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Trial registered on ANZCTR


Registration number
ACTRN12618001174279
Ethics application status
Approved
Date submitted
9/07/2018
Date registered
16/07/2018
Date last updated
12/10/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Vitamin D supplementation to prevent acute respiratory infections among Indigenous children in the Northern Territory: a randomised controlled trial
Scientific title
Vitamin D supplementation to prevent acute respiratory infections among Indigenous children in the Northern Territory: a randomised controlled trial
Secondary ID [1] 295117 0
NHMRC 1138604
Universal Trial Number (UTN)
U1111-1215-1826
Trial acronym
D-Kids
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Respiratory Infection 308199 0
Condition category
Condition code
Respiratory 307236 307236 0 0
Other respiratory disorders / diseases
Inflammatory and Immune System 307237 307237 0 0
Normal development and function of the immune system
Diet and Nutrition 307238 307238 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1:Interventional Group
Mother: 2 drops of 1000IU vitamin D orally once daily, total 2000IU/day, from 28-34 weeks gestation (inclusive) until delivery.
Infant: 1 drop of 600IU oral vitamin D orally once daily, total 600IU/day, from birth until 4 months of age

A study specific mobile phone application will be supplied and downloaded to the participant’s primary mobile device. This application will generate daily alerts to remind participants to take their supplement and gauge adherence via a YES or NO button that must be tapped once that supplement is taken to remove the reminder. This information will link directly to the study database and will be monitored in real time by the study team. Non-adherence of more than 3 days will be followed up by phone or in person by a member of the study team. For those using a paper based diary, regular contact and reminders will be performed by the onsite study staff/community liaison officers or via a suitable electronic media. Study staff will aim to speak with the participant every second week during the active phase of the medication administration (from 34 weeks gestation until the infant age 4 months, inclusive) to check general health and assess the adherence.
Medication labels will include a measuring scale. Volume and weight of medication bottles will be recorded at randomisation and at supplementation end. If a bottle cannot be collected after the supplementation phase a photograph of the bottle will be requested. If no bottle or photo can be retrieved the participant’s verbal account of the medication use will be documented.

Intervention code [1] 301451 0
Treatment: Drugs
Intervention code [2] 301452 0
Prevention
Comparator / control treatment
Arm 2: Control Group
Mother: 2 drops of placebo orally once daily, from 28-34 weeks gestation (inclusive) until delivery.
Infant: 1 drop of placebo orally once daily, from birth until 4 months of age
Placebo composition is medium chain triglyceride oil.

Adherence will be monitored as described above for the intervention.
Control group
Placebo

Outcomes
Primary outcome [1] 306188 0
New Acute Respiratory Infection (ARI) episodes (hospital or primary-care) in the first year of life.

ARI presentations will be identified from medical records (electronic or otherwise). ARI will encompass both lower (LRI) and upper (URI) respiratory infections. LRI diagnosis: documented LRI and/or by the following algorithm: fever (greater than or equal to 38°C), acute cough, tachypnoea (under 2mo: greater than or equal to 60 breaths/minute; 2-12mo: greater than or equal to 50 breaths/minute), abnormal chest exam or radiographic findings or specific treatment with at least 2 days of enteral antibiotics. URI diagnosis: documented URI or signs/symptoms including fever, runny/blocked nose, red/inflamed/sore throat or pharyngitis/laryngitis. International Classification of Diseases coding (ICD-10-AM) J00-J22 and A37-A37.9 recorded in the Northern Territory government hospital discharge dataset will be used to support the hospital medical record audit. Episodes will be monitored from birth until age 12 months and be considered unique if separated by greater than or equal to 14 days. We will include all episodes from birth.
Timepoint [1] 306188 0
From birth until 12 months of age
Secondary outcome [1] 347788 0
Circulating vitamin D levels of mothers.

Capillary blood spots for vitamin D testing will be collected longitudinally from mothers at baseline and at birth. Circulating vitamin D (25OHD) will be measured in the dried blood spot (DBS) samples using isotope dilution-liquid chromatography-tandem mass spectrometry (gold standard). VitD concentrations from DBS may be adjusted due to the higher haematocrit of capillary blood as informed by our validation study.
Timepoint [1] 347788 0
Baseline (28-34 wks gestation) and at birth.
Secondary outcome [2] 347789 0
Vitamin D levels in cord blood.

Cord blood serum for vitamin D testing will be collected at birth. Serum vitamin D (25OHD) will be measured using isotope dilution-liquid chromatography-tandem mass spectrometry (gold standard).
Timepoint [2] 347789 0
Birth.


Secondary outcome [3] 347790 0
Circulating vitamin D levels of infants.

Capillary blood spots for vitamin D testing will be collected longitudinally from infants at birth, age 4 and 12 months. Circulating vitamin D (25OHD) will be measured in the dried blood spot (DBS) samples using isotope dilution-liquid chromatography-tandem mass spectrometry (gold standard). VitD concentrations from DBS may be adjusted due to the higher haematocrit of capillary blood as informed by our validation study.
Timepoint [3] 347790 0
Birth, age 4 months and age 12 months.
Secondary outcome [4] 349412 0
Cord blood immune function.

In cord blood the relative proportions of lymphocyte and monocyte populations, as well as mediators of inflammation (eg IL-1ß, IL-6, IL-8, TNFa) will be measured directly.

In cord blood the immune response of mononuclear cells to challenge with S. pneumoniae (Sp), H. influenzae (Hi) and respiratory syncytial virus (RSV), important respiratory pathogens in the target population, will be measured. Measures will include pro-inflammatory cytokines (IFN-gamma, TNF-a, IL-1ß, IL-6), anti-inflammatory cytokines (IL-4, IL-10, IL-13) and cathelicidin. Cytokines will be measured by immunoassay.
Timepoint [4] 349412 0
Birth
Secondary outcome [5] 349413 0
Infant immune function.

We will measure the response of infant blood mononuclear cells to challenge with S. pneumoniae (Sp), H. influenzae (Hi) and respiratory syncytial virus (RSV), important respiratory pathogens in the target population. Measures will include pro-inflammatory cytokines (IFN-gamma, TNF-a, IL-1ß, IL-6), anti-inflammatory cytokines (IL-4, IL-10, IL-13) and cathelicidin. Cytokines will be measures by immunoassay.
Timepoint [5] 349413 0
Infant age 4 months.
Secondary outcome [6] 349414 0
Prevalence of respiratory pathogens.

Streptococcus Pneumoniae, non-typeable Haemophilus Influenzae and Moraxella Catarrhalis will be isolated and identified from nasopharyngeal swabs using standard microbiological methods. RSV will be detected by PCR.
Timepoint [6] 349414 0
Infants at ages 4 and 12 months.

Eligibility
Key inclusion criteria
Mother
1. Pregnant with current gestation of 28 to 34 weeks, inclusive.
2. Aged over 17 to less than or equal to 40 years at the time of written informed consent
3. Aboriginal and/or Torres Strait Islander descent
4. A resident in urban Darwin, Alice Springs or one of the participating communities at the time of enrolment and intending to stay in a study community until the infants is 12 months of age
Minimum age
0 Years
Maximum age
40 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Mother:
1. History of kidney stones
2. Hypercalcaemia
3. Enrolled in other clinical trials studies that may influence the outcomes of this study
4. Previously enrolled in the D-kids trial
5. Taking health practitioner prescribed vit D
6. Self-supplementing with vit D and not willing to cease
7. Multiple births or high-risk pregnancy as decided by attending clinician; Eg. pre-eclampsia, diabetes)

Infant
1. Born less than or equal to 34 weeks gestation
2. Congenital abnormality
3. Required respiratory support (except low flow O2 for less than 48 hours) that influences future respiratory function

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
A study statistician, not directly involved in the data analysis, will generate the randomisation codes and store them in a secure database. The randomisation list will be computer-generated, using appropriate block sizes and be stratified by community (urban and remote). The allocation ratio within these strata will be 1:1 (vitamin D:placebo). Mothers and their infants will be assigned the same randomisation number to ensure they both receive either an active or placebo supplement.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Eligible pregnant women will be randomised 1:1. Randomisation will be stratified by community (urban and remote). To ensure an even distribution, computer randomised permuted blocks will be used. Allocation will be via pre-randomised, sequentially coded supplement label numbers which will be assigned to the appropriate medication bottle. Therefore the allocation sequence will be concealed from all investigators, research staff and study participants until completion of the study
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
We aim to recruit 440 mother-infant pairs, randomised 1:1 into each group. This sample size provides greater than 90% power to detect an 11% absolute reduction in any (vs none) Acute Respiratory Infection episodes (from 95% in controls to 84% in supplemented), 90% power to detect small between group differences in vitamin D and cytokine levels and 80% power to detect a 29% reduction in individual pathogen prevalence at age 4 months assuming 50% prevalence in controls.

The primary outcome will compare the Acute Respiratory Infection rate (episodes per child over the 12 months ) between supplemented and unsupplemented infants. This will be done with a negative binomial regression model producing an estimate of the incidence rate ratio (IRR; with 95% CI). Supplementation efficacy will be defined as (1-IRR) x 100. Additionally we will assess the proportion of children having any Acute Respiratory Infection episode less than 12 months (effects will be presented as risk ratios) using generalised linear model; time to first Acute Respiratory Infection presentation (Cox regression); and will examine the diagnostic subsets of Acute Respiratory Infection: Lower Respiratory Infection and Upper Respiratory Infection.

Secondary outcome will compare between study groups differences in mean 25OHD levels at each time point using the Student’s t-test and in challenge induced cytokine levels in cord blood and infant blood at 4 months using the Wilcoxon rank-sum test.

Vitamin D receptor (VDR) and vitamin D binding protein (VDBP) genotypes will be determined using real-time PCR followed by high resolution melt analysis. The relationship between infant VDBP and VDR genotypes (major, minor and heterozygous) and the study outcomes (ARI rate, 25OHD and cytokine concentrations) will be analysed using appropriate regression models.


Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NT
Recruitment hospital [1] 11097 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [2] 11098 0
Gove District Hospital - Nhulunbuy
Recruitment hospital [3] 11099 0
Katherine Hospital - Katherine
Recruitment hospital [4] 11100 0
Alice Springs Hospital - Alice Springs
Recruitment postcode(s) [1] 22909 0
0810 - Tiwi
Recruitment postcode(s) [2] 22910 0
0880 - Nhulunbuy
Recruitment postcode(s) [3] 22911 0
0850 - Katherine
Recruitment postcode(s) [4] 22912 0
0870 - Alice Springs

Funding & Sponsors
Funding source category [1] 299699 0
Government body
Name [1] 299699 0
NHMRC Project Grant #1138604
Address [1] 299699 0
GPO Box 1421
Canberra
ACT
2601
Country [1] 299699 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Menzies School of Health Research
Address
PO Box 41096
Casuarina
NT
0811
Country
Australia
Secondary sponsor category [1] 299039 0
None
Name [1] 299039 0
Address [1] 299039 0
Country [1] 299039 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300599 0
Human Research Ethics Committee of Northern Territory Department of Health and Menzies School of Health Research (EC00153)
Ethics committee address [1] 300599 0
John Matthews Building (BLDG 58)
Royal Darwin Hospital Campus
Rocklands Drive
Casuarina
NT
0810
Ethics committee country [1] 300599 0
Australia
Date submitted for ethics approval [1] 300599 0
06/06/2018
Approval date [1] 300599 0
03/10/2018
Ethics approval number [1] 300599 0
2018-3202

Summary
Brief summary
A double-blind (allocation concealed) randomised controlled trial conducted among Indigenous mother-infant pairs in the Northern Territory. To determine whether daily vitamin D supplementation (compared to placebo) given to mothers (between 28 to 34 weeks gestation (inclusive) until birth) and their infants (birth until age 4 months) reduces the incidence of acute respiratory infection (hospitalisations or primary care presentations) in the infants first 12 months of life.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 84170 0
Dr Michael Binks
Address 84170 0
Menzies School of Health Research
PO Box 41096
Casuarina
NT 0811
Country 84170 0
Australia
Phone 84170 0
+61 8 8946 8508
Fax 84170 0
Email 84170 0
michael.binks@menzies.edu.au
Contact person for public queries
Name 84171 0
Dr Michael Binks
Address 84171 0
Menzies School of Health Research
PO Box 41096
Casuarina
NT 0811
Country 84171 0
Australia
Phone 84171 0
+61 8 8946 8508
Fax 84171 0
Email 84171 0
michael.binks@menzies.edu.au
Contact person for scientific queries
Name 84172 0
Dr Michael Binks
Address 84172 0
Menzies School of Health Research
PO Box 41096
Casuarina
NT 0811
Country 84172 0
Australia
Phone 84172 0
+61 8 8946 8508
Fax 84172 0
Email 84172 0
michael.binks@menzies.edu.au

No information has been provided regarding IPD availability
Summary results
No Results