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    Clinical Trial Results:
    Randomised trial of Teriparatide followed by Zoledronic acid versus standard care to prevent fractures in adults with Osteogenesis Imperfecta (OI)

    Summary
    EudraCT number
    		 2016-003228-22
    Trial protocol
    		 GB   IE   DK   FR   NL  
    Global end of trial date
    16 Feb 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Mar 2026
    First version publication date
    26 Mar 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC16092
    Additional study identifiers
    ISRCTN number
    		 ISRCTN15313991
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Edinburgh and NHS Lothian
    Sponsor organisation address
    Usher Building The University of Edinburgh Edinburgh BioQuarter 5-7 Little France Road, Edinburgh, United Kingdom, EH16 4UX
    Public contact
    Prof. Stuart Ralston, Institute of Genetics and Cancer, University of Edinburgh , 44 131-651-8743 , stuart.ralston@ed.ac.uk
    Scientific contact
    Prof. Stuart Ralston, Institute of Genetics and Cancer, University of Edinburgh , 44 131-651-8743 , stuart.ralston@ed.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
    20 Aug 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Feb 2025
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Feb 2025
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objective To investigate if a two-year course of TPTD followed by antiresorptive therapy with a single infusion of zoledronic acid (ZA) in adults with OI reduces the proportion of patients who experience a fracture as compared with standard care Secondary Objectives To investigate if a two-year course of TPTD followed by antiresorptive therapy with a single infusion of ZA in adults with OI reduces the total number of fractures, reduces the risk of vertebral fractures; or affects bone pain, quality of life and functional status as compared with standard care. Mechanistic Objective To understand which baseline characteristics of adults with OI, such as age, clinical subtype of OI, genetic diagnosis, bone turnover, BMD, and previous treatment influences the occurrence of fractures and/or the response to treatment
    Protection of trial subjects
    Specific measures were implemented to protect trial participants and minimise potential risk, pain, and distress. Participants randomised to the interventional arm received structured training by appropriately qualified healthcare professionals on the correct use of the investigational medicinal product (IMP) injection pen, including clear written and verbal instructions on administration and correct storage, including refrigeration requirements. Participant-completed injection pen diaries were used to support adherence and facilitate early identification of potential issues. A predefined safety monitoring plan was implemented and overseen by the study sponsor, with independent oversight provided by a Data Monitoring Committee (DMC). Prior to initiation of study medication, safety blood tests were performed to assess serum creatinine, serum calcium, albumin, serum total alkaline phosphatase (ALP), and estimated glomerular filtration rate (eGFR), with serum 25-hydroxyvitamin D measured where clinically indicated, to ensure there were no contraindications to teriparatide or bisphosphonate therapy. Participants were monitored for adverse events throughout the study and were free to withdraw at any time without impact on their standard clinical care.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    26 Jun 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    United Kingdom: 303
    Country: Number of subjects enrolled
    Denmark: 18
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Ireland: 10
    Worldwide total number of subjects
    349
    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)
    319
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From 26th June 2017 to 16th February 2023 we recruited adults with a clinical diagnosis of osteogenesis imperfecta to the trial from 27 referral centres for bone disease located in five different countries. The distribution was UK (n=303, 87%), Republic of Ireland (n=10, 3%), Holland (n=9, 3%), France (n=10, 3%), and Denmark (n=18, 5%).

    Pre-assignment
    Screening details
    		 A total of 792 subjects with osteogenesis imperfecta were identified. Of these, 361 (45.5%) consented and entered screening; 11 were not eligible due to failed or incomplete eligibility assessment, entry in error, or low body weight. Overall, 350 subjects were randomised (176 TPTD/ZA; 174 standard care). Study population reflects protocol criteria.

