Rapid normalization of vitamin D deficiency in PICU (VITdALIZE-KIDS): study protocol for a phase III, multicenter randomized controlled trial.

Humans Double-Blind Method Critical Illness Vitamin D Deficiency / drug therapy Cholecalciferol / administration & dosage Intensive Care Units, Pediatric Child Child, Preschool Multicenter Studies as Topic Vitamin D / analogs & derivatives Infant Adolescent Clinical Trials, Phase III as Topic Canada Pragmatic Clinical Trials as Topic Treatment Outcome Male Female Time Factors Infant, Newborn Biomarkers / blood Quality of Life

Critical care Health-related quality of life Pediatrics Randomized controlled trial Vitamin D Vitamin D deficiency

Journal

Trials

ISSN: 1745-6215

Titre abrégé: Trials

Pays: England

ID NLM: 101263253

Informations de publication

Date de publication:
19 Sep 2024

Historique:

received: 24 04 2024

accepted: 05 09 2024

medline: 20 9 2024

pubmed: 20 9 2024

entrez: 19 9 2024

Statut: epublish

Résumé

The rate of vitamin D deficiency (VDD) in critically ill children worldwide has been estimated at 50%. These children are at risk of multiple organ dysfunction, chronic morbidity, and decreased health related quality of life (HRQL). Pediatric and adult ICU clinical trials suggest that VDD is associated with worse clinical outcomes, although data from supplementation trials are limited and inconclusive. Our group's phase II multicenter dose evaluation pilot study established the efficacy and safety of an enteral weight-based cholecalciferol loading dose to rapidly restore vitamin D levels in critically ill children. Our aim is to evaluate the impact of this dosing regimen on clinical outcomes. VITdALIZE-KIDS is a pragmatic, phase III, multicenter, double-blind RCT aiming to randomize 766 critically ill children from Canadian PICUs. Participants are randomized using a 1:1 scheme to receive a single dose at enrollment of enteral cholecalciferol (10,000 IU/kg, max 400,000 IU) or placebo. Eligibility criteria include critically ill children aged newborn (> 37 weeks corrected gestational age) to < 18 years who have blood total 25-hydroxyvitamin D < 50 nmol/L. The primary objective is to determine if rapid normalization of vitamin D status improves HRQL at 28 days following enrollment. The secondary objective is to evaluate the impact of rapid normalization of vitamin D status on multiple organ dysfunction. The study includes additional tertiary outcomes including functional status, HRQL and mortality at hospital discharge and 90 days, PICU and hospital length of stay, and adverse events related to vitamin D toxicity. Additionally, we are performing comprehensive vitamin D speciation and non-targeted metabolite profiling as part of a sub-study for the first 100 participants from whom an enrollment and at least one post-intervention blood and urine sample were obtained. The VITdALIZE-KIDS trial is the first phase III, multicenter trial to evaluate whether rapid normalization of vitamin D status could represent a simple, inexpensive, and safe means of improving outcomes following pediatric critical illness. Recruitment was initiated in June 2019 and is expected to continue to March 2026. Clinicaltrials.gov, NCT03742505. Study first submitted on November 12, 2018 https://clinicaltrials.gov/study/NCT03742505.

Sections du résumé

BACKGROUND BACKGROUND

METHODS METHODS

Our aim is to evaluate the impact of this dosing regimen on clinical outcomes. VITdALIZE-KIDS is a pragmatic, phase III, multicenter, double-blind RCT aiming to randomize 766 critically ill children from Canadian PICUs. Participants are randomized using a 1:1 scheme to receive a single dose at enrollment of enteral cholecalciferol (10,000 IU/kg, max 400,000 IU) or placebo. Eligibility criteria include critically ill children aged newborn (> 37 weeks corrected gestational age) to < 18 years who have blood total 25-hydroxyvitamin D < 50 nmol/L. The primary objective is to determine if rapid normalization of vitamin D status improves HRQL at 28 days following enrollment. The secondary objective is to evaluate the impact of rapid normalization of vitamin D status on multiple organ dysfunction. The study includes additional tertiary outcomes including functional status, HRQL and mortality at hospital discharge and 90 days, PICU and hospital length of stay, and adverse events related to vitamin D toxicity. Additionally, we are performing comprehensive vitamin D speciation and non-targeted metabolite profiling as part of a sub-study for the first 100 participants from whom an enrollment and at least one post-intervention blood and urine sample were obtained.

