Clinical Trial Results:
A Double-Blind Randomised Placebo-Controlled Trial of Vitamin D Supplements for Pregnant Women with Low Levels of Vitamin D in Early Pregnancy
Summary
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EudraCT number |
2007-001716-23 |
Trial protocol |
GB |
Global end of trial date |
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Results information
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Results version number |
v1(current) |
This version publication date |
25 Oct 2019
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First version publication date |
25 Oct 2019
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Other versions |
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Summary report(s) |
MAVIDOS main results Lancet DE 2016 MAVIDOS supplementary data Lancet DE 2016 MAVIDOS report to age 4 years for MHRA |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
452622
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Additional study identifiers
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ISRCTN number |
ISRCTN82927713 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
University Hospital Southampton NHS Foundation Trust Research & Development
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Sponsor organisation address |
Tremona Road, Southampton, United Kingdom, SO16 6YD
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Public contact |
Professor Cyrus Cooper, University Hospitals Southampton NHS Foundation Trust Research and Development, 023 80 777624, cc@mrc.soton.ac.uk
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Scientific contact |
Professor Cyrus Cooper, University Hospitals Southampton NHS Foundation Trust Research and Development, 023 80 777624, cc@mrc.soton.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Interim
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Date of interim/final analysis |
21 Jan 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
18 Oct 2018
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Global end of trial reached? |
No
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General information about the trial
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Main objective of the trial |
To test the hypothesis that vitamin D supplementation during pregnancy of women who are have low levels of vitamin D will result in improved neonatal bone mineral content.
The primary completion date encompasses the 4 year followup of the trial.
We have an ongoing grant to follow the children to age 8 years (due to complete in 2021), this has ethics approval under the original ethics number 07/H0502/113.
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Protection of trial subjects |
Ethical considerations
The study involves the participants undergoing various procedures with which they may not be familiar. Detailed information sheets are given to the participantsand they have opportunities to discuss any concerns in detail with study personnel. The infant DXA assessments are associated with a low dose of radiation exposure equivalent to 2 days background radiation in Cornwall (UK) or 7 days in other parts of the UK. Data from the Princess Anne Cohort study showed a small excess of atopic asthma in children born to mothers with the highest levels of vitamin D in pregnancy. However, other studies have suggested neutral or negative associations. The dose of vitamin D supplementation has been chosen to bring women just into the normal range, to avoid elevating it to supranormal levels.
For safety reasons, only women with serum 25(OH)D concentrations between 25-100nmol/l could be included in the study.
Reporting of adverse events
A system of adverse event reporting is described in the study protocol (Harvey et al, Trials 2012, 13;13). In summary, any adverse reaction felt in any way to be related to the IMP was immediately reported to the sponsor, followed by a detailed report on the event. The local Principal Investigator decides whether to expedite reports of adverse events felt to be unrelated to the IMP. A record of all
serious adverse events is kept in the trial master file regardless of whether reported within 24 hours to the sponsor. The sponsor keeps detailed records of all adverse events relating to a clinical trial which are reported to them by the investigators for the trial. These records may be sent to the licensing authority if required.
Suspected unexpected serious adverse reactions are reported as soon as possible to the MHRA and the relevant ethics/data monitoring committee.
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Background therapy |
Women were able to take pregnancy vitamin supplements containing up to 400 IU cholecalciferol. | ||
Evidence for comparator |
The comparators were cholecalciferol 1000 IU versus placebo. Prior to the study, we did a systematic review of studies relating maternal vitamin 25-hydroxyvitamin D (25[OH]D) concentrations, UVB exposure, dietary vitamin D intake, or use of vitamin D supplements during pregnancy to maternal and offspring health outcomes (Harvey NC, Holroyd C, Ntani G, et al. Vitamin D supplementation in pregnancy: a systematic review. Health Technol Assess 2014; 18: 1–190). We identified eight observational studies relating maternal gestational vitamin D status to offspring bone mass, all of which were assessed as having a medium to low risk of bias. Of these, five reported a significant positive relation between maternal vitamin D status and offspring bone outcomes, which included whole-body, lumbar, femoral, and tibial bone mineral content (BMC), and whole-body and lumbar spine bone mineral density (BMD). Of the remaining studies, no significant association was reported between maternal vitamin D status and offspring radial and whole-body BMC. Differences in study design did not permit meta-analysis. We identified one small intervention study, judged to be at high risk of bias, which found no difference in offspring forearm BMC (measured within 5 days of birth) between supplemented and unsupplemented mothers. We subsequently updated the search in August, 2014, identifying two further observational studies, both judged to have a low to medium risk of bias; one, using the Avon Longitudinal Study of Parents and Children cohort, found no association between maternal 25(OH)D concentrations in pregnancy and offspring bone mass at 9 years. By contrast, the second study, from the Western Australian Pregnancy Cohort (RAINE), documented positive associations between maternal gestational 25(OH)D concentrations and off spring bone mass at 20 years. | ||
Actual start date of recruitment |
10 Oct 2008
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy, Scientific research | ||
Long term follow-up duration |
8 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 1134
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Worldwide total number of subjects |
1134
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EEA total number of subjects |
1134
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
1134
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Pregnant women were recruited when attending early pregnancy ultrasound screening at three study sites (University Hospital Southampton National Health Service [NHS] Foundation Trust, Southampton, UK; Oxford University Hospitals NHS Trust, Oxford, UK; Sheffield Hospitals NHS Trust [University of Sheffield], Sheffield, UK). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Women were eligible if they were older than 18 years, had a singleton pregnancy, had gestation of less than 17 weeks based on last menstrual period and ultrasound measurements, and were aiming to give birth at the local maternity hospital. See Cooper et al, Lancet Diabetes and Endocrinology 2016. 1449 were screened, 1134 randomly assigned. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Outcomes in neonatal period (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
Women were randomly assigned at 14 weeks’ gestation to either cholecalciferol 1000 IU/day or matched placebo (Merck KGaA, Darmstadt, Germany).
Packs of study treatment were randomly assigned in a 1:1 ratio by Sharp Clinical Services (Crickhowell, UK; previously DHP-Bilcare) by a computer-generated sequence in randomly permuted blocks of ten, starting randomly midway through the block, dispensed in order by study pharmacist. Both participant and research team were blinded to treatment allocation
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Cholecalciferol 1000 IU | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Women receiving 1000 IU cholecalciferol from 14 weeks gestation to delivery. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Active comparator | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Cholecalciferol 1000 IU /day
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Investigational medicinal product code |
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Other name |
Vitamin D3
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Pharmaceutical forms |
Coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
1000 IU Cholecalciferol, one tablet to be taken orally daily from randomisaton at 14 weeks’ gestation
(or as soon as possible before 17 weeks’ gestation if recruited later) until the day of delivery.
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Arm title
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Placebo arm | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Women receiving placebo tablet | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Matched capsule, one to be taken orally daily from 14 weeks gestation to delivery
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Baseline characteristics reporting groups
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Reporting group title |
Cholecalciferol 1000 IU
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Reporting group description |
Women receiving 1000 IU cholecalciferol from 14 weeks gestation to delivery. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo arm
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Reporting group description |
Women receiving placebo tablet | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cholecalciferol 1000 IU
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Reporting group description |
Women receiving 1000 IU cholecalciferol from 14 weeks gestation to delivery. | ||
Reporting group title |
Placebo arm
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Reporting group description |
Women receiving placebo tablet |
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End point title |
Child bone mineral content (neonatal) | ||||||||||||
End point description |
Measured by DXA
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End point type |
Primary
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End point timeframe |
Within 2 weeks of delivery
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Statistical analysis title |
T test between groups | ||||||||||||
Statistical analysis description |
Hypothesis tests on primary outcome (BMC, grams) between groups of neonates, cholecalciferol vs. placebo
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Comparison groups |
Cholecalciferol 1000 IU v Placebo arm
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Number of subjects included in analysis |
665
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||
P-value |
= 0.21 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Child bone mineral density (neonatal) | ||||||||||||
End point description |
Measured by DXA of neonate
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End point type |
Primary
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End point timeframe |
Within 2 weeks of delivery
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Statistical analysis title |
Difference in means (BMD) | ||||||||||||
Comparison groups |
Cholecalciferol 1000 IU v Placebo arm
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Number of subjects included in analysis |
665
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
P-value |
= 0.96 [2] | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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Notes [1] - T test [2] - There was no difference in neonatal BMD between the groups |
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End point title |
Child lean mass (neonatal) | ||||||||||||
End point description |
Lean mass measured by DXA
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End point type |
Primary
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End point timeframe |
Neonatal
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Statistical analysis title |
T test between groups | ||||||||||||
Comparison groups |
Cholecalciferol 1000 IU v Placebo arm
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Number of subjects included in analysis |
665
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||
P-value |
= 0.23 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Child bone mineral content (age 4 years) | ||||||||||||
End point description |
MAVIDOS children recruited in the Southampton arm of the trial were followed up at age 4 years. The results comprise a secondary analysis.
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End point type |
Secondary
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End point timeframe |
Four year follow up - median (IQR) age 4.07 years (4.03, 4.15) cholecalciferol 1000 IU/day group; 4.08 years (4.03, 4.16) placebo group.
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Statistical analysis title |
T test between groups | ||||||||||||
Statistical analysis description |
Differnce in BMC between groups
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Comparison groups |
Cholecalciferol 1000 IU v Placebo arm
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Number of subjects included in analysis |
494
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Analysis specification |
Post-hoc
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Analysis type |
non-inferiority | ||||||||||||
P-value |
= 0.252 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Child bone mineral density (age 4 years) | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Child followup of MAVIDOS trial at age 4 years
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Statistical analysis title |
T test between groups | ||||||||||||
Comparison groups |
Cholecalciferol 1000 IU v Placebo arm
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Number of subjects included in analysis |
494
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Analysis specification |
Post-hoc
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Analysis type |
non-inferiority | ||||||||||||
P-value |
= 0.048 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Child lean mass (age 4 years) | ||||||||||||
End point description |
Whole body (less head) lean mass
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End point type |
Secondary
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End point timeframe |
4 year followup DXA scan
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Statistical analysis title |
T test between groups | ||||||||||||
Comparison groups |
Cholecalciferol 1000 IU v Placebo arm
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Number of subjects included in analysis |
496
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Analysis specification |
Post-hoc
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Analysis type |
non-inferiority | ||||||||||||
P-value |
= 0.051 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Seasonal analysis of BMC (neonatal)-Winter births | ||||||||||||
End point description |
Bone mineral content in winter-born infants (Dec-Feb)
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End point type |
Other pre-specified
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End point timeframe |
Neonatal
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Statistical analysis title |
T test between groups | ||||||||||||
Comparison groups |
Cholecalciferol 1000 IU v Placebo arm
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Number of subjects included in analysis |
138
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||
P-value |
= 0.004 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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End point title |
Seasonal analysis of BMD (neonatal)-Winter births | ||||||||||||
End point description |
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End point type |
Other pre-specified
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End point timeframe |
Neonatal
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Statistical analysis title |
T test between groups | ||||||||||||
Comparison groups |
Cholecalciferol 1000 IU v Placebo arm
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Number of subjects included in analysis |
133
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority | ||||||||||||
P-value |
= 0.04 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Recruitment (11 weeks-14 weeks) to delivery
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Adverse event reporting additional description |
Maternal adverse events
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MAVIDOS dictionary | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
1.1
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Reporting groups
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Reporting group title |
Cholecalciferol 1000 IU/day
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Reporting group description |
Maternal / neonatal outcomes. There was 1 intrauterine/neonatal death, no maternal deaths (hence not listed below). Severe adverse events: Preterm delivery / premature birth Instrumental delivery Severe postpartum haemorrhage Intrauterine or neonatal death Congenital abnormalities Adverse events: Infection Nausea/vomiting Diarrhoea Abdominal pain Headache Hypertension Hypercalcaemia (>= 2.75 mmol / l at 34 weeks gestation) Fetal growth retardation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo group
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Reporting group description |
Maternal / neonatal outcomes. There was 1 intrauterine/neonatal death, no maternal deaths (hence not listed below). Severe adverse events: Preterm delivery / premature birth Instrumental delivery Severe postpartum haemorrhage Intrauterine or neonatal death Congenital abnormalities Adverse events: Infection Nausea/vomiting Diarrhoea Abdominal pain Headache Hypertension Hypercalcaemia (>= 2.75 mmol / l at 34 weeks gestation) Fetal growth retardation | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
Full results of the MAVIDOS trial neonatal followup are published in the Lancet Diabetes and Endocrinology: Lancet Diabetes Endocrinol 2016; 4: 393–402 (link below). Limitations are discussed on p 399-400. | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/30321476 http://www.ncbi.nlm.nih.gov/pubmed/30669280 http://www.ncbi.nlm.nih.gov/pubmed/27549309 http://www.ncbi.nlm.nih.gov/pubmed/26944421 http://www.ncbi.nlm.nih.gov/pubmed/22314083 |