RCTs on high dose vitamin D and MS, is to test the hypothesis that higher vitamin D levels will improve MS status.

Recruitment was planned for 348 participants from all over Europe, both south and north to account for latitude. To be eligible, participants must be between 18-50 years of age, have RRMS, and have a vitamin D level < 60 ng/ml (150 nmol/L). Additionally, they must be taking IFN beta-1a Tiw, a MS interferon drug, which they will continue to take throughout the study. Vitamin D will not be a substitute for their MS drugs.

What is the study protocol?

Prior to enrollment, all potential participants will have their serum 25(OH)D level measured, and only those with serum levels < 60 ng/ml will be included in the double-blind study. They expect to have about 10 patients who enter the study with vitamin D levels > 60 ng/ml. With these "supra physiological" levels they will not supplement with vitamin D, but instead will study the genetics of these patients - why do they have higher levels? And also understand whether these higher levels have led to a more benign form of RRMS.

Of the rest, they will divide equally into a control (placebo) and a treatment group.

The treatment group will start with 7000 IU/day for 4 weeks. At that point they will check for tolerance, and if all is clear transition to the higher dose of 14,000 IU/day, where they will stay for the remainder of the study (96 weeks).

The tolerance check will screen for hypercalcemia. Measurements will include serum calcium as well as urinary ratio of calcium to creatinine. These measurements will be made throughout the study and if a participant has levels outside the limits, their vitamin D supplementation will be reduced to 7000 IU/day or stop supplementation for a month, depending on the level.

Higher dose vitamin D

Smolders et al. hypothesize that if they start with patients who have 25(OH)D levels less than 60 ng/ml and are given 14,000 IU/day, they will not exceed 150 ng/ml by the end of the study, and will thus remain below the potential toxicity threshold of 200 ng/ml.

Study data

They will assess efficacy of the treatment by the number of lesions in an MRI (done at weeks 0, 48, and 96); the number of relapses; Expanded Disability Status Scale (EDSS) progression; and change in cognitive function as measured by the Symbol Digit Modalities Test (SDMT).

They will also collect the following measurements throughout the study: bone mass density; serum calcium levels; urine calcium/creatinine levels; serum 25(OH)D; serum 1,25(OH)D; gene expression profiling; and pharmacogenetic biomarkers.

Read Study Summary

Scientist Editorial

Reinhold Vieth, PhD

Professor, Departments of Nutrional Sciences, Department of Laboratory Medicine & Pathobiology, University of Toronto

Prof. Reinhold Vieth recently retired as director of the Bone and Mineral Group Laboratory at Mount Sinai Hospital and remains active as a Professor. He is an expert on the clinical nutrition, pharmacology and safety of vitamin D, and he has served as an expert adviser on vitamin D related matters for the Institutes of Medicine, the Centers for Disease Control in Washington, the American Geriatric Society and Health Canada. He has been the principal investigator on many clinical trials involving vitamin D, ranging from osteoporosis, to MS and prostate cancer. Currently, his work relates to the utility of higher doses of vitamin D in health maintenance.

Connecting Vitamin D to MS... Scientifically

In December 2011, the National Multiple Sclerosis Society convened a two-day meeting of 40 MS experts from around the world. They were neurologists, epidemiologists, clinical trial specialists, laboratorians like me, molecular biologists, geneticists, and statisticians. They were asked to put their collaborative heads together to develop a research protocol that could provide the highest level of evidence as to whether taking vitamin D can help to prevent MS. There were no vitamin D cynics in this group of bright, enthusiastic individuals. But despite everyone's best efforts, nothing came of the meeting (see next article).

How do you "prove" that if people take vitamin D, their risk of developing MS will be lower, the way sunshine and higher serum 25(OH)D levels in populations are related to lower risk of MS? The answer to this question starts from an appreciation of what is called the evidence pyramid.

