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    Clinical Trial Results:
    A randomized, double-blind, multicenter integrated phase I/III study in postmenopausal women with osteoporosis to compare the pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity of GP2411 (proposed biosimilar denosumab) and Prolia® (EU-authorized)

    Summary
    EudraCT number
    		 2018-003523-11
    Trial protocol
    		 CZ   ES   BG  
    Global end of trial date
    22 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Feb 2023
    First version publication date
    23 Feb 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CGP24112301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03974100
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hexal AG
    Sponsor organisation address
    Industriestr. 25, Holzkirchen, Germany, 83607
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    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
    22 Apr 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of the trial were: • To demonstrate similar efficacy between GP2411 and EU-Prolia, in terms of bone mineral density (BMD) • To demonstrate similar pharmacodynamics (PD) between GP2411 and EU-Prolia, in terms of the bone resorption marker Carboxy-terminal crosslinked telopeptides of type I collagen (CTX) • To demonstrate similar pharmacokinetics (PK) between GP2411 and EU-Prolia
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Jun 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 20
    Country: Number of subjects enrolled
    Bulgaria: 103
    Country: Number of subjects enrolled
    Czechia: 160
    Country: Number of subjects enrolled
    Japan: 46
    Country: Number of subjects enrolled
    Poland: 170
    Country: Number of subjects enrolled
    Spain: 28
    Worldwide total number of subjects
    527
    EEA total number of subjects
    461
    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)
    276
    From 65 to 84 years
    251
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in 43 investigative sites in 6 countries.

    Pre-assignment
    Screening details
    		 There was a screening period of up to 5 weeks. On Day 1, participants were randomized 1:1 to GP2411 or EU-Prolia for Treatment Period 1 (TP1). At Week 52, participants in the EU-Prolia group were re-randomized 1:1 to continue with EU-Prolia or switch to GP2411 for Treatment Period 2 (TP2). Participants in GP2411 group continued with GP2411 for TP2

    Period 1
    Period 1 title
    TP1 - Day 1 to Week 52
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GP2411
    Arm description
    		 Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1
    Arm type
    		 Experimental

    Investigational medicinal product name
    GP2411
    Investigational medicinal product code
    Other name
    proposed biosimilar denosumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    60 mg /mL subcutaneous injection of GP2411 every 6 months (Day 1 and Week 26)

    Arm title
    		 EU-Prolia
    Arm description
    		 Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
    Arm type
    		 Active comparator

    Investigational medicinal product name
    EU-Prolia
    Investigational medicinal product code
    Other name
    denosumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    60 mg /mL subcutaneous injection of EU-Prolia every 6 months (Day 1 and Week 26)

    Number of subjects in period 1
    		GP2411 EU-Prolia
    Started
    263
    264
    Per-Protocol Set (PPS)
    233 [1]
    230 [2]
    TP1 Full Analysis Set (TP1 FAS)
    255
    257
    Pharmacodynamic Analysis Set (PDS)
    228 [3]
    213 [4]
    Pharmacokinetic Analysis Set (PKS)
    260
    258
    TP1 Safety Analysis Set
    263
    264
    Completed
    253
    249
    Not completed
    10
    15
         Physician decision
    -
    2
         Adverse Event
    1
    3
         Subject decision
    8
    9
         Death
    1
    -
         Lost to follow-up
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The intermediate milestones correspond to the Analysis Sets.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The intermediate milestones correspond to the Analysis Sets.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The intermediate milestones correspond to the Analysis Sets.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The intermediate milestones correspond to the Analysis Sets.
    Period 2
    Period 2 title
    TP2- Week 52 to Week 78
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GP2411/GP2411
    Arm description
    		 Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2
    Arm type
    		 Experimental

    Investigational medicinal product name
    GP2411
    Investigational medicinal product code
    Other name
    proposed biosimilar denosumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants in GP2411 group in TP1 continued with a third dose of GP2411 in TP2. GP2411 was administered as a 60 mg /mL subcutaneous injection at Week 52.

    Arm title
    		 EU-Prolia/EU-Prolia
    Arm description
    		 Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2
    Arm type
    		 Active comparator

    Investigational medicinal product name
    EU-Prolia
    Investigational medicinal product code
    Other name
    denosumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants in EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2. EU-Prolia was administered as a 60 mg /mL subcutaneous injection at Week 52.

    Arm title
    		 EU-Prolia/GP2411
    Arm description
    		 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
    Arm type
    		 Experimental

    Investigational medicinal product name
    EU-Prolia and GP2411
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants in EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2. GP2411 was administered as a 60 mg /mL subcutaneous injection at Week 52.

    Number of subjects in period 2
    		GP2411/GP2411 EU-Prolia/EU-Prolia EU-Prolia/GP2411
    Started
    253
    125
    124
    TP2 Full Analysis Set (TP2 FAS)
    253
    124
    124
    TP2 Safety Analysis Set
    253
    125
    124
    Completed
    253
    123
    124
    Not completed
    0
    2
    0
         Subject decision
    -
    1
    -
         Lost to follow-up
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GP2411
    Reporting group description
    		 Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1

    Reporting group title
    EU-Prolia
    Reporting group description
    		 Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1

    Reporting group values
    		 GP2411 EU-Prolia Total
    Number of subjects
    		 263 264 527
    Age categorical
    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)
    		 137 139 276
        From 65-84 years
    		 126 125 251
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.6 ± 6.08 64.7 ± 5.78 -
    Sex: Female, Male
    Units: participants
        Female
    		 263 264 527
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 23 24 47
        Multiple
    		 1 0 1
        White
    		 239 240 479

    End points

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    End points reporting groups
    Reporting group title
    GP2411
    Reporting group description
    		 Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1

