Trial Outcomes & Findings for Rapid Normalization of Vitamin D in Critically Ill Children: A Phase II Dose Evaluation Randomized Controlled Trial (NCT NCT02452762)

NCT ID: NCT02452762

Last Updated: 2021-08-13

Results Overview

The percentage of critically ill children who achieve a blood 25OHD concentration above 75 nmol/L by day 7

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 67 participants
• Primary outcome timeframe: 7 days
• Results posted on: 2021-08-13

Participant Flow

Eligible participants were recruited from participating PICUs and one Neonatal Intensive Care Unit (NICU) between January 2016 to August 2017

This study did not involve a wash out or run-in period. The trial intervention initially involved two doses of study drug (placebo or cholecalciferol): i) At time of enrollment, and i) a day 3 dose dependent on the 25(OH)D concentration achieved. However, after randomization of the first 12 patients the intervention was adjusted to a single-dose protocol. Seven children who were enrolled under the two-dose protocol received >1 loading dose of cholecalciferol and were excluded from the analysis.

Participant milestones

Measure	Enteral Loading Arm Vitamin D3 (cholecalciferol) - Single dose at enrolment of 10000 IU/kg of cholecalciferol (max 400000 IU) Vitamin D3	Placebo Arm Patients will receive a placebo solution equivalent in volume to the dose of cholecalciferol administered to patients in the enteral loading arm. Placebo
Overall Study STARTED	45	22
Overall Study COMPLETED	40	19
Overall Study NOT COMPLETED	5	3

Reasons for withdrawal

Measure	Enteral Loading Arm Vitamin D3 (cholecalciferol) - Single dose at enrolment of 10000 IU/kg of cholecalciferol (max 400000 IU) Vitamin D3	Placebo Arm Patients will receive a placebo solution equivalent in volume to the dose of cholecalciferol administered to patients in the enteral loading arm. Placebo
Overall Study Received >1 loading dose of cholecalciferol and analyzed separately	4	3
Overall Study Withdrawal by Subject	1	0

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Measure	Enteral Loading Arm n=40 Participants Vitamin D3 (cholecalciferol) - Single dose at enrolment of 10000 IU/kg of cholecalciferol (max 400000 IU) Vitamin D3	Placebo Arm n=19 Participants Patients will receive a placebo solution equivalent in volume to the dose of cholecalciferol administered to patients in the enteral loading arm. Placebo	Total n=59 Participants Total of all reporting groups
Age, Continuous	13.4 Months n=40 Participants	11.8 Months n=19 Participants	12.8 Months n=59 Participants
Sex: Female, Male Female	16 Participants n=40 Participants	9 Participants n=19 Participants	25 Participants n=59 Participants
Sex: Female, Male Male	24 Participants n=40 Participants	10 Participants n=19 Participants	34 Participants n=59 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Region of Enrollment Canada	33 participants n=40 Participants	16 participants n=19 Participants	49 participants n=59 Participants
Region of Enrollment Austria	1 participants n=40 Participants	1 participants n=19 Participants	2 participants n=59 Participants
Region of Enrollment Chile	6 participants n=40 Participants	2 participants n=19 Participants	8 participants n=59 Participants
Mechanical ventilation required, frequency	32 Participants n=40 Participants	16 Participants n=19 Participants	48 Participants n=59 Participants
Received catecholamines, frequency	20 Participants n=40 Participants	9 Participants n=19 Participants	29 Participants n=59 Participants
ICU type, frequency Pediatric Intensive Care Unit	37 Participants n=40 Participants	17 Participants n=19 Participants	54 Participants n=59 Participants
ICU type, frequency Neonatal Intensive Care Unit	3 Participants n=40 Participants	2 Participants n=19 Participants	5 Participants n=59 Participants
ICU Admission season, frequency Fall	8 Participants n=40 Participants	4 Participants n=19 Participants	12 Participants n=59 Participants
ICU Admission season, frequency Winter	11 Participants n=40 Participants	7 Participants n=19 Participants	18 Participants n=59 Participants
ICU Admission season, frequency Spring	9 Participants n=40 Participants	4 Participants n=19 Participants	13 Participants n=59 Participants
ICU Admission season, frequency Summer	12 Participants n=40 Participants	4 Participants n=19 Participants	16 Participants n=59 Participants

PRIMARY outcome

Timeframe: 7 days

Population: A blood sample for the primary outcome analysis was available for 56 participants, 38 in the treatment arm and 18 in the placebo arm.

