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A phase II dose evaluation pilot feasibility randomized controlled trial of cholecalciferol in critically ill
Katie O'Hearn1, Kusum Menon1,2, Hope A Weiler3
1Research Institute, Children's Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada.
Insights
A single enteral loading dose of vitamin D safely normalized levels in critically ill children with vitamin D deficiency (VDD). This study supports the feasibility of a larger trial for rapid VDD restoration in pediatric intensive care units.
Area of Science:
- Pediatric Critical Care Medicine
- Nutritional Science
- Clinical Pharmacology
Background:
- Vitamin D deficiency (VDD) is common in pediatric intensive care units (ICUs) and linked to poorer outcomes.
- Adult ICU trials show rapid vitamin D repletion via enteral loading doses is safe and potentially beneficial.
- No prior studies have investigated rapid VDD normalization in critically ill children.
Purpose of the Study:
- To assess the safety and efficacy of a high-dose enteral cholecalciferol loading dose for rapid vitamin D repletion in critically ill children.
- To determine the feasibility of conducting a larger phase III trial based on recruitment rates and data collection.
- To evaluate patient and family priorities for future clinical trial outcomes.
Main Methods:
- A multicenter, placebo-controlled, randomized phase II pilot feasibility trial.
- 67 critically ill children with VDD received either a 10,000 IU/kg enteral cholecalciferol loading dose or placebo.
- Primary endpoint was achieving 25(OH)D > 75 nmol/L; secondary endpoints included safety and feasibility.
Main Results:
- 81.6% of the treatment group achieved target 25(OH)D levels versus 5.6% in the placebo group.
- The mean 25(OH)D level in the treatment arm was 125.9 nmol/L, with no evidence of toxicity.
- The study demonstrated feasibility for a larger trial, with an accrual rate of 3.4 patients/month.
Conclusions:
- A single enteral loading dose of 10,000 IU/kg cholecalciferol can rapidly and safely normalize vitamin D status in critically ill children.
- The feasibility of a phase III multicenter trial was established.
- Future trials should consider strategies to minimize loss to follow-up for outcomes like health-related quality of life.
Background:
Vitamin D deficiency (VDD) is highly prevalent in the pediatric intensive care unit (ICU) and associated with worse clinical course. Trials in adult ICU demonstrate rapid restoration of vitamin D status using an enteral loading dose is safe and may improve outcomes. There have been no published trials of rapid normalization of VDD in the pediatric ICU.
Methods:
We conducted a multicenter placebo-controlled phase II pilot feasibility randomized clinical trial from 2016 to 2017. We randomized 67 critically ill children with VDD from ICUs in Canada, Chile and Austria using a 2:1 randomization ratio to receive a loading dose of enteral cholecalciferol (10,000 IU/kg, maximum of 400,000 IU) or placebo. Participants, care givers, and outcomes assessors were blinded. The primary objective was to determine whether the loading dose normalized vitamin D status (25(OH)D > 75 nmol/L). Secondary objectives were to evaluate for adverse events and assess the feasibility of a phase III trial.
Results:
Of 67 randomized participants, one was withdrawn and seven received more than one dose of cholecalciferol before the protocol was amended to a single loading dose, leaving 59 participants in the primary analyses (40 treatment, 19 placebo). Thirty-one/38 (81.6%) participants in the treatment arm achieved a plasma 25(OH)D concentration > 75 nmol/L versus 1/18 (5.6%) the placebo arm. The mean 25(OH)D concentration in the treatment arm was 125.9 nmol/L (SD 63.4). There was no evidence of vitamin D toxicity and no major drug or safety protocol violations. The accrual rate was 3.4 patients/month, supporting feasibility of a larger trial. A day 7 blood sample was collected for 84% of patients. A survey administered to 40 participating families showed that health-related quality of life (HRQL) was the most important outcome for families for the main trial (30, 75%).
Conclusions:
A single 10,000 IU/kg dose can rapidly and safely normalize plasma 25(OH)D concentrations in critically ill children with VDD, but with significant variability in 25(OH)D concentrations. We established that a phase III multicentre trial is feasible. Using an outcome collected after hospital discharge (HRQL) will require strategies to minimize loss-to-follow-up.
Clinicaltrials:
gov NCT02452762 Registered 25/05/2015.
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