The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Trial ID
ACTRN12613000732785
Ethics application status
Approved
Date submitted
20/06/2013
Date registered
2/07/2013
Date last updated
2/07/2013
Type of registration
Retrospectively registered

Titles & IDs
Public title
The efficacy of vitamin D supplementation in infants on bone mineral content: A double blind randomized controlled trial.
Scientific title
Vitamin D Infant Bone Mineral Content Study
Secondary ID [1] 282715 0
Nil
Universal Trial Number (UTN)
U1111-1144-8142
Trial acronym
Gen-D Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Improving bone health 289432 0
Condition category
Condition code
Musculoskeletal 289762 289762 0 0
Osteoporosis
Public Health 289856 289856 0 0
Other public health

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: cholecalciferol (vitamin D)
Dose: 400 IU/day
Form: liquid - 2 drops containing 200 IU/drop.
mode of administration: Droppler
Duration: 2 years
Measuring compliance: One bottle should last 6 months. At the three month review, the bottle will be weighed and the weight will be recorded by the study nurse in the questionnaire. From the weight, the volume can be calculated. New bottles will be mailed out after 5 months, requesting the mothers to return the near empty bottle and a date when they stopped using one bottle and started a new one. The remaining volume will be measured and compliance can be measured using the starting and end date.
Intervention code [1] 287375 0
Treatment: Drugs
Intervention code [2] 287446 0
Prevention
Comparator / control treatment
Inert placebo
Form: liquid - 2 drops/drop.
mode of administration: Droppler
Duration: 2 years
Control group
Placebo

Outcomes
Primary outcome [1] 289844 0
Whole body bone mineral content (BMC), using dual-energy X-ray absorptiometry (DEXA).
Timepoint [1] 289844 0
Age 2 and age 4 years
Secondary outcome [1] 303371 0
whole body Bone Mineral Density (BMD), using dual-energy X-ray absorptiometry (DEXA).
Timepoint [1] 303371 0
At age 2 and 4 years

Eligibility
Key inclusion criteria
1. Healthy singleton term (>=37 weeks) babies under <1 months of age;
2. Being fully breastfed;
3. 25(OH)D cord blood level 25 - 74 nmol/L;
4. Having a mother who is willing and capable of giving the baby 2 drops of liquid treatment each day;
5. Having a mother who has sufficient English and cognitive ability to understand the study requirements.
Minimum age
0 Weeks
Maximum age
4 Weeks
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Known complications at birth (low birth weight (<2500 g); admission to neonatal intensive care or special care nursery);
2. Infant conditions that interfere with the vitamin D metabolism (cholestatic liver disease, chronic renal insufficiency).

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)
Enrolment: Women will be recruited during pregnancy by their treating obstetrician or midwife. The midwife/obstetrician will provide the women a study brochure and will ask to pass on their contact details to the Study Nurse. The Study Nurse will contact each person, explain more about the study and answer any questions. The Nurse will check about the Recruitment Eligibility Criteria for the mother (intention to prolonged breastfeeding (>6 months), willingness and capable of giving the baby 2 drops of liquid treatment each day, carrying singleton baby, sufficient English and cognitive function to conduct the study, age >=18 years). If the women is eligible and wishes to participate, the Phase 1 Consent Form will be sent out (consent for a cord blood sample at birth and access to their medical records). The vitamin D levels in the cord blood sample will be assessed within a few days to determine eligibility. If the infant fulfils the eligibility criteria, the women will be invited to the Baseline Interview and Phase 2 Consent will be obtained for the full study.

Treatment allocation: Allocation concealment will be ensured by the use of an identical inert placebo, and the use of a automated allocation procedure, with security in place to ensure allocation data cannot be accessed or influenced by any person. An independent person will arrange the treatment allocation. The investigators, staff working on the study, and laboratory staff are blinded from the treatment allocation. Thus the trial will be double blind.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Allocation of participants will be based on computer generated random numbers. For efficiency purposes, randomisation is stratified by cord blood 25(OH)D level (25-49 nmol/L; 50-74 nmol/L), ensuring equal numbers in both strata.
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
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Primary analysis
The primary analysis will be by intention to treat. The primary endpoint is whole body BMC at age 2 and 4 years. Descriptive statistics of baseline characteristics of all recruited subjects will be reported by randomised arm. Linear regression methods will be used to analyse change in the outcome variable after transformation (eg by taking logarithms) to remove skewness. The regression model will include a binary (0/1) covariates for treatment arm. All statistical tests will be performed two-sided, and confidence intervals will be calculated to provide 95% coverage. The statistician will not be blinded to the allocation.

Secondary analyses
- Missing data - The complete-case analysis assumes any loss to follow-up results in data that are missing completely at random. We will investigate the relevance of missing data by repeating the analyses with a filled-in data method and, if appropriate, by using multiple imputation.
- Per protocol analysis - We will perform a sensitivity per-protocol analysis restricted to participants who conformed to their allocated treatment as defined in the study protocols and confirmed by pharmacodynamic analysis.
- We will examine the effect of supplementation on total body BMC separately in vitamin D deficient (25-49 nmol/L) and replete (50-74 nmol/L) children.
- We will examine whether the magnitude of effect of supplementation on health outcomes is higher in infants who have a higher total intake (formula-fed infants).