    Pre-assignment period milestones
    Number of subjects started
    		 349
    Number of subjects completed
    		 349

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard Care
    Arm description
    		 Participants in the standard care group were permitted to continue with existing bone modifying treatment (i.e., bisphosphonate treatment) or be given no active bone modifying treatment, according to the clinical judgement of the local investigator. Bisphosphonates could be continued, stopped or started during the study at the discretion of the local investigator. Other bone modifying drugs could also be given at the discretion of the local investigator with the exception of teriparatide and investigational (experimental) agents with effects on bone metabolism
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Active treatment group
    Arm description
    		 TPTD 20mcg daily, given subcutaneously using a self-administered injection device for two years followed by a single intravenous infusion of ZA 5mg. If TPTD given for < 12 months no ZA infusion is required. Bisphosphonates, denosumab and strontium ranelate were stopped in the active treatment group at baseline and prohibited during treatment with TPTD since these may alter the therapeutic response to TPTD (18). Bisphosphonates were prohibited following treatment with ZA for at least 12 months to avoid over suppression of bone turnover.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Teriparatide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    20mcg daily, given subcutaneously using a self-administered injection device in participants ≥30Kg 20mcg given twice weekly, given subcutaneously using a self-administered injection device in participants <30kg

    Investigational medicinal product name
    Zoledronic Acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Solution for infusion
    Dosage and administration details
    Zoledronic Acid 5 mg/100ml solution for single infusion

    Number of subjects in period 1
    		Standard Care Active treatment group
    Started
    173
    176
    Completed
    152
    150
    Not completed
    21
    26
         Adverse event, serious fatal
    6
    4
         Physician decision
    7
    9
         Consent withdrawn by subject
    8
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard Care
    Reporting group description
    		 Participants in the standard care group were permitted to continue with existing bone modifying treatment (i.e., bisphosphonate treatment) or be given no active bone modifying treatment, according to the clinical judgement of the local investigator. Bisphosphonates could be continued, stopped or started during the study at the discretion of the local investigator. Other bone modifying drugs could also be given at the discretion of the local investigator with the exception of teriparatide and investigational (experimental) agents with effects on bone metabolism

    Reporting group title
    Active treatment group
    Reporting group description
    		 TPTD 20mcg daily, given subcutaneously using a self-administered injection device for two years followed by a single intravenous infusion of ZA 5mg. If TPTD given for < 12 months no ZA infusion is required. Bisphosphonates, denosumab and strontium ranelate were stopped in the active treatment group at baseline and prohibited during treatment with TPTD since these may alter the therapeutic response to TPTD (18). Bisphosphonates were prohibited following treatment with ZA for at least 12 months to avoid over suppression of bone turnover.

