Trial Outcomes & Findings for Study Investigating PK, PD, Efficacy, Safety, and Immunogenicity of Biosimilar Denosumab (GP2411) in Patients With Postmenopausal Osteoporosis (NCT NCT03974100)

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

527 participants

Primary outcome timeframe

Baseline (screening), up to Week 52

Results posted on

2023-03-08

Participant Flow

Participants took part in 43 investigative sites in 6 countries.

The screening period of up to 5 weeks began after the subject had provided written informed consent and ended at the randomization visit (Day 1). On Day 1, participants were randomized in a 1:1 ratio to receive either GP2411 or EU-Prolia during Treatment Period 1 (TP1). At Week 52, participants in the EU-Prolia group were re-randomized 1:1 to either continue with EU-Prolia or switch to GP2411 for Treatment Period 2 (TP2). Participants in the GP2411 group continued with GP2411 for TP2.

Participant milestones

Participant milestones
Measure	GP2411 Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	GP2411/GP2411 Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	EU-Prolia/EU-Prolia Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
TP1 - Day 1 to Week 52 STARTED	263	264	0	0	0
TP1 - Day 1 to Week 52 Per-Protocol Set (PPS)	233	230	0	0	0
TP1 - Day 1 to Week 52 TP1 Full Analysis Set (TP1 FAS)	255	257	0	0	0
TP1 - Day 1 to Week 52 Pharmacodynamic Analysis Set (PDS)	228	213	0	0	0
TP1 - Day 1 to Week 52 Pharmacokinetic Analysis Set (PKS)	260	258	0	0	0
TP1 - Day 1 to Week 52 TP1 Safety Analysis Set	263	264	0	0	0
TP1 - Day 1 to Week 52 COMPLETED	253	249	0	0	0
TP1 - Day 1 to Week 52 NOT COMPLETED	10	15	0	0	0
TP2- Week 52 to Week 78 STARTED	0	0	253	125	124
TP2- Week 52 to Week 78 TP2 Full Analysis Set (TP2 FAS)	0	0	253	124	124
TP2- Week 52 to Week 78 TP2 Safety Analysis Set	0	0	253	125	124
TP2- Week 52 to Week 78 COMPLETED	0	0	253	123	124
TP2- Week 52 to Week 78 NOT COMPLETED	0	0	0	2	0

Reasons for withdrawal

Reasons for withdrawal
Measure	GP2411 Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/EU-Prolia Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2
TP1 - Day 1 to Week 52 Adverse Event	1	3	0
TP1 - Day 1 to Week 52 Death	1	0	0
TP1 - Day 1 to Week 52 Lost to Follow-up	0	1	0
TP1 - Day 1 to Week 52 Physician Decision	0	2	0
TP1 - Day 1 to Week 52 Subject decision	8	9	0
TP2- Week 52 to Week 78 Lost to Follow-up	0	0	1
TP2- Week 52 to Week 78 Subject decision	0	0	1

Baseline Characteristics

Study Investigating PK, PD, Efficacy, Safety, and Immunogenicity of Biosimilar Denosumab (GP2411) in Patients With Postmenopausal Osteoporosis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	GP2411 n=263 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=264 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	Total n=527 Participants Total of all reporting groups
Age, Continuous	64.6 years STANDARD_DEVIATION 6.08 • n=5 Participants	64.7 years STANDARD_DEVIATION 5.78 • n=7 Participants	64.7 years STANDARD_DEVIATION 5.92 • n=5 Participants
Sex: Female, Male Female	263 Participants n=5 Participants	264 Participants n=7 Participants	527 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Asian	23 Participants n=5 Participants	24 Participants n=7 Participants	47 Participants n=5 Participants
Race/Ethnicity, Customized Multiple	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized White	239 Participants n=5 Participants	240 Participants n=7 Participants	479 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (screening), up to Week 52

Population: Per-Protocol Set (PPS) defined as participants who were randomized into TP1 and met the following criteria: the LS-BMD assessments at baseline and Week 52 are available, they received treatment according to protocol on Day 1 and Week 26 and they did not experience relevant protocol deviations which would affect LS-BMD up to Week 52.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=233 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=230 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 52 - Per-Protocol Set	4.955 Percentage change (%) Standard Error 0.2634	5.099 Percentage change (%) Standard Error 0.2618	—