DISCUSSION CONCLUSIONS

The VITdALIZE-KIDS trial is the first phase III, multicenter trial to evaluate whether rapid normalization of vitamin D status could represent a simple, inexpensive, and safe means of improving outcomes following pediatric critical illness. Recruitment was initiated in June 2019 and is expected to continue to March 2026.

TRIAL REGISTRATION BACKGROUND

Clinicaltrials.gov, NCT03742505. Study first submitted on November 12, 2018 https://clinicaltrials.gov/study/NCT03742505.

Identifiants

DOI: 10.1186/s13063-024-08461-7 PMID: 39300483

pubmed: 39300483

doi: 10.1186/s13063-024-08461-7

pii: 10.1186/s13063-024-08461-7

doi:

Substances chimiques

Cholecalciferol 1C6V77QF41

Vitamin D 1406-16-2

25-hydroxyvitamin D A288AR3C9H

Biomarkers 0

Banques de données

ClinicalTrials.gov

['NCT03742505']

Types de publication

Journal Article Clinical Trial Protocol

Langues

eng

Sous-ensembles de citation

Pagination

619

Informations de copyright

Références

Pollack MM, Holubkov R, Funai T, et al. Simultaneous prediction of new morbidity, mortality, and survival without new morbidity from pediatric intensive care: a new paradigm for outcomes assessment. Crit Care Med. 2015;43(8):1699.

pubmed: 25985385 pmcid: 4657566 doi: 10.1097/CCM.0000000000001081

Aspesberro F, Mangione-Smith R, Zimmerman JJ. Health-related quality of life following pediatric critical illness. Intensive Care Med. 2015;41(7):1235–46.

pubmed: 25851391 doi: 10.1007/s00134-015-3780-7

Conlon NP, Breatnach C, O’Hare BP, et al. Health-related quality of life after prolonged pediatric intensive care unit stay. Pediatr Crit Care Med. 2009;10(1):41–4.

pubmed: 19057434 doi: 10.1097/PCC.0b013e31819371f6

Pinto NP, Rhinesmith EW, Kim TY, et al. Long-term function after pediatric critical illness: results from the survivor outcomes study. Pediatr Crit Care Med. 2017;18(3):e122–30.

pubmed: 28107265 doi: 10.1097/PCC.0000000000001070

Lee P, Nair P, Eisman JA, et al. Vitamin D deficiency in the intensive care unit: an invisible accomplice to morbidity and mortality? Intensive Care Med. 2009;35(12):2028–32.

pubmed: 19756497 doi: 10.1007/s00134-009-1642-x

Amrein K, Venkatesh B. Vitamin D and the critically ill patient. Curr Opin Clin Nutr Metab Care. 2012;15(2):188–93.

pubmed: 22186356 doi: 10.1097/MCO.0b013e32834f0027

Gauthier B, Trachtman H, Di Carmine F, et al. Hypocalcemia and hypercalcitoninemia in critically ill children. Crit Care Med. 1990;18(11):1215–9.

pubmed: 2225888 doi: 10.1097/00003246-199011000-00005

Baeke F, Gysemans C, Korf H, et al. Vitamin D insufficiency: implications for the immune system. Pediatr Nephrol. 2010;25:1597–606.

pubmed: 20180136 doi: 10.1007/s00467-010-1452-y

Jeng L, Yamshchikov AV, Judd SE, et al. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med. 2009;7:1–9.

doi: 10.1186/1479-5876-7-28

Banwell B, Mildner R, Hassall A, et al. Muscle weakness in critically ill children. Neurology. 2003;61(12):1779–82.

pubmed: 14694046 doi: 10.1212/01.WNL.0000098886.90030.67

Al-Said YA, Al-Rached HS, Al-Qahtani HA, et al. Severe proximal myopathy with remarkable recovery after vitamin D treatment. Can J Neurol Sci. 2009;36(3):336–9.

pubmed: 19534335 doi: 10.1017/S0317167100007083

McNally JD, Menon K, Chakraborty P, et al. The association of vitamin D status with pediatric critical illness. Pediatrics. 2012;130(3):429–36.