The percentage of critically ill children who achieve a blood 25OHD concentration above 75 nmol/L by day 7

Outcome measures

Measure	Enteral Loading Arm n=38 Participants Vitamin D3 (cholecalciferol) - Single dose at enrolment of 10000 IU/kg of cholecalciferol (max 400000 IU) Vitamin D3	Placebo Arm n=18 Participants Patients will receive a placebo solution equivalent in volume to the dose of cholecalciferol administered to patients in the enteral loading arm. Placebo
Vitamin D Status	81.6 Percentage of participants in study arm Interval 66.6 to 90.8	5.6 Percentage of participants in study arm Interval 1.0 to 25.8

SECONDARY outcome

Timeframe: 2 years

Population: The number of patients per enrolled per month per centre

The investigators will determine the feasibility of a subsequent multicentre phase III interventional study through an evaluation of patient accrual rate. The expected patient accrual rate is 88 patients over a 2-year period (2-5 patients per month per centre; low estimate 60 patients (0-2 per month per centre). The study will be considered feasible if the patient accrual rate is achieved

Outcome measures

Measure	Enteral Loading Arm n=67 Participants Vitamin D3 (cholecalciferol) - Single dose at enrolment of 10000 IU/kg of cholecalciferol (max 400000 IU) Vitamin D3	Placebo Arm Patients will receive a placebo solution equivalent in volume to the dose of cholecalciferol administered to patients in the enteral loading arm. Placebo
Patient Accrual Rate	3.35 Number of patients enrolled per month	—

SECONDARY outcome

Timeframe: On days 1, 2, 3, 7, hospital discharge (expected average of 2 weeks)

A measurable difference in clinically significant adverse events between the loading dose and placebo arms in unlikely in a phase II study. Therefore, the investigators will evaluate for potential toxicity using two well accepted surrogate outcome measures: (1) Hypercalcemia - The investigators will define hypercalcemia as an ionized calcium level above 1.40 mmol/L (children under 8 weeks as > 1.45 mmol/l); and (2) Hypercalciuria - Hypercalciuria will be defined as an elevated calcium:creatinine ratio above age-based normal values

Outcome measures

Measure	Enteral Loading Arm n=40 Participants Vitamin D3 (cholecalciferol) - Single dose at enrolment of 10000 IU/kg of cholecalciferol (max 400000 IU) Vitamin D3	Placebo Arm n=19 Participants Patients will receive a placebo solution equivalent in volume to the dose of cholecalciferol administered to patients in the enteral loading arm. Placebo
Vitamin D Related Adverse Events Hypercalcemia	0 Participants	0 Participants
Vitamin D Related Adverse Events Hypdercalciuria	6 Participants	4 Participants
Vitamin D Related Adverse Events No Hypercalcemia or Hypercaliuria	34 Participants	15 Participants

SECONDARY outcome

Timeframe: On day 0, 3, 7, hospital discharge (expected average of 2 weeks)

Improved signalling through the vitamin D axis will be evaluated through an evaluation of blood calcium levels (i.e. calcium metabolism). Calcium levels will be reported as median plus interquartile range and will be compared between the 2 study groups.

Outcome measures

Measure	Enteral Loading Arm n=40 Participants Vitamin D3 (cholecalciferol) - Single dose at enrolment of 10000 IU/kg of cholecalciferol (max 400000 IU) Vitamin D3	Placebo Arm n=19 Participants Patients will receive a placebo solution equivalent in volume to the dose of cholecalciferol administered to patients in the enteral loading arm. Placebo
Vitamin D Axis Function - Calcium Day 3 - Highest ionized calcium concentration	1.21 mmol/mmol Interval 1.15 to 1.29	1.27 mmol/mmol Interval 1.14 to 1.27
Vitamin D Axis Function - Calcium Day 0 - Lowest	1.17 mmol/mmol Interval 1.13 to 1.2	1.18 mmol/mmol Interval 1.14 to 1.23
Vitamin D Axis Function - Calcium Day 0 - Highest	1.22 mmol/mmol Interval 1.17 to 1.28	1.21 mmol/mmol Interval 1.17 to 1.29
Vitamin D Axis Function - Calcium Day 3 - Lowest ionized calcium concentration	1.16 mmol/mmol Interval 1.06 to 1.26	1.12 mmol/mmol Interval 1.09 to 1.18
Vitamin D Axis Function - Calcium Day 7 - Lowest ionized calcium concentration	1.17 mmol/mmol Interval 1.12 to 1.23	1.17 mmol/mmol Interval 1.1 to 1.19
Vitamin D Axis Function - Calcium Day 7 - Highest ionized calcium concentration	1.22 mmol/mmol Interval 1.18 to 1.27	1.18 mmol/mmol Interval 1.17 to 1.3
Vitamin D Axis Function - Calcium Hospital discharge - Lowest ionized calcium concentration	1.24 mmol/mmol Interval 1.18 to 1.32	1.20 mmol/mmol Interval 1.15 to 1.27
Vitamin D Axis Function - Calcium Hospital discharge - Highest ionized calcium concentration	1.26 mmol/mmol Interval 1.18 to 1.32	1.24 mmol/mmol Interval 1.18 to 1.29

SECONDARY outcome

Timeframe: On day 3, 7, hospital discharge (expected average of 2 weeks)

Population: Data was not collected for this outcome. Due to insufficient funding and insufficient blood sample volume after analysis of the primary outcome, we were unable to complete this analysis.