Sample size
We estimate that a sample size of 138 infants (69 in each arm) would provide 80% power (p=0.05) in the primary analysis to detect the clinically-meaningful effect of a 2.5% increase in whole body BMC per year of treatment, with treatment continuing for two years and the difference sustained until the end of year four. The calculations are based on mean whole body BMC of 76.0g (SD=13.4) for neonates in the first week after birth and 374.5g (SD=46.0) for 4 year old children, and assume a correlation between measurements of r = 0.80. Because of the large difference in the variation of BMC at birth and at age 4 years, we estimated the mean and standard deviation at each time point after first applying a logarithmic transformation to stabilise variance (as would be done in analysis of the results). The means of the log-transformed data are 4.316 (SD=0.175) at birth, and 5.917 (SD=0.123) at age 4 years. We further powered for the scenario that this effect only occurs in those who are vitamin D deficient (50% of the sample), and allowed a drop-out rate of 15%. Tasmanian drop-out rates in RCTs in adults are very low (10%), and the drop-out rate in RCTs in infants after 2 years is <10% (experience CIB). Based on that, we might expect a drop-out of 10% at year 2 and a further 5% at year 4. This means we require 324 infants.

Recruitment
Recruitment status
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)
TAS
Recruitment hospital [1] 1145 0
Royal Hobart Hospital - Hobart
Recruitment hospital [2] 1146 0
Calvary Health Care Tasmania - Hobart - Lenah Valley
Recruitment postcode(s) [1] 6992 0
7000 - Hobart
Recruitment postcode(s) [2] 6993 0
7008 - Lenah Valley

Funding & Sponsors
Funding source category [1] 287485 0
Charities/Societies/Foundations
Name [1] 287485 0
The Marian & E H Flack Trust
Address [1] 287485 0
PO Box 1473, Camberwell East, VIC, 3126
Country [1] 287485 0
Australia
Funding source category [2] 287486 0
Hospital
Name [2] 287486 0
Royal Hobart Hospital Research Foundation
Address [2] 287486 0
Level 5, 25 Argyle Street, Hobart, TAS, 7000
Country [2] 287486 0
Australia
Primary sponsor type
University
Name
University of Tasmania
Address
17 Liverpool Street, Hobart, TAS, 7000
Country
Australia
Secondary sponsor category [1] 286226 0
None
Name [1] 286226 0
Address [1] 286226 0
Country [1] 286226 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 289462 0
Human Research Ethics Committee (Tasmania) Network
Ethics committee address [1] 289462 0
Private Bag 1, Hobart, TAS, 7001
Ethics committee country [1] 289462 0
Australia
Date submitted for ethics approval [1] 289462 0
Approval date [1] 289462 0
06/12/2012
Ethics approval number [1] 289462 0
H0012866

Summary
Brief summary
Vitamin D deficiency is a public health issue in developed countries. Many countries recommend supplementing infants with 400 IU/day of vitamin D. These recommendations have been introduced based on the evidence that supplementation
reduces the risk of rickets, which occurs generally among those with moderate to severe vitamin D deficiency. There is debate whether a similar policy should be introduced in Australia where rickets only occurs in high risk groups which can be easily identified. While vitamin D has potential benefits for bone health beyond the prevention of rickets by improving bone acquisition, the current evidence in infants is sparse,
inconsistent and cannot even rule out a detrimental effect on bone. An expansion from supplementation of at-risk to supplementing all infants should only occur if there are health benefits beyond rickets. However, practice is starting to run ahead of the evidence, and infants are now increasingly being supplemented in the absence of this evidence. High quality and well-powered randomised controlled trial (RCT) evidence is required to show that supplementation of mildly deficient infants is beneficial and does not cause harm.
Aim – To determine whether vitamin D supplementation of 400 IU/day of cholecalciferol from birth to age 2 yrs improves bone health outcomes
Hypothesis – Compared to placebo, vitamin D supplementation from birth to age 2 years improves whole body bone mineral content at age 2 and 4 years.
Significance – Irrespective of its outcome, this study is critical to our ability to make evidence-based decisions around vitamin D supplementation programs in infancy. If our hypothesis is supported, it has the potential to reduce childhood fracture risk by ~50% with a 5% increase in bone mineral density and to delay the onset of osteoporosis in later life by as much as 13 years with a 10% increase in peak bone
mass.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 40950 0
Dr Ingrid van der Mei
Address 40950 0
University of Tasmania
Menzies Research Institute Tasmania
17 Liverpool Street, Hobart, TAS, 7000
Country 40950 0
Australia
Phone 40950 0
+61 3 62267710
Fax 40950 0
Email 40950 0
Ingrid.vanderMei@utas.edu.au
Contact person for public queries
Name 40951 0
Dr Ingrid van der Mei
Address 40951 0
University of Tasmania
Menzies Research Institute Tasmania
17 Liverpool Street, Hobart, TAS, 7000
Country 40951 0
Australia
Phone 40951 0
+61 3 62267710
Fax 40951 0
Email 40951 0
Ingrid.vanderMei@utas.edu.au
Contact person for scientific queries
Name 40952 0
Dr Ingrid van der Mei
Address 40952 0
University of Tasmania
Menzies Research Institute Tasmania
17 Liverpool Street, Hobart, TAS, 7000
Country 40952 0
Australia
Phone 40952 0
+61 3 62267710
Fax 40952 0
Email 40952 0
Ingrid.vanderMei@utas.edu.au