    Reporting group title
    EU-Prolia
    Reporting group description
    		 Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
    Reporting group title
    GP2411/GP2411
    Reporting group description
    		 Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2

    Reporting group title
    EU-Prolia/EU-Prolia
    Reporting group description
    		 Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2

    Reporting group title
    EU-Prolia/GP2411
    Reporting group description
    		 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2

    Primary: Percent change from baseline in lumbar spine bone mineral density (LS-BMD) at Week 52 – Per-Protocol Set

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    End point title
    		 Percent change from baseline in lumbar spine bone mineral density (LS-BMD) at Week 52 – Per-Protocol Set
    End point description
    Bone density measurements were performed by dual energy X-ray absorptiometry (DXA). Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in LS-BMD for all post-baseline time points up to Week 52. Values at Week 52 were estimated from the model and are presented in the table.
    End point type
    Primary
    End point timeframe
    Baseline (screening), up to Week 52
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    233
    230
    Units: Percentage change (%)
        least squares mean (standard error)
    4.955 ± 0.2634
    5.099 ± 0.2618
    Statistical analysis title
    		 GP2411 vs. EU-Prolia
    Statistical analysis description
    MMRM included treatment, prior bisphosphonate use, DXA machine type, visit, visit-treatment interaction, and baseline LS-BMD as a continuous covariate.
    Comparison groups
    GP2411 v EU-Prolia
    Number of subjects included in analysis
    463
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    		 Mixed-model repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.145
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.798
         upper limit
    		 0.509
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3325
    Notes
    [1] - Equivalence criteria (analysis set PPS): 95% CI for difference in means contained in [-1.45%, 1.45%]

    Primary: Percent change from baseline in lumbar spine bone mineral density (LS-BMD) at Week 52 – TP1 Full Analysis Set

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    End point title
    		 Percent change from baseline in lumbar spine bone mineral density (LS-BMD) at Week 52 – TP1 Full Analysis Set
    End point description
    Bone density measurements were performed by DXA. Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis. A MMRM was fitted to the changes from baseline in LS-BMD for all post-baseline time points up to Week 52. Missing values were assumed to be missing at random (MAR) using the MMRM model. Values at Week 52 were estimated from the model and are presented in the table.
    End point type
    Primary
    End point timeframe
    Baseline (screening), up to Week 52
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    255
    257
    Units: Percentage change (%)
        least squares mean (standard error)
    4.963 ± 0.2630
    5.140 ± 0.2627
    Statistical analysis title
    		 GP2411 vs. EU-Prolia
    Statistical analysis description
    MMRM included treatment, prior bisphosphonate use, DXA machine type, visit, visit-treatment interaction, and baseline LS-BMD as a continuous covariate.
    Comparison groups
    GP2411 v EU-Prolia
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    Method
    		 Mixed-model repeated measures (MMRM)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.177
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.83
         upper limit
    		 0.475
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3321
    Notes
    [2] - Equivalence criteria (analysis set TP1 FAS): 95% CI for difference in means contained in [-1.45%, 1.45%] (criteria 1) or in [-2.00%, 2.00%] (criteria 2)

    Primary: Area under the effect-time curve (AUEC) of percentage change from baseline in serum CTX concentrations after first dose – Pharmacodynamic Analysis Set

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    End point title
    		 Area under the effect-time curve (AUEC) of percentage change from baseline in serum CTX concentrations after first dose – Pharmacodynamic Analysis Set
    End point description
    Carboxy-terminal crosslinked telopeptides of type I collagen (CTX) is a bone resorption biomarker. Serum CTX concentration-time data were analyzed by non-compartmental methods. The AUEC of baseline corrected serum CTX concentrations (% change from baseline) was calculated using the linear trapezoidal method. Values below the lower limit of quantification (LLOQ) were imputed with the actual value for the LLOQ.
    End point type
    Primary
    End point timeframe
    Baseline (pre-dose Day 1), up to Week 26
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    228
    213
    Units: percentage change (%)*day
        geometric mean (geometric coefficient of variation)
    15700 ± 15.8
    15900 ± 14.0
    Statistical analysis title
    		 GP2411 vs. EU-Prolia - 90% CI
    Statistical analysis description
    ANCOVA was performed on log-transformed AUEC including treatment and log baseline CTX value as a continuous covariate.
    Comparison groups
    GP2411 v EU-Prolia
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    		 ANCOVA
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.01
    Notes
    [3] - Equivalence criteria (analysis set PDS): 90% CI for ratio of geometric means contained in [0.80, 1.25%]
    Statistical analysis title
    		 GP2411 vs. EU-Prolia - 95%CI
    Statistical analysis description
    ANCOVA was performed on log-transformed AUEC including treatment and log baseline CTX value as a continuous covariate.
    Comparison groups
    GP2411 v EU-Prolia
    Number of subjects included in analysis
    441
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    Method
    		 ANCOVA
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 1.01
    Notes
    [4] - Equivalence criteria (analysis set PDS): 95% CI for ratio of geometric means contained in [0.80, 1.25%]

    Primary: Maximum observed serum concentration (Cmax) of denosumab after first dose

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    End point title
    		 Maximum observed serum concentration (Cmax) of denosumab after first dose
    End point description
    Serum denosumab concentration-time data were analyzed by non-compartmental methods. Missing denosumab serum concentrations or concentrations below the LLOQ were not imputed and handled as missing values, except for the pre-dose sample which were treated as zero.
    End point type
    Primary
    End point timeframe
    Baseline (pre-dose Day 1), up to Week 26
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    260
    258
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    6970 ± 45.8
    7050 ± 44.2
    Statistical analysis title
    		 GP2411 vs. EU-Prolia
    Statistical analysis description
    ANCOVA was performed on log-transformed Cmax including treatment and weight as a continuous covariate.
    Comparison groups
    GP2411 v EU-Prolia
    Number of subjects included in analysis
    518
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    Method
    		 ANCOVA
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.97
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.03
    Notes
    [5] - Equivalence criteria (analysis set PKS): 90% CI for ratio of geometric means contained in [0.80, 1.25%]

