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    Clinical Trial Results:
    Treatment of Primary Hyperparathyroidism with Denosumab and Cinacalcet

    Summary
    EudraCT number
    		 2016-001510-20
    Trial protocol
    		 DK  
    Global end of trial date
    01 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Apr 2020
    First version publication date
    08 Apr 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    180987
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03027557
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aalborg University Hospital
    Sponsor organisation address
    Moelleparkvej 4, Aalborg, Denmark, 9000
    Public contact
    Department of Endocrinology, Aalborg University Hospital, p.vestergaard@rn.dk
    Scientific contact
    Department of Endocrinology, Aalborg University Hospital, p.vestergaard@rn.dk
    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
    12 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effects of Denosumab alone, and in combination with Cinacalcet, as a medical treatment for patients suffering from primary hyperparathyroidism, with mild osteoporosis. Patients included do not meet the criteria for, or have no wish for a surgical procedure. The main endpoints will be the effect of treatment on BMD and bone structure measured by DXA, VFA and QCT. Calcifications and the effect of treatment here on, in coronary arteries, the pancreas and kidneys will also be evaluated.
    Protection of trial subjects
    After completion all participants were referred to continued monitoring and management at the outpatient Clinic of the Department of Endocrinology, Aalborg University Hospital.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2017
    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
    Denmark: 46
    Worldwide total number of subjects
    46
    EEA total number of subjects
    46
    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)
    16
    From 65 to 84 years
    29
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 46 patients were recruited from March 14th 2017 to March 16th 2018. The trial ended with last patient last visit.

    Pre-assignment
    Screening details
    		 285 patients were screened for eligibility in relation to a visit in the Outpatient Clinic, the Department of Endocrinology, Aalborg University Hospital. 94 were invited to receive information about the study. 53 participated in a baseline examination and 46 were randomly allocated to the three study arms.

    Period 1
    Period 1 title
    Intervention-period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer, Assessor
    Blinding implementation details
    All investiagtors, subjects and data-assessors were blinded throughout the study until the end of data-analysis. All handling, distribution, ordering and accounting of medicine was performed by selected unblinded staff under strict division from blinded personelle. Monitors from the GCP-unit were allowed to investigate allocation/randomization and drug-handling. The intervention lasted 52 weeks followed by 2 weeks of followup. Blinding persisted until completion of data-analysis.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Denosumab + Placebo
    Arm description
    		 The participants in this arm were treated with denosumab-injections (60 mg s.c.) at baseline and week 24. They also received placebo for Mimpara (one tablet) daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    2
    Other name
    Prolia
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    60 mg s.c. from a prepacked syringe on the back of the upper arm twice a year.

    Investigational medicinal product name
    Placebo for Mimpara
    Investigational medicinal product code
    Placebo 2
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One coated tablet from an opaque cannister daily throughout the treatment-period.

    Arm title
    		 Cinacalcet + Denosumab
    Arm description
    		 The participants received the two active IMPs. Hence, they received Mimpara (cinacalcet, 30 mg, orally) once daily, and Prolia (denosumab, 60 mg, s.c.) at baseline and week 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cinacalcet
    Investigational medicinal product code
    1
    Other name
    Mimpara
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Mimpara (one tablet, 30 mg daily) was administered in an opaque cannister (28 pcs each).

    Investigational medicinal product name
    Denosumab
    Investigational medicinal product code
    2
    Other name
    Prolia
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    60 mg s.c. from a prepacked syringe on the back of the upper arm twice a year.

    Arm title
    		 Placebo
    Arm description
    		 The participants in this arm received placebo for Mimpara (placebo for cinacalcet) daily, and placebo for Prolia (placebo for denosumab) at baseline and week 24.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for Mimpara
    Investigational medicinal product code
    Placebo 2
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One coated tablet from an opaque cannister daily throughout the treatment-period.

