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    Clinical Trial Results:
    THE EFFECT OF A DAILY AND WEEKLY ADMINISTRATION OF DIFFERENT DOSES OF CALCIDIOL ON 25(OH)D3 SERUM LEVELS AND ON MINERAL AND BONE METABOLIC MARKERS IN POSTMENOPAUSAL FEMALE SUBJECTS OVER 55 YEARS OF AGE WITH INADEQUATE LEVELS OR DEFICIT OF 25(OH)D3

    Summary
    EudraCT number
    		 2013-002648-10
    Trial protocol
    		 IT  
    Global end of trial date
    03 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Mar 2020
    First version publication date
    21 Mar 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ADDI-D
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bruno Farmaceutici S.p.a
    Sponsor organisation address
    Via delle Ande 15, Rome, Italy, 00144
    Public contact
    Reception, Bruno Farmaceutici S.p.a., +39 (0)66050601, adriana.pignatelli@brunofarmaceutici.it
    Scientific contact
    Reception, Bruno Farmaceutici S.p.a., +39 (0)66050601, adriana.pignatelli@brunofarmaceutici.it
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 May 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effects on the increase of circulating levels of 25(OH)D3 of three different therapeutic regimens of Calcidiol (Didrogyl)
    Protection of trial subjects
    Laboratory examinations were performed at each visit to identify potential adverse events that may cause pain and distress in patients involved in the study
    Background therapy
    		 No treatment that are not tests or comparator products were used across all arms in the trial.
    Evidence for comparator
    		 No comparators were used in this trial.
    Actual start date of recruitment
    01 Mar 2014
    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
    Italy: 84
    Worldwide total number of subjects
    84
    EEA total number of subjects
    84
    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)
    30
    From 65 to 84 years
    54
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited in two hospitals in Italy from March 2014 to June 2015. Postmenopausal female subjects, aged >55, with inadequate levels or deficit of 25(OH)D3, were enrolled. 87 patient were enrolled; three of them did not assume any treatment and were excluded from all analysis.

    Pre-assignment
    Screening details
    		 Potentially eligible women were subjected to an assessment visit, consisting of medical history, clinical (vitals, weight, height, physical examination including blood pressure and pulse rate), and biochemical evaluations. An estimate of calcium intake was performed by administering a specific nutritional questionnaire.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Baseline 4 drops
    Arm description
    		 This arm included patients receiving oral calcidiol 20 μg (Didrogyl® 4 drops) daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Didrogyl®
    Investigational medicinal product code
    Other name
    oral calcidiol
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    20 μg daily

    Arm title
    		 Baseline 8 drops
    Arm description
    		 This arm included patients receiving calcidiol 40 μg (Didrogyl® 8 drops) daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Didrogyl®
    Investigational medicinal product code
    Other name
    oral calcidiol
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 μg daily

    Arm title
    		 Baseline 25 drops
    Arm description
    		 This arm included patients receiving 125 μg of oral calcidiol (Didrogyl® 25 drops) weekly.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Didrogyl®
    Investigational medicinal product code
    Other name
    oral calcidiol
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    125 μg of oral calcidiol weekly

    Number of subjects in period 1
    		Baseline 4 drops Baseline 8 drops Baseline 25 drops
    Started
    27
    28
    29
    Completed
    27
    28
    29
    Period 2
    Period 2 title
    Visit 7
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Visit 7 4 drops
    Arm description
    		 This arm included patients receiving oral calcidiol 20 μg (Didrogyl® 4 drops) daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Didrogyl®
    Investigational medicinal product code
    Other name
    oral calcidiol
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    20 μg daily

    Arm title
    		 Visit 7 8 drops
    Arm description
    		 This arm included patients receiving oral calcidiol 20 μg (Didrogyl® 4 drops) daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Didrogyl®
    Investigational medicinal product code
    Other name
    oral calcidiol
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    40 μg daily

    Arm title
    		 Visit 7 25 drops
    Arm description
    		 This arm included patients receiving 125 μg of oral calcidiol (Didrogyl® 25 drops) weekly.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Didrogyl®
    Investigational medicinal product code
    Other name
    oral calcidiol
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    125 μg of oral calcidiol weekly

    Number of subjects in period 2
    		Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Started
    27
    28
    29
    Completed
    27
    28
    29

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline 4 drops
    Reporting group description
    		 This arm included patients receiving oral calcidiol 20 μg (Didrogyl® 4 drops) daily.

    Reporting group title
    Baseline 8 drops
    Reporting group description
    		 This arm included patients receiving calcidiol 40 μg (Didrogyl® 8 drops) daily.

    Reporting group title
    Baseline 25 drops
    Reporting group description
    		 This arm included patients receiving 125 μg of oral calcidiol (Didrogyl® 25 drops) weekly.

    Reporting group values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Total
    Number of subjects
    		 27 28 29 84
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 17 18 19 54
        From 65-84 years
    		 10 10 10 30
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.9 ± 7.98 64.4 ± 6.80 66.2 ± 7.83 -
    Gender categorical
    Units: Subjects
        Female
    		 27 28 29 84
        Male
    		 0 0 0 0
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 160.0 ± 7.36 160.9 ± 6.68 158.7 ± 6.27 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 63.9 ± 7.26 64.0 ± 8.58 62.9 ± 9.90 -
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 25.0 ± 3.04 24.7 ± 2.63 25.0 ± 3.78 -
    Body Surface Area
    Units: m^2
        arithmetic mean (standard deviation)
    		 1.7 ± 0.11 1.7 ± 0.14 1.7 ± 0.14 -
    Age of menache
    Units: Years
        arithmetic mean (standard deviation)
    		 12.6 ± 1.64 12.4 ± 1.50 13.1 ± 1.75 -
    Age of Menopause
    Units: Years
        arithmetic mean (standard deviation)
    		 47.6 ± 5.82 49.3 ± 3.60 49.0 ± 5.30 -
    Calcium Intake
    Units: mg
        arithmetic mean (standard deviation)
    		 1035.7 ± 323.63 912.8 ± 386.42 964.6 ± 426.74 -

    End points

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    End points reporting groups
    Reporting group title
    Baseline 4 drops
    Reporting group description
    		 This arm included patients receiving oral calcidiol 20 μg (Didrogyl® 4 drops) daily.

    Reporting group title
    Baseline 8 drops
    Reporting group description
    		 This arm included patients receiving calcidiol 40 μg (Didrogyl® 8 drops) daily.

    Reporting group title
    Baseline 25 drops
    Reporting group description
    		 This arm included patients receiving 125 μg of oral calcidiol (Didrogyl® 25 drops) weekly.
    Reporting group title
    Visit 7 4 drops
    Reporting group description
    		 This arm included patients receiving oral calcidiol 20 μg (Didrogyl® 4 drops) daily.

    Reporting group title
    Visit 7 8 drops
    Reporting group description
    		 This arm included patients receiving oral calcidiol 20 μg (Didrogyl® 4 drops) daily.

    Reporting group title
    Visit 7 25 drops
    Reporting group description
    		 This arm included patients receiving 125 μg of oral calcidiol (Didrogyl® 25 drops) weekly.

    Primary: Plasma levels of 25(OH)D3

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    End point title
    		 Plasma levels of 25(OH)D3
    End point description
    Plasma levels were measured also in other time-points: screening, visit 2 (day 7), visit 3 (day 14), visit 4 (day 21), visit 5 (day 30), visit 6 (day 60). These data are reported in the attached table.
    End point type
    Primary
    End point timeframe
    At the visit 1 (day 1) and visit 7 (day 90)
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    27
    28
    29
    26
    28
    28
    Units: ng/ml
        arithmetic mean (standard deviation)
    15.4 ± 7.07
    18.2 ± 6.56
    16.4 ± 8.52
    49.3 ± 19.46
    74.8 ± 22.47
    46.4 ± 15.05
    Attachments
    		 Untitled (Filename: Plasma levels of Vitamin D.pdf)
    Statistical analysis title
    		 Change from baseline 4
    Comparison groups
    Baseline 4 drops v Visit 7 4 drops
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -34.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -40.99
         upper limit
    		 -28.02
    Variability estimate
    Standard deviation
    Dispersion value
    16.1
    Statistical analysis title
    		 Change from baseline 8
    Comparison groups
    Baseline 8 drops v Visit 7 8 drops
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -57.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -67.25
         upper limit
    		 -48.63
    Variability estimate
    Standard deviation
    Dispersion value
    24
    Statistical analysis title
    		 Change from baseline 25
    Comparison groups
    Baseline 25 drops v Visit 7 25 drops
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -29.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.1
         upper limit
    		 -22.86
    Variability estimate
    Standard deviation
    Dispersion value
    17.1

    Primary: Plasma levels of vitamin D 1,25(OH)D3

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    End point title
    		 Plasma levels of vitamin D 1,25(OH)D3 [1]
    End point description
    End point type
    Primary
    End point timeframe
    At the screening visit and visit 7
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No differences between treatment groups were found.
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops
    Number of subjects analysed
    26 [2]
    28 [3]
    28 [4]
    Units: ng/ml
    arithmetic mean (standard deviation)
        Screening
    0.07 ± 0.024
    0.07 ± 0.023
    0.06 ± 0.026
        Visit 7
    0.1 ± 0.02
    0.1 ± 0.03
    0.1 ± 0.02
    Notes
    [2] - In the screening visit 19 subjects were considered
    [3] - In the screening visit 21 subjects were considered
    [4] - In the screening visit 22 subjects were considered
    No statistical analyses for this end point

    Secondary: Serum calcium

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    End point title
    		 Serum calcium
    End point description
    Plasma levels were measured also in other time-points: visit 1 (day 1), visit 2 (day 7), visit 3 (day 14), visit 4 (day 21), visit 5 (day 30), visit 6 (day 60). These data are reported in the attached table.
    End point type
    Secondary
    End point timeframe
    In the screening visit and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    12
    15
    14
    26
    28
    28
    Units: mg/dl
        arithmetic mean (standard deviation)
    8.7 ± 0.39
    8.9 ± 0.47
    9.0 ± 0.61
    9.1 ± 0.76
    9.0 ± 1.13
    9.2 ± 0.44
    Attachments
    		 Untitled (Filename: Serum Calcium.pdf)
    No statistical analyses for this end point

    Secondary: Ionized Calcium

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    End point title
    		 Ionized Calcium
    End point description
    Plasma levels were measured also in other time-points: visit 1 (day 1), visit 2 (day 7), visit 3 (day 14), visit 4 (day 21), visit 5 (day 30), visit 6 (day 60). These data are reported in the attached table.
    End point type
    Secondary
    End point timeframe
    In the screening visit and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    12
    14
    14
    25
    28
    28
    Units: mg/dl
        arithmetic mean (standard deviation)
    4.9 ± 0.14
    5.0 ± 0.11
    5.0 ± 0.27
    5.1 ± 0.23
    5.1 ± 0.22
    5.1 ± 0.22
    Attachments
    		 Ionized calcium
    No statistical analyses for this end point

    Secondary: Inorganic Phosphate

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    End point title
    		 Inorganic Phosphate
    End point description
    Plasma levels were measured also in other time-points: visit 1 (day 1), visit 2 (day 7), visit 3 (day 14), visit 4 (day 21), visit 5 (day 30), visit 6 (day 60). These data are reported in the attached table.
    End point type
    Secondary
    End point timeframe
    In the screening and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    12
    15
    14
    26
    28
    28
    Units: mg/dl
        arithmetic mean (standard deviation)
    3.5 ± 0.52
    3.3 ± 0.79
    3.5 ± 0.64
    3.5 ± 5.8
    3.5 ± 0.56
    3.7 ± 0.56
    Attachments
    		 Inorganic Phosphate
    No statistical analyses for this end point

    Secondary: Bone Alkaline Phosphatase

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    End point title
    		 Bone Alkaline Phosphatase
    End point description
    Plasma levels were measured also in other time-points: visit 1 (day 1), visit 2 (day 7), visit 3 (day 14), visit 4 (day 21), visit 5 (day 30), visit 6 (day 60). These data are reported in the attached table.
    End point type
    Secondary
    End point timeframe
    In the screening visit and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    11
    15
    14
    26
    26
    28
    Units: μg/L
        arithmetic mean (standard deviation)
    21.7 ± 20.17
    18.2 ± 5.43
    19.7 ± 9.59
    17.8 ± 11.58
    15.6 ± 5.53
    16.7 ± 6.82
    Attachments
    		 Bone alkaline phosphatase
    No statistical analyses for this end point

    Secondary: C-terminal telopeptides of Type I collagen

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    End point title
    		 C-terminal telopeptides of Type I collagen
    End point description
    Plasma levels were measured also in other time-points: visit 1 (day 1), visit 2 (day 7), visit 3 (day 14), visit 4 (day 21), visit 5 (day 30), visit 6 (day 60). These data are reported in the attached table.
    End point type
    Secondary
    End point timeframe
    In the screening visit and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    12
    15
    14
    26
    28
    28
    Units: ng/ml
        arithmetic mean (standard deviation)
    0.3 ± 0.14
    0.4 ± 0.14
    0.4 ± 0.23
    0.3 ± 0.17
    0.3 ± 0.14
    0.3 ± 0.23
    Attachments
    		 C-terminal telopeptide
    No statistical analyses for this end point

    Secondary: Parathyroid Hormones

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    End point title
    		 Parathyroid Hormones
    End point description
    End point type
    Secondary
    End point timeframe
    In the screening and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    19
    21
    22
    25
    26
    27
    Units: pmoli/L
        arithmetic mean (standard deviation)
    7.0 ± 2.35
    6.9 ± 2.46
    6.6 ± 3.19
    4.8 ± 1.62
    4.9 ± 2.34
    4.9 ± 2.71
    No statistical analyses for this end point

    Secondary: Fibroblast Growth Factor 23

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    End point title
    		 Fibroblast Growth Factor 23
    End point description
    End point type
    Secondary
    End point timeframe
    In the screening visit and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    27
    28
    29
    26
    27
    28
    Units: pg/mL
        arithmetic mean (standard deviation)
    16.2 ± 2.48
    35.8 ± 97.30
    33.0 ± 81.47
    18.7 ± 6.68
    20.2 ± 9.68
    20.7 ± 8.33
    No statistical analyses for this end point

    Secondary: Vitamin D Binding Protein (D-BP)

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    End point title
    		 Vitamin D Binding Protein (D-BP)
    End point description
    Plasma levels were measured also in other time-points: visit 1 (day 1), visit 2 (day 7), visit 3 (day 14), visit 4 (day 21), visit 5 (day 30), visit 6 (day 60). These data are reported in the attached table.
    End point type
    Secondary
    End point timeframe
    In the screening visit and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    12
    15
    15
    26
    28
    28
    Units: mg/mL
        arithmetic mean (standard deviation)
    373.4 ± 120.89
    337.1 ± 160.01
    380.6 ± 144.50
    426.2 ± 82.01
    486.4 ± 82.77
    499.2 ± 100.19
    Attachments
    		 Vitamin D binding protein
    No statistical analyses for this end point

    Secondary: Bone Alkaline Phosphatase

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    End point title
    		 Bone Alkaline Phosphatase
    End point description
    End point type
    Secondary
    End point timeframe
    In the screening visit and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    19
    23
    21
    26
    28
    28
    Units: μg/L
        arithmetic mean (standard deviation)
    81.7 ± 29.09
    82.9 ± 19.92
    81.6 ± 19.37
    85.7 ± 62.87
    72.5 ± 20.62
    79.0 ± 19.49
    No statistical analyses for this end point

    Secondary: Serum Creatinine

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    End point title
    		 Serum Creatinine
    End point description
    Plasma levels were measured also in other time-points: visit 1 (day 1), visit 2 (day 7), visit 3 (day 14), visit 4 (day 21), visit 5 (day 30), visit 6 (day 60). These data are reported in the attached table.
    End point type
    Secondary
    End point timeframe
    In the screening visit and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    12
    15
    15
    26
    28
    28
    Units: mg/dL
        arithmetic mean (standard deviation)
    0.7 ± 0.09
    0.7 ± 0.13
    0.8 ± 0.25
    0.7 ± 0.1
    0.7 ± 0.14
    0.8 ± 0.12
    Attachments
    		 Creatinine
    No statistical analyses for this end point

    Secondary: Total protein

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    End point title
    		 Total protein
    End point description
    Plasma levels were measured also in other time-points: visit 1 (day 1), visit 2 (day 7), visit 3 (day 14), visit 4 (day 21), visit 5 (day 30), visit 6 (day 60). These data are reported in the attached table.
    End point type
    Secondary
    End point timeframe
    In the screening visit and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    11
    15
    14
    26
    28
    28
    Units: g/dL
        arithmetic mean (standard deviation)
    7.0 ± 0.32
    7.3 ± 0.41
    7.0 ± 0.43
    7.1 ± 0.79
    7.1 ± 1.06
    7.2 ± 0.44
    Attachments
    		 Total protein
    No statistical analyses for this end point

    Secondary: Albumin

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    End point title
    		 Albumin
    End point description
    Plasma levels were measured also in other time-points: visit 1 (day 1), visit 2 (day 7), visit 3 (day 14), visit 4 (day 21), visit 5 (day 30), visit 6 (day 60). These data are reported in the attached table.
    End point type
    Secondary
    End point timeframe
    In the screening visit and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    12
    15
    15
    26
    28
    28
    Units: g/L
        arithmetic mean (standard deviation)
    4.3 ± 0.23
    4.3 ± 0.34
    4.3 ± 0.39
    4.3 ± 0.55
    4.2 ± 0.61
    4.2 ± 0.39
    Attachments
    		 Albumin
    No statistical analyses for this end point

    Secondary: ALT, AST, γGT

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    End point title
    		 ALT, AST, γGT
    End point description
    End point type
    Secondary
    End point timeframe
    In the screening visit and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    19
    23 [5]
    22
    26
    28
    28
    Units: UI/L
    arithmetic mean (standard deviation)
        ALT
    21.2 ± 7.15
    19.4 ± 7.15
    22.7 ± 11.61
    21.2 ± 10.56
    20.5 ± 8.57
    23.1 ± 13.35
        AST
    18.1 ± 3.87
    16.7 ± 4.91
    19.5 ± 7.84
    17.9 ± 5.93
    17.9 ± 6.57
    19.1 ± 8.71
        GGT
    28.5 ± 15.75
    29.0 ± 26.55
    28.2 ± 21.41
    29.1 ± 42.28
    26.9 ± 20.87
    27.5 ± 23.24
    Notes
    [5] - Data of 22 subjects were available for GGT
    No statistical analyses for this end point

    Secondary: Sodium, Potassium, Chloride

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    End point title
    		 Sodium, Potassium, Chloride
    End point description
    End point type
    Secondary
    End point timeframe
    In the screening visit and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    18 [6]
    23 [7]
    21 [8]
    26 [9]
    28 [10]
    28
    Units: mEq/L
    arithmetic mean (standard deviation)
        Sodium
    138.8 ± 2.39
    139.3 ± 1.72
    138.9 ± 2.59
    139.2 ± 5.65
    137.5 ± 7.70
    139.6 ± 2.66
        Potassium
    4.1 ± 0.28
    4.3 ± 0.31
    4.2 ± 0.32
    4.3 ± 0.51
    4.3 ± 0.65
    4.2 ± 0.40
        Chloride
    103.8 ± 2.27
    104.2 ± 1.83
    104.3 ± 2.33
    103.6 ± 4.08
    102.5 ± 5.78
    103.6 ± 3.29
    Notes
    [6] - Data of 16 subjects were available for chloride
    [7] - Data of 22 subjects were available for potassium Data of 19subjects were available for chloride
    [8] - Data of 19 subjects were available for chloride
    [9] - Data of 25 subjects were available for potassium Data of 25 subjects were available for chloride
    [10] - Data of 26 subjects were available for chloride
    No statistical analyses for this end point

    Secondary: Urinary Calcium and Inorganic Phosphate

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    End point title
    		 Urinary Calcium and Inorganic Phosphate
    End point description
    Plasma levels were measured also in other time-points: visit 1 (day 1), visit 2 (day 7), visit 3 (day 14), visit 4 (day 21), visit 5 (day 30), visit 6 (day 60). These data are reported in the attached table.
    End point type
    Secondary
    End point timeframe
    In the screening visit and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    12
    14 [11]
    14 [12]
    26 [13]
    27
    28 [14]
    Units: mg/24H
    arithmetic mean (standard deviation)
        Calcium
    218.2 ± 86.23
    183.0 ± 177.05
    133.4 ± 80.62
    166.4 ± 101.94
    197.2 ± 112.19
    150.3 ± 106.09
        Phosphate
    794.3 ± 260.03
    664.2 ± 304.41
    597.5 ± 236.60
    523.0 ± 249.16
    547.6 ± 257.10
    571.2 ± 395.23
    Attachments
    		 Calcium and inorganic phosphate
    Notes
    [11] - Data of 15 subjects were available for phosphate
    [12] - Data of 15 subjects were available for phosphate
    [13] - Data of 24 subjects were available for phosphate
    [14] - Data of 27 subjects were available for phosphate
    No statistical analyses for this end point

    Secondary: Urinary Creatinine and Deoxypyridoline

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    End point title
    		 Urinary Creatinine and Deoxypyridoline
    End point description
    Plasma levels were measured also in other time-points: visit 1 (day 1), visit 2 (day 7), visit 3 (day 14), visit 4 (day 21), visit 5 (day 30), visit 6 (day 60). These data are reported in the attached table. Deoxypyridoline (DPD) was measured as nMol/mMol
    End point type
    Secondary
    End point timeframe
    In the screening visit and visit 7
    End point values
    		 Baseline 4 drops Baseline 8 drops Baseline 25 drops Visit 7 4 drops Visit 7 8 drops Visit 7 25 drops
    Number of subjects analysed
    12
    15
    15
    22 [15]
    22 [16]
    23 [17]
    Units: g/24H
    arithmetic mean (standard deviation)
        creatinine
    1.2 ± 0.35
    1.0 ± 0.40
    0.9 ± 0.25
    0.8 ± 0.57
    0.8 ± 0.53
    0.8 ± 0.53
        DPD
    7.2 ± 1.00
    8.1 ± 3.63
    7.4 ± 3.28
    7.8 ± 3.72
    6.6 ± 2.11
    7.4 ± 4.31
    Attachments
    		 Creatinine and DPD
    Notes
    [15] - Data of 26 subjects were available for DPD
    [16] - Data of 26 subjects were available for DPD
    [17] - Data of 28 subjects were available for DPD
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Screening visit to visit 7
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Overall population
    Reporting group description
    		 All patients who received at least one dose of drug were included in the safety analysis

    Serious adverse events
    		 Overall population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Overall population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    General disorders and administration site conditions
    Flu-like symptoms
         subjects affected / exposed
    4 / 5 (80.00%)
         occurrences all number
    4
    Endocrine disorders
    Hypercalcaemia
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences all number
    1

    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.
    No limitations and caveats are applicable to this summary of the results

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28815282
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