    Primary: Area under the serum concentration-time curve from time zero to infinity (AUCinf) of denosumab after first dose

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    End point title
    		 Area under the serum concentration-time curve from time zero to infinity (AUCinf) of denosumab after first dose
    End point description
    Serum denosumab concentration-time data were analyzed by non-compartmental methods. Missing denosumab serum concentrations or concentrations below the LLOQ were not imputed and handled as missing values, except for the pre-dose sample which were treated as zero. The linear-up log-down trapezoidal method was used for the AUCinf calculation.
    End point type
    Primary
    End point timeframe
    Baseline (pre-dose Day 1), up to Week 26
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    247
    246
    Units: day*ng/mL
        geometric mean (geometric coefficient of variation)
    370000 ± 47.8
    365000 ± 43.3
    Statistical analysis title
    		 GP2411 vs. EU-Prolia
    Statistical analysis description
    ANCOVA was performed on log-transformed AUCinf including treatment and weight as a continuous covariate.
    Comparison groups
    GP2411 v EU-Prolia
    Number of subjects included in analysis
    493
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    Method
    		 ANCOVA
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.05
    Notes
    [6] - Equivalence criteria (analysis set PKS): 90% CI for ratio of geometric means contained in [0.80, 1.25%]

    Secondary: Percent change from baseline in lumbar spine bone mineral density (LS-BMD) at Week 26 – Treatment Period 1 (Per-Protocol Set)

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    End point title
    		 Percent change from baseline in lumbar spine bone mineral density (LS-BMD) at Week 26 – Treatment Period 1 (Per-Protocol Set)
    End point description
    Bone density measurements were performed by DXA. Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (screening), Week 26
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    233
    229
    Units: percentage change (%)
        arithmetic mean (standard deviation)
    3.6501 ± 3.76952
    3.6700 ± 3.68816
    No statistical analyses for this end point

    Secondary: Percent change from baseline in lumbar spine bone mineral density (LS-BMD) at Week 26 – Treatment Period 1 (TP1 Full Analysis Set)

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    End point title
    		 Percent change from baseline in lumbar spine bone mineral density (LS-BMD) at Week 26 – Treatment Period 1 (TP1 Full Analysis Set)
    End point description
    Bone density measurements were performed by DXA. Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (screening), Week 26
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    255
    256
    Units: percentage change (%)
        arithmetic mean (standard deviation)
    3.5877 ± 3.73579
    3.7144 ± 3.89730
    No statistical analyses for this end point

    Secondary: Percent change from baseline in lumbar spine bone mineral density (LS-BMD) at Week 78 – Treatment Period 2 (TP2 Full Analysis Set)

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    End point title
    		 Percent change from baseline in lumbar spine bone mineral density (LS-BMD) at Week 78 – Treatment Period 2 (TP2 Full Analysis Set)
    End point description
    Bone density measurement were performed by DXA. Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (screening), Week 78
    End point values
    		 GP2411/GP2411 EU-Prolia/EU-Prolia EU-Prolia/GP2411
    Number of subjects analysed
    249
    123
    122
    Units: Percentage change (%)
        arithmetic mean (standard deviation)
    6.8222 ± 3.95225
    7.0694 ± 4.72955
    6.4212 ± 4.47102
    No statistical analyses for this end point

    Secondary: Percent change from baseline in femoral neck bone mineral density (FN-BMD) at Week 26 and Week 52 – Treatment Period 1 (Per-Protocol Set)

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    End point title
    		 Percent change from baseline in femoral neck bone mineral density (FN-BMD) at Week 26 and Week 52 – Treatment Period 1 (Per-Protocol Set)
    End point description
    Bone density measurements were performed by DXA. For proximal femur, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (screening), Week 26 and Week 52
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    233
    230
    Units: percentage change (%)
    arithmetic mean (standard deviation)
        Week 26 (n=232,229)
    2.0818 ± 3.38039
    1.8087 ± 3.18505
        Week 52 (n=233,229)
    2.4200 ± 3.70552
    2.6157 ± 3.26119
    No statistical analyses for this end point

    Secondary: Percent change from baseline in femoral neck bone mineral density (FN-BMD) at Week 26 and Week 52 – Treatment Period 1 (TP1 Full Analysis Set)

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    End point title
    		 Percent change from baseline in femoral neck bone mineral density (FN-BMD) at Week 26 and Week 52 – Treatment Period 1 (TP1 Full Analysis Set)
    End point description
    Bone density measurements were performed by DXA. For proximal femur, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (screening), Week 26 and Week 52
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    255
    257
    Units: percentage change (%)
    arithmetic mean (standard deviation)
        Week 26 (n=254,256)
    2.0343 ± 3.43682
    1.8210 ± 3.11073
        Week 52 (n=253,248)
    2.3686 ± 3.69145
    2.5717 ± 3.29726
    No statistical analyses for this end point

    Secondary: Percent change from baseline in femoral neck bone mineral density (FN-BMD) at Week 78 – Treatment Period 2 (TP2 Full Analysis Set)

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    End point title
    		 Percent change from baseline in femoral neck bone mineral density (FN-BMD) at Week 78 – Treatment Period 2 (TP2 Full Analysis Set)
    End point description
    Bone density measurements were performed by DXA. For proximal femur, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (screening), Week 78
    End point values
    		 GP2411/GP2411 EU-Prolia/EU-Prolia EU-Prolia/GP2411
    Number of subjects analysed
    247
    122
    122
    Units: Percentage change (%)
        arithmetic mean (standard deviation)
    3.2220 ± 4.03733
    2.9406 ± 3.92115
    2.6857 ± 3.64193
    No statistical analyses for this end point