PRIMARY outcome

Timeframe: Baseline (screening), up to Week 52

Population: TP1 Full Analysis Set (TP1 FAS) defined as participants who were randomized into TP1, who received at least one dose of study drug and for whom at least one post-baseline LS-BMD value (either at Week 26 or Week 52 or at both visits) is available.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=255 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=257 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 52 - TP1 Full Analysis Set	4.963 Percentage change (%) Standard Error 0.2630	5.140 Percentage change (%) Standard Error 0.2627	—

PRIMARY outcome

Timeframe: Baseline (pre-dose Day 1), up to Week 26

Population: Pharmacodynamic Analysis Set (PDS) defined as participants who were randomized into TP1 and met the following criteria: CTX values are available in order to be able to calculate AUEC, they received treatment according to protocol on Day 1 and they did not experience relevant protocol deviations.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=228 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=213 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Area Under the Effect-time Curve (AUEC) of Percentage Change From Baseline in Serum CTX Concentrations After First Dose - Pharmacodynamic Analysis Set	15700 percentage change (%)*day Geometric Coefficient of Variation 15.8	15900 percentage change (%)*day Geometric Coefficient of Variation 14.0	—

PRIMARY outcome

Timeframe: Baseline (pre-dose Day 1), up to Week 26

Population: Participants in the Pharmacokinetic Analysis Set (PKS) who had valid assessments of Cmax. The PKS is defined as participants who were randomized into TP1 and met the following criteria: at least one PK primary endpoint (Cmax or AUCinf) is evaluable, they received treatment according to protocol on Day 1 and they did not experience relevant protocol deviations.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=260 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=258 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Maximum Observed Serum Concentration (Cmax) of Denosumab After First Dose	6970 ng/mL Geometric Coefficient of Variation 45.8	7050 ng/mL Geometric Coefficient of Variation 44.2	—

PRIMARY outcome

Timeframe: Baseline (pre-dose Day 1), up to Week 26

Population: Participants in the Pharmacokinetic Analysis Set (PKS) who had valid assessments of AUCinf. The PKS is defined as participants who were randomized into TP1 and met the following criteria: at least one PK primary endpoint (Cmax or AUCinf) is evaluable, they received treatment according to protocol on Day 1 and they did not experience relevant protocol deviations.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=247 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=246 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) of Denosumab After First Dose	370000 day*ng/mL Geometric Coefficient of Variation 47.8	365000 day*ng/mL Geometric Coefficient of Variation 43.3	—

SECONDARY outcome

Timeframe: Baseline (screening), Week 26

Population: Participants in the Per-Protocol Set (PPS) who had valid assessments of the outcome measure at both baseline and Week 26.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=233 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=229 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 26 - Treatment Period 1 (Per-Protocol Set)	3.6501 percentage change (%) Standard Deviation 3.76952	3.6700 percentage change (%) Standard Deviation 3.68816	—

SECONDARY outcome

Timeframe: Baseline (screening), Week 26

Population: Participants in the TP1 Full Analysis Set (TP1 FAS) who had valid assessments of the outcome measure at both baseline and Week 26.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=255 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=256 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 26 - Treatment Period 1 (TP1 Full Analysis Set)	3.5877 percentage change (%) Standard Deviation 3.73579	3.7144 percentage change (%) Standard Deviation 3.89730	—

SECONDARY outcome

Timeframe: Baseline (screening), Week 78

Population: Participants in the TP2 Full Analysis Set (TP2 FAS) who had valid assessments of the outcome measure at both baseline and Week 78. TP2 FAS is defined as participants who were re-randomized into TP2 and for whom at least one TP2 efficacy, pharmacokinetics or pharmacodynamics value is available.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=249 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=123 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 n=122 Participants Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set)	6.8222 Percentage change (%) Standard Deviation 3.95225	7.0694 Percentage change (%) Standard Deviation 4.72955	6.4212 Percentage change (%) Standard Deviation 4.47102

SECONDARY outcome

Timeframe: Baseline (screening), Week 26 and Week 52

Population: The overall number of participants analyzed represents the Per-Protocol Set (PPS). The number analyzed per row represents participants with data at baseline and at the corresponding time point.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=233 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=230 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Percent Change From Baseline in Femoral Neck Bone Mineral Density (FN-BMD) at Week 26 and Week 52 - Treatment Period 1 (Per-Protocol Set) Week 26	2.0818 percentage change (%) Standard Deviation 3.38039	1.8087 percentage change (%) Standard Deviation 3.18505	—
Percent Change From Baseline in Femoral Neck Bone Mineral Density (FN-BMD) at Week 26 and Week 52 - Treatment Period 1 (Per-Protocol Set) Week 52	2.4200 percentage change (%) Standard Deviation 3.70552	2.6157 percentage change (%) Standard Deviation 3.26119	—

SECONDARY outcome

Timeframe: Baseline (screening), Week 26 and Week 52

Population: The overall number of participants analyzed represents the TP1 Full Analysis Set (TP1 FAS). The number analyzed per row represents participants with data at baseline and at the corresponding time point.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=255 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=257 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
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) Week 26	2.0343 percentage change (%) Standard Deviation 3.43682	1.8210 percentage change (%) Standard Deviation 3.11073	—
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) Week 52	2.3686 percentage change (%) Standard Deviation 3.69145	2.5717 percentage change (%) Standard Deviation 3.29726	—

SECONDARY outcome

Timeframe: Baseline (screening), Week 78

Population: Participants in the TP2 Full Analysis Set (TP2 FAS) who had valid assessments of the outcome measure at both baseline and Week 78.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=247 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=122 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 n=122 Participants Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Percent Change From Baseline in Femoral Neck Bone Mineral Density (FN-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set)	3.2220 Percentage change (%) Standard Deviation 4.03733	2.9406 Percentage change (%) Standard Deviation 3.92115	2.6857 Percentage change (%) Standard Deviation 3.64193

SECONDARY outcome

Timeframe: Baseline (screening), Week 26 and Week 52

Population: The overall number of participants analyzed represents the Per-Protocol Set (PPS). The number analyzed per row represents participants with data at baseline and at the corresponding time point.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=233 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=230 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Percent Change From Baseline in Total Hip Bone Mineral Density (TH-BMD) at Week 26 and Week 52 - Treatment Period 1 (Per-Protocol Set) Week 26	2.6475 percentage change (%) Standard Deviation 2.43928	2.1178 percentage change (%) Standard Deviation 2.44627	—
Percent Change From Baseline in Total Hip Bone Mineral Density (TH-BMD) at Week 26 and Week 52 - Treatment Period 1 (Per-Protocol Set) Week 52	3.4289 percentage change (%) Standard Deviation 2.71152	3.3211 percentage change (%) Standard Deviation 2.59266	—

SECONDARY outcome

Timeframe: Baseline (screening), Week 26 and Week 52

Population: The overall number of participants analyzed represents the TP1 Full Analysis Set (TP1 FAS). The number analyzed per row represents participants with data at baseline and at the corresponding time point.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=255 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=257 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
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) Week 26	2.5280 percentage change (%) Standard Deviation 2.46669	2.0595 percentage change (%) Standard Deviation 2.51811	—
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) Week 52	3.2882 percentage change (%) Standard Deviation 2.70260	3.2234 percentage change (%) Standard Deviation 2.64633	—

SECONDARY outcome

Timeframe: Baseline (screening), Week 78

Population: Participants in the TP2 Full Analysis Set (TP2 FAS) who had valid assessments of the outcome measure at both baseline and Week 78.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=247 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=122 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 n=122 Participants Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Percent Change From Baseline in Total Hip Bone Mineral Density (TH-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set)	3.8270 Percentage change (%) Standard Deviation 3.28071	4.0898 Percentage change (%) Standard Deviation 2.96530	3.9987 Percentage change (%) Standard Deviation 3.33311

