Vitamin D and RCTs (Randomized Controlled Trials)

Definition of RCT

Randomized controlled trial Wikipedia
"Randomized controlled trial: (RCT) A study in which people are allocated at random (by chance alone) to receive one of several clinical interventions. One of these interventions is the standard of comparison or control. The control may be a standard practice, a placebo ("sugar pill"), or no intervention at all."
There appear to be 3 types of RCT

• 1) Double blinded
• 2) Single Blinded (just the person running the trial knows who gets each treatment)
• 3) Non-blinded- everyone knows. including those analyzing the results

---

Why RCTs are typically needed

Reduces possibility of bias

---

When RCTs are not needed, or are inappropriate

• WikiPedia " RCTs may be unnecessary for treatments that have dramatic and rapid effects relative to the expected stable or progressively worse natural course of the condition treated."
• When there is good other evidence for Vitamin D benefits for long term health problems - which would require very expensive decades long trials

---

Why blinded RCTs are difficult with Vitamin D

Those getting enough vitamin D to make a difference will quickly know because many aches and pains will go away.

• Within a week or 2 if supplementation starts with a loading dose
• Within a month or 2 if just a maintenance dose is given

---

Intervention category listings on Vitamin D Life has 639 items

Examples of categories as of May 2017

	RCT
Breathing	23
Cardiovascular	8
Diabetes	10
Falls/Fractures	10
Hypertension	6
Obesity	7
Pain	11
Pregnancy	31

---

Proof that Vitamin D Works

86 health problems have proven to be prevented/treated as of July 2019
Hypertension, Cardiovascular, Back pain, Diabetes, Influenza, Falls, Hip Fractures, Breast Cancer, Multiple Sclerosis, Raynaud's pain, Menstrual Pain, C-section and pregnancy risks, Low Birth Weight, Chronic Kidney Disease, Cystic Fibrosis, Rheumatoid Arthritis, TB, Rickets, Respiratory Tract Infection, Lupus, Sickle Cell, leg ulcers, traumatic brain injury, Parkinson's Disease, Multiple Sclerosis, Congestive Heart Failure (Infants), Middle Ear Infection (Infants), Gingivitis, stronger senior muscles, antibiotic use in seniors, short Infants, Gestational Diabetes, heart pump better after attack, Prostate Cancer, Asthma, Depression, Vitamin D in Breast Milk, Fibromyalgia, Chronic Hives, Cholesterol, COPD, Asthma, Quality of Life, Survive ICU, Restless Leg Syndrome, Hepatitis-C, Crohn's disease, Pre-term birth, Cluster headaches, Autism, PreDiabetes, Weight loss, Sarcopenia = muscle loss, Growing Pains, Osteoarthritis, ALS, Vertigo, Warts, Metabolic Syndrome, Hay fever, Preeclampsia, Blood cell cancer, Irritable Bowel Syndrome, Urinary Tract Infection, Mite Allergy, Perinatal Depression, Vaginosis, Eczema, NAFLD, Knee Osteoarthritis, Tuberculosis, Ischemic Stroke, Sepsis, Trauma Deaths, Hemodialysis, Fatty liver - child, Fatigue, Poor Sleep, Pneumonia (Ventilator-associated), Male infertility, Waist size, ADHD, Alcoholic liver cirrhosis, Diabetic nephropathy. Ulcerative Colitis. Weight loss

---

Also, The Vitamin D Receptor limits the amount of Vitamin D in the blood actually gets to the tissue

The risk of 40 diseases at least double with poor Vitamin D Receptor as of July 2019

---

There are 436 items with RCT in the title on Vitamin D Life as of May 2017

---

38 Reasons why there can be a low response to Vitamin D

Many of the reasons are not considered by most Vitamin D RCTs
Reasons for low response to vitamin D

---

RCTS are the only appropriate way to demonstrate the role of vitamin D in health – May 2017

The Journal of Steroid Biochemistry and Molecular Biology, online 5 May 2017, https://doi.org/10.1016/j.jsbmb.2017.05.004
Rolf Jordea, b, rolf.jorde at unn.no

Despite thousands of vitamin D studies published, including hundreds of reviews and meta-analyses, it is still uncertain if supplementation with vitamin D will have positive health effects, except for the skeleton. This cannot be answered by doing more observational studies as it is impossible to control for confounding factors and reverse causality.
The only way to firmly prove positive vitamin D effects is by doing the properly designed randomized controlled trials (RCTs).
However, it has been difficult to show the expected positive effects by vitamin D supplementation in RCTs, which may indicate that the effects, if present must be small.
On the other hand, results from Mendelian randomization studies have shown promising results at least for mortality and multiple sclerosis. In the near future, results from several large RCTs with hard endpoints will be available.
If these show positive results, the main question on vitamin D and health is answered.
If they turn out negative, they will be criticized for having included subjects without vitamin D deficiency, and some studies might not have used an optimal dosing regimen. New and better-designed RCTs will then be needed, but will be very hard to perform.
Publisher wants $36 for the PDF

Those perceiving problems with vitamin D were 20X more likely to not participate in an RCT - July 2016

Often problems are due to low Magnesium
Randomized controlled trials: who fails run-in? - July 2016
Trials. 2016 Jul 29;17:374. doi: 10.1186/s13063-016-1451-9.
Rees JR1, Mott LA1, Barry EL1, Baron JA1,2, Figueiredo JC3, Robertson DJ4, Bresalier RS5, Peacock JL6,7.

BACKGROUND:
Early identification of participants at risk of run-in failure (RIF) may present opportunities to improve trial efficiency and generalizability.

METHODS:
We conducted a partial factorial-design, randomized, controlled trial of calcium and vitamin D to prevent colorectal adenoma recurrence at 11 centers in the United States. At baseline, participants completed two self-administered questionnaires (SAQs) and a questionnaire administered by staff. Participants in the full factorial randomization (calcium, vitamin D, both, or neither) received a placebo during a 3-month single-blinded run-in; women electing to take calcium enrolled in a two-group randomization (calcium with vitamin D, or calcium alone) and received calcium during the run-in. Using logistic regression models, we examined baseline factors associated with RIF in three subgroups: men (N = 1606) and women (N = 301) in the full factorial randomization and women in the two-group randomization (N = 666).

RESULTS:
Overall, 314/2573 (12 %) participants failed run-in; 211 (67 %) took fewer than 80 % of their tablets (poor adherence), and 103 (33 %) withdrew or were uncooperative. In multivariable models, 8- to 13-fold variation was seen by study center in odds of RIF risk in the two largest groups. In men, RIF decreased with age (adjusted odds ratio [OR] per 5 years 0.85 [95 % confidence interval, CI; 0.76-0.96]) and was associated with being single (OR 1.65 [95 % CI; 1.10-2.47]), not graduating from high school (OR 2.77 [95 % CI; 1.58-4.85]), and missing SAQ data (OR 1.97 [1.40-2.76]). Among women, RIF was associated primarily with health-related factors; RIF risk was lower with higher physical health score (OR 0.73 [95 % CI; 0.62-0.86]) and baseline multivitamin use (OR 0.44 [95 % CI; 0.26-0.75]). Women in the 5-year colonoscopy surveillance interval were at greater risk of RIF than those with 3-year follow-up (OR 1.91 [95 % CI; 1.08-3.37]), and the number of prescription medicines taken was also positively correlated with RIF (p = 0.03).
Perceived toxicities during run-in were associated with 12- to 29-fold significantly increased odds of RIF.

CONCLUSIONS:
There were few common baseline predictors of run-in failure in the three randomization groups. However, heterogeneity in run-in failure associated with study center, and missing SAQ data reflect potential opportunities for intervention to improve trial efficiency and retention.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT00153816 . Registered September 2005.

PMID: 27474021 PMCID: PMC4966775 DOI: 10.1186/s13063-016-1451-9
 Download the PDF from Vitamin D Life

---

32% of Breast Cancer patients in an RCT failed to consistent take DAILY vitamin D - July 2016

• Impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients: a randomized phase III study
  Much better compliance in the trial which was taking weekly doses
  Free full text is on-line

---

Vitamin D – wait for Random Controlled Trials, rebuttal – not wait and consider UV – Feb 2015

 

• Vitamin D – wait for Random Controlled Trials, rebuttal – not wait and consider UV – Feb 2015

---

Vitamin D clinical trials should be based on Vitamin D tests – Aug 2017

 

• Vitamin D clinical trials should be based on Vitamin D tests – Aug 2017

Founder of Vitamin D Life is a co-author of the paper

---

How to Understand, Refute, and Plan Studies Using Vitamin D - Vaseuez 2017

Excellent
 Download the PDF from Vitamin D Life

• "“This insight also illuminates a double-standard in research: whereas no legitimate drug study would use a subtherapeutic dose of a pharmaceutical agent and then (falsely) assert inefficacy,poorly designed and therapeutically underpowered (eg, using 10% of the known effective dose) nutrition studies are published and make headlines and shape policy (mostly by maintaining the status quo of nutritional inaction and ignorance) on weekly basis. "
• "For example, a study using an antibiotic or antiseizure drug that failed to administer a therapeutic dosage or achieve a therapeutic serum level would never be accepted for publication in a headlining medical journal; yet, underdosed nutrition studies are commonly published in headlining journals and then reported to mainstream media as proof of the inefficacy of nutritional intervention.”

How to Critique Vitamin D Studies—A Checklist
1. Did the study subjects receive at least 4,000-10,000 IU per day? .
2. Is the duration of the study at least 6-9 months?
3. Did the study use vitamin D3 (cholecalciferol) rather than fungally-derived erogcalciferol?
4. Was the product validated for potency?
5. Were serum 25-OH-vitamin D levels measured?
6. Did serum 25-OH-vitamin D levels enter the optimal range at least 2-6 months before the end of the study?
7. Were the patients deficient at the start of the study and then robustly replaced with vitamin D?
8. Vitamin D supplementation should be stopped for roughly 20-30 days before serum testing because 25-hydroxyvitamin D3 (calcidiol) has a half-life of 15
days.

---

Examples of Vitamin D RCTs which did NOT show a benefit

• Muscle strength not increased by Vitamin D - 96 percent were not deficient – RCT April 2017
• Why 100,000 IU of vitamin D monthly did not reduce Cardiovascular Disease – RCT April 2017