Vitamin D In the Prevention of Viral-induced Asthma in Preschoolers (DIVA)

Vitamin D In the Prevention of Viral-induced Asthma in Preschoolers: a Randomized Controlled Multicenter Trial (DIVA)

In this 7-month randomized controlled trial, children aged 1 to less than 6 years, with recurrent 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, and a daily supplement of vitamin D or a placebo. This study will test whether children in vitamin D group 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: Recruiting
• Conditions: Asthma
• Intervention / Treatment: Dietary supplement: Vitamin D; Dietary supplement: Placebo

Detailed Description

This is a multicenter triple-blind randomized parallel-group, placebo-controlled trial of vitamin D3 supplementation. Children aged 1-5 (<6) years with physician-diagnosed asthma predominantly triggered by upper respiratory tract infection will be screened for enrolment in paediatric asthma, respiratory or allergy clinics and the ED departments and randomized between Sept 1 to January 31, annually (4 recruitment years).

Using a computer-generated random list, stratified by site, children will be allocated (1:1) using permuted block randomisation method to enhance concealment.

Children will be followed for 7 months, with 3 visits every 3.5 months with repeated urine (for calcium:creatinine ratio) and blood samples. In addition, ten (10) days after each bolus, urine will be sampled for urinary calcium:creatinine ratio. In case of elevated urine calcium:creatinine ratio, a blood sample may be needed primarily for markers of calcium metabolism and exploratory outcomes. Only patients enrolled at CHU Sainte-Justine and Montreal Children's Hospital will receive a systematic home visit 10 days after first bolus for both urine and blood samples. There will be 6 follow-up phone calls, at week 1 and then monthly, to inquire about exacerbations and URTIs, remind parents to complete questionnaires and to collect a nasal swab at each exacerbation and screen for adverse events.

The main outcome is the number of courses of rescue oral corticosteroids (OCS) per child during the study period. Several secondary outcomes will be documented using biological samples and validated questionnaires to ascertain laboratory-confirmed respiratory infections, intensity and severity of exacerbations, mean number of ED visits, parents' functional status during exacerbations, de-intensification of preventive asthma therapy, cost effectiveness, and safety profile.

A sample of 432 children (400+7,5% attrition) per arm will provide 80% power with a two-tailed alpha of 5% to detect a 25% relative reduction in the mean number of exacerbations requiring OCS per child.

An intention-to-treat (ITT) analysis will be carried out with all randomised children.

• Study Type: Interventional
• Enrollment (Anticipated): 865
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Francine M Ducharme, MD; Phone Number: 4398 514-345-4931; Email: francine.m.ducharme@umontreal.ca
• Study Contact Backup: Name: Andrea Laszlo; Phone Number: 7243 514-345-4931; Email: andrea.laszlo.hsj@ssss.gouv.qc.ca

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • Recruiting
      • British Columbia Children's Hospital
      • Contact: Connie Yang, MD; Phone Number: 4931 1-6048752000; Email: connie.yang@cw.bc.ca
      • Principal Investigator: Connie Yang, MD
  • Ontario
    • London, Ontario, Canada, N6A 2V5
      • Recruiting
      • Children's Hospital of London Health Sciences Centre
      • Contact: Dirk Bock, MD; Phone Number: 1-5196858824; Email: Dirk.Bock@lhsc.on.ca
      • Principal Investigator: Dirk Bock, MD
    • Ottawa, Ontario, Canada, K1H 8L1
      • Recruiting
      • Children's Hospital of Eastern Ontario
      • Contact: Dhenuka Radhakrishnan, MD; Phone Number: 2868 1-6137377600; Email: dradhakrishnan@cheo.on.ca
      • Principal Investigator: Dhenuka Radhakrishnan, MD
    • Toronto, Ontario, Canada, M5G 1X8
      • Recruiting
      • The Hospital For Sick Children
      • Contact: Lucy Perrem, MD; Phone Number: 328077 416-813-7654; Email: Lucy.Perrem@sickkids.ca
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • Recruiting
      • Montreal Children's Hospital
      • Contact: Reza Alizadehfar, MD; Email: reza.alizadehfar@muhc.mcgill.ca
      • Contact: Duncan Lejtenyi, MSc; Phone Number: 22369 1-514-412-4400; Email: duncan.lejtenyi@muhc.mcgill.ca
      • Principal Investigator: Reza Alizadehfar, MD
    • Montreal, Quebec, Canada, H3T1C5
      • Recruiting
      • CHU Sainte Justine
      • Contact: Sze Man Tse; Phone Number: 54 514-345-4931; Email: sze.man.tse@umontreal.ca
      • Principal Investigator: Sze Man Tse
    • Montreal, Quebec, Canada
      • Recruiting
      • Maisonneuve-Rosemont Hospital
      • Contact: Marc-Andre Turcot, MD; Email: marc-andre.turcot@umontreal.ca
      • Principal Investigator: Marc-Andre Turcot
    • Québec, Quebec, Canada, G1V 4G2
      • Recruiting
      • CHU de Quebec-Universite Laval
      • Contact: Patrick Daigneault, MD; Email: Patrick.Daigneault@mail.chuq.qc.ca
      • Contact: Louise Gosselin; Phone Number: 48290 418-525-4444; Email: louise.gosselin@chudequebec.ca
      • Principal Investigator: Patrick Daigneault, MD
    • Sherbrooke, Quebec, Canada, J1G 2E8
      • Active, not recruiting
      • CHU de Sherbrooke

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 2015 Canadian Position Paper on the diagnosis of preschool asthma)
• ≥1 asthma exacerbation requiring rescue oral corticosteroids (OCS) in the past 6 months or ≥2 in the past 12 months (as documented by pharmacy/medical records)
• ≥4 upper respiratory tract infections (URTIs) in the past 12 months (as per parental report)
• URTIs as the main asthma trigger (as per parental report)

Exclusion Criteria:

• Intake > 400 IU/day of vitamin D3 supplements or fish oil in the past 3 months
• Intention to use > 400 IU/day of vitamin D3 supplements or fish oil in the fall and winter
• Extreme prematurity (< 28 week gestation)
• No vitamin D supplementation (if breast-fed in the last 6 months)
• Vitamin D restrictive diets, that is, minimal intake of vitamin D fortified milk (<250 mL/day for 1-3 years or <375 mL/day for 4-6 years AND no other (or <200 IU/day) vitamin D supplement
• Recent immigrants from regions at high risk of rickets (in the past 12 months)
• Recent refugees (in the past 12 months)
• Undernourished children
• Other chronic respiratory disease (e.g. Cystic fibrosis, Bronchopulmonary dysplasia) or chronic kidney, gastrointestinal, endocrinological or cardiac diseases, or sickle cell anemia?
• History of bone disorder disease (e.g. rickets, osteomalacia)
• Intake of oral anti-epileptic, diuretic or anti-fungal medications
• Anticipated difficulty with follow-up or with adherence to the intervention or the procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Vitamin D; Vitamin D supplement (100,000 IU) orally at baseline and at 3.5 months with daily 400 IU vitamin D for 7 months	Dietary supplement: Vitamin D; 2 mL of 50,000 IU/mL at baseline and at 3.5 months with a daily dose of 1 mL (400 IU/mL) for 7 months; Other Names: Cholecalciferol
Placebo Comparator: Placebo; Placebo orally at baseline and at 3.5 months with daily placebo during 7 months	Dietary supplement: Placebo; 2 mL of placebo at baseline and at 3.5 months with a daily dose of placebo (1 mL) for 7 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of asthma exacerbations per child treated with rescue oral corticosteroids	Group difference in the mean number of exacerbations treated with rescue oral corticosteroids/child	7 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Laboratory-confirmed respiratory infections	Group difference in mean number of laboratory-confirmed respiratory infections during asthma exacerbations	7 months
Severity of asthma symptoms during asthma exacerbations	Group difference in the mean severity of asthma symptoms documented on the 'Asthma Flare-up Diary for Young Children'	7 months
Duration of asthma symptoms during asthma exacerbations	Group difference in the mean duration of asthma symptoms documented on the validated 'Asthma Flare-up Diary for Young Children'	7 months
Intensity of use of rescue β2-agonists during asthma exacerbations	Group difference in the mean cumulative use of rescue β2-agonists during exacerbations documented on the validated 'Asthma Flare-up Diary for Young Children'	7 months
Parents' functional status during asthma exacerbations	Group difference in the mean parents' functional status during exacerbation as documented on the validated 'Effect of a child's asthma flare-up on parents questionnaire'	7 months
Mean number of ED visits for asthma exacerbations	Group difference in mean number of ED visits for asthma exacerbations	7 months
De-intensification of preventive asthma therapy	Group difference in proportion of children with de-intensification of preventive asthma therapy	7 months
Intervention cost-effectiveness	Cost of intervention vs. cost (family expenses and health care) of exacerbations	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 ratio >1.38 mmol/mmol for children aged 1-<2 years, or >1.1 mmol/mmol for children aged 2-<5 years, or >0.77 mmol/mmol for children aged ≥5 years)	7 months
Hypercalcemia	Group difference in the proportion of children with clinically significant hypercalcemia (>2.63 mmol/L)	7 months
Elevated serum 25-hydroxyvitamin D	Group difference in the proportion of children with ≥1 occurrence of elevated serum 25OHD (greater than 250 nmol/L)	7 months
Adverse Health Events	Group difference in the distribution of adverse health events	7 months
Gene expression	Group difference in the change in gene expression levels (between baseline and 3.5 months) in blood peripherical mononuclear cells, adjusted for cell distribution estimated from lymphocyte differentiation in a subset of patients	3.5 months

Collaborators and Investigators

• Sponsor: Professor Francine Ducharme
• Collaborators: Canadian Institutes of Health Research (CIHR); EURO-PHARM International Canada, Inc.
• Investigators: Principal Investigator: Francine M Ducharme, MD, Study Principal Investigator

Publications and helpful links

General Publications

• Jensen ME, Ducharme FM, Alos N, Mailhot G, Masse B, White JH, Sadatsafavi M, Khamessan A, Tse SM, Alizadehfar R, Bock DE, Daigneault P, Lemire C, Yang C, Radhakrishnan D. Vitamin D in the prevention of exacerbations of asthma in preschoolers (DIVA): protocol for a multicentre randomised placebo-controlled triple-blind trial. BMJ Open. 2019 Dec 30;9(12):e033075. doi: 10.1136/bmjopen-2019-033075.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2018
• Primary Completion (Anticipated): July 1, 2025
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: December 3, 2017
• First Submitted That Met QC Criteria: December 3, 2017
• First Posted (Actual): December 7, 2017

Study Record Updates

• Last Update Posted (Actual): January 31, 2023
• Last Update Submitted That Met QC Criteria: January 30, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Vitamin D; Randomized controlled trial; Children; Asthma exacerbations; Respiratory viral infection
• 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: MP-21-2018-1657

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No