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| Name | Class |
|---|---|
| The Hospital for Sick Children | OTHER |
| Centre de recherche du Centre hospitalier universitaire de Sherbrooke | OTHER |
| Montreal Children's Hospital of the MUHC | OTHER |
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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo | Placebo Comparator | 2 ml identical placebo taken by mouth at baseline and 3.5 months. |
|
| Vitamin D | Experimental | Vitamin D (100,000IU) given in a 2 ml oral dose at baseline and 3.5months. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| vitamin D | Dietary Supplement | Two doses of cholecalciferol 100,000 unit (2 mL) given 3.5 months apart, once in the fall, once in the winter |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Serum 25OHD | Group difference in the adjusted change from baseline 25OHD over 7 months | During the 7-month follow-up period |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Total 25OHD ≥75 Nmol/L | Group difference in the number of participants with total 25OHD ≥75 nmol/L | at 3.5 and 7 months |
| Emergency Department Visit for an Asthma Flare-up |
| Measure | Description | Time Frame |
|---|---|---|
| Hypercalciuria | Group difference in the number of participants 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) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Francine M Ducharme, MD | St. Justine's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| CHU Sainte Justine | Montreal | Quebec | H3T1C5 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30777118 | Result | 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. | |
| 33305842 | Derived | 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. |
| Label | URL |
|---|---|
| article | View source |
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo | Two doses of identical placebo (2 mL) given 3.5 months part, once in the fall, once in the winter |
| FG001 | Vitamin D | Two doses of cholecalciferol 100,000 unit (2 mL) given 3.5 months apart, once in the fall, once in the winter |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Two doses of identical placebo (2 mL) given 3.5 months part, once in the fall, once in the winter |
| BG001 | Vitamin D | Two doses of cholecalciferol 100,000 unit (2 mL) given 3.5 months apart, once in the fall, once in the winter |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline in Serum 25OHD | Group difference in the adjusted change from baseline 25OHD over 7 months | Posted | Mean | 95% Confidence Interval | nmol/L | During the 7-month follow-up period |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo | 2 ml identical placebo taken by mouth at baseline and 3.5 months. placebo: Two doses of identical placebo (2 mL) given 3.5 months part, once in the fall, once in the winter |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| peribronchitis | Respiratory, thoracic and mediastinal disorders | requin hospitalisation |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| General (SOC) | General disorders | System Organ Class | Systematic Assessment | Includes: FEVER, FATIGUE, PAIN IN BOTH LEGS, PAIN LEFT HAND, TOOTHACHE, SLEEP DISORDER |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr Francine Ducharme | StJustineH | 5143454931 | 4398 | Francine.m.ducharme@umontreal.ca |
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| ID | Term |
|---|---|
| D001249 | Asthma |
| D014777 | Virus Diseases |
| ID | Term |
|---|---|
| D001982 | Bronchial Diseases |
| D012140 | Respiratory Tract Diseases |
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
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| ID | Term |
|---|---|
| D014807 | Vitamin D |
| D002762 | Cholecalciferol |
| ID | Term |
|---|---|
| D012632 | Secosteroids |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
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| British Columbia Children's Hospital |
| OTHER |
| London Health Sciences Centre | OTHER |
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identical placebo
| placebo | Dietary Supplement | Two doses of identical placebo (2 mL) given 3.5 months part, once in the fall, once in the winter |
|
Group difference in the number of emergency department visits for asthma per child
| During the 7-month follow-up period |
Number of Participants with ≥1 occurrence of elevated serum 25OHD (greater than 225 nmol/L) |
| At any point during the 7-month follow-up period |
| Perturbation of the Calcium Homeostasis | Number of participants with ≥1 occurrence of a clinically significant 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 |
| Number of URTIs (Verbal Report) | Adjusted Incidence proportion of URTIs (the event rate per child occurring during the 7-month follow up period) | 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 reported in the ADYC diary. | During the 7-month follow-up period |
| Rescue β2-agonist Use During an Asthma Flare-up (Standardized Over 7 Days) | Group difference in the cumulative daily use of rescue β2-agonist use, standardized over 1 week, as documented by parents on the 'Asthma Flare-up Diary for Young CHildren' (ADYCs) during a URTI or an asthma exacerbation. A cumulative number of inhalations documented in ADYC were divided by the number of days of asthma exacerbation and multiplied by 7 days. Albuterol doses received during acute care visits and hospital admissions were not considered. | During the 7-month follow-up period |
| Severity of Asthma Symptoms During an Asthma Flare-up (Cumulative Daily Score Standardized Over 7 Days) | 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 where best =1, worst = 7 on each day during asthma flare-up. Since the flare-up typically lasts several days, the cumulative daily score, standarized over 7 days (total possible scale range: 7-49), may increase due to severity or due to the duration of the event. Lower scores indicate lowest severity, higher score indicate longer or higher severity of symptoms. | During an URTI or flare-up during the 7-month follow-up period |
| Duration of Asthma Symptoms During a Flare-up (by Diary) | 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 |
| Number of Asthma Exacerbations/Child | The number of asthma exacerbations requiring rescue oral corticosteroids per child | 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' (ECAP) questionnaire (best =7, worst = 1) | During an URTI or flare-up during the 7-month follow-up period |
| Caregivers' Workday Lost (in Days Per Flare-up) | Mean group difference in the caregivers' number of workdays lost per exacerbation, reported in number of days per flare-up | During an URTI or flare-up during the 7-month follow-up period |
| Percent of Participants With at Least 1 Exacerbation Requiring Rescue Oral Corticosteroids | The percentage of participants with ≥1 reported asthma exacerbations requiring rescue oral corticosteroids | During the 7-month follow-up period |
| Duration of Asthma Symptoms During a Flare-up (Verbal Report) | Group difference in the duration of asthma symptoms by verbal report. | During an URTI or flare-up during the 7-month follow-up period |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Vitamin D intake IU/day -Median (25%, 75%) | Median | Inter-Quartile Range | IU/day |
|
| Serum vitamin D <75 nmol/L - n (%) | Count of Participants | Participants |
|
| Units | Counts |
|---|---|
| Participants |
|
|
| Secondary | Number of Participants With Total 25OHD ≥75 Nmol/L | Group difference in the number of participants with total 25OHD ≥75 nmol/L | The numbers of participants analyzed in Placebo and Vitamin D groups were 23 and 19 at 3.5 months time point, and 22 and 18 at 7 months time point. | Posted | Count of Participants | Participants | at 3.5 and 7 months |
|
|
|
| Secondary | Emergency Department Visit for an Asthma Flare-up | Group difference in the number of emergency department visits for asthma per child | The numbers of participants analyzed were 24 in Placebo and 23 in Vitamine D groups. | Posted | Mean | 95% Confidence Interval | visits/child | During the 7-month follow-up period |
|
|
|
| Other Pre-specified | Hypercalciuria | Group difference in the number of participants 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) | Posted | Count of Participants | Participants | At any point during the 7-month follow-up period |
|
|
|
| Other Pre-specified | Elevated Serum 25-hydroxyvitamin D (25OHD) | Number of Participants with ≥1 occurrence of elevated serum 25OHD (greater than 225 nmol/L) | Posted | Count of Participants | Participants | At any point during the 7-month follow-up period |
|
|
|
| Other Pre-specified | Perturbation of the Calcium Homeostasis | Number of participants with ≥1 occurrence of a clinically significant perturbation of the calcium homeostasis (serum Ca, Ph, Alkaline phosphatase), defined as outside normal laboratory values | Posted | Count of Participants | Participants | At any point during the 7-month follow-up period |
|
|
|
| Other Pre-specified | Number of URTIs (Verbal Report) | Adjusted Incidence proportion of URTIs (the event rate per child occurring during the 7-month follow up period) | Posted | Mean | 95% Confidence Interval | number of URTI/child | During the 7-month follow-up period |
|
|
|
| Other Pre-specified | Viral Upper Respiratory Tract Infections (URTI) | Group difference in the number of reported viral upper respiratory tract infections reported in the ADYC diary. | Posted | Mean | 95% Confidence Interval | Viral URTI/child | During the 7-month follow-up period |
|
|
|
| Other Pre-specified | Rescue β2-agonist Use During an Asthma Flare-up (Standardized Over 7 Days) | Group difference in the cumulative daily use of rescue β2-agonist use, standardized over 1 week, as documented by parents on the 'Asthma Flare-up Diary for Young CHildren' (ADYCs) during a URTI or an asthma exacerbation. A cumulative number of inhalations documented in ADYC were divided by the number of days of asthma exacerbation and multiplied by 7 days. Albuterol doses received during acute care visits and hospital admissions were not considered. | Posted | Mean | 95% Confidence Interval | cumulative number of puffs standardized | During the 7-month follow-up period |
|
|
|
| Other Pre-specified | Severity of Asthma Symptoms During an Asthma Flare-up (Cumulative Daily Score Standardized Over 7 Days) | 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 where best =1, worst = 7 on each day during asthma flare-up. Since the flare-up typically lasts several days, the cumulative daily score, standarized over 7 days (total possible scale range: 7-49), may increase due to severity or due to the duration of the event. Lower scores indicate lowest severity, higher score indicate longer or higher severity of symptoms. | Posted | Mean | 95% Confidence Interval | score on a ADYC scale | During an URTI or flare-up during the 7-month follow-up period |
|
|
|
| Other Pre-specified | Duration of Asthma Symptoms During a Flare-up (by Diary) | Group difference in the duration of asthma symptoms documented on the 'Asthma FLare-up DIary for Young Children' questionnaire | Posted | Mean | 95% Confidence Interval | days/exacerbation | During an URTI or flare-up during the 7-month follow-up period |
|
|
|
| Other Pre-specified | Number of Asthma Exacerbations/Child | The number of asthma exacerbations requiring rescue oral corticosteroids per child | Posted | Mean | 95% Confidence Interval | Courses of oral steroids/child | During the 7-month follow-up period |
|
|
|
| Other Pre-specified | 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' (ECAP) questionnaire (best =7, worst = 1) | Posted | Mean | 95% Confidence Interval | Score of a scale | During an URTI or flare-up during the 7-month follow-up period |
|
|
|
| Other Pre-specified | Caregivers' Workday Lost (in Days Per Flare-up) | Mean group difference in the caregivers' number of workdays lost per exacerbation, reported in number of days per flare-up | Posted | Mean | 95% Confidence Interval | days per flare-up | During an URTI or flare-up during the 7-month follow-up period |
|
|
|
| Other Pre-specified | Percent of Participants With at Least 1 Exacerbation Requiring Rescue Oral Corticosteroids | The percentage of participants with ≥1 reported asthma exacerbations requiring rescue oral corticosteroids | Posted | Number | percentage of participants | During the 7-month follow-up period |
|
|
|
| Other Pre-specified | Duration of Asthma Symptoms During a Flare-up (Verbal Report) | Group difference in the duration of asthma symptoms by verbal report. | Posted | Mean | 95% Confidence Interval | days/exacerbation | During an URTI or flare-up during the 7-month follow-up period |
|
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|
| 0 |
| 24 |
| 1 |
| 24 |
| 17 |
| 24 |
| EG001 | Vitamin D | Vitamin D (100,000IU) given in a 2 ml oral dose at baseline and 3.5months. vitamin D: Two doses of cholecalciferol 100,000 unit (2 mL) given 3.5 months apart, once in the fall, once in the winter | 0 | 23 | 0 | 23 | 19 | 23 |
|
| infections and infestations (SOC) | Infections and infestations | System Organ Class | Systematic Assessment | Includes: OTITIS, PNEUMONIA, PHARYNGITIS, GASTROENTERITIS, STREPTOCOCCUS PHARYNGITIS, SINUSITIS, CONJONCTIVITIS etc. |
|
| Respiratory (SOC) | Respiratory, thoracic and mediastinal disorders | System Organ Class | Includes: BRONCHITIS/BRONCHIOLITIS, COUGH, ADENOID HYPERTROPHY, CHRONIC RHINITIS, SNEEZING |
|
| Blood and lymphatic system disorders (SOC) | Blood and lymphatic system disorders | System Organ Class | Systematic Assessment | Includes: HETEROZYGOTIE AC, ANEMIA, EPISTAXIS, SPLENOMEGALY |
|
| Ear and labyrinth disorders (SOC) | Ear and labyrinth disorders | System Organ Class | Systematic Assessment | Includes: Otalgia , Ruptured tympanic membrane |
|
| Eye disorders (SOC) | Eye disorders | System Organ Class | Strabism |
|
| Gastrointestinal disorders (SOC) | Gastrointestinal disorders | System Organ Class | Includes: VOMITING, CONSTIPATION, DIARRHEA, RECTAL PROLAPSUS |
|
| Immune system disorders (SOC) | Immune system disorders | System Organ Class | Allergy |
|
| Investigations (SOC) | Investigations | System Organ Class | Includes: ELEVATED CA:CR RATIO, INCREASE BLOOD PHOSPHORUS, LOW ALP, INCREASE IN BLOOD CALCIUM |
|
| Musculoskeletal disorders (SOC) | Musculoskeletal and connective tissue disorders | System Organ Class | PULLED ELBOW |
|
| Nervous system disorder (SOC) | Nervous system disorders | System Organ Class | Includes: SEIZURE, PERVASIVE DEVELOPMENT DISORDERS |
|
| Reproductive system (SOC) | Reproductive system and breast disorders | System Organ Class | PHIMOSIS |
|
| Skin and subcutaneous tissue disorders (SOC) | Skin and subcutaneous tissue disorders | System Organ Class | Includes: RASH/ERYTHEMA, ECZEMA, GIANOTTI CROSTI SYNDROME, LÉSIONS |
|
| Surgical and medical procedures (SOC) | Surgical and medical procedures | System Organ Class | Includes: FACE TRAUMA TEETH EXTRACTION, MYRINGOTOMY AND TUBE PLACEMENT |
|
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| D012130 |
| Respiratory Hypersensitivity |
| D006969 | Hypersensitivity, Immediate |
| D006967 | Hypersensitivity |
| D007154 | Immune System Diseases |
| D007239 | Infections |
| D002782 |
| Cholestenes |
| D002776 | Cholestanes |
| D013261 | Sterols |
| D008563 | Membrane Lipids |
| D008055 | Lipids |
| at 7 months |
|
|