pubmed: 22869837 doi: 10.1542/peds.2011-3059

Rippel C, South M, Butt WW, et al. Vitamin D status in critically ill children. Intensive Care Med. 2012;38(12):2055–62.

pubmed: 23052958 doi: 10.1007/s00134-012-2718-6

Cariolou M, Cupp MA, Evangelou E, et al. Importance of vitamin D in acute and critically ill children with subgroup analyses of sepsis and respiratory tract infections: a systematic review and meta-analysis. BMJ Open. 2019;9(5): e027666.

pubmed: 31122993 pmcid: 6538078 doi: 10.1136/bmjopen-2018-027666

He M, Cao T, Wang J, et al. Vitamin D deficiency relation to sepsis, paediatric risk of mortality III score, need for ventilation support, length of hospital stay, and duration of mechanical ventilation in critically ill children: a meta-analysis. Int J Clin Pract. 2021;75(4): e13908.

pubmed: 33280208 doi: 10.1111/ijcp.13908

McNally JD, Nama N, O’Hearn K, et al. Vitamin D deficiency in critically ill children: a systematic review and meta-analysis. Crit Care. 2017;21(1):1–13.

doi: 10.1186/s13054-017-1875-y

McNally JD, Doherty DR, Lawson ML, et al. The relationship between vitamin D status and adrenal insufficiency in critically ill children. J Clin Endocrinol Metab. 2013;98(5):E877–81.

pubmed: 23547046 doi: 10.1210/jc.2013-1126

Abou-Zahr R, Kandil SB. A pediatric critical care perspective on vitamin D. Pediatr Res. 2015;77(1):164–7.

pubmed: 25314583 doi: 10.1038/pr.2014.167

Suzuki AS, Berbel BT. Pediatric multiple organ dysfunction syndrome promising therapies: what about vitamin D supplementation? Pediatr Crit Care Med. 2017;18(7):731.

pubmed: 28691970 doi: 10.1097/PCC.0000000000001202

McNally JD. Vitamin D as a modifiable risk factor in critical illness: questions and answers provided by observational studies. Journal de Pediatria (Rio J). 2014;90(2):99–101.

doi: 10.1016/j.jped.2013.12.002

Lee P. Vitamin D metabolism and deficiency in critical illness. Best Pract Res Clin Endocrinol Metab. 2011;25(5):769–81.

pubmed: 21925077 doi: 10.1016/j.beem.2011.03.001

Higgins DM, Wischmeyer PE, Queensland KM, et al. Relationship of vitamin D deficiency to clinical outcomes in critically ill patients. J Parenter Enter Nutr. 2012;36(6):713–20.

doi: 10.1177/0148607112444449

Menger J, Lee Z-Y, Notz Q, et al. Administration of vitamin D and its metabolites in critically ill adult patients: an updated systematic review with meta-analysis of randomized controlled trials. Crit Care. 2022;26(1):268.

pubmed: 36068584 pmcid: 9446655 doi: 10.1186/s13054-022-04139-1

Hill A, Starchl C, Dresen E, et al. An update of the effects of vitamins D and C in critical illness. Front Med. 2023;9: 1083760.

doi: 10.3389/fmed.2022.1083760

Zajic P, Amrein K. Vitamin D deficiency in the ICU: a systematic review. Minerva Endocrinology. 2014;39(4):275–87.

Kaur M, Soni KD, Trikha A. Does vitamin D improve all-cause mortality in critically ill adults? An updated systematic review and meta-analysis of randomized controlled trials. Indian Journal of Critical Care Medicine: Peer-Reviewed, Official Publication of Indian Society of Critical Care Medicine. 2022;26(7):853.

pubmed: 36864868 doi: 10.5005/jp-journals-10071-24260

Langlois PL, Szwec C, D’Aragon F, et al. Vitamin D supplementation in the critically ill: a systematic review and meta-analysis. Clin Nutr. 2018;37(4):1238–46.

pubmed: 28549527 doi: 10.1016/j.clnu.2017.05.006

Amrein K, Parekh D, Westphal S, et al. Effect of high-dose vitamin D3 on 28-day mortality in adult critically ill patients with severe vitamin D deficiency: a study protocol of a multicentre, placebo-controlled double-blind phase III RCT (the VITDALIZE study). BMJ Open. 2019;9(11): e031083.

pubmed: 31722941 pmcid: 6858186 doi: 10.1136/bmjopen-2019-031083

Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53–8.

pubmed: 21118827 doi: 10.1210/jc.2010-2704

Lewis RD, Laing E, Hill Gallant K, et al. A randomized trial of vitamin D3 supplementation in children: dose-response effects on vitamin D metabolites and calcium absorption. J Clin Endocrinol Metab. 2013;98(12):4816–25.

pubmed: 24092833 pmcid: 3849678 doi: 10.1210/jc.2013-2728

Amrein K, Schnedl C, Holl A, et al. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA. 2014;312(15):1520–30.

pubmed: 25268295 doi: 10.1001/jama.2014.13204

McNally JD, Iliriani K, Pojsupap S, et al. Rapid normalization of vitamin D levels: a meta-analysis. Pediatrics. 2015;135(1):e152–66.

pubmed: 25511115 doi: 10.1542/peds.2014-1703

Gottschlich MM, Mayes T, Khoury J, et al. Clinical trial of vitamin D2 vs D3 supplementation in critically ill pediatric burn patients. J Parenter Enter Nutr. 2017;41(3):412–21.

doi: 10.1177/0148607115587948

O’Hearn K, Menon K, Weiler HA, et al. A phase II dose evaluation pilot feasibility randomized controlled trial of cholecalciferol in critically ill children with vitamin D deficiency (VITdAL-PICU study). BMC Pediatr. 2023;23(1):397.

pubmed: 37580663 pmcid: 10424361 doi: 10.1186/s12887-023-04205-9

Sahu MK, Bipin C, Niraghatam HV, et al. Vitamin D deficiency and its response to supplementation as “stoss therapy” in children with cyanotic congenital heart disease undergoing open heart surgery. Journal of Cardiac Critical Care TSS. 2019;3(01):17–23.

doi: 10.1055/s-0039-1696910

Labib JR, Ibrahem SK, Ismail MM, et al. Vitamin D supplementation and improvement of pneumonic children at a tertiary pediatric hospital in Egypt: a randomized controlled trial. Medicine. 2021;100(13):e25011.

Wang Y, Yang Z, Gao L, et al. Effects of a single dose of vitamin D in septic children: a randomized, double-blinded, controlled trial. J Int Med Res. 2020;48(6):0300060520926890.

pubmed: 32485124 pmcid: 7273772 doi: 10.1177/0300060520926890

El-Gendy FM, Khattab AA, Naser RG, et al. Association between vitamin D deficiency and sepsis in pediatric ICU. Menoufia Medical Journal. 2021;34(1):210.

doi: 10.4103/mmj.mmj_210_19

Merritt C, Menon K, Agus MS, et al. Beyond survival: pediatric critical care interventional trial outcome measure preferences of families and healthcare professionals. Pediatr Crit Care Med. 2018;19(2):e105–11.

pubmed: 29394234 doi: 10.1097/PCC.0000000000001409

Gaudry S, Messika J, Ricard J-D, et al. Patient-important outcomes in randomized controlled trials in critically ill patients: a systematic review. Ann Intensive Care. 2017;7(1):1–11.

doi: 10.1186/s13613-017-0243-z

Varni JW, Burwinkle TM, Seid M, et al. The PedsQL™* 4.0 as a pediatric population health measure: feasibility, reliability, and validity. Ambulatory Pediatrics. 2003;3(6):329–41.

pubmed: 14616041 doi: 10.1367/1539-4409(2003)003<0329:TPAAPP>2.0.CO;2

Aspesberro F, Fesinmeyer MD, Zhou C, et al. Construct validity and responsiveness of the pediatric quality of life inventory 4.0 generic core scales and infant scales in the PICU. Pediatr Crit Care Med. 2016;17(6):e272–9.

pubmed: 27261668 doi: 10.1097/PCC.0000000000000727

Colville GA, Pierce CM. Children’s self-reported quality of life after intensive care treatment. Pediatr Crit Care Med. 2013;14(2):e85–92.

pubmed: 23337805 doi: 10.1097/PCC.0b013e3182712997

Ebrahim S, Singh S, Hutchison JS, et al. Adaptive behavior, functional outcomes, and quality of life outcomes of children requiring urgent ICU admission. Pediatr Crit Care Med. 2013;14(1):10–8.

pubmed: 23132399 doi: 10.1097/PCC.0b013e31825b64b3

Dritsaki M, Achana F, Mason J, et al. Methodological issues surrounding the use of baseline health-related quality of life data to inform trial-based economic evaluations of interventions within emergency and critical care settings: a systematic literature review. Pharmacoeconomics. 2017;35(5):501–15.

pubmed: 28063084 doi: 10.1007/s40273-016-0485-x

Christopher KB. Nutritional metabolomics in critical illness. Curr Opin Clin Nutr Metab Care. 2018;21(2):121.

pubmed: 29251691 pmcid: 5826639 doi: 10.1097/MCO.0000000000000451

Jenkinson C. The vitamin D metabolome: an update on analysis and function. Cell Biochem Funct. 2019;37(6):408–23.

pubmed: 31328813 doi: 10.1002/cbf.3421

Lasky-Su J, Dahlin A, Litonjua AA, et al. Metabolome alterations in severe critical illness and vitamin D status. Crit Care. 2017;21:1–10.

doi: 10.1186/s13054-017-1794-y

Cook D, Lauzier F, Rocha MG, et al. Serious adverse events in academic critical care research. CMAJ. 2008;178(9):1181–4.

pubmed: 18427095 pmcid: 2292790 doi: 10.1503/cmaj.071366

Wyrwich KW, Tierney WM, Wolinsky FD. Further evidence supporting an SEM-based criterion for identifying meaningful intra-individual changes in health-related quality of life. J Clin Epidemiol. 1999;52(9):861–73.

pubmed: 10529027 doi: 10.1016/S0895-4356(99)00071-2

Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure–definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:1–9.

doi: 10.1186/cc2872

Shanmuganathan M, Kroezen Z, Gill B, et al. The maternal serum metabolome by multisegment injection-capillary electrophoresis-mass spectrometry: a high-throughput platform and standardized data workflow for large-scale epidemiological studies. Nat Protoc. 2021;16(4):1966–94.

pubmed: 33674789 doi: 10.1038/s41596-020-00475-0

Kuehnbaum NL, Kormendi A, Britz-McKibbin P. Multisegment injection-capillary electrophoresis-mass spectrometry: a high-throughput platform for metabolomics with high data fidelity. Anal Chem. 2013;85(22):10664–9.

pubmed: 24195601 doi: 10.1021/ac403171u

Ketha H, Thacher TD, Oberhelman SS, et al. Comparison of the effect of daily versus bolus dose maternal vitamin D3 supplementation on the 24, 25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 ratio. Bone. 2018;110:321–5.

pubmed: 29486367 pmcid: 5878742 doi: 10.1016/j.bone.2018.02.024

Helmeczi E, Fries E, Perry L, et al. A high-throughput platform for the rapid screening of vitamin D status by direct infusion-MS/MS. J Lipid Res. 2022;63(5):100204.

pubmed: 35337847 pmcid: 9062421 doi: 10.1016/j.jlr.2022.100204

Griffin G, Hewison M, Hopkin J, et al. Perspective: vitamin D supplementation prevents rickets and acute respiratory infections when given as daily maintenance but not as intermittent bolus: Implications for COVID-19. Clin Med. 2021;21(2): e144.

doi: 10.7861/clinmed.2021-0035

Amrein K, Lasky-Su JA, Dobnig H, et al. Metabolomic basis for response to high dose vitamin D in critical illness. Clin Nutr. 2021;40(4):2053–60.

pubmed: 33087250 doi: 10.1016/j.clnu.2020.09.028

Yamamoto M, Pinto-Sanchez MI, Bercik P, et al. Metabolomics reveals elevated urinary excretion of collagen degradation and epithelial cell turnover products in irritable bowel syndrome patients. Metabolomics. 2019;15:1–18.

doi: 10.1007/s11306-019-1543-0

Orkin AM, Gill PJ, Ghersi D, et al. Guidelines for reporting trial protocols and completed trials modified due to the COVID-19 pandemic and other extenuating circumstances: the CONSERVE 2021 statement. JAMA. 2021;326(3):257–65.

pubmed: 34152382 doi: 10.1001/jama.2021.9941