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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 VitaminDWiki has 786 items

Examples of categories as of May 2017

Breathing 23
Cardiovascular 8
Diabetes 10

Proof that Vitamin D Works

86 health problems have proven to be prevented/treated as of July 2019
ADHD,  Alcoholic Liver Cirrhosis,  ALS,  Alzheimer's,  Antibiotic Use in Seniors,  Asthma,  Autism,  Autoimmune Diseases,   Back pain,  Blood Cell Cancer,   Breast Cancer,   Cardiovascular,  Cholesterol,  Chronic Hives,  Chronic Kidney Disease,  Cluster Headaches,  Congestive Heart Failure (Infants),  COPD,  Crohn's Disease,  C-Section and Pregnancy Risks,  Cystic Fibrosis,  Depression,   Diabetes,  Diabetic Neuropathy,  Eczema,   Falls,  Fatigue,  Fatty Liver (Child),  Fibromyalgia,  Gestational Diabetes,  Gingivitis,  Growing Pains,  Hay Fever,  Heart Attack,  Hemodialysis,  Hepatitis-C,   Hip Fractures,  Hypertension,  Influenza,  Irritable Bowel Syndrome,  Ischemic Stroke,  Knee Osteoarthritis,  Leg Ulcers,   Low Birth Weight,  Lupus,  Male Infertility,   Menstrual Pain,  Metabolic Syndrome,  Middle Ear Infection (Infants),  Mite Allergy,  Multiple Sclerosis,  Non-Alcoholic Fatty Liver Disease,  Osteoarthritis,  Parkinson's Disease,  Perinatal Depression,  Pneumonia (Ventilator-associated),  Poor Sleep,  PreDiabetes,  Preeclampsia,  Pre-term Birth,  Prostate Cancer,  Quality of Life,   Raynaud's Pain,   Respiratory Tract Infection,  Restless Leg Syndrome,   Rheumatoid Arthritis,   Rickets,  Sarcopenia,  Sepsis,  Short Neonates,  Sickle Cell,  Stronger Senior Muscles,  Survive ICU,  TB,  Trauma Death,  Traumatic Brain Injury,  Tuberculosis,  Ulcerative Colitis,  Urinary Tract Infection,  Vaginosis,  Vertigo,  Warts,  Weight Loss

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Click on underlined items for details

Health Problem Treat
Reduction by Vit DRCT = Randomized Controlled Trial
   * = link to additional RCT
CT = Clinical Trial
149 to 142 mm Hg
HT risk reduced 10X
RCT*  *, 2400 IU.  100,000 IU*
When Vitamin D > 40 ng
Cardiovascular after attack T 32 % fewer deaths CT 1000 IU
Diabetes Type 1 P 85 % 12,000 kids, 2000 IU
Diabetes Type 2T 62 % RCT* CRP reduction, 4000 IU
Injection is far better - RCT *
RCT 50,000 IU/2weeks + probiotics
RCT 5,000 IU daily 6 months
Back Pain T 95 %
reduced 50%
5000/10000 IU
60,000 IU weekly
Influenza P 90 % RCT *, 2000 IU
Falls P 50%RCT, 100,000 IU monthly
RCT with Meals on Wheels 2016
Hip Fractures P 30 % RCT * 800 IU
Rickets P 98 % Turkey, 400 IU
NOT RCT, given to all children
Raynaud's Syndrome T 40 % RCT, visual scale, 20000 IU Avg
Menstrual pain P 76 % RCT, 7000 IU Avg,
70% reduction 2018
PMS reduced by half
Pregnancy risks P 50 % RCT, 4000 IU
C-section, unplanned P 50 % RCT, 4000 IU, small study
Low birth weight P 60 % RCT * 1000 IU of D2
TBP 60 % RCT, 800 IU
Breast Cancer P 60 % RCT, 1100 IU (2007)
Rheumatoid Arthritis pain T 40 % RCT, 500 IU, added to prescription
Cystic Fibrosis T 75 %
2nd study improved
RCT, pilot 4X fewer deaths 250,000 IU
RCT, pilot 8,200 IU
Chronic Kidney T 90 to 70 PTH RCT, 3500 IU,
Respiratory Tract Infection P 63 % 3 RCT, 4000 IU 1 year 2nd 2000/800 IU
20,000 IU weekly
Lupus T
zero flares
Pain reduced
Loading then 100,000 IU monthly,
RCT too
RCT 4,000 IU
Sickle Cell T Less pain
RCT, up to 100,000 IU/week
Leg ulcer healing T 4X faster RCT, 50,0000 IU/week, small study
Traumatic Brain Injury T 2X RCT, 20,0000 IU/day with progesterone
Parkinson's DiseaseT StabilizedRCT, 1200 IU/day
Multiple SclerosisP
95% were CURED
RCT, 7100 IU prevent pre-MS ==> MS
20,000 to 140,000 IU/day
Congestive Heart Failure T 90 % RCT, 1000 IU infants (also: Adults, not RCT)
Middle Ear Infection P 30 % RCT, 1000 IU infants
GingivitisT 88 %RCT, 2000 IU
Muscle in seniors T 17 % more muscle RCT, 4000 IU
Antibiotic use when >70y T 47 % RCT, 60,000 IU monthly
Infants tallerBenefit1 cm tall RCT, 50,000 IU weekly,
for 8 weeks while pregnant
Gestational Diabetes T Reduced 3X RCT, 2 doses of 50,000 IU
After Heart Attack T +6% ejection fraction RCT, 800,000 IU one time
Prostate Cancer T Fewer +cores RCT, 4000 IU (2012)
Asthma P   T Reduced symptoms RCT, 60K IU/month;
RCT 50K IU/week
Need good D at 4 weeks into preg.
Depression T Reduced RCT 300,000 IU injection
RCT 1500 IU helped Prozac
RCT 50,000 IU weekly, elderly
Low vitamin D
while breastfed
P All infants > 20 mg RCT, 5,000 IU
Fibromyalgia T Half of many still has FibroRCT, 30-48 ng
RCT 50K IU/week
Hives, Chronic T Reduced 40% RCT, 4000 IU added
CholesterolT Reduced 4 mg RCT, 400 IU + Ca
Weight Loss T lost 5 more lbs RCT, 2000 IU +diet +exercise
Gestational DiabetesP 40% RCT * , 5,000 IU
Chronic Obstructive
Pulmonary Disease
T 17X improvement CT, 50,000 IU weekly
RCT 100,000 IU monthly
Asthma T 1/2 Asthma attacks RCT >42 mg of vitamin D
Quality of Life (QoL) T Nursing Home QoL CT, 4,000 IU in daily bread
Death of Critically Ill
T 20% increase in survivability RCT 540 K IU loading than 90K monthly
Restless Leg Syndrome T Score 26 ==> 10 CT, Vitamin D dose size
not stated in abstract
