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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Asthma	Dietary Supplement: Vitamin D; Dietary Supplement: Placebo	Phase 3

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 November 30, 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 7 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, de-intensification of preventive asthma therapy, cost effectiveness, and safety profile. A sample of 432 per arm (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 number of exacerbations requiring OCS per child.

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

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	865 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Intervention Model Description:	This is a randomised, quadruble-blind, placebo-controlled, parallel-group multicentre trial of vitamin D3 supplementation.
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:	The manufacturer, Europharm, will provide the active vitamin D3 and placebo preparations, identical in appearance and taste, in coded latex-free bottles. A web-based randomisation system will allow Site pharmacies to login, obtain allocated treatment, prepare the 2 mL bolus in coded syringes and the coded bottles containing the daily dose, and dispense study drugs in masked kits.
Primary Purpose:	Prevention
Official Title:	Vitamin D In the Prevention of Viral-induced Asthma in Preschoolers: a Randomized Controlled Multicenter Trial
Estimated Study Start Date :	September 2018
Estimated Primary Completion Date :	May 2022
Estimated Study Completion Date :	December 2022

Arms and Interventions

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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 Name: 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

Outcome Measures

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Primary Outcome Measures :

1. Number of asthma exacerbations per child treated with rescue oral corticosteroids [ Time Frame: 7 months ]
   Group difference in the mean number of exacerbations treated with rescue oral corticosteroids/child

Secondary Outcome Measures :

1. Laboratory-confirmed respiratory infections [ Time Frame: 7 months ]
   Group difference in mean number of laboratory-confirmed respiratory infections during asthma exacerbations
2. Severity of asthma symptoms during asthma exacerbations [ Time Frame: 7 months ]
   Group difference in the mean severity of asthma symptoms documented on the 'Asthma Flare-up Diary for Young Children'
3. Duration of asthma symptoms during asthma exacerbations [ Time Frame: 7 months ]
   Group difference in the mean duration of asthma symptoms documented on the validated 'Asthma Flare-up Diary for Young Children'
4. Intensity of use of rescue β2-agonists during asthma exacerbations [ Time Frame: 7 months ]
   Group difference in the mean cumulative use of rescue β2-agonists during exacerbations documented on the validated 'Asthma Flare-up Diary for Young Children'
5. Parents' functional status during asthma exacerbations [ Time Frame: 7 months ]
   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'
6. Mean number of ED visits for asthma exacerbations [ Time Frame: 7 months ]
   Group difference in number of ED visits for asthma exacerbations
7. De-intensification of preventive asthma therapy [ Time Frame: 7 months ]
   Group difference in proportion of children with de-intensification of preventive asthma therapy
8. Intervention cost-effectiveness [ Time Frame: 7 months ]
   Cost of intervention vs. cost (family expenses and health care) of exacerbations

Other Outcome Measures:

1. Hypercalciuria [ Time Frame: 7 months ]
   Group difference in the proportion of children with ≥1 occurrence of hypercalciuria (urinary calcium: creatinine greater than 1.25 mmol/mmol for children aged 1-2 yrs, or greater than 1 mmol/mmol for those aged 2-5 yrs)
2. Hypercalcemia [ Time Frame: 7 months ]
   Group difference in the proportion of children with ≥1 occurrence of hypercalcemia
3. Elevated serum 25-hydroxyvitamin D [ Time Frame: 7 months ]
   Group difference in the proportion of children with ≥1 occurrence of elevated serum 25OHD (greater than 250 nmol/L)
4. Adverse Health Events [ Time Frame: 7 months ]
   Group difference in the distribution of adverse health events
5. Gene expression [ Time Frame: 3.5 months ]
   Group difference in the change in gene expression between baseline and 3.5 months
6. Serum and nasal metabolome [ Time Frame: 7 months ]
   Group difference in the change in serum and nasal metabolome over 7 months
7. Distribution of laboratory-confirmed respiratory infections [ Time Frame: 7 months ]
   Group difference in the distribution of laboratory-confirmed respiratory infections
8. Lung function [ Time Frame: 7 months ]
   Group difference in the change from baseline in lung function measured by respiratory resistance or lung clearance index at 7 months
9. Bone remodelling [ Time Frame: 3.5 months ]
   Group difference in the change in markers of bone remodelling
10. Severity of respiratory infection [ Time Frame: 7 months ]
    Group difference in the severity of respiratory infection ascertained on the adapted 'Respiratory Symptoms Questionnaire'

Eligibility Criteria

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Ages Eligible for Study:	1 Year to 5 Years (Child)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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 (pharmacy/medical records)
• ≥4 URTIs in the past 12 months (parental report)
• URTIs as the main asthma trigger (parental report)

Exclusion Criteria:

• Intake or intention to use > 400 IU/day of vitamin D3 supplements
• Extreme prematurity (< 28 week gestation)
• No vitamin D supplementation when breast-fed
• Vitamin D restrictive diets, that is, minimal milk intake
• Recent immigrants from regions at high risk of rickets
• Recent refugees
• Undernourished children
• Other chronic respiratory disease
• Condition(s) or drug(s) that alter calcium or vitamin D absorption or metabolism
• Anticipated difficulty with follow-up

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Francine M Ducharme, MD	514-345-4931 ext 4398	francine.m.ducharme@umontreal.ca
Contact: Ilona Shemyakina, BSc	514-345-4931 Ext. 7243 ext 4053	ilona.shemyakina@umontreal.ca

Locations

Canada, Alberta
Alberta Children's Hospital	Not yet recruiting
Calgary, Alberta, Canada, T3B 6A9
Contact: Mary Noseworthy, MD mary.noseworthy@ahs.ca
Principal Investigator: Mary Noseworthy, MD
Stollery Children's Hospital	Not yet recruiting
Edmonton, Alberta, Canada, T6G 2B7
Contact: Piushkumar Mandhane, MD mandhane@ualberta.ca
Principal Investigator: Piushkumar Mandhane, MD
Canada, British Columbia
British Columbia Children's Hospital	Not yet recruiting
Vancouver, British Columbia, Canada, V6H 3V4
Contact: Connie Yang, MD 1-6048752000 ext 4931 connie.yang@cw.bc.ca
Principal Investigator: Connie Yang, MD
Canada, Ontario
Children's Hospital of London Health Sciences Centre	Not yet recruiting
London, Ontario, Canada, N6A 2V5
Contact: Dirk Bock, MD 1-5196858824 Dirk.Bock@lhsc.on.ca
Principal Investigator: Dirk Bock, MD
Children's Hospital of Eastern Ontario	Not yet recruiting
Ottawa, Ontario, Canada, K1H 8L1
Contact: Dhenuka Radhakrishnan, MD 1-6137377600 ext 2868 dradhakrishnan@cheo.on.ca
Principal Investigator: Dhenuka Radhakrishnan, MD
Hospital for Sick Children	Not yet recruiting
Toronto, Ontario, Canada, M5G 1X8
Contact: Padmaja Subbarao, MD padmaja.subbarao@sickkids.ca
Principal Investigator: Padmaja Subbarao, MD
Canada, Quebec
Montreal Children's Hospital (MCH)	Not yet recruiting
Montreal, Quebec, Canada, H3H 1P3
Contact: Duncan Lejtenyi, MSc 1-5144124400 ext 22369 duncan.lejtenyi@muhc.mcgill.ca
Principal Investigator: Reza Alizadehfar, MD
CHU Sainte Justine
Montreal, Quebec, Canada, H3T1C5
CHU de Québec-Université Laval	Not yet recruiting
Québec, Quebec, Canada, G1V 4G2
Contact: Patrick Daigneault, MD patrick.daigneault@mail.chuq.qc.ca
Principal Investigator: Patrick Daigneault, MD
CHU de Sherbrooke	Not yet recruiting
Sherbrooke, Quebec, Canada, J1G 2E8
Contact: Chantal Lemire, MD Chantal.Lemire@USherbrooke.ca
Principal Investigator: Chantal Lemire, MD

Sponsors and Collaborators

St. Justine's Hospital

Canadian Institutes of Health Research (CIHR)

EURO-PHARM International Canada inc.

Investigators

Principal Investigator:	Francine M Ducharme, MD	Study Principal Investigator

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Professor Francine Ducharme, Pediatrician, St. Justine's Hospital
ClinicalTrials.gov Identifier:	NCT03365687 History of Changes
Other Study ID Numbers:	MP-21-2018-1657
First Posted:	December 7, 2017
Last Update Posted:	December 7, 2017
Last Verified:	December 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Professor Francine Ducharme, St. Justine's Hospital:

Children; Vitamin D; Respiratory viral infection; Randomized controlled trial; Asthma exacerbations

Additional relevant MeSH terms:

Asthma; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases	Vitamins; Vitamin D; Ergocalciferols; Cholecalciferol; Micronutrients; Growth Substances; Physiological Effects of Drugs; Bone Density Conservation Agents