At the wide, low end of the evidence pyramid is what was once known as expert opinion, i.e. what the esteemed professor says. This is a wide base because there are a lot of experts and everyone has an opinion. Opinion is not proof of anything. Next up, is evidence from the laboratory, be it cellular biology or animal research; which generate scientific data relatively easily, but which are hard to translate to clinical practice. Higher on the pyramid still, are case histories, or case reports that present the experience of individual patients. Those lack a context, since you would not know what would happen without, say, the vitamin D.

Still higher up the pyramid is the important field of epidemiology, the study of disease in populations. Epidemiology is powerful; it put anti-smoking and seatbelt use into public policy. Epidemiology demonstrates relationships, but it is not absolute proof that a lack of vitamin D causes multiple sclerosis. In a court of law, epidemiology would still be called circumstantial evidence.

Yes, some will argue that a set of considerations known as the Hill criteria will amount to "proof" in epidemiology. This idea stems from work of Bradford Hill who "proved", through logic, that smoking is a cause of lung cancer. However, the same kind of analysis has been presented to me relating vitamin D to MS, and that relationship is much less powerful than smoking to lung cancer, and much tougher to prove. I am absolutely on the side of vitamin D, but I have also been in on serious, mainstream efforts to "prove it".

My conclusion about vitamin D and MS prevention: there are some disease connections, such as vitamin D and MS prevention, that are indeed real, but the top of the evidence pyramid - double-blind, placebo-controlled (RCT) evidence - is not likely to happen. Nonetheless, like many things in life, we need to decide our actions without perfect knowledge.

The role of vitamin D in the treatment of MS

The ultimate level in evidence-based medicine is a stamp of approval from a Cochrane review. This is an international collaboration set up to be a sort of a Consumers Reports of medicine. They once claimed to have been wrong only once in a thousand of their reviews - normally, statistical results in science aim for a risk of being wrong that is not more than once in twenty. It is important to realize, that Cochrane reviews do not consider it an error, if they deny efficacy of something that actually works. This fear of being wrong affects many policy makers, even MS societies. So far, the Cochrane people are luke-warm about vitamin D as an add-on for treatment of MS. Last time they looked, they could only find one RCT of high-dose vitamin D, and with that study, the results were focused on safety (it is safe) and surrogate endpoints (blood tests looking at effects on the immune system, where vitamin D produced good results). The early-stage clinical research shows that vitamin D does good things that one should expect when treating MS, but the hard RCT research does not yet prove that taking vitamin D changes the long-term course of MS, compared to not taking the vitamin D.

Double-blind, placebo-controlled research studies are going on right now, but they have not been published yet. The best such study (my opinion) is still in the data-analysis stage. The SOLAR study (outline above) was designed to find out whether progression of active MS could be slowed in persons receiving 14,000 IU vitamin D3 daily, on top of continued therapy with a potent MS drug, Rebif^R, compared to placebo on top of the Rebif^R. That research was funded by a European drug company, Merck KGaA (not to be confused with Merck USA).

Clinical trials are really tough and that is why there are very few of them. They are placed in the rarified air at the top of the evidence pyramid. Clinical trials are generally too expensive for conventional funding agencies. Agencies such as the National Institutes of Health, and the National Multiple Sclerosis Association need to divide their research funding among as many research studies as possible, because there is pressure to see that a decent percentage of applied-for grants get funded. In contrast, drug companies can direct funds to suit their own priorities. They are efficient, and in my view, drug companies are not at all the bad guys they are often made out to be. In the case of the SOLAR study, Merck KGaA hopes to improve on the treatment success of their existing drug. The broad benefit is that over the next year, we will see what the risk-to-benefit profile is for persons who have MS, to take vitamin D in addition to their usual drug.

Final Comment

After decades of good news stories about vitamin D, many in the media, including the most influential medical journals, have recently preferred to highlight risk or down-side with vitamin D. The latest example was the report about an RCT in the Journal of the American Medical Association, in which rates of fall were higher in the group receiving vitamin D than the placebo group. As in most reports of a surprising down-side to vitamin D, the likely reason for the problem was a prolonged dosing interval in the study design. They gave the large dose once a month.

