Rapid Normalization of Vitamin D in Critically Ill Children: A Phase II Dose Evaluation Randomized Controlled Trial

Documented roles for vitamin D in calcium homeostasis, cardiovascular and respiratory health, inflammation, innate immunity, and neuromuscular function have led to the hypothesis that deficiency might represent a modifiable risk factor for outcomes in critical illness. In recent years, dozens of adult studies have reported both high deficiency rates, and associations between lower vitamin D levels and organ dysfunction, health resource utilization, and mortality in the intensive care unit (ICU). More recently, similar observations have been made in critically ill pediatric populations. The cumulative body of basic science and clinical literature demonstrates that deficiency is common in critical illness and rapid normalization of vitamin D status could improve clinical outcomes and/or reduce health care costs. However, before conducting a phase III trial to determine whether restoration of vitamin D status improves outcomes in the PICU, the appropriate dosing regimen must be identified. Consequently, the investigators propose a phase II, double blind randomized controlled trial to determine a loading therapy dosing regimen that can safely and rapidly normalize vitamin D status in critically ill children.

Background \& Rationale: Documented roles for vitamin D in calcium homeostasis, cardiovascular and respiratory health, inflammation, innate immunity, and neuromuscular function have led to the hypothesis that deficiency might represent a modifiable risk factor for outcomes in critical illness. In recent years, dozens of adult studies have reported both high deficiency rates, and associations between lower vitamin D levels and organ dysfunction, health resource utilization, and mortality in the intensive care unit (ICU). More recently, similar observations have been made in critically ill pediatric populations. The cumulative body of basic science and clinical literature demonstrates that deficiency is common in critical illness and rapid normalization of vitamin D status could improve clinical outcomes and/or reduce health care costs. However, before conducting a phase III trial to determine whether restoration of vitamin D status improves outcomes in the PICU, the appropriate dosing regimen must be identified. Consequently, the investigators propose a phase II, double blind randomized controlled trial to determine a loading therapy dosing regimen that can safely and rapidly normalize vitamin D status in critically ill children.

Objectives:

Primary Objective: Determine whether a weight-based loading protocol can rapidly normalize blood vitamin D levels in critically ill children Secondary Objectives: (1) Evaluate whether a weight-based loading protocol, when compared with usual care, results in a greater occurrence of vitamin D related adverse events (hypercalcemia, hypercalciuria); and (2) determine the barriers to and feasibility of a multicenter phase III randomized control trial evaluating whether rapid vitamin D normalization improves clinical outcome and/or reduces health care spending in critically ill children.

Eligibility Criteria: The inclusion criteria for this study are: (i) Admitted to ICU, (ii) Corrected gestational age \> 37 weeks to age \< 18 years, (iii) Expected ICU admission in excess of 48 hours and expected access for blood work at Day 7 of hospital admission, and (iv) Blood 25(OH)D less than 50 nmol/L (regardless of prior approach to supplementation). Exclusion criteria are: (i) Significant gastrointestinal disorder preventing enteral drug administration (e.g. necrotizing enterocolitis); (ii) Hypercalcemia (excluding transient abnormalities and those related to parenteral calcium administration for hypocalcemia); (iii) Confirmed or suspected William's syndrome; (iv) Patient known to have nephrolithiasis or Nephrocalcinosis; (v) Imminent plan for withdrawal of care or transfer to another ICU; (vi) Physician refusal; (vii) Previous enrollment in the study; (viii) Patient known to have granulomatous disease (tuberculosis or sarcoidosis), (ix) Severe liver dysfunction/liver failure; (x) Patient know to have hypersensitivity or allergy to vitamin D or any of the non-medicinal ingredients of the formulation; (xi) Patient on thiazide diuretics who is also receiving regular ongoing calcium supplementation above the daily recommended intake (for reasons other than hypocalcemia); (xii) Adolescent female of child-bearing age with a positive serum pregnancy test; or (xiii) Patient on digoxin-therapy

Patients meeting inclusion criteria #1-3 and with no exclusion criteria will be approached regarding participation. If consent is given, 25OHD will be determined and those under 50 nmol/L will be randomized. Participants will be stratified by age in two categories (above 30 days of age or below/equal to 30 days of age). Randomization/allocation concealment will be performed using a web-based randomization system.

Interventions: All participants may also receive standard vitamin D dosing (e.g. 400 IU/day). Sixty-seven patients will be randomized 2:1 to the intervention (Enteral loading arm)

1. Enteral loading arm: 10000 IU/kg of cholecalciferol (max 400000 IU)
2. Placebo arm: For blinding purposes, this arm will receive a placebo solution

Data Collection: Blood and urine will be collected on days 0 (enrolment day), 1, 2, 3, 7, hospital discharge, and after interventions or triggers known to influence vitamin D status (e.g. cardiopulmonary bypass, hospital stay \>30 days). Information on demographics, hospital course, adverse events, and health resource utilization will be entered into an electronic case report form.

Sample Size: Randomization of 40 children into the loading arm will provide sufficient power to estimate the proportion achieving target 25OHD with a confidence interval of ±15%. Assuming a 5% non-compliance/drop-out rate in each arm, randomization of 60 patients (total) may be required to achieve the desired power. The dosing regimen for this study was changed from a double dose to a single dose after the first seven patients were enrolled. As a result, the sample size was increased to 67 patients. All patients (n=67) will be included in the final intention to treat analysis. The 60 patients who received a single dose will be included in the per protocol analysis.

Significance: Critical illness occurs in tens of thousands of children each year in North America and can result in death, significant suffering, prolonged periods of rehabilitation, and chronic illness. High vitamin D deficiency rates in PICUs and the recognized interaction between vitamin D status and the health of multiple organ systems suggest that vitamin D could represent an inexpensive, safe means of improving outcomes and reducing health care spending. Unfortunately, approved daily dosing regimens require months to restore vitamin D levels and there have been no studies of loading therapy in pediatric critical illness. Consequently, despite significant literature suggesting vitamin D deficiency to be a modifiable risk factor, there is no evidence to inform physicians on the true benefits or risks of loading therapy. The proposed phase II clinical trial will determine how to provide cholecalciferol loads to facilitate rapid normalization of vitamin D levels, and provide initial information on toxicity.

Eligibility Criteria:
Inclusion Criteria:

(i) Admitted to ICU; (ii) Corrected gestational age \> 37 weeks to age \< 18 years; (iii) Expected ICU admission in excess of 48 hours and expected access for blood work at Day 7 of hospital admission; (iv) Blood 25OHD less than 50 nmol/L (regardless of prior approach to supplementation)

Exclusion Criteria:

(i) Significant gastrointestinal disorder preventing enteral drug administration (e.g. necrotizing enterocolitis); (ii) Hypercalcemia (excluding transient abnormalities and those related to parenteral calcium administration for hypocalcemia); (iii) Confirmed or suspected William's syndrome; (iv) Patient known to have nephrolithiasis or Nephrocalcinosis; (v) Imminent plan for withdrawal of care or transfer to another ICU; (vi) Physician refusal; (vii) Previous enrollment in the study; (viii) Patient known to have granulomatous disease (tuberculosis or sarcoidosis), (ix) Severe liver dysfunction/liver failure; (x) Patient know to have hypersensitivity or allergy to vitamin D or any of the non-medicinal ingredients of the formulation; (xi) Patient on thiazide diuretics who is also receiving regular ongoing calcium supplementation above the daily recommended intake (for reasons other than hypocalcemia); (xii) Adolescent female of child-bearing age with a positive serum pregnancy test; or (xiii) Patient on digoxin-therapy