    Reporting group values
    		 Standard Care Active treatment group Total
    Number of subjects
    		 173 176 349
    Age categorical
    The fracture risk in OI is at least an order of magnitude above that in patients with osteoporosis. Affected individuals are at increased risk of fragility fractures throughout life but the highest rates of fracture are during childhood and above the age of 50 years.
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 159 160 319
        From 65-84 years
    		 14 16 30
        85 years and over
    		 0 0 0
    Age continuous
    The fracture risk in OI is at least an order of magnitude above that in patients with osteoporosis. Affected individuals are at increased risk of fragility fractures throughout life but the highest rates of fracture are during childhood and above the age of 50 years.
    Units: years
        arithmetic mean (standard deviation)
    		 43.8 ( 13.9 ) 43.6 ( 14.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 93 95 188
        Male
    		 80 81 161
    Female Reproduction
    Units: Subjects
        Childbearing potential (yes)
    		 51 57 108
        Childbearing potential (No)
    		 42 38 80
        N/A i.e Male participants
    		 80 81 161
    Disease characteristics - Blue Sclerae
    Units: Subjects
        Blue sclerae (No)
    		 40 27 67
        Blue sclerae (Yes)
    		 133 149 282
    Fracture history - Last 2 years
    Units: Subjects
        Yes
    		 80 83 163
        No
    		 93 93 186
    Clinical examination - bone deformities
    Units: Subjects
        Bone Deformity - Yes
    		 105 115 220
        Bone Deformity - No
    		 68 61 129
    Baseline spine x-ray - Vertebral
    Units: Subjects
        Confirmed vertebral fracture - Yes
    		 83 94 177
        Confirmed vertebral fracture - No
    		 88 82 170
        confirmed vertebral fracture missing
    		 2 0 2
    Genetic biomarkers - Molecular diagnosis
    Units: Subjects
        Qualitative
    		 54 55 109
        Quantitative
    		 69 77 146
        Splice site
    		 29 26 55
        Variant of uncertain significance
    		 3 4 7
        No pathogenic variant
    		 17 14 31
        No result
    		 1 0 1
    Genetic biomarkers - Pathogenic variant
    Units: Subjects
        COL1A1
    		 104 114 218
        COL1A2
    		 44 39 83
        FKBP10
    		 2 0 2
        IFITM5
    		 1 2 3
        P3H1
    		 1 0 1
        PLS3
    		 0 1 1
        SERPINF1
    		 0 1 1
        Variant of uncertain significance
    		 3 4 7
        No pathogenic variant
    		 17 14 31
        Other [1]
    		 0 1 1
        Missing
    		 1 0 1
    Bone targeted medications at, or within 2 years prior to, randomisation - Bisphosphonates
    Other = Non-Bisphosphonates/None
    Units: Subjects
        Bisphosphonates
    		 50 48 98
        Other
    		 123 128 251
    Bone targeted medications at, or any time prior to, randomisation - Bisphosphonates
    Other = Non-bisphosphonates/None
    Units: Subjects
        Targeted Meds - Bisphosphonates
    		 117 128 245
        Other
    		 56 48 104
    Baseline spine xray - Lumbar
    Those participants that did not report a potential fracture, are categorised as 'N/A'
    Units: Subjects
        Confirmed lumbar fracture - Yes
    		 38 44 82
        Confirmed lumbar fracture - No
    		 45 50 95
        N/A
    		 90 82 172
    Baseline spine xray - thoracic
    Those participants that did not report a potential fracture, are categorised as 'N/A'
    Units: Subjects
        Confirmed thoracic fracture - Yes
    		 76 80 156
        Confirmed thoracic fracture - No
    		 7 14 21
        N/A
    		 90 82 172
    Bone targeted medications at, or any time prior to, randomisation - NonBisphosphonates
    Other = Bisphosphonates/None
    Units: Subjects
        Non-Bisphosphonates
    		 97 93 190
        Other
    		 76 83 159
    Bone targeted medications at, or within 2 years prior to, randomisation - NonBisphosphonates
    Other = Bisphosphonates/None
    Units: Subjects
        Non-Bisphosphonates
    		 87 86 173
        Other
    		 86 90 176
    Disease characteristics - Dentinogenesis
    Units: Subjects
        Yes
    		 61 64 125
        No
    		 112 112 224
    Age of menarche
    Units: years
        arithmetic mean (standard deviation)
    		 13 ( 2 ) 13 ( 2 ) -
    Age of menopause
    Units: years
        arithmetic mean (standard deviation)
    		 48 ( 7 ) 49 ( 6 ) -
    Total dietary calcium
    Units: mg/day
        arithmetic mean (standard deviation)
    		 809 ( 412 ) 827 ( 376 ) -
    Clinical examination - Height
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 155 ( 18 ) 156 ( 17 ) -
    Clinical examination - Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 70.9 ( 18.8 ) 68.5 ( 19.9 ) -
    Clinical exam - BMI
    Units: kg/m²
        arithmetic mean (standard deviation)
    		 29.6 ( 7.6 ) 27.8 ( 6.4 ) -
    DEXA scan results - Spine
    Units: BMD (g/cm 2 )
        arithmetic mean (standard deviation)
    		 0.849 ( 0.201 ) 0.862 ( 0.172 ) -
    DEXA scan results - Total hip
    Units: BMD (g/cm 2 )
        arithmetic mean (standard deviation)
    		 0.83 ( 0.149 ) 0.824 ( 0.142 ) -
    DEXA scan results - Femoral neck
    Units: BMD (g/cm 2 )
        arithmetic mean (standard deviation)
    		 0.740 ( 0.151 ) 0.741 ( 0.144 ) -
    DEXA scan results - T-score - Spine
    Units: SD
        arithmetic mean (standard deviation)
    		 -2.11 ( 1.92 ) -2.18 ( 1.57 ) -
    DEXA scan results - T-score -Total hip
    Units: SD
        arithmetic mean (standard deviation)
    		 -1.12 ( 1.26 ) -1.33 ( 1.21 ) -
    DEXA scan results - T-score -Femoral neck
    Units: SD
        arithmetic mean (standard deviation)
    		 -1.41 ( 1.3 ) -1.55 ( 1.22 ) -
    Biochemical biomarkers of bone turnover - C-terminal telopeptide of type I collagen (CTX)
    Units: µg/L
        arithmetic mean (standard deviation)
    		 0.2 ( 0.12 ) 0.21 ( 0.13 ) -
    Biochemical biomarkers of bone turnover - Procollagen type I amino-terminal propeptide
    Units: µg/L
        arithmetic mean (standard deviation)
    		 37.5 ( 23.1 ) 39.7 ( 30.5 ) -
    Per-patient number of fractures - last 2 years
    Units: Subject
        median (full range (min-max))
    		 0 (0 to 8) 0 (0 to 5) -
    Per-patient number of fractures (>2years)
    Units: subjects
        median (full range (min-max))
    		 10 (0 to 257) 11 (0 to 257) -

