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    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
    EudraCT number
    		 2007-001716-23
    Trial protocol
    		 GB  
    Global end of trial date

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Oct 2019
    First version publication date
    25 Oct 2019
    Other versions
    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

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    Trial identification
    Sponsor protocol code
    452622
    Additional study identifiers
    ISRCTN number
    		 ISRCTN82927713
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Southampton NHS Foundation Trust Research & Development
    Sponsor organisation address
    Tremona Road, Southampton, United Kingdom, SO16 6YD
    Public contact
    Professor Cyrus Cooper, University Hospitals Southampton NHS Foundation Trust Research and Development, 023 80 777624, cc@mrc.soton.ac.uk
    Scientific contact
    Professor Cyrus Cooper, University Hospitals Southampton NHS Foundation Trust Research and Development, 023 80 777624, cc@mrc.soton.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    21 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Oct 2018
    Global end of trial reached?
    No
    General information about the trial
    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.
    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.
    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
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Scientific research
    Long term follow-up duration
    		 8 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 1134
    Worldwide total number of subjects
    1134
    EEA total number of subjects
    1134
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    1134
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    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
    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
    Period 1 title
    Outcomes in neonatal period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 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
    Investigational medicinal product code
    Other name
    Vitamin D3
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    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.

    Arm title
    		 Placebo arm
    Arm description
    		 Women receiving placebo tablet
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matched capsule, one to be taken orally daily from 14 weeks gestation to delivery

    Number of subjects in period 1
    		Cholecalciferol 1000 IU Placebo arm
    Started
    565
    569
    Neonatal assessment
    416
    420
    Completed
    367
    370
    Not completed
    198
    199
         Physician decision
    4
    4
         Too busy
    4
    5
         Unwilling/unable to take study drug
    27
    24
         Reason unknown
    19
    17
         Moved away
    2
    1
         Consent withdrawn by subject
    37
    32
         Unusable DXA due to movement artefact
    49
    50
         Adverse event, non-fatal
    3
    11
         Did not attend
    -
    15
         DXA concerns
    2
    -
         Did not attend neonatal assessment
    15
    -
         Miscarriage
    1
    4
         Lost to follow-up
    15
    18
         Refused to attend neonatal followup
    8
    7
         Withdrew after delivery before neonatal DXA
    2
    5
         Protocol deviation
    10
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cholecalciferol 1000 IU
    Reporting group description
    		 Women receiving 1000 IU cholecalciferol from 14 weeks gestation to delivery.

    Reporting group title
    Placebo arm
    Reporting group description
    		 Women receiving placebo tablet

    Reporting group values
    		 Cholecalciferol 1000 IU Placebo arm Total
    Number of subjects
    		 565 569 1134
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 565 569 1134
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Age of women at baseline
    Units: years
        arithmetic mean (standard deviation)
    		 30.5 ( 5.2 ) 30.5 ( 5.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 565 569 1134
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cholecalciferol 1000 IU
    Reporting group description
    		 Women receiving 1000 IU cholecalciferol from 14 weeks gestation to delivery.

    Reporting group title
    Placebo arm
    Reporting group description
    		 Women receiving placebo tablet

    Primary: Child bone mineral content (neonatal)

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    End point title
    		 Child bone mineral content (neonatal)
    End point description
    Measured by DXA
    End point type
    Primary
    End point timeframe
    Within 2 weeks of delivery
    End point values
    		 Cholecalciferol 1000 IU Placebo arm
    Number of subjects analysed
    338
    327
    Units: gram(s)
        arithmetic mean (confidence interval 95%)
    61.6 (60.3 to 62.8)
    60.5 (59.3 to 61.7)
    Statistical analysis title
    		 T test between groups
    Statistical analysis description
    Hypothesis tests on primary outcome (BMC, grams) between groups of neonates, cholecalciferol vs. placebo
    Comparison groups
    Cholecalciferol 1000 IU v Placebo arm
    Number of subjects included in analysis
    665
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.21
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Child bone mineral density (neonatal)

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    End point title
    		 Child bone mineral density (neonatal)
    End point description
    Measured by DXA of neonate
    End point type
    Primary
    End point timeframe
    Within 2 weeks of delivery
    End point values
    		 Cholecalciferol 1000 IU Placebo arm
    Number of subjects analysed
    338
    327
    Units: g/cm2
        arithmetic mean (confidence interval 95%)
    0.203 (0.200 to 0.205)
    0.203 (0.200 to 0.205)
    Statistical analysis title
    		 Difference in means (BMD)
    Comparison groups
    Cholecalciferol 1000 IU v Placebo arm
    Number of subjects included in analysis
    665
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.96 [2]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [1] - T test
    [2] - There was no difference in neonatal BMD between the groups

    Primary: Child lean mass (neonatal)

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    End point title
    		 Child lean mass (neonatal)
    End point description
    Lean mass measured by DXA
    End point type
    Primary
    End point timeframe
    Neonatal
    End point values
    		 Cholecalciferol 1000 IU Placebo arm
    Number of subjects analysed
    338
    327
    Units: grams
        arithmetic mean (confidence interval 95%)
    3055 (3008 to 3101)
    3014 (2965 to 3062)
    Statistical analysis title
    		 T test between groups
    Comparison groups
    Cholecalciferol 1000 IU v Placebo arm
    Number of subjects included in analysis
    665
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.23
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Child bone mineral content (age 4 years)

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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.
    End point type
    Secondary
    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.
    End point values
    		 Cholecalciferol 1000 IU Placebo arm
    Number of subjects analysed
    248
    246
    Units: gram(s)
        arithmetic mean (confidence interval 95%)
    361.21 (355.70 to 366.72)
    356.69 (351.21 to 362.17)
    Statistical analysis title
    		 T test between groups
    Statistical analysis description
    Differnce in BMC between groups
    Comparison groups
    Cholecalciferol 1000 IU v Placebo arm
    Number of subjects included in analysis
    494
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.252
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Child bone mineral density (age 4 years)

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    End point title
    		 Child bone mineral density (age 4 years)
    End point description
    End point type
    Secondary
    End point timeframe
    Child followup of MAVIDOS trial at age 4 years
    End point values
    		 Cholecalciferol 1000 IU Placebo arm
    Number of subjects analysed
    248
    246
    Units: g/cm2
        arithmetic mean (confidence interval 95%)
    0.477 (0.472 to 0.481)
    0.470 (0.466 to 0.475)
    Statistical analysis title
    		 T test between groups
    Comparison groups
    Cholecalciferol 1000 IU v Placebo arm
    Number of subjects included in analysis
    494
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.048
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Child lean mass (age 4 years)

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    End point title
    		 Child lean mass (age 4 years)
    End point description
    Whole body (less head) lean mass
    End point type
    Secondary
    End point timeframe
    4 year followup DXA scan
    End point values
    		 Cholecalciferol 1000 IU Placebo arm
    Number of subjects analysed
    248
    248
    Units: gram(s)
        arithmetic mean (confidence interval 95%)
    9248.25 (9080.01 to 9416.49)
    9006.27 (8830.16 to 9182.38)
    Statistical analysis title
    		 T test between groups
    Comparison groups
    Cholecalciferol 1000 IU v Placebo arm
    Number of subjects included in analysis
    496
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.051
    Method
    		 t-test, 2-sided
    Confidence interval

    Other pre-specified: Seasonal analysis of BMC (neonatal)-Winter births

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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)
    End point type
    Other pre-specified
    End point timeframe
    Neonatal
    End point values
    		 Cholecalciferol 1000 IU Placebo arm
    Number of subjects analysed
    74
    64
    Units: gram(s)
        arithmetic mean (standard deviation)
    63.0 ( 10.8 )
    57.5 ( 10.9 )
    Statistical analysis title
    		 T test between groups
    Comparison groups
    Cholecalciferol 1000 IU v Placebo arm
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.004
    Method
    		 t-test, 2-sided
    Confidence interval

    Other pre-specified: Seasonal analysis of BMD (neonatal)-Winter births

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    End point title
    		 Seasonal analysis of BMD (neonatal)-Winter births
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Neonatal
    End point values
    		 Cholecalciferol 1000 IU Placebo arm
    Number of subjects analysed
    71
    62
    Units: g/cm2
        arithmetic mean (standard deviation)
    0.208 ( 0.024 )
    0.200 ( 0.019 )
    Statistical analysis title
    		 T test between groups
    Comparison groups
    Cholecalciferol 1000 IU v Placebo arm
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.04
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Recruitment (11 weeks-14 weeks) to delivery
    Adverse event reporting additional description
    Maternal adverse events
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MAVIDOS dictionary
    Dictionary version
    1.1
    Reporting groups
    Reporting group title
    Cholecalciferol 1000 IU/day
    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
    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

    Serious adverse events
    		 Cholecalciferol 1000 IU/day Placebo group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    115 / 565 (20.35%)
    149 / 569 (26.19%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Pregnancy, puerperium and perinatal conditions
    Preterm delivery / premature birth
         subjects affected / exposed
    16 / 565 (2.83%)
    10 / 569 (1.76%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Instrumental delivery
         subjects affected / exposed
    25 / 565 (4.42%)
    35 / 569 (6.15%)
         occurrences causally related to treatment / all
    0 / 25
    0 / 35
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Severe postpartum haemorrhage
         subjects affected / exposed
    65 / 565 (11.50%)
    96 / 569 (16.87%)
         occurrences causally related to treatment / all
    0 / 65
    0 / 96
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intrauterine or neonatal death
         subjects affected / exposed
    1 / 565 (0.18%)
    3 / 569 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital abnormalities
         subjects affected / exposed
    8 / 565 (1.42%)
    5 / 569 (0.88%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Cholecalciferol 1000 IU/day Placebo group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 565 (11.68%)
    71 / 569 (12.48%)
    Cardiac disorders
    Hypertension
         subjects affected / exposed
    13 / 565 (2.30%)
    15 / 569 (2.64%)
         occurrences all number
    13
    15
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 565 (1.42%)
    9 / 569 (1.58%)
         occurrences all number
    8
    9
    Gastrointestinal disorders
    Nausea / vomiting
         subjects affected / exposed
    6 / 565 (1.06%)
    7 / 569 (1.23%)
         occurrences all number
    6
    7
    Diarrhoea
         subjects affected / exposed
    6 / 565 (1.06%)
    4 / 569 (0.70%)
         occurrences all number
    6
    4
    Abdominal pain
         subjects affected / exposed
    16 / 565 (2.83%)
    19 / 569 (3.34%)
         occurrences all number
    16
    19
    Infections and infestations
    Infection (any)
         subjects affected / exposed
    17 / 565 (3.01%)
    17 / 569 (2.99%)
         occurrences all number
    17
    17

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    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
    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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