    Secondary: Percent change from baseline in total hip bone mineral density (TH-BMD) at Week 26 and Week 52 – Treatment Period 1 (Per-Protocol Set)

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    End point title
    		 Percent change from baseline in total hip bone mineral density (TH-BMD) at Week 26 and Week 52 – Treatment Period 1 (Per-Protocol Set)
    End point description
    Bone density measurements were performed by DXA. For total hip, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (screening), Week 26 and Week 52
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    233
    230
    Units: percentage change (%)
    arithmetic mean (standard deviation)
        Week 26 (n=232,229)
    2.6475 ± 2.43928
    2.1178 ± 2.44627
        Week 52 (n=233,229)
    3.4289 ± 2.71152
    3.3211 ± 2.59266
    No statistical analyses for this end point

    Secondary: Percent change from baseline in total hip bone mineral density (TH-BMD) at Week 26 and Week 52 – Treatment Period 1 (TP1 Full Analysis Set)

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    End point title
    		 Percent change from baseline in total hip bone mineral density (TH-BMD) at Week 26 and Week 52 – Treatment Period 1 (TP1 Full Analysis Set)
    End point description
    Bone density measurements were performed by DXA. For total hip, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (screening), Week 26 and Week 52
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    255
    257
    Units: percentage change (%)
    arithmetic mean (standard deviation)
        Week 26 (n=254,256)
    2.5280 ± 2.46669
    2.0595 ± 2.51811
        Week 52 (n=253,248)
    3.2882 ± 2.70260
    3.2234 ± 2.64633
    No statistical analyses for this end point

    Secondary: Percent change from baseline in total hip bone mineral density (TH-BMD) at Week 78 – Treatment Period 2 (TP2 Full Analysis Set)

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    End point title
    		 Percent change from baseline in total hip bone mineral density (TH-BMD) at Week 78 – Treatment Period 2 (TP2 Full Analysis Set)
    End point description
    Bone density measurements were performed by DXA. For total hip, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study.
    End point type
    Secondary
    End point timeframe
    Baseline (screening), Week 78
    End point values
    		 GP2411/GP2411 EU-Prolia/EU-Prolia EU-Prolia/GP2411
    Number of subjects analysed
    247
    122
    122
    Units: Percentage change (%)
        arithmetic mean (standard deviation)
    3.8270 ± 3.28071
    4.0898 ± 2.96530
    3.9987 ± 3.33311
    No statistical analyses for this end point

    Secondary: CTX serum concentrations as per visit schedule up to Week 52 - Treatment Period 1

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    End point title
    		 CTX serum concentrations as per visit schedule up to Week 52 - Treatment Period 1
    End point description
    CTX is a bone resorption biomarker. Serum samples were analyzed for CTX concentrations. CTX serum concentrations were determined by a validated ligand-binding immunoassay. Values below the LLOQ were imputed with the actual value for the LLOQ.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose Day 1), Day 2, Day 4, Week 8, Week 18, Week 22, Week 26, Week 39 and Week 52
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    228
    213
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline (n=228,213)
    0.437 ± 0.249
    0.450 ± 0.264
        Day 2 (n=226,212)
    0.0904 ± 0.110
    0.0859 ± 0.0923
        Day 4 (n=226,211)
    0.0383 ± 0.0272
    0.0407 ± 0.0537
        Week 8 (n=222,206)
    0.0339 ± 0.0134
    0.0332 ± 0.00334
        Week 18 (n=219,200)
    0.0355 ± 0.0205
    0.0362 ± 0.0225
        Week 22 (n=226,211)
    0.0428 ± 0.0546
    0.0422 ± 0.0406
        Week 26 (n=228,213)
    0.0661 ± 0.0954
    0.0651 ± 0.0708
        Week 39 (n=227,206)
    0.0342 ± 0.0116
    0.0345 ± 0.0110
        Week 52 (n=224,207)
    0.0845 ± 0.116
    0.0807 ± 0.0883
    No statistical analyses for this end point

    Secondary: CTX serum concentrations as per visit schedule from Week 52 up to Week 78 - Treatment Period 2

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    End point title
    		 CTX serum concentrations as per visit schedule from Week 52 up to Week 78 - Treatment Period 2
    End point description
    CTX is a bone resorption biomarker. Serum samples were analyzed for CTX concentrations. CTX serum concentrations were determined by a validated ligand-binding immunoassay. Values below the LLOQ were imputed with the actual value for the LLOQ.
    End point type
    Secondary
    End point timeframe
    Week 56, Week 65 and Week 78
    End point values
    		 GP2411/GP2411 EU-Prolia/EU-Prolia EU-Prolia/GP2411
    Number of subjects analysed
    253
    124
    124
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 56 (n=247,116,117)
    0.0335 ± 0.00685
    0.0358 ± 0.0259
    0.0330 ± 0.00
        Week 65 (n=246,117,118)
    0.0335 ± 0.00714
    0.0352 ± 0.0159
    0.0359 ± 0.0281
        Week 78 (n=248,117,117)
    0.125 ± 0.190
    0.144 ± 0.155
    0.101 ± 0.149
    No statistical analyses for this end point

    Secondary: PINP serum concentrations as per visit schedule up to Week 52 - Treatment Period 1