    End points

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    End points reporting groups
    Reporting group title
    Standard Care
    Reporting group description
    		 Participants in the standard care group were permitted to continue with existing bone modifying treatment (i.e., bisphosphonate treatment) or be given no active bone modifying treatment, according to the clinical judgement of the local investigator. Bisphosphonates could be continued, stopped or started during the study at the discretion of the local investigator. Other bone modifying drugs could also be given at the discretion of the local investigator with the exception of teriparatide and investigational (experimental) agents with effects on bone metabolism

    Reporting group title
    Active treatment group
    Reporting group description
    		 TPTD 20mcg daily, given subcutaneously using a self-administered injection device for two years followed by a single intravenous infusion of ZA 5mg. If TPTD given for < 12 months no ZA infusion is required. Bisphosphonates, denosumab and strontium ranelate were stopped in the active treatment group at baseline and prohibited during treatment with TPTD since these may alter the therapeutic response to TPTD (18). Bisphosphonates were prohibited following treatment with ZA for at least 12 months to avoid over suppression of bone turnover.

    Subject analysis set title
    Intent-to-Treat (ITT) Analysis Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population is all randomised patients, analysed according to randomised treatment. 176 TPTD and 173 standard care.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety population will include all patients who were randomised. Patients were summarised according to treatment received. For TPTD safety has 177 participants and standard care has 172.

    Primary: The proportion of participants experiencing a clinical fracture validated by x-ray or other imaging.

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    End point title
    		 The proportion of participants experiencing a clinical fracture validated by x-ray or other imaging.
    End point description
    End point type
    Primary
    End point timeframe
    From randomisation until final study visit.
    End point values
    		 Standard Care Active treatment group
    Number of subjects analysed
    173
    176
    Units: Participants
    63
    65
    Statistical analysis title
    		 Primary analysis – Cox proportional hazard
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.872
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.38
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 secondary analysis - BinaryLogisticRegression
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.937
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.59
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Sensitivity analysis - interval censoring
    Statistical analysis description
    Interval censoring takes account of fractures identified at the end of study x-ray where the exact time of fracture is unknown. Fractures are known to have occurred at some point between baseline x-ray (or the last incidental x-ray date for those patients where the x-ray didn't result in a confirmed non-vertebral fracture) and end of study x-rays.
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8561
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.46
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 sensitivity analysis - Dept.Rand Trt.
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.854 [1]
    Method
    		 CACE
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.38
    Variability estimate
    Standard error of the mean
    Notes
    [1] - Complier-average causal effect (CACE)