Hepatitis-C T Aided normal drugs RCT 2.000 IU
Crohn's disease T improved when > 30 ng
2nd study fewer relapses
RCT 2,000 IU
10,000 IU RCT
Pre-term birth P 2.5X decrease, also: fewer
c-section & better Apgar
RCT 2,000 IU India
Cluster headaches T CH eliminated in 60% 10,000 IU, Mg, Omega-3, etc
Autism T 80% improved CT 300 IU/kg/day for 3 months
PreDiabetes T ~20% reduced RCT 60,000 IU/month
Weight loss:
Overweight and Obese
T 12 lbs in 6 months RCT 100,000 IU/month
Sarcopenia = muscle loss T 27% increase RCT 1,000 IU
Growing Pains T 60% decrease ~100,000 IU/month -NOT RCT
2nd study, similar results
Osteoarthritis pain T 60% decrease 50,000 IU/weekly - NOT RCT
ALS T helped 2,000 IU - NOT RCT, given to all
Vertigo T 3X reduction if raised > 10ng 600,000 IU load, then maint.
NOT RCT, given to all
Warts T 80% eliminated injection NOT RCT
60,000 IU/injection
Metabolic Syndrome P reduced 44% when VitD
increased by 30 ng
NOT RCT, given to all
Hay fever P reduced 48% RCT   1,000 IU for 30 days
Preeclampsia P Recurrance cut in half
3 RCT 3.6 X less likely if > 30 ng
50,000 IU every 2 weeks
4,000 IU daily
Blood cell cancer
Multiple Myeloma
T Survival 90% vs 50%10,000 IU/week
NOT RCT, given to all
Irritable Bowel Syndrome T Reduced3,000 IU spray RCT
Urinary Tract Infection P 50% reduction RCT 20,000 IU weekly
Mite Allergy P 5X reductionRCT 2,000 IU preg, 800 IU child
Perinatal depression
(depression near birth)
T 50% reduction RCT 2,000 IU for just a few weeks
Vaginosis T 10X reductionRCT 2,000 IU
Eczema T Reduced2 RCT 1,600 IU
Fatty Liver Disease
T Reduced RCT 20,000 IU weekly
Knee Osteoartiritis T Pain Reduced RCT 60,000 IU monthly after loading dose
Tuberculosis T Faster Recovery RCT single 450,000 IU dose
Stroke - Ischemic T Faster Recovery RCT single 600,000 IU injection
RCT single 300,000 IU injection
Sepsis T Reduce ICU and Hospital
length of stay by 7 days each
RCT 400,000 IU
Trauma deaths T 50% fewer deaths Vitamin D & Glutamine
NOT RCT, given to all
Hemodialysis patients T helped 50,000 IU weekly NOT RCT, given to all
Fatty liver - child T 2 X reduction RCT  Vitamin D & DHA
Fatigue T Reduced 100,000 IU single dose
NOT RCT, given to all
Sleep Disorders T Nicely treated RCT  50.000 IU bi-weekly
T RCT   Death rate cut in half300,000 IU injection
Infertile males T birth rate doubled RCT   300,000 IU + maint
Waist size T Waist size reduced 3 cm 100,000 IU loading + maint for 6 months
for those with Metabolic Syndrome
NOT RCT, given to all
Attention Deficient
Hyperactivity Disorder
T Reduced
RCT  3,000 IU for 12 weeks
RCT  50,000 IU weekly
Alcoholic liver cirrhosis T improved survival1,000 IU of vitamin D NOT RCT
Diabetic nephropathy T Reduced HOMA-IR, FRS RCT 50,000 IU weekly
Ulcerative Colitis T Reduced 60% RCT 50,000 IU nano daily for a week
Obese weight loss T Lost 3X more pounds $10 of Vitamin D added to
  calorie restriction & walking
Endometriosis T Nicely treated RCT  50.000 IU bi-weekly
Diabetic Wounds T 4X more likely to heal RCT  6,400 daily
Alzheimer's T Often reverseEach person gets a different amount of
Vit D, Omega-3, B12, Iron, etc
Autoimmune P Decrease 30% RCT  Vit D + Omega-3
Smoking T reduce problems RCT  50,000 bi-weekly

Most proofs are RCT (Randomized Controlled Trials), where not even the doctor knows who gets it vitamin D

  • 2 are meta-analysis of multiple RCTs
  • Vitamin D was given to ALL infants in the entire country (Rickets) - not an RCT
  • In several studies researchers felt that it was unethical to not give vitamin D to everyone
  • In some studies the dose size varied with the needs of the person (overweight, etc)
  • In some studies the COFACTORS were adjusted with the needs of the patient%
    • Curing requires the dose size and cofactors to be adjusted to the needs of each patient.

Many Clinical Trials have not found a benefit because of one or more of the following failures:

  1. Fails to use a large enough dose of vitamin D (often < 1,100 IU)
    The Even larger dose needed if: 1) obese, 2) poor gut, 3) sick (many diseases consume lots of vitamin D)
  2. Fails to have given vitamin D for a long enough time (a few RCT lasted less than 5 weeks)
  3. Fails to have given Vitamin D frequently enough. At least every 2 months for D3) - and at least weekly for D2
    Note: Infrequent dosing also causes unbalancing of the body's chemistry
  4. Fails to provide a loading dose, or had too short a duration to restore the vitamin D levels
  5. Fails to use D3 form, instead uses the less effective D2 form
  6. Fails to have a healthy range of Calcium or other important cofactors (especially for bone-related trials
    Also, differences in Magnesium can result in 30% change in response to vitamin D
    Magnesium is dependent on water, food, supplements
  7. Fails to notice the pre-existing vitamin D levels - only those who are low will likely show a benefit
  8. Fails to notice how/when the vitamin D was taken (which can change the response by as much as 2X)
  9. Fails to report on compliance (in one case 40% of the participants did not take the supplements consistently)

Many Meta-Analyses also do not find a benefit because one or more of the above failures
In addition, many meta-analysis average together ALL of the trials
Imagine a story about a meta-analysis of aspirin (which has never been done)
   There would be scores of RCT for aspirin not working with 3 mg doses
   There would be a many RCT of aspirin not working with 30 mg doses
   There would be a few studies of aspirin WORKING with 300+ mg doses
   There would be many studies of small amounts of Willow bark (Vitamin D2 instead of Vitamin D3)
   Then there would be a meta-analysis of aspirin and Willow Bark
   - That meta-analysis would conclude that aspirin and Willow bark do not work.

While about 200 RCTs will be published during 2014, I anticipate only adding 50 to the proofs table due to the reasons listed above
   Also, some trials will not get started due to lack of people willing to go for years with < 500 IU of vitamin D

See also VitaminDWiki: Random Controlled Trials with vitamin D  intervention

More intervention trials for Vitamin D than for the TOTAL of Vitamins A + C + K combined

Vitamin D = 2199, Others = 1803 Vitamin A 702 + Vitamin C 768 + Vitamin K 333    as of Aug 2020

See also VitaminDWiki

Less Sun Less D Less Health
CLICK ON chart for more information and translation

Vitamin D is especially needed during pregnancy

0. Chance of not conceiving3.4 times Observe
1. Miscarriage 2.5 times Observe
2. Pre-eclampsia 3.6 timesRCT
3. Gestational Diabetes 3 times RCT
4. Good 2nd trimester sleep quality 3.5 times Observe
5. Premature birth 2 times RCT
6. C-section - unplanned 1.6 timesObserve
     Stillbirth - OMEGA-3 4 timesRCT - Omega-3
7. Depression AFTER pregnancy 1.4 times RCT
8. Small for Gestational Age 1.6 times meta-analysis
9. Infant height, weight, head size
     within normal limits
10. Childhood Wheezing 1.3 times RCT
11. Additional child is Autistic 4 times Intervention
12.Young adult Multiple Sclerosis 1.9 timesObserve
13. Preeclampsia in young adult 3.5 timesRCT
14. Good motor skills @ age 31.4 times Observe
15. Childhood Mite allergy 5 times RCT
16. Childhood Respiratory Tract visits 2.5 times RCT

RCT = Randomized Controlled Trial

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

The risk of 45 diseases at least double with poor Vitamin D Receptor as of Nov 2022

There are 436 items with RCT in the title on VitaminDWiki 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.

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

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).

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.

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 VitaminDWiki

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

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


Founder of VitaminDWiki is a co-author of the paper

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

 Download the PDF from VitaminDWiki

  • "“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

Examples of Vitamin D RCTs which did NOT show a benefit

Attached files

ID Name Comment Uploaded Size Downloads
9086 How to Understand, Refute, and Plan Studies Using Vitamin D-min.pdf PDF 2017 admin 31 Dec, 2017 22:23 1.86 Mb 1007
7980 Randomized controlled trials - who fails run-in.pdf PDF 2016 admin 11 May, 2017 01:02 496.17 Kb 736