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    End point title
    		 PINP serum concentrations as per visit schedule up to Week 52 - Treatment Period 1
    End point description
    Procollagen I N-terminal propeptide (PINP) is a bone formation biomarker. Serum samples were analyzed for PINP concentrations. PINP serum concentrations were determined by a validated ligand-binding immunoassay. Values below the LLOQ were imputed with the actual value for the LLOQ.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose Day 1), Day 2, Day 4, Week 8, Week 18, Week 22, Week 26, Week 39 and Week 52
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    228
    213
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline (n=228,213)
    60.3 ± 27.1
    62.2 ± 30.0
        Day 2 (n=228,213)
    58.5 ± 25.9
    60.2 ± 29.3
        Day 4 (n=227,213)
    56.8 ± 23.2
    58.8 ± 26.8
        Week 8 (n=223,207)
    21.2 ± 9.53
    21.0 ± 7.58
        Week 18 (n=221,200)
    12.1 ± 4.52
    12.6 ± 5.10
        Week 22 (n=227,212)
    13.5 ± 5.92
    13.3 ± 4.59
        Week 26 (n=228,213)
    15.4 ± 7.44
    15.9 ± 6.71
        Week 39 (n=227,208)
    10.5 ± 3.14
    10.7 ± 3.43
        Week 52 (n=225,207)
    15.0 ± 5.95
    15.7 ± 7.11
    No statistical analyses for this end point

    Secondary: PINP serum concentrations as per visit schedule from Week 52 up to Week 78 - Treatment Period 2

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    End point title
    		 PINP serum concentrations as per visit schedule from Week 52 up to Week 78 - Treatment Period 2
    End point description
    PINP is a bone formation biomarker. Serum samples were analyzed for PINP concentrations. PINP serum concentrations were determined by a validated ligand-binding immunoassay. Values below the LLOQ were imputed with the actual value for the LLOQ.
    End point type
    Secondary
    End point timeframe
    Week 56, Week 65 and Week 78
    End point values
    		 GP2411/GP2411 EU-Prolia/EU-Prolia EU-Prolia/GP2411
    Number of subjects analysed
    253
    124
    124
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 56 (n=252,122,124)
    13.7 ± 8.06
    13.9 ± 5.39
    14.4 ± 11.0
        Week 65 (n=250,123,123)
    10.5 ± 3.40
    10.9 ± 3.43
    11.1 ± 3.85
        Week 78 (n=252,123,124)
    17.5 ± 14.1
    20.3 ± 20.4
    17.1 ± 8.37
    No statistical analyses for this end point

    Secondary: Number of participants with Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs up to Week 52 - Treatment Period 1

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    End point title
    		 Number of participants with Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs up to Week 52 - Treatment Period 1
    End point description
    Number of participants with TEAEs and serious TEAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs during Treatment Period 1. The number of participants in each category is reported in the table.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment on Day 1 up to pre-dose at Week 52
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    263
    264
    Units: participants
        TEAE
    157
    181
        Treatment-related TEAE
    36
    49
        Serious TEAE
    12
    8
        Treatment-related serious TEAE
    0
    0
    No statistical analyses for this end point

    Secondary: Number of participants with Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs from Week 52 up to Week 78 - Treatment Period 2

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    End point title
    		 Number of participants with Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs from Week 52 up to Week 78 - Treatment Period 2
    End point description
    Number of participants with TEAEs and serious TEAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs during Treatment Period 2. The number of participants in each category is reported in the table.
    End point type
    Secondary
    End point timeframe
    From dosing of study treatment at Week 52 up to Week 78
    End point values
    		 GP2411/GP2411 EU-Prolia/EU-Prolia EU-Prolia/GP2411
    Number of subjects analysed
    253
    125
    124
    Units: participants
        TEAE
    68
    47
    48
        Treatment-related TEAE
    7
    7
    5
        Serious TEAE
    4
    2
    0
        Treatment-related serious TEAE
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of participants with vertebral fractures up to Week 52 - Treatment Period 1

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    End point title
    		 Number of participants with vertebral fractures up to Week 52 - Treatment Period 1
    End point description
    Vertebral fractures were assessed by independent radiologists at the central imaging vendor. The radiologists assessed lateral thoracic (vertebrae T4 to T12) and lumbar (vertebrae L1 to L4) spine radiographs for vertebral fractures. New and worsening vertebral fractures are defined as occurrence of new fracture (i.e. change in Genant score from 0 at baseline to 1 or higher at a later time point) or worsening fracture (i.e. increase in Genant score from baseline at a later time point) in any assessed vertebra. The Genant classification of vertebral fractures is based on the vertebral shape, with respect to vertebral height loss involving the anterior, posterior, and/or middle vertebral body and ranges between 0 (normal) and 3 (severe fracture, >40% loss of height). The number of participants in each category is reported in the table.
    End point type
    Secondary
    End point timeframe
    Baseline (screening) and Week 52
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    263
    264
    Units: participants
        At least one vertebral fracture at baseline
    123
    116
        New vertebral fractures at Week 52
    15
    24
        Worsening vertebral fractures at Week 52
    3
    3
    No statistical analyses for this end point

    Secondary: Number of participants with vertebral fractures from Week 52 up to Week 78 - Treatment Period 2

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    End point title
    		 Number of participants with vertebral fractures from Week 52 up to Week 78 - Treatment Period 2
    End point description
    Vertebral fractures were assessed by independent radiologists at the central imaging vendor. The radiologists assessed lateral thoracic (vertebrae T4 to T12) and lumbar (vertebrae L1 to L4) spine radiographs for vertebral fractures. New and worsening vertebral fractures are defined as occurrence of new fracture (i.e. change in Genant score from 0 at Week 52 to 1 or higher at a later time point) or worsening fracture (i.e. increase in Genant score from Week 52 at a later time point) in any assessed vertebra. The Genant classification of vertebral fractures is based on the vertebral shape, with respect to vertebral height loss involving the anterior, posterior, and/or middle vertebral body and ranges between 0 (normal) and 3 (severe fracture, >40% loss of height). The number of participants in each category is reported in the table.
    End point type
    Secondary
    End point timeframe
    Week 52 and Week 78
    End point values
    		 GP2411/GP2411 EU-Prolia/EU-Prolia EU-Prolia/GP2411
    Number of subjects analysed
    253
    125
    124
    Units: participants
        At least one vertebral fracture at Week 52
    126
    57
    65
        New vertebral fractures at Week 78
    12
    3
    8
        Worsening vertebral fractures at Week 78
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Number of participants with nonvertebral fractures up to Week 52 - Treatment Period 1

