|Outcome||Explanation of outcome analysis criteria|
|Vitamin D-related adverse events||
We will evaluate for potential toxicity using two well-accepted surrogate outcome measures:|
• Hypercalcemia—defined as an ionized calcium level above 1.40 mmol/L (children under 8 weeks as > 1.45 mmol/L).
• Hypercalciuria—defined using age-specific norms and thresholds for calcium-creatinine ratios (see Table 4)
We will also evaluate for, and report on, the occurrence of serious adverse events that could potentially be related to vitamin D.
|Vitamin D axis function||Evaluated through an analysis of blood calcium, parathyroid hormone, and 1,25(OH)2D.|
|Immune function||Evaluated through an analysis of inflammatory markers (C-reactive protein, procalcitonin) and antimicrobial peptide levels (cathelicidin).a|
Protocol non-adherence: protocol adherence will be considered successful if (a) major protocol deviations occur with regard to study drug administration or safety procedures in < 20% of enrolled patients.|
Study drop out: a study dropout rate of < 10% will be considered acceptable.
Evaluation of the proposed eligibility criteria: defined as our ability to predict ICU stay longer than 48 h and bloodwork access at 7 days.
Patient accrual rate: defined as the number of patients enrolled over a 2-year period. We will consider the patient accrual rate acceptable if we are able to successfully enroll 67 patients within 2 years.
Ability to maintain blinding: ability to maintain blinding will be considered successful if the frequency of unblinding requests from the clinical care team and from the pharmacy is < 10%.
|Phase III trial outcomes||We will assess potential outcomes for a phase III trial to better inform sample size for subsequent phases of this research program. The phase III trial outcomes that will be assessed are (i) multiorgan dysfunction (PELOD-2 score; days 0, 3, 7, and every 30 days until discharge or 90 days), (ii) readiness for PICU discharge, and (iii) quality of life measure (PedsQL™)|