SECONDARY outcome

Timeframe: Baseline (pre-dose Day 1), Day 2, Day 4, Week 8, Week 18, Week 22, Week 26, Week 39 and Week 52

Population: The overall number of participants analyzed represents the Pharmacodynamic Analysis Set (PDS). The number analyzed per row represents participants with data at the corresponding time point.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=228 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=213 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
CTX Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Baseline	0.437 ng/mL Standard Deviation 0.249	0.450 ng/mL Standard Deviation 0.264	—
CTX Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Day 2	0.0904 ng/mL Standard Deviation 0.110	0.0859 ng/mL Standard Deviation 0.0923	—
CTX Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Day 4	0.0383 ng/mL Standard Deviation 0.0272	0.0407 ng/mL Standard Deviation 0.0537	—
CTX Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 8	0.0339 ng/mL Standard Deviation 0.0134	0.0332 ng/mL Standard Deviation 0.00334	—
CTX Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 18	0.0355 ng/mL Standard Deviation 0.0205	0.0362 ng/mL Standard Deviation 0.0225	—
CTX Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 22	0.0428 ng/mL Standard Deviation 0.0546	0.0422 ng/mL Standard Deviation 0.0406	—
CTX Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 26	0.0661 ng/mL Standard Deviation 0.0954	0.0651 ng/mL Standard Deviation 0.0708	—
CTX Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 39	0.0342 ng/mL Standard Deviation 0.0116	0.0345 ng/mL Standard Deviation 0.0110	—
CTX Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 52	0.0845 ng/mL Standard Deviation 0.116	0.0807 ng/mL Standard Deviation 0.0883	—

SECONDARY outcome

Timeframe: Week 56, Week 65 and Week 78

Population: The overall number of participants analyzed represents the TP2 Full Analysis Set (TP2 FAS). The number analyzed per row represents participants with data at the corresponding time point.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=253 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=124 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 n=124 Participants Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
CTX Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2 Week 56	0.0335 ng/mL Standard Deviation 0.00685	0.0358 ng/mL Standard Deviation 0.0259	0.0330 ng/mL Standard Deviation 0.00
CTX Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2 Week 65	0.0335 ng/mL Standard Deviation 0.00714	0.0352 ng/mL Standard Deviation 0.0159	0.0359 ng/mL Standard Deviation 0.0281
CTX Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2 Week 78	0.125 ng/mL Standard Deviation 0.190	0.144 ng/mL Standard Deviation 0.155	0.101 ng/mL Standard Deviation 0.149

SECONDARY outcome

Timeframe: Baseline (pre-dose Day 1), Day 2, Day 4, Week 8, Week 18, Week 22, Week 26, Week 39 and Week 52

Population: The overall number of participants analyzed represents the Pharmacodynamic Analysis Set (PDS). The number analyzed per row represents participants with data at the corresponding time point.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=228 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=213 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
PINP Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Baseline	60.3 ng/mL Standard Deviation 27.1	62.2 ng/mL Standard Deviation 30.0	—
PINP Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Day 2	58.5 ng/mL Standard Deviation 25.9	60.2 ng/mL Standard Deviation 29.3	—
PINP Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Day 4	56.8 ng/mL Standard Deviation 23.2	58.8 ng/mL Standard Deviation 26.8	—
PINP Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 8	21.2 ng/mL Standard Deviation 9.53	21.0 ng/mL Standard Deviation 7.58	—
PINP Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 18	12.1 ng/mL Standard Deviation 4.52	12.6 ng/mL Standard Deviation 5.10	—
PINP Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 22	13.5 ng/mL Standard Deviation 5.92	13.3 ng/mL Standard Deviation 4.59	—
PINP Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 26	15.4 ng/mL Standard Deviation 7.44	15.9 ng/mL Standard Deviation 6.71	—
PINP Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 39	10.5 ng/mL Standard Deviation 3.14	10.7 ng/mL Standard Deviation 3.43	—
PINP Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 52	15.0 ng/mL Standard Deviation 5.95	15.7 ng/mL Standard Deviation 7.11	—

