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Rapid Normalization of Vitamin D in Critically Ill Children: A Phase II Dose Evaluation Randomized Controlled Trial (VITdAL-PICU)

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ClinicalTrials.gov Identifier: NCT02452762
Recruitment Status : Completed
First Posted : May 25, 2015
Last Update Posted : April 19, 2018
Sponsor:
Information provided by (Responsible Party):
James Dayre McNally, Children's Hospital of Eastern Ontario

Tracking Information
First Submitted Date  ICMJE May 15, 2015
First Posted Date  ICMJE May 25, 2015
Last Update Posted Date April 19, 2018
Actual Study Start Date  ICMJE January 2016
Actual Primary Completion Date November 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 22, 2015)
Vitamin D Status [ Time Frame: 7 days ]
The proportion of critically ill children who achieve a blood 25OHD concentration above 75 nmol/L by day 7
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 22, 2015)
  • Feasibility [ Time Frame: 2 years ]
    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
  • Vitamin D Related Adverse Events [ Time Frame: 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
  • Vitamin D Axis Function - Calcium [ Time Frame: On day 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.
  • Vitamin D Axis Function - 1,25 OHD [ Time Frame: On day 3, 7, hospital discharge (expected average of 2 weeks) ]
    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.
  • Immune Function - Cathelicidin [ Time Frame: On day 3, 7, hospital discharge (expected average of 2 weeks) ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rapid Normalization of Vitamin D in Critically Ill Children: A Phase II Dose Evaluation Randomized Controlled Trial
Official Title  ICMJE Rapid Normalization of Vitamin D in Critically Ill Children: A Phase II Dose Evaluation Randomized Controlled Trial
Brief Summary 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.
Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Hypovitaminosis D
Intervention  ICMJE
  • Drug: Vitamin D3
    Other Name: Cholecalciferol
  • Drug: Placebo
Study Arms  ICMJE
  • Experimental: Enteral Loading Arm
    Vitamin D3 (cholecalciferol) - Single dose at enrolment of 10000 IU/kg of cholecalciferol (max 400000 IU)
    Intervention: Drug: Vitamin D3
  • Placebo Comparator: Placebo Arm
    Patients will receive a placebo solution equivalent in volume to the dose of cholecalciferol administered to patients in the enteral loading arm.
    Intervention: Drug: Placebo
Publications * McNally D, Amrein K, O'Hearn K, Fergusson D, Geier P, Henderson M, Khamessan A, Lawson ML, McIntyre L, Redpath S, Weiler HA, Menon K; Canadian Critical Care Trials Group. Study protocol for a phase II dose evaluation randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study). Pilot Feasibility Stud. 2017 Dec 8;3:70. doi: 10.1186/s40814-017-0214-z. eCollection 2017.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 21, 2017)
67
Original Estimated Enrollment  ICMJE
 (submitted: May 22, 2015)
88
Actual Study Completion Date  ICMJE January 2018
Actual Primary Completion Date November 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Canada,   Chile
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02452762
Other Study ID Numbers  ICMJE VITdAL-PICU-01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party James Dayre McNally, Children's Hospital of Eastern Ontario
Study Sponsor  ICMJE Children's Hospital of Eastern Ontario
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: James D McNally Children's Hospital of Eastern Ontario
Study Chair: Menon Kusum Children's Hospital of Eastern Ontario
Study Chair: McIntyre Lauralyn The Ottawa Hospital
Study Chair: Fergusson Dean The Ottawa Hospital
Study Chair: Amrein Karin Medical University of Graz
PRS Account Children's Hospital of Eastern Ontario
Verification Date April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP