Rapid Vitamin D Supplementation for Vitamin D Deficiency

(VITdALIZE-KIDS Trial)

Recruiting in Palo Alto (17 mi)

+9 other locations

Overseen by Dayre McNally, MD, PhD

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Waitlist Available

Sponsor: Children's Hospital of Eastern Ontario

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

Vitamin D plays an important role in calcium balance, heart and lung health, inflammation, infection prevention, and muscle strength. Due to these roles, it has been suggested that critically ill patients with low vitamin D levels might have higher rates of death and worse long-term health. We believe that identifying critically ill children with vitamin D deficiency and then restoring vitamin D levels quickly could represent a safe, easy and inexpensive means of reducing patient illness, preventing death and improving quality of life. This clinical trial will determine whether rapid normalization of vitamin D deficiency improves survival and health-related quality of life following critical illness. The VITdALIZE-KIDS trial is a multicentre randomized clinical trial in Canadian Pediatric Intensive Care Units (PICUs). Critically ill children who agree to participate (consent given by caregivers) will have their blood vitamin D level measured, and those who are vitamin D deficient will be randomized to receive a single dose of either high-dose vitamin D3 or placebo (no drug). Study participants assigned to the high-dose vitamin D arm will receive 10,000 IU/kg of enteral cholecalciferol (up to a maximum of 400,000 IU). We have tested this dose in a pilot trial, and no patient experienced serious adverse events related to vitamin D administration. Patients will be followed for 90 days to determine whether they survived and had a significant change in their health and quality of life. Vitamin D deficiency is a common problem not only among critically ill Canadian children, but in PICUs worldwide. In addition to being applicable in Canada, our study protocol was designed to be generalizable and meaningful to critically ill children worldwide.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on digoxin-therapy or thiazide diuretics with high calcium supplementation, you may not be eligible to participate.

What data supports the idea that Rapid Vitamin D Supplementation for Vitamin D Deficiency is an effective treatment?

The available research shows that Rapid Vitamin D Supplementation, specifically using vitamin D3, can effectively improve vitamin D levels in people who are deficient. One study found that taking a daily dose of vitamin D3 helped improve vitamin D status in participants. This suggests that the treatment is effective in addressing vitamin D deficiency. However, the research also highlights that many studies have not been designed well enough to show clear benefits, which means more research is needed to fully understand its effectiveness. ^{1 2 3 4 5}

What safety data exists for rapid vitamin D supplementation?

Several studies have evaluated the safety of vitamin D supplementation under different regimens. A study on children compared monthly versus daily vitamin D3 administration and assessed safety. Another study investigated the safety of high-dose cholecalciferol (300,000 IU) in adults, addressing concerns about high-dose safety. A pilot study on healthy volunteers using 2000 IU/day of cholecalciferol found it safe over a month. Additionally, a study on school children evaluated the safety of a single monthly dose of cholecalciferol. Overall, these studies suggest that various dosing regimens of vitamin D3, including high doses, are generally safe. ^{6 7 8 9 10}

Is Cholecalciferol a promising drug for treating Vitamin D deficiency?

Yes, Cholecalciferol, also known as Vitamin D3, is a promising drug for treating Vitamin D deficiency. Studies show that it effectively increases Vitamin D levels in the body, which is important for bone health and other bodily functions. It can quickly raise Vitamin D levels, making it a beneficial option for those with low Vitamin D. ^{5 8 9 11 12}

Research Team

Dayre McNally, MD, PhD

Principal Investigator

Children's Hospital of Eastern Ontario

Eligibility Criteria

This trial is for critically ill children in Canadian PICUs, aged from 37 weeks corrected gestational age to 18 years old, who have a confirmed vitamin D deficiency. It's not suitable for those expected to leave the PICU within three days of enrollment or with certain medical conditions like severe liver failure, hypercalcemia, or allergies to vitamin D.

Inclusion Criteria

I am between 37 weeks of corrected gestational age and 18 years old.

I am currently admitted to the Pediatric Intensive Care Unit.

Vitamin D deficiency, as defined by blood 25OHD < 50 nmol/L at the time of screening

Exclusion Criteria

I have severe liver failure.

Previous enrollment in this trial

Persistent hypercalcemia (ionized calcium >1.40 mmol/L (age >2 months), >1.45 (age <2 months) excluding transient abnormalities and those related to parenteral calcium administration for hypocalcemia

Treatment Details

Interventions

• Cholecalciferol (Vitamin Supplement)
• Placebo (Other)

Trial Overview The study tests if high-dose Vitamin D3 (cholecalciferol) can improve survival and quality of life in vitamin D deficient critically ill children compared to a placebo. Participants will receive either one dose of Vitamin D3 up to 400,000 IU or no drug and be monitored for health changes over 90 days.

Participant Groups

Group I: Vitamin D Experimental Treatment 1 Intervention

Approximately half of the subjects randomized into VITdALIZE-KIDS will be randomized into the Vitamin D Group and will receive a single dose of cholecalciferol at enrolment. Participants may also receive standard vitamin D dosing at the discretion of the care team (e.g. 400-1000 IU/day).

Group II: Placebo Placebo Group 1 Intervention

Approximately half of the subjects randomized into VITdALIZE-KIDS will be randomized into the Placebo Group and will receive a single dose of placebo at enrolment. Participants may also receive standard vitamin D dosing at the discretion of the care team (e.g. 400-1000 IU/day).

Cholecalciferol is already approved in Canada, Japan, China, Switzerland for the following indications:

Approved in Canada as Vitamin D3 for:

• Prevention and treatment of vitamin D deficiency
• Osteoporosis prevention
• Rickets prevention

Approved in Japan as Cholecalciferol for:

• Prevention and treatment of vitamin D deficiency
• Osteoporosis prevention
• Rickets prevention

Approved in China as Vitamin D3 for:

• Prevention and treatment of vitamin D deficiency
• Osteoporosis prevention
• Rickets prevention

Approved in Switzerland as Cholecalciferol for:

• Prevention and treatment of vitamin D deficiency
• Osteoporosis prevention
• Rickets prevention

Who Is Running the Clinical Trial?

Children's Hospital of Eastern Ontario

Lead Sponsor

Trials

134

Recruited

61,000+

Dr. Vera Etches

Children's Hospital of Eastern Ontario

Chief Executive Officer

MD from the University of Western Ontario

Dr. Carrol Pitters

Children's Hospital of Eastern Ontario

Chief Medical Officer since 2010

MD from the University of the West Indies

EURO-PHARM International Canada, Inc.

Collaborator

Trials

2

Recruited

750+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Dr. Paul C. Hébert

Canadian Institutes of Health Research (CIHR)

Chief Executive Officer

MD, University of Ottawa

Dr. Paul C. Hébert

Canadian Institutes of Health Research (CIHR)

Chief Medical Officer

MD, University of Ottawa

Canadian Critical Care Trials Group

Collaborator

Trials

32

Recruited

227,000+

Findings from Research

In a study involving 100 patients with mild to moderate vitamin D deficiency, those treated with cholecalciferol (vitamin D3) showed significant short-term improvement in fibromyalgia assessment scores compared to the placebo group.

However, severely deficient patients did not experience symptom improvement after treatment, indicating that while vitamin D supplementation may help some, it may not be effective for all levels of deficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlation of symptoms with vitamin D deficiency and symptom response to cholecalciferol treatment: a randomized controlled trial. Arvold, DS., Odean, MJ., Dornfeld, MP., et al.[2022]

Daily supplementation of 200 mL of milk fortified with 240 IU of vitamin D2 significantly increased serum 25(OH)D levels in children compared to plain milk, indicating some efficacy in improving vitamin D status.

Despite the increase, the fortified milk did not raise serum 25(OH)D levels to sufficient levels for many children, highlighting that the dosage may be inadequate for addressing vitamin D deficiency in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Daily Supplementation of Milk Fortified With Vitamin D2 for Three Months in Healthy School Children: A Randomized Placebo Controlled Trial. Marwaha, RK., Dabas, A., Puri, S., et al.[2021]

In a study using mice, inducing a state of 25-hydroxyvitamin D deficiency did not affect the vulnerability of dopaminergic neurons to the neurotoxin MPTP, suggesting that low vitamin D levels may not increase the risk of neuronal damage in this model of Parkinson's disease.

The research showed no significant differences in dopamine levels or key protein expressions related to dopamine production between vitamin D-deficient and control mice after exposure to the neurotoxin, indicating that 25(OH)D deficiency may not play a critical role in the neurodegenerative processes associated with Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

25-Hydroxyvitamin D depletion does not exacerbate MPTP-induced dopamine neuron damage in mice. Dean, ED., Mexas, LM., Cápiro, NL., et al.[2021]

A daily oral dose of 20 μg of vitamin D3 significantly improved vitamin D status in participants, with serum 25(OH)D3 levels increasing from 38 nmol/L at baseline to 73 nmol/L after 12 weeks, indicating effective supplementation.

94% of participants receiving vitamin D3 reached sufficient levels of 25(OH)D3 (≥50 nmol/L), demonstrating the efficacy of this dosage in addressing vitamin D deficiency, especially during winter months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vitamin D3 supplementation: Response and predictors of vitamin D3 metabolites - A randomized controlled trial. Lehmann, U., Riedel, A., Hirche, F., et al.[2017]

Many randomized controlled trials (RCTs) on vitamin D have not confirmed health benefits seen in observational studies, likely due to inappropriate study designs that do not account for the non-linear relationships between vitamin D levels and health outcomes.

The authors suggest a new hybrid observational approach for vitamin D RCTs that focuses on individual serum 25-hydroxyvitamin D (25(OH)D) levels, emphasizing the need to measure and adjust vitamin D supplementation based on these levels to better assess health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations. Grant, WB., Boucher, BJ., Bhattoa, HP., et al.[2022]

In a study of 192 children with vitamin D deficiency, monthly administration of vitamin D3 (25,000 IU every 4 weeks) significantly increased serum vitamin D levels compared to daily dosing (1,000 IU), with 78.1% of the monthly group achieving sufficient levels above 20 ng/mL.

The monthly regimen was found to be safe, with no cases of hypercalcemia reported, suggesting that it may enhance compliance and be an effective alternative for treating vitamin D deficiency in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monthly versus daily administration of vitamin D3 in children: a retrospective propensity score-matched study. Choi, J., Choe, Y., Yang, S.[2023]

A single oral dose of 300,000 IU of cholecalciferol or two consecutive doses totaling 600,000 IU can significantly raise vitamin D levels in patients with deficiencies, with nearly all participants achieving levels above 20 ng/mL within one week.

The study, involving 160 inpatients with varying degrees of vitamin D deficiency, found no signs of toxicity from high-dose supplementation, suggesting it is a safe and effective strategy for addressing vitamin D deficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of single or consecutive double high-dose oral cholecalciferol supplementation in adult patients with vitamin D deficiency. Yilmaz, R.[2023]

In a study involving 40 healthy participants, both vitamin D2 and D3, when consumed at low doses (5 or 10 μg/d), significantly increased serum levels of their respective metabolites (25-OH-D2 and 25-OH-D3) over a 4-week period with minimal UV-B exposure.

The results indicated that vitamin D2 and D3 are equally effective in raising serum 25-hydroxy-vitamin D levels, suggesting that either form can be used to improve vitamin D status in individuals with low UV-B exposure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fortified malted milk drinks containing low-dose ergocalciferol and cholecalciferol do not differ in their capacity to raise serum 25-hydroxyvitamin D concentrations in healthy men and women not exposed to UV-B. Fisk, CM., Theobald, HE., Sanders, TA.[2018]

In a pilot study of 21 healthy volunteers taking 2000 IU/day of Vitamin D (VD) for one month, 95% had insufficient VD levels at the start, but this dropped to 62% after supplementation, indicating significant improvement in VD status.

The study found that plasma VD levels increased by a median of 3.09 ng/mL after 7 days and 8.85 ng/mL after 28 days, suggesting that ongoing supplementation is necessary to achieve optimal VD levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monthly Increase in Vitamin D Levels upon Supplementation with 2000 IU/Day in Healthy Volunteers: Result from "Integriamoci", a Pilot Pharmacokinetic Study. Avataneo, V., Palermiti, A., De Nicolò, A., et al.[2022]

A single monthly dose of 60,000 IU of cholecalciferol (vitamin D) significantly increased serum 25-hydroxyvitamin D levels in healthy school children from an average of 12.04 ng/mL to 32.6 ng/mL over 12 months (p<0.001).

The supplementation was found to be safe, as none of the 118 children developed hypercalcemia, indicating that this regimen is both effective and safe for achieving vitamin D sufficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of a single monthly dose of cholecalciferol in healthy school children. Kuchay, MS., Jevalikar, GS., Mithal, A., et al.[2018]

A study of 306 patients treated with ergocalciferol (vitamin D2) showed that regimens providing over 600,000 IU were most effective, achieving vitamin D sufficiency in 64% of cases without causing toxicity.

Common regimens like 50,000 IU weekly or monthly increased vitamin D levels significantly, but only 38% to 82% of patients reached sufficiency, highlighting the need for better treatment guidelines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of vitamin D repletion regimens to correct vitamin D status in adults. Pepper, KJ., Judd, SE., Nanes, MS., et al.[2021]

A study involving 53 healthy young adults found that a new soft capsule formulation of vitamin D3 (100,000 IU) significantly increased serum 25-hydroxyvitamin D levels compared to a traditional oral solution, demonstrating a superior pharmacokinetic profile.

The soft capsule formulation not only reached higher peak levels of vitamin D3 more quickly but also maintained serum levels between 20 and 30 ng/mL for four months, indicating its potential effectiveness in addressing vitamin D deficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of a New Pharmaceutical Form of Vitamin D3 100,000 IU in Soft Capsule. Mentaverri, R., Souberbielle, JC., Brami, G., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

Correlation of symptoms with vitamin D deficiency and symptom response to cholecalciferol treatment: a randomized controlled trial. [2022]

2. India pubmed.ncbi.nlm.nih.gov

Efficacy of Daily Supplementation of Milk Fortified With Vitamin D2 for Three Months in Healthy School Children: A Randomized Placebo Controlled Trial. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

25-Hydroxyvitamin D depletion does not exacerbate MPTP-induced dopamine neuron damage in mice. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Vitamin D3 supplementation: Response and predictors of vitamin D3 metabolites - A randomized controlled trial. [2017]

5. England pubmed.ncbi.nlm.nih.gov

Why vitamin D clinical trials should be based on 25-hydroxyvitamin D concentrations. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Monthly versus daily administration of vitamin D3 in children: a retrospective propensity score-matched study. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of single or consecutive double high-dose oral cholecalciferol supplementation in adult patients with vitamin D deficiency. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Fortified malted milk drinks containing low-dose ergocalciferol and cholecalciferol do not differ in their capacity to raise serum 25-hydroxyvitamin D concentrations in healthy men and women not exposed to UV-B. [2018]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Monthly Increase in Vitamin D Levels upon Supplementation with 2000 IU/Day in Healthy Volunteers: Result from "Integriamoci", a Pilot Pharmacokinetic Study. [2022]

10. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and safety of a single monthly dose of cholecalciferol in healthy school children. [2018]

11. United States pubmed.ncbi.nlm.nih.gov

Evaluation of vitamin D repletion regimens to correct vitamin D status in adults. [2021]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of a New Pharmaceutical Form of Vitamin D3 100,000 IU in Soft Capsule. [2020]