My point is, if you take vitamin D on a daily or weekly basis, it works best, and it is very safe. What the media have chosen not to cover lately, is the good-news clinical work about vitamin D. Good things continue to be published about vitamin D, but editors seem to think that good news about vitamin D is too boring to report as a headline.

Designing a Clinical Trial of MS Prevention with Vitamin D

Written by Dr. Reinhold Vieth

Assume:

MS incidence rate is 10/100,000
Long-term treatment with vitamin D lowers incidence rate by 50%

If these two assumptions are correct, then using Power Calculations we find:

This study design would require over one million person years of randomized treatment and follow-up
MS is a disease of long-term risk; therefore, it would be appropriate for an RCT to divide those million person-years into at least 15 years of follow up on vitamin D treatment or placebo. Hence the RCT would require at least 40,000 subjects randomized, plus at least an additional 10,000 subjects randomized to make up for probable drop outs or loss-to-follow up during the trial.
A long-term study of patients who are healthy, sustained and motivated is very difficult.
There are practical and ethical questions as to how to randomize the cohort. What if there is more than one study subject per household?
There is risk that future news or discoveries will change attitudes of study subjects and these could affect retention in the RCT, or subjects may simply stop or take their own vitamin D. What if the RDA were to change?
Funding problems, sample size, and follow up for this kind of RCT are unprecedented. No funding agency could risk putting so many resources into one experiment.
At $1000 per participant year in the study, this represents a cost of 1 billion dollars.

Editor's Letter

Susan Siljander

Marketing Director, GrassrootsHealth

It was so fun to read the Kaiser Permanente piece on sunshine. I got more and more excited as I read each word - truly moving research into practice!

But one thing is clear - you still need to test. It is impossible to know if vitamin D is working, or at what level it works, until you test. GrassrootsHealth has reported that different conditions require different vitamin D levels for maximum benefit. For example 20 ng/ml seems to be enough to prevent or cure rickets; 40 ng/ml is adequate for pregnancy, while 50 ng/ml is necessary for breast cancer. So, test today - before our 25% off special ends!

Find out your vitamin D level. Write it down in your health journal. Then, as you make changes to your sun exposure and supplements, test again - see how you feel. What is working, what is not. And... you can feel good that you are helping fund a great initiative - moving research into practice!

Thank you for your participation!

Susan Siljander

Marketing Director, GrassrootsHealth

A Public Health Promotion & Research Organization

Moving Research Into Practice NOW!

Order Now

Order Your Home Vitamin D Test TODAY!

Your participation in this project provides information for your answers to D questions and helps fund the GrassrootsHealth projects.

Efficacy of vitamin D3 as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon beta-1a: A Phase II, multicenter, double-blind, randomized, placebo-controlled trial

Joost Smolders et al.

Maastricht University Medical Centre, The Netherlands

Paper describing SOLAR study - currently in the data analysis phase

May 2011

Read Paper

Vitamin D and multiple sclerosis

Colleen E. Hayes et al.

University of Wisconsin-Madison

October 1997

Read Paper

Multiple sclerosis and vitamin D: an update

Barbara M. van Amerongen et al.

VU University Medical Center, Amsterdam

August 2004

Read paper

Higher levels of 25-hydroxyvitamin D are associated with a lower incidence of multiple sclerosis only in women

Jolijn Kragt et al.

VU University Medical Center, Amsterdam

August 2013

Read Paper

Bone health and multiple sclerosis
Ruth Dobson et al.
Barts and the London School of Medicine and Dentistry
October 2012
Read Paper

Multiple Sclerosis Increases Fracture Risk: A Meta-Analysis
Guixian Dong et al.
Harrison International Peace Hospital, China
December 2014
Read Paper