    Secondary: Adjudicated incident fractures

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    End point title
    		 Adjudicated incident fractures
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation to final visit.
    End point values
    		 Standard Care Active treatment group Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    173
    176
    349
    Units: Fracture number
    88
    70
    158
    Statistical analysis title
    		 Poisson regression
    Comparison groups
    Active treatment group v Standard Care
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.911
    Method
    		 Poisson regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.65
    Variability estimate
    Standard error of the mean

    Secondary: Brief pain inventory (BPI) interference score

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    End point title
    		 Brief pain inventory (BPI) interference score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to End of study visit.
    End point values
    		 Standard Care Active treatment group Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    173
    176
    349
    Units: BPI pain interference score (0–10)
        arithmetic mean (standard deviation)
    4.34 ( 2.87 )
    3.28 ( 2.65 )
    3.82 ( 2.81 )
    Statistical analysis title
    		 Repeated measures linear mixed model estimates
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.09
         upper limit
    		 -0.29
    Variability estimate
    Standard error of the mean
    Notes
    [2] - Overall p-value

    Secondary: SF-36 - physical component score

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    End point title
    		 SF-36 - physical component score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to final study visit
    End point values
    		 Standard Care Active treatment group Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    173
    176
    349
    Units: SF-36 Physical Component Score (PCS)
        arithmetic mean (standard deviation)
    33.5 ( 12.3 )
    36.7 ( 13.6 )
    35.1 ( 13 )
    Statistical analysis title
    		 Repeated measures linear mixed model estimates
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.083 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 3.06
    Variability estimate
    Standard error of the mean
    Notes
    [3] - Overall

    Secondary: Pittsburgh sleep quality questionnaire (PSQI)

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    End point title
    		 Pittsburgh sleep quality questionnaire (PSQI)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Final study visit
    End point values
    		 Standard Care Active treatment group Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    173
    176
    289
    Units: PSQI score
        arithmetic mean (standard deviation)
    10.5 ( 3.9 )
    9.8 ( 3.5 )
    10.1 ( 3.7 )
    Statistical analysis title
    		 Repeated measures linear mixed model estimates
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0279 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 -0.06
    Variability estimate
    Standard error of the mean
    Notes
    [4] - Overall

    Secondary: Health Assessment Questionnaire - disability index

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    End point title
    		 Health Assessment Questionnaire - disability index
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to final study visit
    End point values
    		 Standard Care Active treatment group Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    173
    176
    349
    Units: HAQ-DI score
        arithmetic mean (standard deviation)
    1.13 ( 0.79 )
    0.97 ( 0.81 )
    1.05 ( 0.8 )
    Statistical analysis title
    		 Stage 1 – Modelling Probability zero score
    Statistical analysis description
    Stage 1 – Modelling the Probability of a zero (no difficulty) score
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9495 [5]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.72
    Variability estimate
    Standard error of the mean
    Notes
    [5] - overall
    Statistical analysis title
    		 Stage 2 – ModellingDistribution positive scores
    Statistical analysis description
    Stage 2 – Modelling the distribution of positive (non-zero) scores
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0975 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.01
    Variability estimate
    Standard error of the mean
    Notes
    [6] - overall

    Secondary: DEXA scan - femoral neck BMD

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    End point title
    		 DEXA scan - femoral neck BMD
    End point description
    End point type
    Secondary
    End point timeframe
    baseline to final study visit
    End point values
    		 Standard Care Active treatment group Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    173
    176
    349
    Units: Bone Mineral Density (BMD)
        arithmetic mean (standard deviation)
    0.724 ( 0.159 )
    0.726 ( 0.155 )
    0.743 ( 0.158 )
    Statistical analysis title
    		 Repeated measures linear mixed model estimates
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8862 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.027
         upper limit
    		 0.032
    Variability estimate
    Standard error of the mean
    Notes
    [7] - Overall