Improved signalling through the vitamin D axis will be evaluated through an evaluation of blood 1,25OHD levels. 1,25 levels will be reported as median plus interquartile range and will be compared between the 2 study groups.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: On day 3, 7, hospital discharge (expected average of 2 weeks)

Population: Data was not collected for this outcome. Due to insufficient funding and insufficient blood sample volume after analysis of the primary outcome, we were unable to complete this analysis.

Immune function will be evaluated through an evaluation of blood cathelicidin levels. Cathelicidin levels will be reported as median plus interquartile range and will be compared between the 2 study groups.

Outcome measures

Outcome data not reported

Adverse Events

Enteral Loading Arm

Serious events: 0 serious events

Other events: 6 other events

Deaths: 3 deaths

Placebo Arm

Serious events: 0 serious events

Other events: 4 other events

Deaths: 2 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Enteral Loading Arm n=40 participants at risk Vitamin D3 (cholecalciferol) - Single dose at enrolment of 10000 IU/kg of cholecalciferol (max 400000 IU) Vitamin D3	Placebo Arm n=19 participants at risk Patients will receive a placebo solution equivalent in volume to the dose of cholecalciferol administered to patients in the enteral loading arm. Placebo
Investigations Nephrocalcinosis	0.00% 0/40 • Participants were monitored for adverse events from the time of study enrollment (administration of the study drug) until 90 days following enrollment. Ionized calcium levels and urine calcium:creatinine ratios from study samples were monitored in real time by the site investigator for hypercalcemia (study days 1, 2, 3, 7 and at hospital discharge) and hypercalciuria (study day 3, 7 and at hospital discharge). Additionally, the 25(OH)D level at Day 7/discharge was reviewed by the study nephrologist	0.00% 0/19 • Participants were monitored for adverse events from the time of study enrollment (administration of the study drug) until 90 days following enrollment. Ionized calcium levels and urine calcium:creatinine ratios from study samples were monitored in real time by the site investigator for hypercalcemia (study days 1, 2, 3, 7 and at hospital discharge) and hypercalciuria (study day 3, 7 and at hospital discharge). Additionally, the 25(OH)D level at Day 7/discharge was reviewed by the study nephrologist
Endocrine disorders Persistent hypercalcemia	0.00% 0/40 • Participants were monitored for adverse events from the time of study enrollment (administration of the study drug) until 90 days following enrollment. Ionized calcium levels and urine calcium:creatinine ratios from study samples were monitored in real time by the site investigator for hypercalcemia (study days 1, 2, 3, 7 and at hospital discharge) and hypercalciuria (study day 3, 7 and at hospital discharge). Additionally, the 25(OH)D level at Day 7/discharge was reviewed by the study nephrologist	0.00% 0/19 • Participants were monitored for adverse events from the time of study enrollment (administration of the study drug) until 90 days following enrollment. Ionized calcium levels and urine calcium:creatinine ratios from study samples were monitored in real time by the site investigator for hypercalcemia (study days 1, 2, 3, 7 and at hospital discharge) and hypercalciuria (study day 3, 7 and at hospital discharge). Additionally, the 25(OH)D level at Day 7/discharge was reviewed by the study nephrologist
Endocrine disorders Persistent hypercalciuria	15.0% 6/40 • Number of events 6 • Participants were monitored for adverse events from the time of study enrollment (administration of the study drug) until 90 days following enrollment. Ionized calcium levels and urine calcium:creatinine ratios from study samples were monitored in real time by the site investigator for hypercalcemia (study days 1, 2, 3, 7 and at hospital discharge) and hypercalciuria (study day 3, 7 and at hospital discharge). Additionally, the 25(OH)D level at Day 7/discharge was reviewed by the study nephrologist	21.1% 4/19 • Number of events 4 • Participants were monitored for adverse events from the time of study enrollment (administration of the study drug) until 90 days following enrollment. Ionized calcium levels and urine calcium:creatinine ratios from study samples were monitored in real time by the site investigator for hypercalcemia (study days 1, 2, 3, 7 and at hospital discharge) and hypercalciuria (study day 3, 7 and at hospital discharge). Additionally, the 25(OH)D level at Day 7/discharge was reviewed by the study nephrologist

Additional Information

James Dayre McNally, Principal Investigator and Pediatric Intensivist

Children's Hospital of Eastern Ontario

Phone: 613-737-7600

Email: dmcnally@cheo.on.ca

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place