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    Clinical Trial Results:
    Vitamin D Supplementation on Assisted Reproduction Technology (ART) outcomes: a randomized clinical controlled trial and an investigation of the involved biological mechanisms

    Summary
    EudraCT number
    		 2015-004233-27
    Trial protocol
    		 IT  
    Global end of trial date
    31 Dec 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jul 2021
    First version publication date
    23 Jul 2021
    Other versions
    Summary report(s)
    		 Manuscript AJOG

    Trial information

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    Trial identification
    Sponsor protocol code
    RF-2013-02358757
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 SUNDRO: -
    Sponsors
    Sponsor organisation name
    FONDAZIONE IRCCS CA' GRANDA OSPEDALE MAGGIORE POLICLINICO
    Sponsor organisation address
    via Sforza 35, Milan, Italy,
    Public contact
    U.O.S.D. CENTRO P.M.A., FONDAZIONE IRCCS CA' GRANDA OSPEDALE MAGGIORE POLICLINICO, 0039 0255036582, centrosterilita@policlinico.mi.it
    Scientific contact
    U.O.S.D. CENTRO P.M.A., FONDAZIONE IRCCS CA' GRANDA OSPEDALE MAGGIORE POLICLINICO, 0039 0255036582, centrosterilita@policlinico.mi.it
    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
    Final
    Date of interim/final analysis
    30 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    the study aims at determining the potential benefits of vitamin D supplementation in improving clinical pregnancy rate in womenundergoing ART
    Protection of trial subjects
    no particular concerns regarding pain or distress related to the protocol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 May 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Italy: 630
    Worldwide total number of subjects
    630
    EEA total number of subjects
    630
    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)
    630
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Women undergoing IVF with or without intracytoplasmic sperm injection (ICSI) at the infertility units of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico and IRCCS San Raffaele Scientific Institute between October 2016 and January 2019 were considered for study entry. Recruitment was consecutive.

    Pre-assignment
    Screening details
    		 Evauated 2450 subjetcs; Eligile 1128 subjects; enrolled 630 subjects.

    Period 1
    Period 1 title
    first (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vitamin D
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    DBase
    Investigational medicinal product code
    36635035
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    Supplementation was given as a single administration of oral 600,000 IU of vitamin D3 to ensure maximal adherence. This modality is expected to properly maintain peripheral levels of vitamin D above 30 ng/mL for 3 months,

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo olive oil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution in single-dose container
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was given as a single administration of oral olive oil.

    Number of subjects in period 1
    		Vitamin D Placebo
    Started
    308
    322
    Completed
    308
    322

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vitamin D
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Vitamin D Placebo Total
    Number of subjects
    		 308 322 630
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 35 (32 to 37) 35 (33 to 37) -
    Gender categorical
    Units: Subjects
        Female
    		 308 322 630
        Male
    		 0 0 0
    Subject analysis sets

    Subject analysis set title
    Pregnancy rate
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    IVF cycle outcome in the 2 study groups

    Subject analysis set title
    Supplemented
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    women receiving vitamin D

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Women receiving placebo

    Subject analysis sets values
    		 Pregnancy rate Supplemented Placebo
    Number of subjects
    630
    308
    322
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    Gender categorical
    Units: Subjects
        Female
    630
    308
    322
        Male
    0
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Vitamin D
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    Pregnancy rate
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    IVF cycle outcome in the 2 study groups

    Subject analysis set title
    Supplemented
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    women receiving vitamin D

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Women receiving placebo

    Primary: Pregnancy rate

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    End point title
    		 Pregnancy rate
    End point description
    End point type
    Primary
    End point timeframe
    5 weeks after last treatment
    End point values
    		 Vitamin D Placebo Pregnancy rate Supplemented Placebo
    Number of subjects analysed
    308
    322
    573
    322
    308
    Units: patients
        Pregnancy
    113
    130
    243
    113
    130
    Statistical analysis title
    		 Clinical pregnancy rate
    Statistical analysis description
    cumulative clinical pregnancy rate
    Comparison groups
    Vitamin D v Placebo
    Number of subjects included in analysis
    630
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.11

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Only maternal events occurring within 3 months from randomization were considered because a single dose of 600,000 IU is expected to raise peripheral levels for no more than 3 months.
    Adverse event reporting additional description
    Given the well-known pharmacologic and safety profile of vitamin D3, we did not deem necessary a strict monitoring of the included women, and only severe adverse events were recorded (death, life-threatening conditions, new or prolonged hospitalization, persistent or relevant disability, or congenital anomalies).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    vitamin D
    Reporting group description
    		 -

    Reporting group title
    placebo
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Given the well-known pharmacologic and safety profile of vitamin D3,17,22 we did not deem necessary a strict monitoring of the included women, and only severe adverse events were recorded (death, life-threatening conditions, new or prolonged hospitalization, persistent or relevant disability, or congenital anomalies).
    Serious adverse events
    		 vitamin D placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 308 (0.00%)
    2 / 322 (0.62%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Congenital, familial and genetic disorders
    genetic disorders
         subjects affected / exposed
    0 / 308 (0.00%)
    2 / 322 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 vitamin D placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 308 (0.00%)
    0 / 322 (0.00%)

    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.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/3389415
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    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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