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    End point title
    		 Number of participants with nonvertebral fractures up to Week 52 - Treatment Period 1
    End point description
    Information about any nonvertebral fractures while on study were recorded as adverse events. The diagnosis of nonvertebral fractures did not require central X-ray reading and was based on local radiology reports. The number of participants in each category is reported in the table.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment on Day 1 up to pre-dose at Week 52
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    263
    264
    Units: participants
        Hip fracture
    2
    0
        Femoral neck fracture
    1
    0
        Femur fracture
    0
    1
        Ankle fracture
    1
    1
        Wrist fracture
    1
    0
        Radius fracture
    0
    1
    No statistical analyses for this end point

    Secondary: Number of participants with nonvertebral fractures from Week 52 up to Week 78 - Treatment Period 2

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    End point title
    		 Number of participants with nonvertebral fractures from Week 52 up to Week 78 - Treatment Period 2
    End point description
    Information about any nonvertebral fractures while on study were recorded as adverse events. The diagnosis of nonvertebral fractures did not require central X-ray reading and was based on local radiology reports. The number of participants in each category is reported in the table.
    End point type
    Secondary
    End point timeframe
    From dosing of study treatment at Week 52 up to Week 78
    End point values
    		 GP2411/GP2411 EU-Prolia/EU-Prolia EU-Prolia/GP2411
    Number of subjects analysed
    253
    125
    124
    Units: participants
        Hip fracture
    1
    0
    0
        Fibula fracture
    1
    0
    0
        Hand fracture
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of participants with Injection Site Reactions (ISRs) up to Week 52 - Treatment Period 1

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    End point title
    		 Number of participants with Injection Site Reactions (ISRs) up to Week 52 - Treatment Period 1
    End point description
    The injection site reaction (ISR) assessment was done by the investigator/designee. It consisted of grading the severity of each injection reaction based on criteria the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The ISR grading was defined as follows: • Grade 1: Tenderness with or without associated symptoms (e.g., warmth, erythema, itching) • Grade 2: Pain; lipodystrophy; edema; phlebitis • Grade 3: Ulceration or necrosis; severe tissue damage; operative intervention indicated • Grade 4: Life-threatening consequences; urgent intervention indicated The number of participants in each category is reported in the table.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment on Day 1 up to pre-dose at Week 52
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    263
    264
    Units: participants
        ISR Grade 1
    6
    9
        ISR Grade 2
    1
    1
        ISR Grade 3
    0
    0
        ISR Grade 4
    0
    0
    No statistical analyses for this end point

    Secondary: Number of participants with Injection Site Reactions (ISRs) from Week 52 up to Week 78 - Treatment Period 2

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    End point title
    		 Number of participants with Injection Site Reactions (ISRs) from Week 52 up to Week 78 - Treatment Period 2
    End point description
    The injection site reaction (ISR) assessment was done by the investigator/designee. It consisted of grading the severity of each injection reaction based on criteria the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The ISR grading was defined as follows: • Grade 1: Tenderness with or without associated symptoms (e.g., warmth, erythema, itching) • Grade 2: Pain; lipodystrophy; edema; phlebitis • Grade 3: Ulceration or necrosis; severe tissue damage; operative intervention indicated • Grade 4: Life-threatening consequences; urgent intervention indicated The number of participants in each category is reported in the table.
    End point type
    Secondary
    End point timeframe
    From dosing of study treatment at Week 52 up to Week 78
    End point values
    		 GP2411/GP2411 EU-Prolia/EU-Prolia EU-Prolia/GP2411
    Number of subjects analysed
    253
    125
    124
    Units: participants
        ISR Grade 1
    1
    0
    0
        ISR Grade 2
    0
    0
    0
        ISR Grade 3
    0
    0
    0
        ISR Grade 4
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of participants with anti-drug antibodies (ADA) up to Week 52 - Treatment Period 1

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    End point title
    		 Number of participants with anti-drug antibodies (ADA) up to Week 52 - Treatment Period 1
    End point description
    Immunogenicity was evaluated in serum. Samples were screened for potential anti-drug antibodies (ADA) and positive screen results were confirmed using a confirmatory assay. For confirmed ADA positive samples, titers were determined. Confirmed ADAs were also analyzed for their neutralization potential. Patient ADA status was defined as follows: • ADA Positive: ADA-positive sample at any time point during TP1 • ADA Positive, Persistent: ‘Persistent‘ indicates a subject experiencing a positive ADA result at the final visit and with at least 2 consecutive positive ADA results • ADA Positive, Transient: ‘Transient’ indicates a subject experiencing positive ADA result but not qualifying as ‘Persistent‘ • ADA titer positive: ADA-positive sample with a titer result ≥ 20 ng/mL • NAb Positive: ADA-positive sample with presence of neutralizing antibodies (NAb) The number of participants in each category is reported in the table.
    End point type
    Secondary
    End point timeframe
    From Week 2 up to Week 52
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    263
    264
    Units: participants
        ADA Positive
    93
    108
        ADA Positive, Persistent
    7
    4
        ADA Positive, Transient
    86
    104
        ADA titer positive
    2
    2
        NAb positive
    3
    1
    No statistical analyses for this end point

    Secondary: Number of participants with anti-drug antibodies (ADA) from Week 52 up to Week 78 - Treatment Period 2

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    End point title
    		 Number of participants with anti-drug antibodies (ADA) from Week 52 up to Week 78 - Treatment Period 2
    End point description
    Immunogenicity was evaluated in serum. Samples were screened for potential anti-drug antibodies (ADA) and positive screen results were confirmed using a confirmatory assay. For confirmed ADA positive samples, titers were determined. Confirmed ADAs were also analyzed for their neutralization potential. Patient ADA status was defined as follows: • ADA Positive: ADA-positive sample at any time point during TP1 • ADA Positive, Persistent: ‘Persistent‘ indicates a subject experiencing a positive ADA result at the final visit and with at least 2 consecutive positive ADA results • ADA Positive, Transient: ‘Transient’ indicates a subject experiencing positive ADA result but not qualifying as ‘Persistent‘ • ADA titer positive: ADA-positive sample with a titer result ≥ 20 ng/mL • NAb Positive: ADA-positive sample with presence of neutralizing antibodies (NAb) The number of participants in each category is reported in the table.
    End point type
    Secondary
    End point timeframe
    From Week 56 up to Week 78
    End point values
    		 GP2411/GP2411 EU-Prolia/EU-Prolia EU-Prolia/GP2411
    Number of subjects analysed
    253
    125
    124
    Units: participants
        ADA Positive
    42
    26
    26
        ADA Positive, Persistent
    3
    3
    0
        ADA Positive, Transient
    39
    23
    26
        ADA titer positive
    0
    1
    0
        NAb positive
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Denosumab serum concentrations as per visit schedule up to Week 52 - Treatment Period 1

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    End point title
    		 Denosumab serum concentrations as per visit schedule up to Week 52 - Treatment Period 1
    End point description
    Serum samples were analyzed for concentrations of free denosumab by using a validated ligand binding assay. Briefly, the concentration of free denosumab was determined by binding to coated ligand molecules. Denosumab concentrations below the LLOQ were set to zero in order to calculate arithmetic means.
    End point type
    Secondary
    End point timeframe
    Baseline (pre-dose Day 1), Day 4, Week 1, Week 2, Week 8, Week 14, Week 18, Week 22, Week 26, Week 39 and Week 52
    End point values
    		 GP2411 EU-Prolia
    Number of subjects analysed
    260
    258
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 (n=256,257)
    0.00 ± 0.00
    0.928 ± 14.9
        Day 4 (n=258,258)
    4930 ± 2530
    5250 ± 2660
        Week 1 (n=259,254)
    6820 ± 3220
    6890 ± 3320
        Week 2 (n=259,256)
    6940 ± 3040
    6760 ± 2890
        Week 8 (n=253,251)
    3160 ± 1500
    3070 ± 1510
        Week 14 (n=250,249)
    1130 ± 740
    1090 ± 797
        Week 18 (n=248,241)
    536 ± 516
    495 ± 487
        Week 22 (n=256,254)
    208 ± 277
    198 ± 392
        Week 26 (n=252,253)
    95.9 ± 415
    47.9 ± 114
        Week 39 (n=250,245)
    1490 ± 902
    1390 ± 787
        Week 52 (n=250,244)
    91.9 ± 186
    58.3 ± 126
    No statistical analyses for this end point

    Secondary: Denosumab serum concentrations as per visit schedule from Week 52 up to Week 78 - Treatment Period 2

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    End point title
    		 Denosumab serum concentrations as per visit schedule from Week 52 up to Week 78 - Treatment Period 2
    End point description
    Serum samples were analyzed for concentrations of free denosumab by using a validated ligand binding assay. Briefly, the concentration of free denosumab was determined by binding to coated ligand molecules. Denosumab concentrations below the LLOQ were set to zero in order to calculate arithmetic means.
    End point type
    Secondary
    End point timeframe
    Week 56, Week 65 and Week 78
    End point values
    		 GP2411/GP2411 EU-Prolia/EU-Prolia EU-Prolia/GP2411
    Number of subjects analysed
    253
    124
    124
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 56 (n=252,122,124)
    6010 ± 2200
    5550 ± 1900
    6220 ± 2130
        Week 65 (n=250,123,122)
    1540 ± 880
    1330 ± 753
    1640 ± 962
        Week 78 (n=251,123,124)
    122 ± 406
    53.2 ± 133
    147 ± 652
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study treatment on Day 1 up to Week 78.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    EU-Prolia
    Reporting group description
    		 Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1

    Reporting group title
    GP2411
    Reporting group description
    		 Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1

    Reporting group title
    EU-Prolia/EU-Prolia
    Reporting group description
    		 Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2

    Reporting group title
    EU-Prolia/GP2411
    Reporting group description
    		 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2

    Reporting group title
    GP2411/GP2411
    Reporting group description
    		 Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2

