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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
3/04/2024
Date data sharing statement initially provided
18/09/2019
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: 0.4 ml (~35 IU/µl) of liquid vitamin D supplement orally once per week, total 14000 IU/week (equivalent 2000 IU/day), from 28-34 weeks gestation (inclusive) until delivery.
Infant: 0.2 ml (~21 IU/µl) of liquid vitamin D supplement orally once per week, total 4200 IU/week (equivalent 600 IU/day), from birth until 4 months of age

Reduced dose for infants discharged from hospital with a routine recommendation to take oral vitamin D 400 IU/day:
Infant: 0.14 ml (~21 IU/µl) of liquid vitamin D supplement orally once per week, total of 3000 IU/week (equivalent to 430 IU/day), from birth until 4 months of age.
Maximum possible dose received by infant is 5800 IU/week (830 IU/day). Safe tolerable upper limit for neonates is 7000 IU/week.



Administration of study medication:
Participants will be allocated to weekly supervised administration of study medication. Study staff or midwives, child health nurses and community workers in allocated clinics will be tasked with locating/recalling participants and administering the supervised dose of study medication. Those participants who cannot be located within 3 days of scheduled dose will be considered as having a ‘missed dose’. These participants will move on to the next dose. There will be no catch up dose.
Intervention code [1] 301451 0
Treatment: Drugs
Intervention code [2] 301452 0
Prevention
Comparator / control treatment
Arm 2: Control Group
Mother: 0.4 ml of liquid placebo orally once per week, from 28-34 weeks gestation (inclusive) until delivery.
Infant: 0.2 ml of liquid placebo orally once per week, from birth until 4 months of age.

Administration of study medication:
Participants will be allocated to weekly supervised administration of study medication. Study staff or midwives, child health nurses and community workers in allocated clinics will be tasked with locating/recalling participants and administering the supervised dose of study medication. Those participants who cannot be located within 3 days of scheduled dose will be considered as having a ‘missed dose’. These participants will move on to the next dose. There will be no catch up dose. The active and placebo supplement are both tasteless and identical in appearance and packaging.
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 for vitamin D testing will be collected longitudinally from mothers at baseline and at birth. Circulating vitamin D (25OHD) will be measured from either dried blood spot (DBS) or serum samples using isotope dilution-liquid chromatography-tandem mass spectrometry (gold standard). Vitamin D concentrations from DBS may be adjusted for haematocrit 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 for vitamin D testing will be collected longitudinally from infants at birth, age 4 and 12 months. Circulating vitamin D (25OHD) will be measured from dried blood spot (DBS) or serum samples using isotope dilution-liquid chromatography-tandem mass spectrometry (gold standard). Vitamin D concentrations from DBS may be adjusted for haematocrit 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 measured 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.
Secondary outcome [7] 374954 0
Serum calcium concentration.
Timepoint [7] 374954 0
Serum calcium will be assessed in mothers at baseline (history via routine pathology) then measured directly in mothers after birth (2-14 days) and in infants at age 4 months (3.5-6 months).
Secondary outcome [8] 374955 0
Maternal pertussis vaccine induced antibody concentrations (pertussis toxin, pertactin, fimbriae and/or filamentous haemagluttinin) in serum and breast milk.
Timepoint [8] 374955 0
Maternal serum (less than 14 days post-partum) at birth
Breast milk (less than 14 days post-partum) at birth.
Secondary outcome [9] 374956 0
Breast milk vitamin D concentrations.
Timepoint [9] 374956 0
At birth (less than 14 days post partum)
Secondary outcome [10] 374957 0
Salivary IgA,
Timepoint [10] 374957 0
At birth (less than 14 days post partum).
Secondary outcome [11] 374958 0
Salivary antibodies IgA
Timepoint [11] 374958 0
At infant age 4 months (end of supplementation)
Secondary outcome [12] 374959 0
Salivary Cathelicidin.
Timepoint [12] 374959 0
At birth (less than 14 days post partum; end of maternal supplementation).
Secondary outcome [13] 374960 0
Salivary Cathelicidin.
Timepoint [13] 374960 0
At infants age 4 months (end of infant supplementation)
Secondary outcome [14] 374961 0
Salivary IgG
Timepoint [14] 374961 0
At infant age 4 months (end of supplementation)
Secondary outcome [15] 374962 0
Salivary IgG
Timepoint [15] 374962 0
At birth (less than 14 days post partum).

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
Eligibility will include:
• Dichorionic Diamniotic (DCDA) twin pregnancies (two amniotic sacs, two or shared placentas)
• Previously enrolled mothers
Minimum age
0 Years
Maximum age
40 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Mother
1. Enrolled in other studies that may influence the outcomes of this study
2. Taking prescribed vitamin D in pregnancy >400 IU/day (or equivalent)
3. Self-supplementing with vitamin D >400 IU/day (or equivalent) and not willing to cease
4. Hypercalcaemia this pregnancy (serum calcium >2.8 mmol/L or a urinary calcium:creatinine ratio >1 on two occasions)
5. Uncontrolled thyroid disorders influencing parathyroid hormone
6. Chronic kidney disease (greater than or equal to stage 4)
7. Known anaphylactic allergies
8. Current drug use this pregnancy (excluding marijuana and alcohol)
9. History of or current kidney/bladder stones
10. Monohorionic Diamniotic (MCDA) twins (one placenta, two amniotic sacs)

Clinician approval to commence study medicine will be sought for:
11. History >2 preterm births <34 weeks gestation
12. Low risk Dichorionic Diamniotic (DCDA) twins (two amniotic sacs, two or shared placentas)
13. Other high risk pregnancies

Infant
Clinician approval to commence study medicine will be sought for those:
1. Born <36 weeks
2. Admitted to intensive or special care units
4. With a congenital anomaly

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

Primary analysis of primary outcome:
Will compare the acute respiratory infection rate (episodes/child/12 months) between supplemented and unsupplemented infants. Primary analysis will be intention to treat. 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.

Secondary analysis of primary outcome:
Will assess the proportion of children having any acute respiratory illness episode less than 12 months (effects will be presented as risk ratios) using generalised linear model and the time to first acute respiratory infection presentation using Cox regression (effects presented as hazard ratios).

Secondary outcome analyses:
Will compare between study groups differences in the following using the Students t-test:
• Mean serum 25OHD levels at each visit
• Mean breast milk 25OHD levels at birth (within 2 weeks post birth)
• Mean serum calcium levels in mothers at birth and infant at the 4 month visit
• Geometric mean pertussis vaccine IgG concentrations in maternal serum at birth.
• Geometric mean pertussis vaccine antigen induced IgG and IgA concentrations in breast milk at birth (within 2 weeks post birth).
• Geometric mean PCV induced IgG and IgA concentrations in saliva at birth (baseline) and at the 4 month visit (after at least one vaccine dose).

Will compare between study groups differences in the following using the rank-sum test.
• Median immune cell population counts in cord blood at birth and infant blood at the 4 month visit.
• Median circulating cytokine levels in cord blood at birth and infant blood at the 4 month visit.
• Median CBMC challenge induced cytokine levels.
• Median whole blood immune cell challenge induced cytokine levels at the 4 month visit

Subgroup analyses:
Analyses will be done for the following subgroups using the same statistical approach as for the main analysis. Whether there is an interaction between the subgroup and treatment group will be examined in the model. The outcomes acute respiratory infection rate, 25OHD, cytokine and antibody concentrations will all be assessed for the listed subgroups.
• VDBP genotypes (major, minor and heterozygous)
• VDR genotypes (major, minor and heterozygous)
• Other vitamin D metabolism genotypes

The effect of vitamin D on clinical acute respiratory infection subgroups: upper respiratory infection (URI with subcategory of otitis media), lower respiratory infection (LRI with additional subcategories pneumonia, bronchiolitis and wheeze) will be performed as per the methodology for the primary outcome (negative binomial, linear and cox regression models).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
14/01/2019
Actual
5/02/2019
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
31/12/2025
Actual
Sample size
Target
314
Accrual to date
236
Final
Recruitment in Australia
Recruitment state(s)
NT
Recruitment hospital [1] 11097 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [2] 11099 0
Katherine Hospital - Katherine
Recruitment hospital [3] 11100 0
Alice Springs Hospital - Alice Springs
Recruitment postcode(s) [1] 22909 0
0810 - Tiwi
Recruitment postcode(s) [2] 22911 0
0850 - Katherine
Recruitment postcode(s) [3] 22912 0
0870 - Alice Springs
Recruitment postcode(s) [4] 28069 0
0822 - Wadeye
Recruitment postcode(s) [5] 28070 0
0822 - Maningrida
Recruitment postcode(s) [6] 28071 0
0822 - Gunbalanya

Funding & Sponsors
Funding source category [1] 299699 0
Government body
Name [1] 299699 0
NHMRC Project Grant #1138604
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
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
2018-3160

Summary
Brief summary
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
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
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

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Our current ethics approval does not support this.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseRandomised controlled trial of perinatal vitamin D supplementation to prevent early-onset acute respiratory infections among Australian First Nations children: The D-Kids' study protocol.2023https://dx.doi.org/10.1136/bmjresp-2023-001646
N.B. These documents automatically identified may not have been verified by the study sponsor.