SECONDARY outcome

Timeframe: Week 56, Week 65 and Week 78

Population: The overall number of participants analyzed represents the TP2 Full Analysis Set (TP2 FAS). The number analyzed per row represents participants with data at the corresponding time point.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=253 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=124 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 n=124 Participants Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
PINP Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2 Week 56	13.7 ng/mL Standard Deviation 8.06	13.9 ng/mL Standard Deviation 5.39	14.4 ng/mL Standard Deviation 11.0
PINP Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2 Week 65	10.5 ng/mL Standard Deviation 3.40	10.9 ng/mL Standard Deviation 3.43	11.1 ng/mL Standard Deviation 3.85
PINP Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2 Week 78	17.5 ng/mL Standard Deviation 14.1	20.3 ng/mL Standard Deviation 20.4	17.1 ng/mL Standard Deviation 8.37

SECONDARY outcome

Timeframe: From first dose of study treatment on Day 1 up to pre-dose at Week 52

Population: TP1 Safety Analysis Set defined as participants who received at least one dose of study drug in Treatment Period 1.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=263 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=264 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs up to Week 52 - Treatment Period 1 TEAE	157 Participants	181 Participants	—
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs up to Week 52 - Treatment Period 1 Treatment-related TEAE	36 Participants	49 Participants	—
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs up to Week 52 - Treatment Period 1 Serious TEAE	12 Participants	8 Participants	—
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs up to Week 52 - Treatment Period 1 Treatment-related serious TEAE	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: From dosing of study treatment at Week 52 up to Week 78

Population: TP2 Safety Analysis Set defined as participants who received at least one dose of study drug in Treatment Period 2.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=253 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=125 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 n=124 Participants Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs From Week 52 up to Week 78 - Treatment Period 2 TEAE	68 Participants	47 Participants	48 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs From Week 52 up to Week 78 - Treatment Period 2 Treatment-related TEAE	7 Participants	7 Participants	5 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs From Week 52 up to Week 78 - Treatment Period 2 Serious TEAE	4 Participants	2 Participants	0 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs From Week 52 up to Week 78 - Treatment Period 2 Treatment-related serious TEAE	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (screening) and Week 52

Population: All participants in the TP1 Safety Analysis Set

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.

Outcome measures

Outcome measures
Measure	GP2411 n=263 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=264 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Number of Participants With Vertebral Fractures up to Week 52 - Treatment Period 1 At least one vertebral fracture at baseline	123 Participants	116 Participants	—
Number of Participants With Vertebral Fractures up to Week 52 - Treatment Period 1 New vertebral fractures at Week 52	15 Participants	24 Participants	—
Number of Participants With Vertebral Fractures up to Week 52 - Treatment Period 1 Worsening vertebral fractures at Week 52	3 Participants	3 Participants	—

SECONDARY outcome

Timeframe: Week 52 and Week 78

Population: All participants in the TP2 Safety Analysis Set

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.

Outcome measures

Outcome measures
Measure	GP2411 n=253 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=125 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 n=124 Participants Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Number of Participants With Vertebral Fractures From Week 52 up to Week 78 - Treatment Period 2 At least one vertebral fracture at Week 52	126 Participants	57 Participants	65 Participants
Number of Participants With Vertebral Fractures From Week 52 up to Week 78 - Treatment Period 2 New vertebral fractures at Week 78	12 Participants	3 Participants	8 Participants
Number of Participants With Vertebral Fractures From Week 52 up to Week 78 - Treatment Period 2 Worsening vertebral fractures at Week 78	1 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From first dose of study treatment on Day 1 up to pre-dose at Week 52

Population: All participants in the TP1 Safety Analysis Set

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.

Outcome measures

Outcome measures
Measure	GP2411 n=263 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=264 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Number of Participants With Nonvertebral Fractures up to Week 52 - Treatment Period 1 Hip fracture	2 Participants	0 Participants	—
Number of Participants With Nonvertebral Fractures up to Week 52 - Treatment Period 1 Femoral neck fracture	1 Participants	0 Participants	—
Number of Participants With Nonvertebral Fractures up to Week 52 - Treatment Period 1 Femur fracture	0 Participants	1 Participants	—
Number of Participants With Nonvertebral Fractures up to Week 52 - Treatment Period 1 Ankle fracture	1 Participants	1 Participants	—
Number of Participants With Nonvertebral Fractures up to Week 52 - Treatment Period 1 Wrist fracture	1 Participants	0 Participants	—
Number of Participants With Nonvertebral Fractures up to Week 52 - Treatment Period 1 Radius fracture	0 Participants	1 Participants	—

SECONDARY outcome

Timeframe: From dosing of study treatment at Week 52 up to Week 78

Population: All participants in the TP2 Safety Analysis Set

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.