    Investigational medicinal product name
    Placebo for Prolia
    Investigational medicinal product code
    Placebo 1
    Other name
    Placebo for denosumab (saline
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The placebo was a saline solution in a prepared syringe. Injections were given at the back of the upper arm at baseline and week 24. Participants were not allowed to see the syringe (which was also the case for the prolia-syringes in the other arms).

    Number of subjects in period 1
    		Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Started
    16
    15
    15
    Completed
    16
    14
    15
    Not completed
    0
    1
    0
         Adverse event, non-fatal
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Denosumab + Placebo
    Reporting group description
    		 The participants in this arm were treated with denosumab-injections (60 mg s.c.) at baseline and week 24. They also received placebo for Mimpara (one tablet) daily.

    Reporting group title
    Cinacalcet + Denosumab
    Reporting group description
    		 The participants received the two active IMPs. Hence, they received Mimpara (cinacalcet, 30 mg, orally) once daily, and Prolia (denosumab, 60 mg, s.c.) at baseline and week 24.

    Reporting group title
    Placebo
    Reporting group description
    		 The participants in this arm received placebo for Mimpara (placebo for cinacalcet) daily, and placebo for Prolia (placebo for denosumab) at baseline and week 24.

    Reporting group values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo Total
    Number of subjects
    		 16 15 15 46
    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
    Age was collected in relation to the baseline DXA-scans.
    Units: years
        arithmetic mean (standard deviation)
    		 65.4 ± 8.8 65.1 ± 13.2 68.0 ± 7.0 -
    Gender categorical
    Number of subjects
    Units: Subjects
        Female
    		 13 14 12 39
        Male
    		 3 1 3 7
    Nephrolithiasis
    Subjects with nephrolithiasis at baseline.
    Units: Subjects
        Yes
    		 3 0 1 4
        No
    		 13 15 14 42
    Nephrocalcinosis
    Subjects with nephrocalcinosis at baseline.
    Units: Subjects
        Yes
    		 1 2 3 6
        No
    		 15 13 12 40
    Pancreas calcifications
    Subjects with pancreatic calcifications at baseline.
    Units: Subjects
        Yes
    		 1 0 2 3
        No
    		 15 15 13 43
    Fracture by VFA
    Fracture by Vertebral Fracture Assessment at baseline.
    Units: Subjects
        Yes
    		 3 1 2 6
        No
    		 13 14 13 40
    BMI
    Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 27.4 ± 4.8 27.7 ± 3.5 28.4 ± 3.9 -
    T-score LS
    Baseline T-score of the lumbar spine by DXA.
    Units: T-score
        arithmetic mean (standard deviation)
    		 -2.0 ± 0.68 -1.9 ± 0.93 -1.3 ± 0.85 -
    T-score TH
    Baseline T-score Total Hip by DXA.
    Units: T-score
        arithmetic mean (standard deviation)
    		 -1.4 ± 0.6 -1.4 ± 0.5 -1.1 ± 0.5 -
    T-score FN
    Baseline T-score femoral neck by DXA.
    Units: T-score
        arithmetic mean (standard deviation)
    		 -1.9 ± 0.7 -2.0 ± 0.7 -1.7 ± 0.6 -
    T-score 1/3 FA
    Baseline T-score 1/3 distal forearm by DXA..
    Units: T-score
        arithmetic mean (standard deviation)
    		 -2.4 ± 1.2 -2.4 ± 1.2 -2.8 ± 0.9 -
    vBMD LS
    Baseline lumbar spine BMD by QCT
    Units: mg/cm^3
        arithmetic mean (standard deviation)
    		 99.7 ± 24 96.4 ± 28.1 94.2 ± 25.4 -
    vBMD distal forearm
    Bone Mineral Density at the distal forearm by QCT
    Units: mg/cm^3
        arithmetic mean (standard deviation)
    		 194.9 ± 37.6 183.5 ± 32.0 181.4 ± 35.5 -
    Cortical width .
    Baseline cortical Width of the distal forearm.
    Units: mm
        arithmetic mean (standard deviation)
    		 1.19 ± 0.5 1.23 ± 0.5 1.14 ± 0.4 -
    Ionized Calcium
    Baseline ionized calcium levels.
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 1.39 ± 0.078 1.39 ± 0.08 1.39 ± 0.08 -
    P-PTH
    Baseline Parathyroid Hormone level.
    Units: pmol/l
        arithmetic mean (standard deviation)
    		 13.1 ± 6.4 12.1 ± 6.2 11.2 ± 4.3 -
    Agatston Score
    Agatston Score Baseline.
    Units: Score-value
        median (inter-quartile range (Q1-Q3))
    		 10.1 (0.3 to 470.3) 4.9 (0.7 to 25.9) 55.7 (6.8 to 144.6) -
    mU-Calcium
    Baseline urine calcium excretion.
    Units: mg/d
        median (inter-quartile range (Q1-Q3))
    		 276 (218 to 555) 338 (159 to 419) 314 (222 to 373) -
    mU-Phosphorous
    Baseline daily excretion of phosphorous in urine.
    Units: mmol/d
        median (inter-quartile range (Q1-Q3))
    		 32.2 (26.5 to 37.0) 28.5 (25.7 to 33.6) 35.2 (23.6 to 39.5) -
    P-Phosphorous
    Baseline p-phosphorous.
    Units: mmol/l
        arithmetic mean (standard deviation)
    		 0.77 ± 0.16 0.77 ± 0.15 0.79 ± 0.12 -
    Major Depression Inventory score
    Baseline score
    Units: MDI-points
        median (inter-quartile range (Q1-Q3))
    		 5 (1.5 to 8.5) 5 (2 to 11) 5 (2 to 7) -

    End points

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    End points reporting groups
    Reporting group title
    Denosumab + Placebo
    Reporting group description
    		 The participants in this arm were treated with denosumab-injections (60 mg s.c.) at baseline and week 24. They also received placebo for Mimpara (one tablet) daily.

    Reporting group title
    Cinacalcet + Denosumab
    Reporting group description
    		 The participants received the two active IMPs. Hence, they received Mimpara (cinacalcet, 30 mg, orally) once daily, and Prolia (denosumab, 60 mg, s.c.) at baseline and week 24.

    Reporting group title
    Placebo
    Reporting group description
    		 The participants in this arm received placebo for Mimpara (placebo for cinacalcet) daily, and placebo for Prolia (placebo for denosumab) at baseline and week 24.

    Primary: Change in LS-BMD (DXA)

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    End point title
    		 Change in LS-BMD (DXA)
    End point description
    End point type
    Primary
    End point timeframe
    Baseline - End of Study. (One year of treatment.)
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: g/cm^2
        arithmetic mean (standard error)
    0.042 ± 0.009
    0.030 ± 0.009
    -0.016 ± 0.007
    Statistical analysis title
    		 Difference between treatment arms in LS-BMD
    Comparison groups
    Cinacalcet + Denosumab v Denosumab + Placebo v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.00001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Primary: Change in TH-BMD (DXA)

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    End point title
    		 Change in TH-BMD (DXA)
    End point description
    Results are given in g/cm^2
    End point type
    Primary
    End point timeframe
    Baseline - End of Study (One year of treatment.).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    14
    Units: mg/cm^2
        arithmetic mean (standard error)
    0.021 ± 0.003
    0.027 ± 0.006
    -0.013 ± 0.006
    Statistical analysis title
    		 Difference between treatment-arms in TH-BMD
    Statistical analysis description
    Change in absolute values.
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.00001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Primary: Change in FN-BMD (DXA)

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    End point title
    		 Change in FN-BMD (DXA)
    End point description
    Results are given in g/cm^2
    End point type
    Primary
    End point timeframe
    Baseline - End of Trial (One year of treatment.).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    14
    Units: mg/cm^2
        arithmetic mean (standard error)
    0.020 ± 0.005
    0.023 ± 0.006
    -0.007 ± 0.006
    Statistical analysis title
    		 Absolute change in FN-BMD
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0019
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Primary: Change in 1/3 FA-BMD (DXA)

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    End point title
    		 Change in 1/3 FA-BMD (DXA)
    End point description
    Results are given in g/cm^2
    End point type
    Primary
    End point timeframe
    Baseline - End of Study (One year of treatment.).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    15
    14
    15
    Units: mg/cm^2
        arithmetic mean (standard error)
    0.005 ± 0.003
    0.005 ± 0.003
    -0.005 ± 0.004
    Statistical analysis title
    		 Absolute change in 1/3 FA BMD
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.096
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Primary: Percentage Change in LS-BMD (DXA)

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    End point title
    		 Percentage Change in LS-BMD (DXA)
    End point description
    End point type
    Primary
    End point timeframe
    Baseline - End of Study (One year of treatment.).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: Percentage
        arithmetic mean (standard error)
    5.1 ± 1.1
    3.6 ± 1.1
    -1.8 ± 0.8
    Statistical analysis title
    		 Difference in percentage change between groups
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Primary: Percentage Change in TH-BMD (DXA)

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    End point title
    		 Percentage Change in TH-BMD (DXA)
    End point description
    End point type
    Primary
    End point timeframe
    Baseline - End of Study (One year of treatment.).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    14
    Units: Percentage
        arithmetic mean (standard error)
    2.64 ± 0.41
    3.45 ± 0.72
    -1.50 ± 0.72
    Statistical analysis title
    		 Difference in percentage change in TH-BMD
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.00001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Primary: Percentage Change in FN-BMD (DXA)

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    End point title
    		 Percentage Change in FN-BMD (DXA)
    End point description
    End point type
    Primary
    End point timeframe
    Baseline - End of Study (one year of treatment.).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    14
    Units: Percentage
        arithmetic mean (standard error)
    3.03 ± 0.86
    3.70 ± 0.98
    -0.78 ± 0.9
    Statistical analysis title
    		 Difference in FN-BMD in percentage change
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0027
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Primary: Percentage Change in 1/3 FA-BMD (DXA)

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    End point title
    		 Percentage Change in 1/3 FA-BMD (DXA)
    End point description
    End point type
    Primary
    End point timeframe
    Baseline - End of Study (one year of treatment.).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    15
    14
    15
    Units: Percentage
        arithmetic mean (standard error)
    0.88 ± 0.5
    0.94 ± 0.7
    -0.91 ± 0.7
    Statistical analysis title
    		 Difference in percentage change of 1/3 FA-BMD
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.081
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Secondary: Change in LS-vBMD (QCT)

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    End point title
    		 Change in LS-vBMD (QCT)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline - End of Study (one year of treatment.).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    13
    15
    Units: mg/cm^3
        arithmetic mean (standard error)
    5.35 ± 1.91
    4.93 ± 2.15
    -2.56 ± 1.6
    Statistical analysis title
    		 Difference in absolute change vBMD-LS
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0071
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Secondary: Percentage Change in LS-vBMD (QCT)

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    End point title
    		 Percentage Change in LS-vBMD (QCT)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline - End of Study (one year of treatment).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    13
    15
    Units: Percentage
        arithmetic mean (standard error)
    5.66 ± 1.85
    6.18 ± 3.14
    -2.94 ± 1.96
    Statistical analysis title
    		 Difference in percentage change of LS-vBMD
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.011
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Secondary: Change in Forearm-BMD (QCT)

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    End point title
    		 Change in Forearm-BMD (QCT)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline - End of Study (one year of treatment.).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    13
    12
    14
    Units: mg/cm^3
        arithmetic mean (standard error)
    9.6 ± 3.7
    1.0 ± 2.1
    -1.1 ± 4.6
    Statistical analysis title
    		 Difference in absolute change in FA-BMD
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0077
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Secondary: Percentage Change in Forearm-BMD (QCT)

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    End point title
    		 Percentage Change in Forearm-BMD (QCT)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline - End of Study (one year of treatment.).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    13
    12
    14
    Units: Percentage
        arithmetic mean (standard error)
    5.2 ± 1.0
    0.53 ± 1.2
    -0.74 ± 2.6
    Statistical analysis title
    		 Difference in percentage change in FA-BMD
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0065
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Secondary: Change in Cortical Width

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    End point title
    		 Change in Cortical Width
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline - End of Study (one year of treatment.).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    14
    12
    14
    Units: mm
        arithmetic mean (standard error)
    0.02 ± 0.08
    -0.04 ± 0.1
    0.04 ± 0.05
    Statistical analysis title
    		 Difference in change in cortical width
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Secondary: Mean p-calcium during treatment

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    End point title
    		 Mean p-calcium during treatment
    End point description
    Mean p-ion-calcium thorughout the treatment-period.
    End point type
    Secondary
    End point timeframe
    Baseline - End of Treatment
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16 [1]
    15 [2]
    15 [3]
    Units: mmol/l
        arithmetic mean (standard error)
    1.38 ± 0.006
    1.28 ± 0.007
    1.40 ± 0.004
    Notes
    [1] - 240 measurements
    [2] - 210 measurements
    [3] - 224 measurements
    Statistical analysis title
    		 Difference between treatment p-calcium levels
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Secondary: Mean treatment p-PTH level.

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    End point title
    		 Mean treatment p-PTH level.
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline - End of Treatment (52 weeks).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16 [4]
    15 [5]
    15 [6]
    Units: pmol/l
        median (confidence interval 95%)
    13.4 (12.7 to 14.2)
    12.0 (11.1 to 12.9)
    9.9 (9.5 to 10.4)
    Notes
    [4] - 240 measurements
    [5] - 211 measurements
    [6] - 225 measurements
    Statistical analysis title
    		 Difference in median p-PTH treatment-levels
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Kruskal-wallis
    Parameter type
    		 Median difference (net)
    Confidence interval

    Secondary: Mean treatment p-phosphate levels

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    End point title
    		 Mean treatment p-phosphate levels
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline - End of Treatment (52 weeks).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16 [7]
    15 [8]
    15 [9]
    Units: mmol/l
        arithmetic mean (standard error)
    0.76 ± 0.012
    0.83 ± 0.013
    0.083 ± 0.011
    Notes
    [7] - 240 measurements
    [8] - 211 measurements
    [9] - 225
    Statistical analysis title
    		 Difference in mean treatment p-phosphate levels
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.00001
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Secondary: Change in daily u-calcium excretion

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    End point title
    		 Change in daily u-calcium excretion
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline - End of Treatment (48 weeks).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    15
    14
    15
    Units: mg/d
        arithmetic mean (standard error)
    4.8 ± 40.0
    -23.1 ± 31.6
    0.2 ± 39.9
    Statistical analysis title
    		 Difference in change in u-calcium excretion
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Secondary: Change in daily u-phosphate excretion

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    End point title
    		 Change in daily u-phosphate excretion
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline - End of Treatement (48 weeks).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    15
    14
    15
    Units: mmol/d
        arithmetic mean (standard error)
    3.21 ± 2.3
    -3.27 ± 3.0
    1.28 ± 1.8
    Statistical analysis title
    		 Difference in change in u-phosphate excretion
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.057
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Confidence interval

    Secondary: Change in p-CTX

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    End point title
    		 Change in p-CTX
    End point description
    Change in bone turnover marker - level.
    End point type
    Secondary
    End point timeframe
    Baseline vs week 48.
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    -58.2 (-76.7 to -44.3)
    -48.7 (-73.2 to -15.8)
    11.8 (1.96 to 40.0)
    Statistical analysis title
    		 Difference in CTX-development
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Kruskal-wallis
    Parameter type
    		 Median difference (net)
    Confidence interval

    Secondary: Change in p-P1NP

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    End point title
    		 Change in p-P1NP
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline vs week 48
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    -66.1 (-75.9 to -55.4)
    -63.1 (-66.9 to -57.2)
    17.8 (-11.0 to 31.5)
    Statistical analysis title
    		 Difference in change in p-P1NP
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Kruskal-wallis
    Parameter type
    		 Median difference (net)
    Confidence interval

    Secondary: Change in p-Osteocalcin

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    End point title
    		 Change in p-Osteocalcin
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline vs. wk 48
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    -58.9 (-66.9 to -49.0)
    -60.0 (-69.8 to -36.9)
    7.0 (-0.9 to 36.9)
    Statistical analysis title
    		 Difference in change of p-osteocalcin
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Median difference (net)
    Confidence interval

    Secondary: Change in s- BAP

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    End point title
    		 Change in s- BAP
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline vs. week 48
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    -46.3 (-51.5 to -38.4)
    -40.0 (-46.3 to -24.1)
    9.7 (-7.9 to 32.5)
    Statistical analysis title
    		 Difference in change in s-BAP
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Kruskal-wallis
    Parameter type
    		 Median difference (net)
    Confidence interval

    Secondary: Change in p-Trap5b

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    End point title
    		 Change in p-Trap5b
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline vs wk 48
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    -36.7 (-51.8 to -16.4)
    -27.8 (-34.1 to -2.3)
    2.3 (-4.9 to 19.6)
    Statistical analysis title
    		 Difference in change in s-Trap5b
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 ANOVA
    Parameter type
    		 Median difference (net)
    Confidence interval

    Secondary: Change in p-sclerostin

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    End point title
    		 Change in p-sclerostin
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline vs. wk 48
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    6.5 (0.9 to 15.9)
    10.0 (3.1 to 21.1)
    4.8 (-2.3 to 13.9)
    Statistical analysis title
    		 Difference in change in p-sclerostin
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5
    Method
    		 Kruskal-wallis
    Parameter type
    		 Median difference (net)
    Confidence interval

    Secondary: Change in p-FGF23

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    End point title
    		 Change in p-FGF23
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline vs wk 48.
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    20.4 (-13.6 to 58.2)
    35.8 (0.0 to 52.9)
    28.0 (-25.9 to 64.7)
    Statistical analysis title
    		 Difference in change in p-FGF23
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.85
    Method
    		 ANOVA
    Parameter type
    		 Median difference (net)
    Confidence interval

    Secondary: Change in p 25 vit D

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    End point title
    		 Change in p 25 vit D
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline vs wk 48
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: nmol/l
        median (inter-quartile range (Q1-Q3))
    16.0 (4.1 to 22.0)
    22.1 (13.3 to 32.6)
    21.2 (8.2 to 30.5)
    Statistical analysis title
    		 Difference in change in p-25-vitD
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.22
    Method
    		 ANOVA
    Parameter type
    		 Median difference (net)
    Confidence interval

    Secondary: Change in s-1,25-vitD

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    End point title
    		 Change in s-1,25-vitD
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline vs wk 48
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: pmol/l
        median (inter-quartile range (Q1-Q3))
    4.5 (-15.0 to 25.5)
    7.5 (-4.0 to 35.0)
    26.0 (14.0 to 36.0)
    Statistical analysis title
    		 Difference in change in s-1,25-vitD
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 Kruskal-wallis
    Parameter type
    		 Median difference (net)
    Confidence interval

    Secondary: Median Agatstons Score Final

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    End point title
    		 Median Agatstons Score Final
    End point description
    There was no significant difference in agatstons-score development between the arms.
    End point type
    Secondary
    End point timeframe
    Baseline vs. End of Study (one year of treatment.).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    12
    13
    Units: Agatston Score
        median (inter-quartile range (Q1-Q3))
    24.3 (0.7 to 602.1)
    5.0 (0.0 to 78.1)
    117.8 (6.8 to 182.6)
    Statistical analysis title
    		 Difference in final agaston score
    Comparison groups
    Denosumab + Placebo v Cinacalcet + Denosumab v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 Kruskal-wallis
    Parameter type
    		 Median difference (net)
    Confidence interval

    Secondary: Patients with nephrolithiasis final scan.

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    End point title
    		 Patients with nephrolithiasis final scan.
    End point description
    No new cases of nephrolithiasis emerged/developed during the study-period. Severity/size similarly remained unchanged.
    End point type
    Secondary
    End point timeframe
    Final scan
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: Number of affected patients.
    3
    0
    1
    No statistical analyses for this end point

    Secondary: Patients with nephrocalcinosis final scan.

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    End point title
    		 Patients with nephrocalcinosis final scan.
    End point description
    No new cases occured at the final scan. Severity similaly remained unchanged.
    End point type
    Secondary
    End point timeframe
    Final scan
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: Number of patients with nephrocalcinosis
    1
    2
    3
    No statistical analyses for this end point

    Secondary: Patients with pancreas-calcifications final scan.

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    End point title
    		 Patients with pancreas-calcifications final scan.
    End point description
    No Development in number or size from baseline.
    End point type
    Secondary
    End point timeframe
    Final scan.
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: Affected patients
    1
    0
    2
    No statistical analyses for this end point

    Secondary: Change MDI-score

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    End point title
    		 Change MDI-score
    End point description
    Median change in MDI-score
    End point type
    Secondary
    End point timeframe
    Baseline vs wk 52
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: MDI-score
        median (inter-quartile range (Q1-Q3))
    -0.5 (-4.5 to 1.0)
    0.0 (-4.0 to 1.0)
    0.0 (-3.0 to 0.0)
    Statistical analysis title
    		 Difference in MDI-development.
    Comparison groups
    Cinacalcet + Denosumab v Placebo v Denosumab + Placebo
    Number of subjects included in analysis
    45
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83
    Method
    		 Kruskal-wallis
    Parameter type
    		 Median difference (net)
    Confidence interval

    Secondary: Vertebral Fracture Assessment - final scan

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    End point title
    		 Vertebral Fracture Assessment - final scan
    End point description
    No new vertebral fractures emerged during the treatment-period.
    End point type
    Secondary
    End point timeframe
    Final scan (week 52).
    End point values
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Number of subjects analysed
    16
    14
    15
    Units: Number of patients with fractures
    3
    1
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected for each participant from baseline until two weeks after treatment-cessation. Adverse events were thus collected from enrollment of first patient (March 14th 2017) until last patient's last visit (March 28th 2019).
    Adverse event reporting additional description
    Patients filled in a questionnaire at every visit (approx. every 4th week). The questionnaire contained prespecified symptoms (nausea and paraesthesia). And spaces for experienced "non-prespecified" symptoms. Patients were also interviewed by a physician at each visit. Reported symptoms (AE and SAE) were collected in an individual AE-report.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Denosumab + Placebo
    Reporting group description
    		 The participants in this arm were treated with denosumab-injections (60 mg s.c.) at baseline and week 24. They also received placebo for Mimpara (one tablet) daily.

    Reporting group title
    Cinacalcet + Denosumab
    Reporting group description
    		 The participants received the two active IMPs. Hence, they received Mimpara (cinacalcet, 30 mg, orally) once daily, and Prolia (denosumab, 60 mg, s.c.) at baseline and week 24.

    Reporting group title
    Placebo
    Reporting group description
    		 The participants in this arm received placebo for Mimpara (placebo for cinacalcet) daily, and placebo for Prolia (placebo for denosumab) at baseline and week 24.

    Serious adverse events
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    3 / 15 (20.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Angina unstable
    Additional description: Treated with PCI.
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
    Additional description: Investigated (including hospitalization) for atypical focal epilepsy at the department of neurology during her participation. Symptoms were present prior to enrollment in the study, and did not involve seizures or change during participation.
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 15 (0.00%)
    0 / 15 (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
    Polycythaemia vera
    Additional description: Diagnosed with polycytemia vera during participation. Followed at the department of haematology since.
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (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
    Gastrointestinal disorders
    Inflammatory bowel disease
    Additional description: One patient was diagnosed with Chron's Disease while participating. Symptoms had been present for a long time before enrollment, and continued after discontinuation of the study medicine. Had received treatment >6 months prior to diagnosis.
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 15 (6.67%)
    0 / 15 (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
    Gastritis
    Additional description: One participant was hospitalized for observation with suspected gastritis, which was not potentially life threatening or disabling, and the outcome had no sequelae.
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erysipelas
    Additional description: One patient had a traumatic skin-lesion while abroad. Was hospitalized and treated for a potential secondary erysipelas. Despite no fever, and low CRP, she was hospitalized for some days, and treated with antibiotics.
         subjects affected / exposed
    0 / 16 (0.00%)
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Denosumab + Placebo Cinacalcet + Denosumab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 16 (93.75%)
    13 / 15 (86.67%)
    15 / 15 (100.00%)
    Surgical and medical procedures
    Swelling
    Additional description: Leg edema
         subjects affected / exposed
    2 / 16 (12.50%)
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    7
    1
    0
    Nervous system disorders
    Paraesthesia hands
    Additional description: Paresthesia of the hands.
         subjects affected / exposed
    3 / 16 (18.75%)
    6 / 15 (40.00%)
    4 / 15 (26.67%)
         occurrences all number
    15
    36
    20
    Paraesthesia feet
    Additional description: Parasthesia of the feet.
         subjects affected / exposed
    3 / 16 (18.75%)
    4 / 15 (26.67%)
    2 / 15 (13.33%)
         occurrences all number
    27
    17
    23
    Headache
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    1
    4
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
         occurrences all number
    2
    2
    5
    Ear and labyrinth disorders
    Dizziness
         subjects affected / exposed
    4 / 16 (25.00%)
    1 / 15 (6.67%)
    3 / 15 (20.00%)
         occurrences all number
    7
    3
    17
    Gastrointestinal disorders
    Nausea
    Additional description: Nausea was a prespecified adverse-event as it is a commen side-effect to cinacalcet-treatment.
         subjects affected / exposed
    9 / 16 (56.25%)
    7 / 15 (46.67%)
    4 / 15 (26.67%)
         occurrences all number
    21
    18
    5
    Abdominal pain
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 15 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    6
    6
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 16 (0.00%)
    3 / 15 (20.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    5
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 16 (25.00%)
    1 / 15 (6.67%)
    2 / 15 (13.33%)
         occurrences all number
    9
    1
    2
    Dyspnoea
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    6
    2
    0
    Renal and urinary disorders
    Cystitis
         subjects affected / exposed
    1 / 16 (6.25%)
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    5
    2
    0
    Endocrine disorders
    Hypocalcaemia
    Additional description: Hypocalcaemia was an expected effect of the combined treatment.
         subjects affected / exposed
    0 / 16 (0.00%)
    6 / 15 (40.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    33
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
    Additional description: Muscle and joint pain.
         subjects affected / exposed
    6 / 16 (37.50%)
    6 / 15 (40.00%)
    3 / 15 (20.00%)
         occurrences all number
    17
    14
    20
    Back pain
    Additional description: These numbers are not included in the musculoskeletal pain reported elsewhere.
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    12
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 16 (37.50%)
    5 / 15 (33.33%)
    4 / 15 (26.67%)
         occurrences all number
    20
    12
    5

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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
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