    Secondary: DEXA scan - total hip BMD

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    End point title
    		 DEXA scan - total hip BMD
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to final study visit
    End point values
    		 Standard Care Active treatment group Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    173
    176
    349
    Units: Bone Mineral Density (BMD)
        arithmetic mean (standard deviation)
    0.836 ( 0.154 )
    0.872 ( 0.164 )
    0.854 ( 0.160 )
    Statistical analysis title
    		 Repeated measures linear mixed model estimates
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0156 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.021
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.004
         upper limit
    		 0.038
    Variability estimate
    Standard error of the mean
    Notes
    [8] - Overall

    Secondary: DEXA scan - spine BMD

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    End point title
    		 DEXA scan - spine BMD
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to final study visit
    End point values
    		 Standard Care Active treatment group Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    173
    176
    349
    Units: Bone Mineral Density (BMD)
        arithmetic mean (standard deviation)
    0.879 ( 0.209 )
    0.927 ( 0.183 )
    0.903 ( 0.197 )
    Statistical analysis title
    		 Repeated measures linear mixed model estimates
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [9]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.032
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.018
         upper limit
    		 0.045
    Variability estimate
    Standard error of the mean
    Notes
    [9] - Overall

    Secondary: Brief pain inventory (BPI) Severity score

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    End point title
    		 Brief pain inventory (BPI) Severity score
    End point description
    End point type
    Secondary
    End point timeframe
    Randomisation to final study visit
    End point values
    		 Standard Care Active treatment group Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    173
    176
    349
    Units: BPI pain severity score (0-10)
        arithmetic mean (standard deviation)
    4.07 ( 2.42 )
    3.24 ( 2.14 )
    3.67 ( 2.32 )
    Statistical analysis title
    		 Repeated measures linear mixed model estimates
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0134
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.67
         upper limit
    		 -0.08
    Variability estimate
    Standard error of the mean

    Secondary: Adjudicated fractures at end of study

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    End point title
    		 Adjudicated fractures at end of study
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Final study visit
    End point values
    		 Standard Care Active treatment group Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    173
    176
    349
    Units: Fractures
    85
    125
    210
    Statistical analysis title
    		 Poisson regression
    Comparison groups
    Active treatment group v Standard Care
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28
    Method
    		 Poisson regression
    Parameter type
    		 Incidence rate ratio
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.78
         upper limit
    		 2.36
    Variability estimate
    Standard error of the mean

    Secondary: SF-36 -mental component score

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    End point title
    		 SF-36 -mental component score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Final study visit
    End point values
    		 Standard Care Active treatment group Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    173
    176
    349
    Units: SF-36 Mental Component Score (MCS)
        arithmetic mean (standard deviation)
    44 ( 14.5 )
    46.7 ( 14 )
    45.4 ( 14.3 )
    Statistical analysis title
    		 Repeated measures linear mixed model estimates
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1768 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 3.33
    Variability estimate
    Standard error of the mean
    Notes
    [10] - Overall

    Secondary: EQ5D-3L index score

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    End point title
    		 EQ5D-3L index score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to final study visit
    End point values
    		 Standard Care Active treatment group Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    173
    176
    349
    Units: EQ5D-3L index score
        arithmetic mean (standard deviation)
    0.62 ( 0.21 )
    0.68 ( 0.21 )
    0.65 ( 0.21 )
    Statistical analysis title
    		 Repeated measures linear mixed model estimates
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.214 [11]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.06
    Variability estimate
    Standard error of the mean
    Notes
    [11] - Overall

    Secondary: EQ5D-3L Visual Analogue Scale (VAS)

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    End point title
    		 EQ5D-3L Visual Analogue Scale (VAS)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to final study visit
    End point values
    		 Standard Care Active treatment group Intent-to-Treat (ITT) Analysis Set
    Number of subjects analysed
    173
    176
    349
    Units: EQ5D-3L Visual Analogue Scale (VAS)
        arithmetic mean (standard deviation)
    60.2 ( 22.5 )
    64.6 ( 23.1 )
    62.4 ( 22.9 )
    Statistical analysis title
    		 Repeated measures linear mixed model estimates
    Comparison groups
    Standard Care v Active treatment group
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0023 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.74
         upper limit
    		 7.94
    Variability estimate
    Standard error of the mean
    Notes
    [12] - Overall

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    TPTD
    Reporting group description
    		 -

    Reporting group title
    Standard care
    Reporting group description
    		 -

    Serious adverse events
    		 TPTD Standard care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    39 / 172 (22.67%)
    41 / 177 (23.16%)
         number of deaths (all causes)
    3
    7
         number of deaths resulting from adverse events
    3
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    missing
    Additional description: missing
         subjects affected / exposed
    4 / 172 (2.33%)
    6 / 177 (3.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    missing
    Additional description: missing
         subjects affected / exposed
    0 / 172 (0.00%)
    3 / 177 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    missing
    Additional description: missing
         subjects affected / exposed
    8 / 172 (4.65%)
    8 / 177 (4.52%)
         occurrences causally related to treatment / all
    0 / 10
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    missing
    Additional description: missing
         subjects affected / exposed
    2 / 172 (1.16%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    missing
    Additional description: missing
         subjects affected / exposed
    4 / 172 (2.33%)
    5 / 177 (2.82%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 5
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Psychiatric disorders
    missing
    Additional description: missing
         subjects affected / exposed
    4 / 172 (2.33%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    missing
    Additional description: missing
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    missing
    Additional description: missing
         subjects affected / exposed
    6 / 172 (3.49%)
    4 / 177 (2.26%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    missing
    Additional description: missing
         subjects affected / exposed
    2 / 172 (1.16%)
    3 / 177 (1.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Nervous system disorders
    missing
    Additional description: missing
         subjects affected / exposed
    3 / 172 (1.74%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    missing
    Additional description: missing
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    missing
    Additional description: missing
         subjects affected / exposed
    4 / 172 (2.33%)
    4 / 177 (2.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    missing
    Additional description: missing
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    missing
    Additional description: missing
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    missing
    Additional description: missing
         subjects affected / exposed
    2 / 172 (1.16%)
    0 / 177 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    missing
    Additional description: missing
         subjects affected / exposed
    0 / 172 (0.00%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    missing
    Additional description: missing
         subjects affected / exposed
    5 / 172 (2.91%)
    1 / 177 (0.56%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infections and infestations
    missing
    Additional description: missing
         subjects affected / exposed
    8 / 172 (4.65%)
    5 / 177 (2.82%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 TPTD Standard care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    137 / 172 (79.65%)
    135 / 177 (76.27%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    missing
    Additional description: missing
         subjects affected / exposed
    6 / 172 (3.49%)
    7 / 177 (3.95%)
         occurrences all number
    6
    11
    Vascular disorders
    missing
    Additional description: missing
         subjects affected / exposed
    6 / 172 (3.49%)
    9 / 177 (5.08%)
         occurrences all number
    21
    10
    Surgical and medical procedures
    missing
    Additional description: missing
         subjects affected / exposed
    22 / 172 (12.79%)
    22 / 177 (12.43%)
         occurrences all number
    28
    30
    Pregnancy, puerperium and perinatal conditions
    missing
    Additional description: missing
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    missing
    Additional description: missing
         subjects affected / exposed
    3 / 172 (1.74%)
    1 / 177 (0.56%)
         occurrences all number
    3
    1
    Reproductive system and breast disorders
    missing
    Additional description: missing
         subjects affected / exposed
    9 / 172 (5.23%)
    8 / 177 (4.52%)
         occurrences all number
    10
    11
    Respiratory, thoracic and mediastinal disorders
    missing
    Additional description: missing
         subjects affected / exposed
    20 / 172 (11.63%)
    19 / 177 (10.73%)
         occurrences all number
    27
    24
    Psychiatric disorders
    missing
    Additional description: missing
         subjects affected / exposed
    10 / 172 (5.81%)
    11 / 177 (6.21%)
         occurrences all number
    13
    15
    Product issues
    missing
    Additional description: missing
         subjects affected / exposed
    1 / 172 (0.58%)
    0 / 177 (0.00%)
         occurrences all number
    1
    0
    Investigations
    missing
    Additional description: missing
         subjects affected / exposed
    28 / 172 (16.28%)
    15 / 177 (8.47%)
         occurrences all number
    39
    23
    Injury, poisoning and procedural complications
    missing
    Additional description: missing
         subjects affected / exposed
    48 / 172 (27.91%)
    51 / 177 (28.81%)
         occurrences all number
    82
    98
    Congenital, familial and genetic disorders
    missing
    Additional description: missing
         subjects affected / exposed
    2 / 172 (1.16%)
    1 / 177 (0.56%)
         occurrences all number
    2
    1
    Cardiac disorders
    missing
    Additional description: missing
         subjects affected / exposed
    11 / 172 (6.40%)
    8 / 177 (4.52%)
         occurrences all number
    13
    10
    Nervous system disorders
    missing
    Additional description: missing
         subjects affected / exposed
    42 / 172 (24.42%)
    16 / 177 (9.04%)
         occurrences all number
    57
    20
    Blood and lymphatic system disorders
    missing
    Additional description: missing
         subjects affected / exposed
    4 / 172 (2.33%)
    1 / 177 (0.56%)
         occurrences all number
    4
    1
    Ear and labyrinth disorders
    missing
    Additional description: missing
         subjects affected / exposed
    10 / 172 (5.81%)
    8 / 177 (4.52%)
         occurrences all number
    11
    8
    Eye disorders
    missing
    Additional description: missing
         subjects affected / exposed
    10 / 172 (5.81%)
    7 / 177 (3.95%)
         occurrences all number
    11
    9
    Gastrointestinal disorders
    missing
    Additional description: missing
         subjects affected / exposed
    29 / 172 (16.86%)
    20 / 177 (11.30%)
         occurrences all number
    60
    31
    Hepatobiliary disorders
    missing
    Additional description: missing
         subjects affected / exposed
    2 / 172 (1.16%)
    2 / 177 (1.13%)
         occurrences all number
    2
    2
    Skin and subcutaneous tissue disorders
    missing
    Additional description: missing
         subjects affected / exposed
    15 / 172 (8.72%)
    13 / 177 (7.34%)
         occurrences all number
    18
    17
    Renal and urinary disorders
    missing
    Additional description: missing
         subjects affected / exposed
    7 / 172 (4.07%)
    5 / 177 (2.82%)
         occurrences all number
    7
    5
    Musculoskeletal and connective tissue disorders
    missing
    Additional description: missing
         subjects affected / exposed
    94 / 172 (54.65%)
    86 / 177 (48.59%)
         occurrences all number
    259
    193
    Infections and infestations
    missing
    Additional description: missing
         subjects affected / exposed
    69 / 172 (40.12%)
    58 / 177 (32.77%)
         occurrences all number
    134
    119
    Metabolism and nutrition disorders
    missing
    Additional description: missing
         subjects affected / exposed
    5 / 172 (2.91%)
    10 / 177 (5.65%)
         occurrences all number
    11
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Aug 2024
    1. The participating sites section and funder details are updated. Correction of typos and grammatical errors. The details of the SWAT study have been removed. Provided an additional rationale for reducing the sample size. 2. Introduction of the option to locally purchase teriparatide and labelling updates 3. The primary and secondary mechanistic objectives of the protocol have been updated and added. There is clarification around onward reporting of SARs/SUSARs when using generic TPTD. The method of ascertaining adherence for both arms of the study has been changed. 4. The Clinical study site agreement will have to be amended for sites with patients who require IMP beyond 31 October 2024. 5. Biochemical markers will be analysed at the University of East Anglia. 6. Update to the following representative SPC's for the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Mar 2020
    1 Recruitment, screening and randomisation has been temporarily halted following a Sponsor communication on 17th March 2020. 2 Study visits will be conducted remotely by telephone or videocall wherever possible to reduce patient travel to hospitals during the Covid19 emergency. Any study procedure that cannot be performed remotely will be carried out a later date and marked in the interim as a protocol deviation. 3 IMP shipments will be transported from site pharmacies to participant homes via courier service to reduce patient travel to hospital.
    16 Sep 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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