    Serious adverse events
    		 EU-Prolia GP2411 EU-Prolia/EU-Prolia EU-Prolia/GP2411 GP2411/GP2411
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 264 (3.03%)
    12 / 263 (4.56%)
    2 / 125 (1.60%)
    0 / 124 (0.00%)
    4 / 253 (1.58%)
         number of deaths (all causes)
    0
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 264 (0.38%)
    1 / 263 (0.38%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 263 (0.00%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    1 / 253 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm of ampulla of Vater
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 263 (0.38%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    1 / 253 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 263 (0.00%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 263 (0.00%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 263 (0.38%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 263 (0.38%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 264 (0.00%)
    2 / 263 (0.76%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    1 / 253 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Thrombophlebitis
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 263 (0.00%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 263 (0.38%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 263 (0.38%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Epiretinal membrane
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 263 (0.00%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Chronic gastritis
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 263 (0.38%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 263 (0.38%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 263 (0.00%)
    1 / 125 (0.80%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 263 (0.00%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    1 / 253 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic fistula
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 263 (0.00%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    1 / 253 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 263 (0.00%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 263 (0.00%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    1 / 253 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 264 (0.00%)
    1 / 263 (0.38%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 263 (0.00%)
    1 / 125 (0.80%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 264 (0.38%)
    1 / 263 (0.38%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 263 (0.00%)
    1 / 125 (0.80%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 264 (0.38%)
    0 / 263 (0.00%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal candidiasis
         subjects affected / exposed
    0 / 264 (0.00%)
    0 / 263 (0.00%)
    1 / 125 (0.80%)
    0 / 124 (0.00%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 EU-Prolia GP2411 EU-Prolia/EU-Prolia EU-Prolia/GP2411 GP2411/GP2411
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    119 / 264 (45.08%)
    89 / 263 (33.84%)
    29 / 125 (23.20%)
    24 / 124 (19.35%)
    33 / 253 (13.04%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    6 / 264 (2.27%)
    3 / 263 (1.14%)
    1 / 125 (0.80%)
    4 / 124 (3.23%)
    1 / 253 (0.40%)
         occurrences all number
    6
    3
    1
    4
    1
    Spinal compression fracture
         subjects affected / exposed
    5 / 264 (1.89%)
    1 / 263 (0.38%)
    2 / 125 (1.60%)
    4 / 124 (3.23%)
    2 / 253 (0.79%)
         occurrences all number
    6
    1
    3
    4
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 264 (4.92%)
    6 / 263 (2.28%)
    2 / 125 (1.60%)
    3 / 124 (2.42%)
    1 / 253 (0.40%)
         occurrences all number
    16
    6
    2
    3
    1
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    10 / 264 (3.79%)
    7 / 263 (2.66%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    1 / 253 (0.40%)
         occurrences all number
    10
    7
    0
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 264 (2.65%)
    3 / 263 (1.14%)
    4 / 125 (3.20%)
    0 / 124 (0.00%)
    1 / 253 (0.40%)
         occurrences all number
    11
    3
    4
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 264 (3.03%)
    12 / 263 (4.56%)
    5 / 125 (4.00%)
    2 / 124 (1.61%)
    7 / 253 (2.77%)
         occurrences all number
    9
    15
    5
    3
    11
    Spinal osteoarthritis
         subjects affected / exposed
    9 / 264 (3.41%)
    4 / 263 (1.52%)
    2 / 125 (1.60%)
    1 / 124 (0.81%)
    0 / 253 (0.00%)
         occurrences all number
    10
    4
    2
    1
    0
    Back pain
         subjects affected / exposed
    9 / 264 (3.41%)
    10 / 263 (3.80%)
    2 / 125 (1.60%)
    1 / 124 (0.81%)
    2 / 253 (0.79%)
         occurrences all number
    10
    14
    2
    1
    2
    Infections and infestations
    COVID-19
         subjects affected / exposed
    13 / 264 (4.92%)
    9 / 263 (3.42%)
    7 / 125 (5.60%)
    2 / 124 (1.61%)
    6 / 253 (2.37%)
         occurrences all number
    13
    9
    7
    2
    6
    Cystitis
         subjects affected / exposed
    9 / 264 (3.41%)
    1 / 263 (0.38%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    1 / 253 (0.40%)
         occurrences all number
    10
    2
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    16 / 264 (6.06%)
    23 / 263 (8.75%)
    4 / 125 (3.20%)
    6 / 124 (4.84%)
    5 / 253 (1.98%)
         occurrences all number
    17
    26
    4
    6
    5
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 264 (3.03%)
    4 / 263 (1.52%)
    2 / 125 (1.60%)
    2 / 124 (1.61%)
    1 / 253 (0.40%)
         occurrences all number
    8
    4
    3
    2
    1
    Urinary tract infection
         subjects affected / exposed
    10 / 264 (3.79%)
    5 / 263 (1.90%)
    2 / 125 (1.60%)
    0 / 124 (0.00%)
    2 / 253 (0.79%)
         occurrences all number
    12
    7
    2
    0
    2
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    26 / 264 (9.85%)
    28 / 263 (10.65%)
    0 / 125 (0.00%)
    0 / 124 (0.00%)
    1 / 253 (0.40%)
         occurrences all number
    26
    29
    0
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    12 / 264 (4.55%)
    7 / 263 (2.66%)
    3 / 125 (2.40%)
    3 / 124 (2.42%)
    2 / 253 (0.79%)
         occurrences all number
    12
    7
    3
    3
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Dec 2018
    The main purpose of this amendment was to use appropriate terminology, e.g. when referring to US-licensed Prolia and EU-authorized Prolia.
    15 Mar 2019
    The following main changes were implemented: • The sample size calculations were updated to change the CI for the LS-BMD for the FDA requirements to use a 95% CI in the similarity assessment of the primary endpoint. • The inclusion and exclusion criteria were updated, additional PK, PD and ADA sampling time points were added, the definition of the analysis sets was updated, handling of missing efficacy values was clarified, and a sensitivity analysis was planned. In addition, severity grading of ISRs and other AEs was updated. • Severity grading of ISRs was updated to align with the CTCAE classification.
    21 Feb 2020
    The following changes were made: • SD estimate of %CfB in LS-BMD at Week 52 was updated and analysis set for the primary analysis of %CfB in LS-BMD for FDA was updated from PPS to TP1 FAS, which resulted in a reduction of the sample size. • This amendment also changed the calcium assessment by shifting from the parameter “albumin adjusted serum calcium” to the parameter “total serum calcium”. • Screening period was prolonged from 28 to 35 days.
    30 Oct 2020
    Following changes were made: • The statistical testing strategy was updated from one overall study testing strategy to three separate testing strategies which address different health authority requirements •Details were added on the MMRM model, and the handling and statistical analysis of missing data.

    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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    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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