Vitamin D in Preschoolers With Viral-induced Asthma (DIVA)

Vitamin D In the Prevention of Viral-induced Asthma of Preschoolers: a Randomised Controlled Trial (RCT)- (DIVA)

In this 7-month randomized controlled trial, children aged 1-6 years with asthma attacks triggered mostly by colds, will receive a high dose of vitamin D or a placebo every 3.5 months during their usual clinic visit. This study will test whether children receiving a high dose of vitamin D have less frequent and less severe asthma exacerbations compared with those receiving placebo.The study will also document the safety profile of this strategy.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Dietary supplement: placebo; Dietary supplement: vitamin D

Detailed Description

IMPORTANT NOTE: Due to receiving a 2-year partial funding enabling only a single-centre pilot trial, rather than an adequately-powered multicentre study, the primary outcome was modified post hoc for the overall change from baseline in total serum 25OHD during the study as well as at 3.5 and 7 months, similar to our previous pilot study.(NCT01999907) Post hoc secondary outcomes included the group difference in the proportion of children with total 25OHD ≥75 nmol/L at 3.5 and 7 months and in the rate of oral corticosteroid courses per child. Other a priory specified outcomes included the proportion of children with hypercalciuria (Ca:Cr) >1.25 (1-2 years), >1 (2-5 years) nmol/nmol at any point in time; proportion of children with ≥1 exacerbation requiring rescue oral steroids (former primary outcome); number of emergency department (ED) visits; intensity and duration of asthma symptoms and cumulative use of rescue ß2-agonist use, documented on Asthma Flare-up Diary for Young Children (ADYC); the impact of parents' functional status during exacerbations ascertained on the Effect of a child's asthma flare-up on parents; and duration of URTI.

Based on this analysis of this new post-hoc primary outcome, we have changed the intervention and the primary outcome and obtained funding for a new large multicentre study NCT03365687. it is thus important to share the results of this current trial with other investigators

PRIOR REPORTED DESCRIPTION Design: A multicenter triple-blind randomized parallel-group, placebo-controlled trial of vitamin D3 supplementation. Children aged 1-5 years with (i) physician-diagnosed asthma, predominantly triggered by upper respiratory tract infections (URTIs), (ii) ≥4 reported URTIs in the past year, and (iii) ≥1 exacerbation requiring OCS (a recognised marker of moderate and severe exacerbations) in the past 6 months or ≥2 in the past 12 months, will be randomly allocated to one of two treatments in blocks of 4-6, stratified on recruitment site: Intervention group (n=432)-100,000 IU oral vitamin D3; control group (n=432)-identical placebo, for 2 oral doses, 3.5 months apart. Co-intervention with asthma therapy (preventive or pre-emptive ICS) will be left to the discretion of the physician and documented. Children will be followed every 3.5 months as per usual practice, with a home visit 10 days after each bolus, during which urine and blood will be sampled for urinary calcium:creatinine ratio, serum vitamin D, markers of calcium metabolism, and mechanistic exploration. A validated diary will serve to document the intensity and severity of exacerbations. In two sites, preschool lung function will be documented (if ≥ 3yrs). Outcomes: Primary endpoint-number of exacerbations requiring rescue oral corticosteroids (OCS) per child, documented by medical and pharmacy records. Secondary outcomes: duration and severity of exacerbations (symptoms & β2-agonist use, by diary; emergency visits, by medical records), parental functional status (by validated instrument), asthma therapy intensification and health care and direct costs (by health records & parent reports). Safety, mechanistic, exploratory outcomes: hypercalciuria, calcium metabolism, excess vitamin D, change in serum gene expression at 10 days (first 25 patients); and change from baseline at 7 months in preschool lung function (2 sites). Based on 3 published RCTs, a sample of 432 per arm (400+7.5% attrition) will provide 80% power (2-tailed alpha of 5%) to detect a 25% reduction in number of exacerbations requiring OCS/child (0.55 vs. 0.4125).

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3T1C5
      • CHU Sainte Justine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 5 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age 1-5 years
• physician-diagnosed asthma as per the Global Initiative for Asthma (GINA) guidelines
• URTIs as the main asthma trigger (parental report)
• ≥4 URTIs in the past 12 months (parental report)
• ≥1 asthma exacerbation requiring rescue oral corticosteroids (OCS) in the past 6 months or ≥2 in the past 12 months

Exclusion Criteria:

• intake or intention to use more than 400 IU/day of vitamin D supplement
• extreme prematurity (<28 weeks gestation)
• infants <12 months of age
• no vitamin D supplementation when breast-fed
• recent (<1 year) immigrants from a region at high risk of rickets
• children with vitamin D restrictive diets e.g. vegans
• other chronic respiratory disease (broncho-pulmonary dysplasia; cystic fibrosis)
• condition(s) that alter calcium or vitamin D metabolism/absorption (hypo/hyperparathyroidism, kidney/liver disease, inflammatory bowel disease)
• medications that interfere with vitamin D metabolism (anti-epileptics, diuretics, antacids, anti-fungal drug)
• vitamin D supplementation >1000 IU/ day in last 3 months
• anticipated difficult follow-up (unable to attend clinic visits; plan to leave the province).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 2 ml identical placebo taken by mouth at baseline and 3.5 months.	Dietary supplement: placebo; Two doses of identical placebo (2 mL) given 3.5 months part, once in the fall, once in the winter
Active Comparator: Vitamin D; Vitamin D (100,000IU) given in a 2 ml oral dose at baseline and 3.5months.	Dietary supplement: vitamin D; Two doses of cholecalciferol 100,000 unit (2 mL) given 3.5 months apart, once in the fall, once in the winter; Other Names: cholecalciferol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in serum 25OHD	Group difference in the adjusted change from baseline 25OHD over time and specifically at 3.5 and 7 months	During the 7-month follow-up period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of children with total 25OHD ≥75 nmol/L	Group difference in the proportion of children with total 25OHD ≥75 nmol/L	at 3.5 and 7 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hypercalciuria	Group difference in the proportion of children with ≥1 occurrence of hypercalciuria (urinary calcium: creatinine greater than 1.25mmol/mmol for children aged 1-2yrs (or greater than 1mmol/mmol for those aged 2-5yrs)	At any point during the 7-month follow-up period
Elevated serum 25-hydroxyvitamin D (25OHD)	Proportion of children with ≥1 occurrence of elevated serum 25OHD (greater than 250nmol/L)	At any point during the 7-month follow-up period
Perturbation of the calcium homeostasis	Proportion of children with ≥1 occurrence of a perturbation of the calcium homeostasis (serum Ca, Ph, Alkaline phosphatase), defined as outside normal laboratory values	At any point during the 7-month follow-up period
RNA expression	Group difference in the change from baseline in RNA expression measured between 0, 10 days, 3.5 months and 7 months post initial dose of Vit D/Placebo	Over the 7 months after the intial dose of Vit D/Placebo
Duration of URTIs	Group difference in the duration of URTI as documented by parents at the end of each episode	During an URTI during the 7-month follow-up period
Viral upper respiratory tract infections (URTI)	Group difference in the number of reported viral upper respiratory tract infections	During the 7-month follow-up period
Emergency department visit for an asthma flare-up	Group difference in the number of emergency department visits for asthma	During the 7-month follow-up period
Rescue β2-agonist use during an asthma flare-up	Group difference in the cumulative daily use of rescue β2-agonist use as documented by parents on the 'Asthma Flare-up Diary for Young CHildren' during a URTI or an asthma exacerbation	During the 7-month follow-up period
Severity of asthma symptoms during an asthma flare-up	Group difference in the severity on the asthma symptoms documented as the sum of daily score on the 'Asthma FLare-up DIary for Young Children' questionnaire	During an URTI or flare-up during the 7-month follow-up period
Duration of asthma symptoms during a flare-up	Group difference in the duration of asthma symptoms documented on the 'Asthma FLare-up DIary for Young Children' questionnaire	During an URTI or flare-up during the 7-month follow-up period
Exacerbations requiring rescue oral corticosteroids	Mean group rate of exacerbations requiring rescue oral corticosteroids/child	During the 7-month follow-up period
Patients with exacerbations requiring rescue oral corticosteroids	Proportion of children with ≥1 exacerbation requiring rescue oral corticosteroids	During the 7-month follow-up period
Impact of exacerbations on caregivers' functional status	Group difference in the caregivers' functional status measured on the 'Effect of a child's asthma flare-up on parents' questionnaire	During an URTI or flare-up during the 7-month follow-up period
Impact of exacerbations on caregivers' workday lost	Group difference in the caregivers' number of workday lost	During an URTI or flare-up during the 7-month follow-up period

Collaborators and Investigators

• Sponsor: St. Justine's Hospital
• Collaborators: The Hospital for Sick Children; Centre de recherche du Centre hospitalier universitaire de Sherbrooke; London Health Sciences Centre; British Columbia Children's Hospital; Montreal Children's Hospital of the MUHC
• Investigators: Principal Investigator: Francine M Ducharme, MD, St. Justine's Hospital

Publications and helpful links

General Publications

• Huey SL, Acharya N, Silver A, Sheni R, Yu EA, Pena-Rosas JP, Mehta S. Effects of oral vitamin D supplementation on linear growth and other health outcomes among children under five years of age. Cochrane Database Syst Rev. 2020 Dec 8;12(12):CD012875. doi: 10.1002/14651858.CD012875.pub2.
• Ducharme FM, Jensen M, Mailhot G, Alos N, White J, Rousseau E, Tse SM, Khamessan A, Vinet B. Impact of two oral doses of 100,000 IU of vitamin D3 in preschoolers with viral-induced asthma: a pilot randomised controlled trial. Trials. 2019 Feb 18;20(1):138. doi: 10.1186/s13063-019-3184-z.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): July 1, 2016
• Study Completion (Actual): July 1, 2016

Study Registration Dates

• First Submitted: July 18, 2014
• First Submitted That Met QC Criteria: July 22, 2014
• First Posted (Estimate): July 23, 2014

Study Record Updates

• Last Update Posted (Actual): June 21, 2018
• Last Update Submitted That Met QC Criteria: June 19, 2018
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: pediatric; asthma; RCT; corticosteroid; virus
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: DIVA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED