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    Clinical Trial Results:
    BEST-D (Biochemical efficacy and safety trial of vitamin D): a dose-finding trial assessing biochemical and vascular effects of high dose vitamin D

    Summary
    EudraCT number
    		 2011-005763-24
    Trial protocol
    		 GB  
    Global end of trial date
    10 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jul 2016
    First version publication date
    28 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CTSUBEST-D
    Additional study identifiers
    ISRCTN number
    		 ISRCTN07034656
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Oxford
    Sponsor organisation address
    CTSU, Richard Doll Building, Old Road Campus, Oxford, United Kingdom, OX3 7LF
    Public contact
    Professor Jane Armitage, University of Oxford, 44 (0)1865 743743, jane.armitage@ndph.ox.ac.uk
    Scientific contact
    Professor Jane Armitage, University of Oxford, 44 (0)1865 743743, jane.armitage@ndph.ox.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
    Final
    Date of interim/final analysis
    15 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study is to determine the optimal safe and effective dose of vitamin D to test in a large scale trial in older people and compare the biochemical effects on blood levels of vitamin D and parathyroid hormone of 100 mcg or 50 mcg or placebo when administered daily for one year.
    Protection of trial subjects
    The participants were provided with a 24-hour Freefone number (0800 585323), should they wish to discuss trial-related medical problems outside of the normal working hours.
    Background therapy
    		 None
    Evidence for comparator
    		 Osteoporosis causes substantial morbidity and mortality in older people, but whether chronic insufficiency of vitamin D is a reversible determinant of osteoporosis and related risk of fractures is controversial. Observational studies indicate that low plasma levels of 25-hydroxyvitamin D [25(OH)D] are associated with higher risks of fractures and with vascular and non-vascular mortality, but it is unclear if these associations are causal. Randomized trials assessing the effects on fracture and other health outcomes have generally failed to demonstrate beneficial effects of vitamin D supplementation. However, few such trials have used sufficient doses of vitamin D3 to achieve and maintain what might be considered optimum plasma levels of 25(OH)D. Although controversial, the available evidence suggests that the optimum plasma levels of 25(OH)D may be around 75 to 90 nmol/L. First, parathyroid hormone (PTH) levels are linearly and inversely associated with plasma 25(OH)D levels until such levels reach about 75 nmol/L. Second, prospective observational studies indicate that the risks of vascular and non-vascular mortality are lowest at plasma 25(OH)D levels of around 90 nmol/L. Thirdly, mean peak plasma 25(OH)D levels at the end of summer in young British adults are also about 90 nmol/L. At plasma 25(OH)D levels below a cut-off point of about 75 nmol/L, the average increase in 25(OH)D per 10 µg of additional vitamin D3 has been estimated to be about 7–10 nmol/L. Hence, from a typical level of 25(OH)D of 55 (SD 26) nmol/L found in older UK adults, a dose of vitamin D3 of at least 50 µg (2000 IU), and possibly as much as 100 µg (4000 IU), may be required to achieve and maintain blood levels >90 nmol/L throughout the year in most people in the UK.
    Actual start date of recruitment
    30 Apr 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 305
    Worldwide total number of subjects
    305
    EEA total number of subjects
    305
    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)
    0
    From 65 to 84 years
    292
    85 years and over
    13

    Subject disposition

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    Recruitment
    Recruitment details
    		 932 subjects were invited to participate, of which 313 (33%) agreed to have a randomization visit from the study nurse and 305 were successfully randomized between 24 September 2012 and 14 March 2013.

    Pre-assignment
    Screening details
    		 Eight participants visited were not randomized (6 declined and 2 were ineligible) and 619 declined or ignored the invitation to participate.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    The trial was placebo-controlled. The data analyst remained blinded until the Statistical Analysis Plan was finalised.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 100 µg D3
    Arm description
    		 Vitamin D3 100 µg (4000 IU) daily
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vitamin D3
    Investigational medicinal product code
    Other name
    Cholecalciferol
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    100μg (4000 IU) daily

    Arm title
    		 50 μg D3
    Arm description
    		 Vitamin D3 50 μg (2000 IU) daily
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Vitamin D3
    Investigational medicinal product code
    Other name
    Cholecalciferol
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    50μg (2000 IU) daily

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were provided with a pair of treatment bottles. Bottles were labeled with participant details to enable identification. Each treatment bottle contained a 7-month supply of capsules containing either vitamin D3 (50μg) or placebo. Participants were asked to take one capsule from the each of the labelled bottles daily. If they forgot to take the two capsules at the usual time, they could still take them later the same day. However, if they missed a whole day or more, they should have continued with their daily dose from the day they restarted.

    Number of subjects in period 1
    		100 µg D3 50 μg D3 Placebo
    Started
    102
    102
    101
    6 month visit
    98
    100
    98
    12 month visit
    97
    98
    95
    Completed
    97
    98
    95
    Not completed
    5
    4
    6
         Adverse event, serious fatal
    -
    -
    3
         Consent withdrawn by subject
    3
    4
    2
         Lost to follow-up
    1
    -
    1
         Protocol deviation
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    100 µg D3
    Reporting group description
    		 Vitamin D3 100 µg (4000 IU) daily

    Reporting group title
    50 μg D3
    Reporting group description
    		 Vitamin D3 50 μg (2000 IU) daily

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 100 µg D3 50 μg D3 Placebo Total
    Number of subjects
    		 102 102 101 305
    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
        arithmetic mean (standard deviation)
    		 71 ( 6 ) 72 ( 6 ) 72 ( 6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 50 51 49 150
        Male
    		 52 51 52 155
    Current smoker
    Units: Subjects
        Yes
    		 7 7 7 21
        No
    		 95 95 94 284
    Prior heart disease
    Defined as heart attack, angina or heart failure.
    Units: Subjects
        Yes
    		 20 11 11 42
        No
    		 82 91 90 263
    Prior stroke/TIA
    Units: Subjects
        Yes
    		 5 8 6 19
        No
    		 97 94 95 286
    Prior hypertension
    Units: Subjects
        Yes
    		 40 44 35 119
        No
    		 62 58 66 186
    Prior diabetes
    Units: Subjects
        Yes
    		 9 9 9 27
        No
    		 93 93 92 278
    Prior fracture (ever)
    Units: Subjects
        Yes
    		 31 30 30 91
        No
    		 71 72 71 214
    Any fall in the past 6 months
    Units: Subjects
        Yes
    		 13 15 12 40
        No
    		 89 87 89 265
    Taking any antihypertensive
    Units: Subjects
        Yes
    		 50 52 46 148
        No
    		 52 50 55 157
    Taking statin
    Units: Subjects
        Yes
    		 32 29 23 84
        No
    		 70 73 78 221
    Taking any antithrombotic
    Units: Subjects
        Yes
    		 20 23 18 61
        No
    		 82 79 83 244
    Taking vitamin D (<=400 IU/day)
    Units: Subjects
        Yes
    		 12 10 13 35
        No
    		 90 92 88 270
    Taking calcium
    Units: Subjects
        Yes
    		 4 1 4 9
        No
    		 98 101 97 296
    Any muscle aches/pains
    Units: Subjects
        Yes
    		 43 35 38 116
        No
    		 59 67 63 189
    Any joint aches/pains
    Units: Subjects
        Yes
    		 66 66 64 196
        No
    		 36 36 37 109
    Albumin-corrected calcium
    Number of subjects with albumin-corrected calcium concentration >2.55 mmol/L at randomization
    Units: Subjects
        Yes
    		 5 1 2 8
        No
    		 97 101 99 297
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 168 ( 10 ) 168 ( 10 ) 167 ( 10 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 77 ( 17 ) 78 ( 15 ) 79 ( 15 ) -
    Body mass index
    Units: kg/m²
        arithmetic mean (standard deviation)
    		 27 ( 5 ) 27 ( 4 ) 28 ( 5 ) -
    Grip strength
    Average of best of 3 left handed tests and best of 3 right handed tests.
    Units: kg
        arithmetic mean (standard deviation)
    		 25 ( 11 ) 25 ( 11 ) 25 ( 11 ) -
    Systolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 132 ( 22 ) 132 ( 17 ) 129 ( 18 ) -
    Diastolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 77 ( 11 ) 77 ( 10 ) 76 ( 12 ) -
    Physical activity rating
    Self rated
    Units: Scale of 1-10
        arithmetic mean (standard deviation)
    		 6.5 ( 2 ) 6.2 ( 2 ) 6.5 ( 2 ) -
    Plasma 25(OH)D
    Units: nmol/L
        arithmetic mean (standard deviation)
    		 49 ( 15 ) 55 ( 23 ) 47 ( 15 ) -
    Total cholesterol
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 5.4 ( 1 ) 5.2 ( 1.2 ) 5.2 ( 1.2 ) -
    HDL cholesterol
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 1.5 ( 0.4 ) 1.5 ( 0.4 ) 1.4 ( 0.4 ) -
    LDL cholesterol
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 3 ( 0.8 ) 2.8 ( 0.9 ) 2.8 ( 0.8 ) -
    Triglycerides
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 1.6 ( 0.8 ) 1.7 ( 1 ) 1.6 ( 0.9 ) -
    Apolipoprotein A1
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 140 ( 21 ) 137 ( 19 ) 136 ( 21 ) -
    Apolipoprotein B
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 97 ( 21 ) 92 ( 23 ) 94 ( 23 ) -
    Albumin
    Units: g/L
        arithmetic mean (standard deviation)
    		 40 ( 2 ) 40 ( 3 ) 40 ( 3 ) -
    Creatinine
    Units: µmol/L
        arithmetic mean (standard deviation)
    		 79 ( 21 ) 80 ( 23 ) 78 ( 18 ) -
    eGFR
    Units: mL/min/1.73m²
        arithmetic mean (standard deviation)
    		 77 ( 15 ) 76 ( 14 ) 78 ( 13 ) -
    Alkaline phosphatase
    Units: IU/L
        arithmetic mean (standard deviation)
    		 60 ( 17 ) 64 ( 19 ) 63 ( 27 ) -
    Albumin-corrected calcium
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 2.3 ( 0.1 ) 2.3 ( 0.1 ) 2.3 ( 0.1 ) -
    Phosphate
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 1.1 ( 0.2 ) 1 ( 0.2 ) 1 ( 0.1 ) -
    Ln intact parathyroid hormone
    Units: ln pmol/L
        arithmetic mean (standard deviation)
    		 1.37 ( 0.5 ) 1.35 ( 0.38 ) 1.32 ( 0.42 ) -
    Ln NT-proBNP
    Units: ln pg/mL
        arithmetic mean (standard deviation)
    		 6.19 ( 1.38 ) 6.19 ( 1.02 ) 5.89 ( 1.1 ) -
    Dietary calcium
    Units: mg/day
        arithmetic mean (standard deviation)
    		 724 ( 287 ) 695 ( 292 ) 713 ( 302 ) -

    End points

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    End points reporting groups
    Reporting group title
    100 µg D3
    Reporting group description
    		 Vitamin D3 100 µg (4000 IU) daily

    Reporting group title
    50 μg D3
    Reporting group description
    		 Vitamin D3 50 μg (2000 IU) daily

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Subject analysis set title
    Randomized
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects

    Subject analysis set title
    Selected for one month visit
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects selected for the one month visit

    Subject analysis set title
    Had 1 month visit
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who attended the 1 month visit.

    Subject analysis set title
    Had 6 month visit
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who attended the 6 month visit

    Subject analysis set title
    Had 12 month visit
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects who attended the 12 month visit

    Primary: Plasma 25(OH)D concentration at scheduled study end

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    End point title
    		 Plasma 25(OH)D concentration at scheduled study end
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: nmol/L
        arithmetic mean (standard error)
    137 ( 2.4 )
    102 ( 2.4 )
    53 ( 2.4 )
    Statistical analysis title
    		 Plasma 25(OH)D at scheduled study end
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - Test for difference

    Primary: Proportion of subjects with a 25(OH)D concentration >90 nmol/L at scheduled study end

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    End point title
    		 Proportion of subjects with a 25(OH)D concentration >90 nmol/L at scheduled study end
    End point description
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: Subjects
    90
    71
    1
    Statistical analysis title
    		 Proportion with 25(OH)D >90 nmol/L at study end
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.0016
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [2] - Test for difference

    Secondary: Plasma 25(OH)D concentration at 1 month

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    End point title
    		 Plasma 25(OH)D concentration at 1 month
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation. Only among those selected for the 1 month sample.
    End point type
    Secondary
    End point timeframe
    1 month
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    34
    35
    33
    Units: nmol/L
        arithmetic mean (standard error)
    81 ( 1.9 )
    69 ( 1.8 )
    49 ( 1.9 )
    Statistical analysis title
    		 Plasma 25(OH)D concentration at 1 month
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [3] - Test for difference
    Statistical analysis title
    		 Plasma 25(OH)D concentration at 1 month
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [4] - Test for difference
    Statistical analysis title
    		 Plasma 25(OH)D concentration at 1 month
    Comparison groups
    50 μg D3 v Placebo
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [5] - Test for difference

    Secondary: Plasma 25(OH)D concentration at 6 months

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    End point title
    		 Plasma 25(OH)D concentration at 6 months
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: nmol/L
        arithmetic mean (standard error)
    126 ( 2.4 )
    97 ( 2.4 )
    55 ( 2.4 )
    Statistical analysis title
    		 Plasma 25(OH)D concentration at 6 months
    Comparison groups
    50 μg D3 v 100 µg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [6] - Test for difference
    Statistical analysis title
    		 Plasma 25(OH)D concentration at 6 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [7] - Test for difference
    Statistical analysis title
    		 Plasma 25(OH)D concentration at 6 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [8] - Test for difference

    Secondary: Proportion of subjects with a 25(OH)D concentration >90 nmol/L at 6 months

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    End point title
    		 Proportion of subjects with a 25(OH)D concentration >90 nmol/L at 6 months
    End point description
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: Subjects
    88
    65
    2
    Statistical analysis title
    		 Proportion with 25(OH)D >90 nmol/L at 6 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.0003
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [9] - Test for difference
    Statistical analysis title
    		 Proportion with 25(OH)D >90 nmol/L at 6 months
    Comparison groups
    Placebo v 100 µg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [10] - Test for difference
    Statistical analysis title
    		 Proportion with 25(OH)D >90 nmol/L at 6 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [11] - Test for difference

    Secondary: Proportion of participants with PTH levels suppressed into the normal range at 6 months

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    End point title
    		 Proportion of participants with PTH levels suppressed into the normal range at 6 months
    End point description
    Proportion of participants with a PTH concentration in the reference interval (1.1-6.8 pmol/L)
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: Subjects
    91
    97
    89
    Statistical analysis title
    		 Proportion with PTH in normal range at 6 months
    Comparison groups
    50 μg D3 v 100 µg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.13
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [12] - Test for difference
    Statistical analysis title
    		 Proportion with PTH in normal range at 6 months
    Comparison groups
    Placebo v 100 µg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.81
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [13] - Test for difference
    Statistical analysis title
    		 Proportion with PTH in normal range at 6 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.08
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [14] - Test for difference

    Secondary: Proportion of participants with PTH levels suppressed into the normal range at 12 months

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    End point title
    		 Proportion of participants with PTH levels suppressed into the normal range at 12 months
    End point description
    Proportion of participants with a PTH concentration in the reference interval (1.1-6.8 pmol/L)
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: Subjects
    93
    97
    88
    Statistical analysis title
    		 Proportion with PTH in normal range at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.27
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [15] - Test for difference
    Statistical analysis title
    		 Proportion with PTH in normal range at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.36
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [16] - Test for difference
    Statistical analysis title
    		 Proportion with PTH in normal range at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.05
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [17] - Test for difference

    Secondary: Proportion of participants with calcium levels above the normal range at 6 months

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    End point title
    		 Proportion of participants with calcium levels above the normal range at 6 months
    End point description
    Proportion of participants with an albumin-corrected calcium concentration above the reference interval (2.15-2.55 mmol/L)
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: Subjects
    5
    1
    0
    Statistical analysis title
    		 Proportion with calcium above normal range at 6 mo
    Comparison groups
    50 μg D3 v 100 µg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.14
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [18] - Test for difference
    Statistical analysis title
    		 Proportion with calcium above normal range at 6 mo
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.07
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [19] - Test for difference
    Statistical analysis title
    		 Proportion with calcium above normal range at 6 mo
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 1
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [20] - Test for difference

    Secondary: Proportion of participants with calcium levels above the normal range at 12 months

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    End point title
    		 Proportion of participants with calcium levels above the normal range at 12 months
    End point description
    Proportion of participants with an albumin-corrected calcium concentration above the reference interval (2.15-2.55 mmol/L)
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: Subjects
    4
    1
    1
    Statistical analysis title
    		 Proportion with calcium above normal range at 12 m
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.21
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [21] - Test for difference
    Statistical analysis title
    		 Proportion with calcium above normal range at 12 m
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    P-value
    		 = 0.21
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [22] - Test for difference
    Statistical analysis title
    		 Proportion with calcium above normal range at 12 m
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [23]
    P-value
    		 = 0.99
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [23] - Test for difference

    Secondary: Plasma albumin at 6 months

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    End point title
    		 Plasma albumin at 6 months
    End point description
    Mean plasma concentration of albumin (g/L). Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: g/L
        arithmetic mean (standard error)
    39.7 ( 0.2 )
    39.7 ( 0.2 )
    39.9 ( 0.2 )
    Statistical analysis title
    		 Plasma albumin at 6 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    P-value
    		 = 0.91
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [24] - Test for difference
    Statistical analysis title
    		 Plasma albumin at 6 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.47
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [25] - Test for difference
    Statistical analysis title
    		 Plasma albumin at 6 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    P-value
    		 = 0.4
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [26] - Test for difference

    Secondary: Plasma albumin at 12 months

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    End point title
    		 Plasma albumin at 12 months
    End point description
    Mean plasma concentration of albumin (g/L). Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: g/L
        arithmetic mean (standard error)
    40 ( 0.19 )
    40.1 ( 0.19 )
    40.6 ( 0.2 )
    Statistical analysis title
    		 Plasma albumin at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.84
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [27] - Test for difference
    Statistical analysis title
    		 Plasma albumin at 12 months
    Comparison groups
    Placebo v 100 µg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [28]
    P-value
    		 = 0.037
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [28] - Test for difference
    Statistical analysis title
    		 Plasma albumin at 12 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    P-value
    		 = 0.06
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [29] - Test for difference

    Secondary: Plasma phosphate at 6 months

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    End point title
    		 Plasma phosphate at 6 months
    End point description
    Mean plasma concentration of phosphate (mmol/L). Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: mmol/L
        arithmetic mean (standard error)
    1.08 ( 0.014 )
    1.04 ( 0.014 )
    1.06 ( 0.014 )
    Statistical analysis title
    		 Plasma phosphate at 6 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [30]
    P-value
    		 = 0.09
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [30] - Test for difference
    Statistical analysis title
    		 Plasma phosphate at 6 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 = 0.38
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [31] - Test for difference
    Statistical analysis title
    		 Plasma phosphate at 6 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [32]
    P-value
    		 = 0.42
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [32] - Test for difference

    Secondary: Plasma phosphate at 12 months

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    End point title
    		 Plasma phosphate at 12 months
    End point description
    Mean plasma concentration of phosphate (mmol/L). Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: mmol/L
        arithmetic mean (standard error)
    1.06 ( 0.013 )
    1.05 ( 0.013 )
    1.06 ( 0.013 )
    Statistical analysis title
    		 Plasma phosphate at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 = 0.46
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [33] - Test for difference
    Statistical analysis title
    		 Plasma phosphate at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    P-value
    		 = 0.71
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [34] - Test for difference
    Statistical analysis title
    		 Plasma phosphate at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 = 0.72
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [35] - Test for difference

    Secondary: Plasma creatinine at 6 months

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    End point title
    		 Plasma creatinine at 6 months
    End point description
    Mean plasma concentration of creatinine (ln µmol/L). Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: ln µmol/L
        arithmetic mean (standard error)
    4.36 ( 0.01 )
    4.35 ( 0.01 )
    4.34 ( 0.01 )
    Statistical analysis title
    		 Plasma creatinine at 6 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [36]
    P-value
    		 = 0.54
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [36] - Test for difference
    Statistical analysis title
    		 Plasma creatinine at 6 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 = 0.15
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [37] - Test for difference
    Statistical analysis title
    		 Plasma creatinine at 6 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [38]
    P-value
    		 = 0.41
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [38] - Test for difference

    Secondary: Plasma creatinine at 12 months

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    End point title
    		 Plasma creatinine at 12 months
    End point description
    Mean plasma concentration of creatinine (ln µmol/L) Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: ln µmol/L
        arithmetic mean (standard error)
    4.36 ( 0.01 )
    4.34 ( 0.01 )
    4.35 ( 0.01 )
    Statistical analysis title
    		 Plasma creatinine at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [39]
    P-value
    		 = 0.15
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [39] - Test for difference
    Statistical analysis title
    		 Plasma creatinine at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [40]
    P-value
    		 = 0.21
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [40] - Test for difference
    Statistical analysis title
    		 Plasma creatinine at 12 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [41]
    P-value
    		 = 0.84
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [41] - Test for difference

    Secondary: Plasma alkaline phosphatase at 6 months

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    End point title
    		 Plasma alkaline phosphatase at 6 months
    End point description
    Mean plasma concentration of alkaline phosphatase (ln IU/L). Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: ln IU/L
        arithmetic mean (standard error)
    4.04 ( 0.012 )
    4.06 ( 0.012 )
    4.08 ( 0.012 )
    Statistical analysis title
    		 Plasma alkaline phosphatase at 6 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [42]
    P-value
    		 = 0.46
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [42] - Test for difference
    Statistical analysis title
    		 Plasma alkaline phosphatase at 6 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [43]
    P-value
    		 = 0.0247
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [43] - Test for difference
    Statistical analysis title
    		 Plasma alkaline phosphatase at 6 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [44]
    P-value
    		 = 0.13
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [44] - Test for difference

    Secondary: Plasma alkaline phosphatase at 12 months

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    End point title
    		 Plasma alkaline phosphatase at 12 months
    End point description
    Mean plasma concentration of alkaline phosphatase (ln IU/L). Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: ln IU/L
        arithmetic mean (standard error)
    4.09 ( 0.016 )
    4.09 ( 0.016 )
    4.09 ( 0.016 )
    Statistical analysis title
    		 Plasma alkaline phosphatase at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [45]
    P-value
    		 = 0.98
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [45] - Test for difference
    Statistical analysis title
    		 Plasma alkaline phosphatase at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [46]
    P-value
    		 = 0.99
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [46] - Test for difference
    Statistical analysis title
    		 Plasma alkaline phosphatase at 12 months
    Comparison groups
    50 μg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [47]
    P-value
    		 = 1
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [47] - Test for difference

    Secondary: Total cholesterol at 12 months

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    End point title
    		 Total cholesterol at 12 months
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: mmol/L
        arithmetic mean (standard error)
    5.26 ( 0.063 )
    5.22 ( 0.064 )
    5.29 ( 0.063 )
    Statistical analysis title
    		 Total cholesterol at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [48]
    P-value
    		 = 0.7
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [48] - Test for difference
    Statistical analysis title
    		 Total cholesterol at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [49]
    P-value
    		 = 0.7
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [49] - Test for difference
    Statistical analysis title
    		 Total cholesterol at 12 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [50]
    P-value
    		 = 0.45
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [50] - Test for difference

    Secondary: LDL cholesterol at 12 months

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    End point title
    		 LDL cholesterol at 12 months
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: mmol/L
        arithmetic mean (standard error)
    2.85 ( 0.05 )
    2.83 ( 0.05 )
    2.83 ( 0.05 )
    Statistical analysis title
    		 LDL cholesterol at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [51]
    P-value
    		 = 0.89
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [51] - Test for difference
    Statistical analysis title
    		 LDL cholesterol at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [52]
    P-value
    		 = 0.86
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [52] - Test for difference
    Statistical analysis title
    		 LDL cholesterol at 12 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [53]
    P-value
    		 = 0.97
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [53] - Test for difference

    Secondary: HDL cholesterol at 12 months

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    End point title
    		 HDL cholesterol at 12 months
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: mmol/L
        arithmetic mean (standard error)
    1.47 ( 0.016 )
    1.46 ( 0.016 )
    1.51 ( 0.016 )
    Statistical analysis title
    		 HDL cholesterol at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [54]
    P-value
    		 = 0.74
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [54] - Test for difference
    Statistical analysis title
    		 HDL cholesterol at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [55]
    P-value
    		 = 0.06
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [55] - Test for difference
    Statistical analysis title
    		 HDL cholesterol at 12 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [56]
    P-value
    		 = 0.0278
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [56] - Test for difference

    Secondary: Triglycerides at 12 months

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    End point title
    		 Triglycerides at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: mmol/L
        arithmetic mean (standard error)
    1.7 ( 0.067 )
    1.72 ( 0.068 )
    1.66 ( 0.067 )
    Statistical analysis title
    		 Triglycerides at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [57]
    P-value
    		 = 0.82
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [57] - Test for difference
    Statistical analysis title
    		 Triglycerides at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [58]
    P-value
    		 = 0.71
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [58] - Test for difference
    Statistical analysis title
    		 Triglycerides at 12 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [59]
    P-value
    		 = 0.55
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [59] - Test for difference

    Secondary: Apolipoprotein A1 at 12 months

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    End point title
    		 Apolipoprotein A1 at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: mg/dL
        arithmetic mean (standard error)
    139 ( 1 )
    138 ( 1 )
    142 ( 1 )
    Statistical analysis title
    		 Apolipoprotein A1 at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [60]
    P-value
    		 = 0.62
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [60] - Test for difference
    Statistical analysis title
    		 Apolipoprotein A1 at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [61]
    P-value
    		 = 0.09
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [61] - Test for difference
    Statistical analysis title
    		 Apolipoprotein A1 at 12 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [62]
    P-value
    		 = 0.0296
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [62] - Test for difference

    Secondary: Apolipoprotein B at 12 months

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    End point title
    		 Apolipoprotein B at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: mg/dL
        arithmetic mean (standard error)
    94 ( 1.3 )
    94 ( 1.3 )
    94 ( 1.3 )
    Statistical analysis title
    		 Apolipoprotein B at 12 months
    Comparison groups
    50 μg D3 v 100 µg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [63]
    P-value
    		 = 0.98
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [63] - Test for difference
    Statistical analysis title
    		 Apolipoprotein B at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [64]
    P-value
    		 = 0.95
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [64] - Test for difference
    Statistical analysis title
    		 Apolipoprotein B at 12 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [65]
    P-value
    		 = 0.97
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [65] - Test for difference

    Secondary: hsCRP at 6 months

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    End point title
    		 hsCRP at 6 months
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: ln mg/dL
        arithmetic mean (standard error)
    4.9 ( 0.007 )
    4.91 ( 0.007 )
    4.92 ( 0.007 )
    Statistical analysis title
    		 hsCRP at 6 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [66]
    P-value
    		 = 0.23
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [66] - Test for difference
    Statistical analysis title
    		 hsCRP at 6 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [67]
    P-value
    		 = 0.16
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [67] - Test for difference
    Statistical analysis title
    		 hsCRP at 6 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [68]
    P-value
    		 = 0.82
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [68] - Test for difference

    Secondary: hsCRP at 12 months

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    End point title
    		 hsCRP at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: ln mg/dL
        arithmetic mean (standard error)
    4.92 ( 0.007 )
    4.92 ( 0.007 )
    4.94 ( 0.007 )
    Statistical analysis title
    		 hsCRP at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [69]
    P-value
    		 = 0.63
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [69] - Test for difference
    Statistical analysis title
    		 hsCRP at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [70]
    P-value
    		 = 0.08
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [70] - Test for difference
    Statistical analysis title
    		 hsCRP at 12 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [71]
    P-value
    		 = 0.0259
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [71] - Test for difference

    Secondary: NT-proBNP at 12 months

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    End point title
    		 NT-proBNP at 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: ln pg/mL
        arithmetic mean (standard error)
    6.17 ( 0.056 )
    6.04 ( 0.057 )
    6.23 ( 0.058 )
    Statistical analysis title
    		 NT-proBNP at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [72]
    P-value
    		 = 0.11
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [72] - Test for difference
    Statistical analysis title
    		 NT-proBNP at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [73]
    P-value
    		 = 0.52
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [73] - Test for difference
    Statistical analysis title
    		 NT-proBNP at 12 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [74]
    P-value
    		 = 0.0281
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [74] - Test for difference

    Secondary: Systolic blood pressure at 6 months

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    End point title
    		 Systolic blood pressure at 6 months
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: mmHg
        arithmetic mean (standard error)
    129.7 ( 1.31 )
    129.9 ( 1.36 )
    127.8 ( 1.44 )
    Statistical analysis title
    		 Systolic blood pressure at 6 months
    Comparison groups
    50 μg D3 v 100 µg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [75]
    P-value
    		 = 0.9
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [75] - Test for difference
    Statistical analysis title
    		 Systolic blood pressure at 6 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [76]
    P-value
    		 = 0.34
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [76] - Test for difference
    Statistical analysis title
    		 Systolic blood pressure at 6 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [77]
    P-value
    		 = 0.29
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [77] - Test for difference

    Secondary: Systolic blood pressure at 12 months

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    End point title
    		 Systolic blood pressure at 12 months
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: mmHg
        arithmetic mean (standard error)
    132.5 ( 1.43 )
    131.8 ( 1.51 )
    131.8 ( 1.51 )
    Statistical analysis title
    		 Systolic blood pressure at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [78]
    P-value
    		 = 0.73
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [78] - Test for difference
    Statistical analysis title
    		 Systolic blood pressure at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [79]
    P-value
    		 = 0.71
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [79] - Test for difference
    Statistical analysis title
    		 Systolic blood pressure at 12 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [80]
    P-value
    		 = 0.98
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [80] - Test for difference

    Secondary: Diastolic blood pressure at 6 months

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    End point title
    		 Diastolic blood pressure at 6 months
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: mmHg
        arithmetic mean (standard error)
    75.9 ( 0.91 )
    76.5 ( 0.95 )
    75.5 ( 1.02 )
    Statistical analysis title
    		 Diastolic blood pressure at 6 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [81]
    P-value
    		 = 0.63
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [81] - Test for difference
    Statistical analysis title
    		 Diastolic blood pressure at 6 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [82]
    P-value
    		 = 0.81
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [82] - Test for difference
    Statistical analysis title
    		 Diastolic blood pressure at 6 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [83]
    P-value
    		 = 0.49
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [83] - Test for difference

    Secondary: Diastolic blood pressure at 12 months

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    End point title
    		 Diastolic blood pressure at 12 months
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: mmHg
        arithmetic mean (standard error)
    77.2 ( 0.89 )
    77 ( 0.94 )
    76.6 ( 0.96 )
    Statistical analysis title
    		 Diastolic blood pressure at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [84]
    P-value
    		 = 0.92
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [84] - Test for difference
    Statistical analysis title
    		 Diastolic blood pressure at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [85]
    P-value
    		 = 0.65
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [85] - Test for difference
    Statistical analysis title
    		 Diastolic blood pressure at 12 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [86]
    P-value
    		 = 0.73
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [86] - Test for difference

    Secondary: Heart rate at 6 months

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    End point title
    		 Heart rate at 6 months
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: beats/min
        arithmetic mean (standard error)
    64.9 ( 0.81 )
    65.3 ( 0.85 )
    66.7 ( 0.92 )
    Statistical analysis title
    		 Heart rate at 6 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [87]
    P-value
    		 = 0.71
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [87] - Test for difference
    Statistical analysis title
    		 Heart rate at 6 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [88]
    P-value
    		 = 0.14
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [88] - Test for difference
    Statistical analysis title
    		 Heart rate at 6 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [89]
    P-value
    		 = 0.27
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [89] - Test for difference

    Secondary: Heart rate at 12 months

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    End point title
    		 Heart rate at 12 months
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: beats/min
        arithmetic mean (standard error)
    66 ( 0.84 )
    66.4 ( 0.87 )
    67 ( 0.87 )
    Statistical analysis title
    		 Heart rate at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [90]
    P-value
    		 = 0.72
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [90] - Test for difference
    Statistical analysis title
    		 Heart rate at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [91]
    P-value
    		 = 0.4
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [91] - Test for difference
    Statistical analysis title
    		 Heart rate at 12 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [92]
    P-value
    		 = 0.64
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [92] - Test for difference

    Secondary: Pulse trace stiffness index at 6 months

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    End point title
    		 Pulse trace stiffness index at 6 months
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: m/s
        arithmetic mean (standard error)
    9.6 ( 0.25 )
    9.6 ( 0.24 )
    9.5 ( 0.24 )
    Statistical analysis title
    		 Pulse trace stiffness index at 6 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [93]
    P-value
    		 = 0.83
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [93] - Test for difference
    Statistical analysis title
    		 Pulse trace stiffness index at 6 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [94]
    P-value
    		 = 0.7
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [94] - Test for difference
    Statistical analysis title
    		 Pulse trace stiffness index at 6 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [95]
    P-value
    		 = 0.85
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [95] - Test for difference

    Secondary: Pulse trace stiffness index at 12 months

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    End point title
    		 Pulse trace stiffness index at 12 months
    End point description
    Adjusted for baseline values with missing data imputed using multiple imputation.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 100 µg D3 50 μg D3 Placebo
    Number of subjects analysed
    102
    102
    101
    Units: m/s
        arithmetic mean (standard error)
    9.4 ( 0.28 )
    9.4 ( 0.27 )
    9.5 ( 0.36 )
    Statistical analysis title
    		 Pulse trace stiffness index at 12 months
    Comparison groups
    100 µg D3 v 50 μg D3
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [96]
    P-value
    		 = 0.96
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [96] - Test for difference
    Statistical analysis title
    		 Pulse trace stiffness index at 12 months
    Comparison groups
    100 µg D3 v Placebo
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [97]
    P-value
    		 = 0.94
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [97] - Test for difference
    Statistical analysis title
    		 Pulse trace stiffness index at 12 months
    Comparison groups
    Placebo v 50 μg D3
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 other [98]
    P-value
    		 = 0.98
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [98] - Test for difference

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 months
    Adverse event reporting additional description
    All serious adverse events were reported on the electronic case report form, but only those non-serious adverse events that were thought to be related to the study treatment and resulted in the participant stopping treatment were reported.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14
    Reporting groups
    Reporting group title
    100 µg D3
    Reporting group description
    		 Randomised to vitamin D3 100 µg (4000 IU) daily

    Reporting group title
    50 µg D3
    Reporting group description
    		 Randomised to vitamin D3 50 μg (2000 IU) daily

    Reporting group title
    Placebo
    Reporting group description
    		 Randomised to placebo

    Serious adverse events
    		 100 µg D3 50 µg D3 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 102 (28.43%)
    30 / 102 (29.41%)
    25 / 101 (24.75%)
         number of deaths (all causes)
    0
    0
    3
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gastric cancer
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Malignant respiratory tract neoplasm
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple myeloma
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parathyroid tumour malignant
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 102 (1.96%)
    3 / 101 (2.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Dupuytren's contracture operation
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye operation
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip arthroplasty
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    3 / 101 (2.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 102 (1.96%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parathyroidectomy
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transurethral bladder resection
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Arthroscopy
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 102 (1.96%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 102 (1.96%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eye disorder
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye haemorrhage
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Dyspepsia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Ankylosing spondylitis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    2 / 102 (1.96%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 102 (0.98%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    2 / 102 (1.96%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 100 µg D3 50 µg D3 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 102 (8.82%)
    8 / 102 (7.84%)
    8 / 101 (7.92%)
    Investigations
    Cystoscopy
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    1
    Vascular test
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Eye disorder
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences all number
    0
    1
    0
    Uveitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    0 / 101 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 102 (0.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 102 (0.98%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Genitourinary tract infection
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 102 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    8 / 102 (7.84%)
    4 / 102 (3.92%)
    4 / 101 (3.96%)
         occurrences all number
    8
    4
    4

    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/25721698
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