Outcome measures

Outcome measures
Measure	GP2411 n=253 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=125 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 n=124 Participants Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Number of Participants With Nonvertebral Fractures From Week 52 up to Week 78 - Treatment Period 2 Hip fracture	1 Participants	0 Participants	0 Participants
Number of Participants With Nonvertebral Fractures From Week 52 up to Week 78 - Treatment Period 2 Fibula fracture	1 Participants	0 Participants	0 Participants
Number of Participants With Nonvertebral Fractures From Week 52 up to Week 78 - Treatment Period 2 Hand fracture	0 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: From first dose of study treatment on Day 1 up to pre-dose at Week 52

Population: All participants in the TP1 Safety Analysis Set

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.

Outcome measures

Outcome measures
Measure	GP2411 n=263 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=264 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Number of Participants With Injection Site Reactions (ISRs) up to Week 52 - Treatment Period 1 ISR Grade 1	6 Participants	9 Participants	—
Number of Participants With Injection Site Reactions (ISRs) up to Week 52 - Treatment Period 1 ISR Grade 2	1 Participants	1 Participants	—
Number of Participants With Injection Site Reactions (ISRs) up to Week 52 - Treatment Period 1 ISR Grade 3	0 Participants	0 Participants	—
Number of Participants With Injection Site Reactions (ISRs) up to Week 52 - Treatment Period 1 ISR Grade 4	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: From dosing of study treatment at Week 52 up to Week 78

Population: All participants in the TP2 Safety Analysis Set

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.

Outcome measures

Outcome measures
Measure	GP2411 n=253 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=125 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 n=124 Participants Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Number of Participants With Injection Site Reactions (ISRs) From Week 52 up to Week 78 - Treatment Period 2 ISR Grade 1	1 Participants	0 Participants	0 Participants
Number of Participants With Injection Site Reactions (ISRs) From Week 52 up to Week 78 - Treatment Period 2 ISR Grade 2	0 Participants	0 Participants	0 Participants
Number of Participants With Injection Site Reactions (ISRs) From Week 52 up to Week 78 - Treatment Period 2 ISR Grade 3	0 Participants	0 Participants	0 Participants
Number of Participants With Injection Site Reactions (ISRs) From Week 52 up to Week 78 - Treatment Period 2 ISR Grade 4	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From Week 2 up to Week 52

Population: All participants in the TP1 Safety Analysis Set

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.

Outcome measures

Outcome measures
Measure	GP2411 n=263 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=264 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Number of Participants With Anti-drug Antibodies (ADA) up to Week 52 - Treatment Period 1 ADA Positive	93 Participants	108 Participants	—
Number of Participants With Anti-drug Antibodies (ADA) up to Week 52 - Treatment Period 1 ADA Positive, Persistent	7 Participants	4 Participants	—
Number of Participants With Anti-drug Antibodies (ADA) up to Week 52 - Treatment Period 1 ADA Positive, Transient	86 Participants	104 Participants	—
Number of Participants With Anti-drug Antibodies (ADA) up to Week 52 - Treatment Period 1 ADA titer positive	2 Participants	2 Participants	—
Number of Participants With Anti-drug Antibodies (ADA) up to Week 52 - Treatment Period 1 NAb positive	3 Participants	1 Participants	—

SECONDARY outcome

Timeframe: From Week 56 up to Week 78

Population: All participants in the TP2 Safety Analysis Set

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.

Outcome measures

Outcome measures
Measure	GP2411 n=253 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=125 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 n=124 Participants Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Number of Participants With Anti-drug Antibodies (ADA) From Week 52 up to Week 78 - Treatment Period 2 ADA Positive	42 Participants	26 Participants	26 Participants
Number of Participants With Anti-drug Antibodies (ADA) From Week 52 up to Week 78 - Treatment Period 2 ADA Positive, Persistent	3 Participants	3 Participants	0 Participants
Number of Participants With Anti-drug Antibodies (ADA) From Week 52 up to Week 78 - Treatment Period 2 ADA Positive, Transient	39 Participants	23 Participants	26 Participants
Number of Participants With Anti-drug Antibodies (ADA) From Week 52 up to Week 78 - Treatment Period 2 ADA titer positive	0 Participants	1 Participants	0 Participants
Number of Participants With Anti-drug Antibodies (ADA) From Week 52 up to Week 78 - Treatment Period 2 NAb positive	1 Participants	0 Participants	1 Participants

SECONDARY outcome

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

Population: The overall number of participants analyzed represents the Pharmacokinetic Analysis Set (PKS). The number analyzed per row represents participants with data at the corresponding time point.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=260 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=258 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Day 1	0.00 ng/mL Standard Deviation 0.00	0.928 ng/mL Standard Deviation 14.9	—
Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Day 4	4930 ng/mL Standard Deviation 2530	5250 ng/mL Standard Deviation 2660	—
Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 1	6820 ng/mL Standard Deviation 3220	6890 ng/mL Standard Deviation 3320	—
Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 2	6940 ng/mL Standard Deviation 3040	6760 ng/mL Standard Deviation 2890	—
Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 8	3160 ng/mL Standard Deviation 1500	3070 ng/mL Standard Deviation 1510	—
Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 14	1130 ng/mL Standard Deviation 740	1090 ng/mL Standard Deviation 797	—
Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 18	536 ng/mL Standard Deviation 516	495 ng/mL Standard Deviation 487	—
Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 22	208 ng/mL Standard Deviation 277	198 ng/mL Standard Deviation 392	—
Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 26	95.9 ng/mL Standard Deviation 415	47.9 ng/mL Standard Deviation 114	—
Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 39	1490 ng/mL Standard Deviation 902	1390 ng/mL Standard Deviation 787	—
Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 Week 52	91.9 ng/mL Standard Deviation 186	58.3 ng/mL Standard Deviation 126	—

SECONDARY outcome

Timeframe: Week 56, Week 65 and Week 78

Population: The overall number of participants analyzed represents the TP2 Full Analysis Set (TP2 FAS). The number analyzed per row represents participants with data at the corresponding time point.

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.

Outcome measures

Outcome measures
Measure	GP2411 n=253 Participants Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=124 Participants Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	EU-Prolia/GP2411 n=124 Participants Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Denosumab Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2 Week 56	6010 ng/mL Standard Deviation 2200	5550 ng/mL Standard Deviation 1900	6220 ng/mL Standard Deviation 2130
Denosumab Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2 Week 65	1540 ng/mL Standard Deviation 880	1330 ng/mL Standard Deviation 753	1640 ng/mL Standard Deviation 962
Denosumab Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2 Week 78	122 ng/mL Standard Deviation 406	53.2 ng/mL Standard Deviation 133	147 ng/mL Standard Deviation 652

Adverse Events

GP2411

Serious events: 12 serious events

Other events: 89 other events

Deaths: 1 deaths

EU-Prolia

Serious events: 8 serious events

Other events: 119 other events

Deaths: 0 deaths

GP2411/GP2411

Serious events: 4 serious events

Other events: 33 other events

Deaths: 0 deaths

EU-Prolia/EU-Prolia

Serious events: 2 serious events

Other events: 29 other events

Deaths: 0 deaths

EU-Prolia/GP2411

Serious events: 0 serious events

Other events: 24 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	GP2411 n=263 participants at risk Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=264 participants at risk Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	GP2411/GP2411 n=253 participants at risk Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	EU-Prolia/EU-Prolia n=125 participants at risk Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	EU-Prolia/GP2411 n=124 participants at risk Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Nervous system disorders Syncope	0.38% 1/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Respiratory, thoracic and mediastinal disorders Pneumothorax spontaneous	0.00% 0/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.40% 1/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Eye disorders Epiretinal membrane	0.00% 0/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.38% 1/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Gastrointestinal disorders Chronic gastritis	0.38% 1/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Gastrointestinal disorders Gastritis erosive	0.38% 1/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Gastrointestinal disorders Gastrointestinal inflammation	0.00% 0/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.80% 1/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Gastrointestinal disorders Intestinal ischaemia	0.00% 0/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.40% 1/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Gastrointestinal disorders Pancreatic fistula	0.00% 0/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.40% 1/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
General disorders Sudden death	0.38% 1/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Hepatobiliary disorders Cholecystitis	0.00% 0/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.38% 1/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Infections and infestations COVID-19	0.38% 1/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.38% 1/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Infections and infestations Gastroenteritis clostridial	0.00% 0/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.80% 1/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Infections and infestations Gastrointestinal candidiasis	0.00% 0/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.80% 1/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Infections and infestations Pneumonia	0.00% 0/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.38% 1/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Injury, poisoning and procedural complications Ankle fracture	0.38% 1/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Injury, poisoning and procedural complications Femoral neck fracture	0.38% 1/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Injury, poisoning and procedural complications Hip fracture	0.76% 2/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.40% 1/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.38% 1/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.80% 1/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.38% 1/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.38% 1/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.00% 0/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.40% 1/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant neoplasm of ampulla of Vater	0.38% 1/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.40% 1/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic neoplasm	0.00% 0/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.38% 1/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer	0.00% 0/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.38% 1/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.38% 1/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Vascular disorders Thrombophlebitis	0.00% 0/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.38% 1/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.

Other adverse events

Other adverse events
Measure	GP2411 n=263 participants at risk Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	EU-Prolia n=264 participants at risk Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	GP2411/GP2411 n=253 participants at risk Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	EU-Prolia/EU-Prolia n=125 participants at risk Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	EU-Prolia/GP2411 n=124 participants at risk Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Gastrointestinal disorders Diarrhoea	1.1% 3/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	2.7% 7/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.40% 1/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	3.2% 4/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
General disorders Injection site reaction	2.7% 7/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	3.8% 10/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.40% 1/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Infections and infestations COVID-19	3.4% 9/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	4.9% 13/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	2.4% 6/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	5.6% 7/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	1.6% 2/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Infections and infestations Cystitis	0.38% 1/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	3.4% 9/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.40% 1/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Infections and infestations Nasopharyngitis	8.7% 23/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	6.1% 16/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	2.0% 5/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	3.2% 4/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	4.8% 6/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Infections and infestations Upper respiratory tract infection	1.5% 4/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	3.0% 8/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.40% 1/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	1.6% 2/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	1.6% 2/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Infections and infestations Urinary tract infection	1.9% 5/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	3.8% 10/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.79% 2/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	1.6% 2/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Injury, poisoning and procedural complications Contusion	1.1% 3/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	2.3% 6/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.40% 1/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.80% 1/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	3.2% 4/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Injury, poisoning and procedural complications Spinal compression fracture	0.38% 1/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	1.9% 5/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.79% 2/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	1.6% 2/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	3.2% 4/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Metabolism and nutrition disorders Hypocalcaemia	10.6% 28/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	9.8% 26/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.40% 1/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Metabolism and nutrition disorders Vitamin D deficiency	2.7% 7/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	4.5% 12/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.79% 2/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	2.4% 3/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	2.4% 3/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Musculoskeletal and connective tissue disorders Arthralgia	4.6% 12/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	3.0% 8/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	2.8% 7/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	4.0% 5/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	1.6% 2/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Musculoskeletal and connective tissue disorders Back pain	3.8% 10/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	3.4% 9/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.79% 2/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	1.6% 2/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.81% 1/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	1.5% 4/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	3.4% 9/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.00% 0/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	1.6% 2/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.81% 1/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Nervous system disorders Headache	2.3% 6/263 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	4.9% 13/264 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	0.40% 1/253 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	1.6% 2/125 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.	2.4% 3/124 • From first dose of study treatment on Day 1 up to Week 78. Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862-778-8300

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. Novartis does not prohibit any investigator from publishing. Any publications from a single site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER