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

• ClinicalTrials.gov Identifier: NCT03974100
• Recruitment Status: Completed
• First Posted: June 4, 2019
• Results First Posted: March 8, 2023
• Last Update Posted: March 8, 2023
• Sponsor: Sandoz
• Collaborator: Hexal AG
• Information provided by (Responsible Party): Sandoz

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Postmenopausal Women With Osteoporosis
• Interventions: Biological: GP2411; Biological: EU-Prolia (EU-authorized Prolia®)
• Enrollment: 527

Participant Flow

Recruitment Details

Participants took part in 43 investigative sites in 6 countries.

Pre-assignment Details

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.

Arm/Group Title	GP2411	EU-Prolia	GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
Arm/Group Description	Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Period Title: TP1 - Day 1 to Week 52
Started	263	264	0	0	0
Per-Protocol Set (PPS)	233	230	0	0	0
TP1 Full Analysis Set (TP1 FAS)	255	257	0	0	0
Pharmacodynamic Analysis Set (PDS)	228	213	0	0	0
Pharmacokinetic Analysis Set (PKS)	260	258	0	0	0
TP1 Safety Analysis Set	263	264	0	0	0
Completed	253	249	0	0	0
Not Completed	10	15	0	0	0
Reason Not Completed
Adverse Event	1	3	0	0	0
Death	1	0	0	0	0
Lost to Follow-up	0	1	0	0	0
Physician Decision	0	2	0	0	0
Subject decision	8	9	0	0	0
Period Title: TP2- Week 52 to Week 78
Started	0	0	253	125	124
TP2 Full Analysis Set (TP2 FAS)	0	0	253	124	124
TP2 Safety Analysis Set	0	0	253	125	124
Completed	0	0	253	123	124
Not Completed	0	0	0	2	0
Reason Not Completed
Lost to Follow-up	0	0	0	1	0
Subject decision	0	0	0	1	0

Baseline Characteristics

Arm/Group Title		GP2411	EU-Prolia	Total
Arm/Group Description		Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	Total of all reporting groups
Overall Number of Baseline Participants		263	264	527
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	263 participants	264 participants	527 participants
		64.6 (6.08)	64.7 (5.78)	64.7 (5.92)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	263 participants	264 participants	527 participants
	Female	263 100.0%	264 100.0%	527 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	263 participants	264 participants	527 participants
	Asian	23 8.7%	24 9.1%	47 8.9%
	Multiple	1 0.4%	0 0.0%	1 0.2%
	White	239 90.9%	240 90.9%	479 90.9%

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 52 - Per-Protocol Set
Description	Bone density measurements were performed by dual energy X-ray absorptiometry (DXA). Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis. A mixed effect model for repeated measurements (MMRM) was fitted to the changes from baseline in LS-BMD for all post-baseline time points up to Week 52. Values at Week 52 were estimated from the model and are presented in the table.
Time Frame	Baseline (screening), up to Week 52

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	GP2411	EU-Prolia
Arm/Group Description:	Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed	233	230
Least Squares Mean (Standard Error); Unit of Measure: Percentage change (%)
	4.955 (0.2634)	5.099 (0.2618)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GP2411, EU-Prolia
	Comments	[Not Specified]
	Type of Statistical Test	Equivalence
	Comments	Equivalence criteria (analysis set PPS): 95% CI for difference in means contained in [-1.45%, 1.45%]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed-model repeated measures (MMRM)
	Comments	MMRM included treatment, prior bisphosphonate use, DXA machine type, visit, visit-treatment interaction, and baseline LS-BMD as a continuous covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.145
	Confidence Interval	(2-Sided) 95%; -0.798 to 0.509
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3325
	Estimation Comments	Difference GP2411 (Test) - EU-Prolia (Reference)

2. Primary Outcome

Title	Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 52 - TP1 Full Analysis Set
Description	Bone density measurements were performed by DXA. Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis. A MMRM was fitted to the changes from baseline in LS-BMD for all post-baseline time points up to Week 52. Missing values were assumed to be missing at random (MAR) using the MMRM model. Values at Week 52 were estimated from the model and are presented in the table.
Time Frame	Baseline (screening), up to Week 52

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	GP2411	EU-Prolia
Arm/Group Description:	Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed	255	257
Least Squares Mean (Standard Error); Unit of Measure: Percentage change (%)
	4.963 (0.2630)	5.140 (0.2627)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GP2411, EU-Prolia
	Comments	[Not Specified]
	Type of Statistical Test	Equivalence
	Comments	Equivalence criteria (analysis set TP1 FAS): 95% CI for difference in means contained in [-1.45%, 1.45%] (criteria 1) or in [-2.00%, 2.00%] (criteria 2)
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed-model repeated measures (MMRM)
	Comments	MMRM included treatment, prior bisphosphonate use, DXA machine type, visit, visit-treatment interaction, and baseline LS-BMD as a continuous covariate
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.177
	Confidence Interval	(2-Sided) 95%; -0.830 to 0.475
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.3321
	Estimation Comments	Difference GP2411 (Test) - EU-Prolia (Reference)

3. Primary Outcome

Title	Area Under the Effect-time Curve (AUEC) of Percentage Change From Baseline in Serum CTX Concentrations After First Dose - Pharmacodynamic Analysis Set
Description	Carboxy-terminal crosslinked telopeptides of type I collagen (CTX) is a bone resorption biomarker. Serum CTX concentration-time data were analyzed by non-compartmental methods. The AUEC of baseline corrected serum CTX concentrations (% change from baseline) was calculated using the linear trapezoidal method. Values below the lower limit of quantification (LLOQ) were imputed with the actual value for the LLOQ.
Time Frame	Baseline (pre-dose Day 1), up to Week 26

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	GP2411	EU-Prolia
Arm/Group Description:	Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed	228	213
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: percentage change (%)*day
	15700; (15.8%)	15900; (14.0%)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GP2411, EU-Prolia
	Comments	[Not Specified]
	Type of Statistical Test	Equivalence
	Comments	Equivalence criteria (analysis set PDS): 95% CI for ratio of geometric means contained in [0.80, 1.25%]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	ANCOVA was performed on log-transformed AUEC including treatment and log baseline CTX value as a continuous covariate
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.98 to 1.01
	Estimation Comments	Geometric mean ratio of GP2411 (Test) to EU-Prolia (Reference)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	GP2411, EU-Prolia
	Comments	[Not Specified]
	Type of Statistical Test	Equivalence
	Comments	Equivalence criteria (analysis set PDS): 90% CI for ratio of geometric means contained in [0.80, 1.25%]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	ANCOVA was performed on log-transformed AUEC including treatment and log baseline CTX value as a continuous covariate
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 90%; 0.98 to 1.01
	Estimation Comments	Geometric mean ratio of GP2411 (Test) to EU-Prolia (Reference)

4. Primary Outcome

Title	Maximum Observed Serum Concentration (Cmax) of Denosumab After First Dose
Description	Serum denosumab concentration-time data were analyzed by non-compartmental methods. Missing denosumab serum concentrations or concentrations below the LLOQ were not imputed and handled as missing values, except for the pre-dose sample which were treated as zero.
Time Frame	Baseline (pre-dose Day 1), up to Week 26

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	GP2411	EU-Prolia
Arm/Group Description:	Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed	260	258
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: ng/mL
	6970; (45.8%)	7050; (44.2%)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GP2411, EU-Prolia
	Comments	[Not Specified]
	Type of Statistical Test	Equivalence
	Comments	Equivalence criteria (analysis set PKS): 90% CI for ratio of geometric means contained in [0.80, 1.25%]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	ANCOVA was performed on log-transformed Cmax including treatment and weight as a continuous covariate
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 90%; 0.92 to 1.03
	Estimation Comments	Geometric mean ratio of GP2411 (Test) to EU-Prolia (Reference)

5. Primary Outcome

Title	Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) of Denosumab After First Dose
Description	Serum denosumab concentration-time data were analyzed by non-compartmental methods. Missing denosumab serum concentrations or concentrations below the LLOQ were not imputed and handled as missing values, except for the pre-dose sample which were treated as zero. The linear-up log-down trapezoidal method was used for the AUCinf calculation.
Time Frame	Baseline (pre-dose Day 1), up to Week 26

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	GP2411	EU-Prolia
Arm/Group Description:	Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed	247	246
Geometric Mean (Geometric Coefficient of Variation); Unit of Measure: day*ng/mL
	370000; (47.8%)	365000; (43.3%)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GP2411, EU-Prolia
	Comments	[Not Specified]
	Type of Statistical Test	Equivalence
	Comments	Equivalence criteria (analysis set PKS): 90% CI for ratio of geometric means contained in [0.80, 1.25%]
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	ANCOVA
	Comments	ANCOVA was performed on log-transformed AUCinf including treatment and weight as a continuous covariate
Method of Estimation	Estimation Parameter	Geometric mean ratio
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 90%; 0.93 to 1.05
	Estimation Comments	Geometric mean ratio of GP2411 (Test) to EU-Prolia (Reference)

6. Secondary Outcome

Title	Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 26 - Treatment Period 1 (Per-Protocol Set)
Description	Bone density measurements were performed by DXA. Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis.
Time Frame	Baseline (screening), Week 26

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GP2411	EU-Prolia
Arm/Group Description:	Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed	233	229
Mean (Standard Deviation); Unit of Measure: percentage change (%)
	3.6501 (3.76952)	3.6700 (3.68816)

7. Secondary Outcome

Title	Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 26 - Treatment Period 1 (TP1 Full Analysis Set)
Description	Bone density measurements were performed by DXA. Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis.
Time Frame	Baseline (screening), Week 26

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GP2411	EU-Prolia
Arm/Group Description:	Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed	255	256
Mean (Standard Deviation); Unit of Measure: percentage change (%)
	3.5877 (3.73579)	3.7144 (3.89730)

8. Secondary Outcome

Title	Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set)
Description	Bone density measurement were performed by DXA. Lumbar spine scan included L1 through L4 vertebrae. All DXA scans were submitted to a central imaging vendor for analysis.
Time Frame	Baseline (screening), Week 78

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
Arm/Group Description:	Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Overall Number of Participants Analyzed	249	123	122
Mean (Standard Deviation); Unit of Measure: Percentage change (%)
	6.8222 (3.95225)	7.0694 (4.72955)	6.4212 (4.47102)

9. Secondary Outcome

Title	Percent Change From Baseline in Femoral Neck Bone Mineral Density (FN-BMD) at Week 26 and Week 52 - Treatment Period 1 (Per-Protocol Set)
Description	Bone density measurements were performed by DXA. For proximal femur, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
Time Frame	Baseline (screening), Week 26 and Week 52

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		GP2411	EU-Prolia
Arm/Group Description:		Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed		233	230
Mean (Standard Deviation); Unit of Measure: percentage change (%)
Week 26	Number Analyzed	232 participants	229 participants
		2.0818 (3.38039)	1.8087 (3.18505)
Week 52	Number Analyzed	233 participants	229 participants
		2.4200 (3.70552)	2.6157 (3.26119)

10. Secondary Outcome

Title	Percent Change From Baseline in Femoral Neck Bone Mineral Density (FN-BMD) at Week 26 and Week 52 - Treatment Period 1 (TP1 Full Analysis Set)
Description	Bone density measurements were performed by DXA. For proximal femur, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
Time Frame	Baseline (screening), Week 26 and Week 52

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		GP2411	EU-Prolia
Arm/Group Description:		Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed		255	257
Mean (Standard Deviation); Unit of Measure: percentage change (%)
Week 26	Number Analyzed	254 participants	256 participants
		2.0343 (3.43682)	1.8210 (3.11073)
Week 52	Number Analyzed	253 participants	248 participants
		2.3686 (3.69145)	2.5717 (3.29726)

11. Secondary Outcome

Title	Percent Change From Baseline in Femoral Neck Bone Mineral Density (FN-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set)
Description	Bone density measurements were performed by DXA. For proximal femur, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
Time Frame	Baseline (screening), Week 78

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
Arm/Group Description:	Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Overall Number of Participants Analyzed	247	122	122
Mean (Standard Deviation); Unit of Measure: Percentage change (%)
	3.2220 (4.03733)	2.9406 (3.92115)	2.6857 (3.64193)

12. Secondary Outcome

Title	Percent Change From Baseline in Total Hip Bone Mineral Density (TH-BMD) at Week 26 and Week 52 - Treatment Period 1 (Per-Protocol Set)
Description	Bone density measurements were performed by DXA. For total hip, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
Time Frame	Baseline (screening), Week 26 and Week 52

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		GP2411	EU-Prolia
Arm/Group Description:		Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed		233	230
Mean (Standard Deviation); Unit of Measure: percentage change (%)
Week 26	Number Analyzed	232 participants	229 participants
		2.6475 (2.43928)	2.1178 (2.44627)
Week 52	Number Analyzed	233 participants	229 participants
		3.4289 (2.71152)	3.3211 (2.59266)

13. Secondary Outcome

Title	Percent Change From Baseline in Total Hip Bone Mineral Density (TH-BMD) at Week 26 and Week 52 - Treatment Period 1 (TP1 Full Analysis Set)
Description	Bone density measurements were performed by DXA. For total hip, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study. All DXA scans were submitted to a central imaging vendor for analysis.
Time Frame	Baseline (screening), Week 26 and Week 52

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		GP2411	EU-Prolia
Arm/Group Description:		Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed		255	257
Mean (Standard Deviation); Unit of Measure: percentage change (%)
Week 26	Number Analyzed	254 participants	256 participants
		2.5280 (2.46669)	2.0595 (2.51811)
Week 52	Number Analyzed	253 participants	248 participants
		3.2882 (2.70260)	3.2234 (2.64633)

14. Secondary Outcome

Title	Percent Change From Baseline in Total Hip Bone Mineral Density (TH-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set)
Description	Bone density measurements were performed by DXA. For total hip, the left side was to be used for all DXA scans at all study visits. If the right side had to be used (e.g., due to implants) or was inadvertently used at baseline, then it was to be used consistently throughout the study.
Time Frame	Baseline (screening), Week 78

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
Arm/Group Description:	Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Overall Number of Participants Analyzed	247	122	122
Mean (Standard Deviation); Unit of Measure: Percentage change (%)
	3.8270 (3.28071)	4.0898 (2.96530)	3.9987 (3.33311)

15. Secondary Outcome

Title	CTX Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1
Description	CTX is a bone resorption biomarker. Serum samples were analyzed for CTX concentrations. CTX serum concentrations were determined by a validated ligand-binding immunoassay. Values below the LLOQ were imputed with the actual value for the LLOQ.
Time Frame	Baseline (pre-dose Day 1), Day 2, Day 4, Week 8, Week 18, Week 22, Week 26, Week 39 and Week 52

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		GP2411	EU-Prolia
Arm/Group Description:		Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed		228	213
Mean (Standard Deviation); Unit of Measure: ng/mL
Baseline	Number Analyzed	228 participants	213 participants
		0.437 (0.249)	0.450 (0.264)
Day 2	Number Analyzed	226 participants	212 participants
		0.0904 (0.110)	0.0859 (0.0923)
Day 4	Number Analyzed	226 participants	211 participants
		0.0383 (0.0272)	0.0407 (0.0537)
Week 8	Number Analyzed	222 participants	206 participants
		0.0339 (0.0134)	0.0332 (0.00334)
Week 18	Number Analyzed	219 participants	200 participants
		0.0355 (0.0205)	0.0362 (0.0225)
Week 22	Number Analyzed	226 participants	211 participants
		0.0428 (0.0546)	0.0422 (0.0406)
Week 26	Number Analyzed	228 participants	213 participants
		0.0661 (0.0954)	0.0651 (0.0708)
Week 39	Number Analyzed	227 participants	206 participants
		0.0342 (0.0116)	0.0345 (0.0110)
Week 52	Number Analyzed	224 participants	207 participants
		0.0845 (0.116)	0.0807 (0.0883)

16. Secondary Outcome

Title	CTX Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2
Description	CTX is a bone resorption biomarker. Serum samples were analyzed for CTX concentrations. CTX serum concentrations were determined by a validated ligand-binding immunoassay. Values below the LLOQ were imputed with the actual value for the LLOQ.
Time Frame	Week 56, Week 65 and Week 78

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
Arm/Group Description:		Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Overall Number of Participants Analyzed		253	124	124
Mean (Standard Deviation); Unit of Measure: ng/mL
Week 56	Number Analyzed	247 participants	116 participants	117 participants
		0.0335 (0.00685)	0.0358 (0.0259)	0.0330 (0.00)
Week 65	Number Analyzed	246 participants	117 participants	118 participants
		0.0335 (0.00714)	0.0352 (0.0159)	0.0359 (0.0281)
Week 78	Number Analyzed	248 participants	117 participants	117 participants
		0.125 (0.190)	0.144 (0.155)	0.101 (0.149)

17. Secondary Outcome

Title	PINP Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1
Description	Procollagen I N-terminal propeptide (PINP) is a bone formation biomarker. Serum samples were analyzed for PINP concentrations. PINP serum concentrations were determined by a validated ligand-binding immunoassay. Values below the LLOQ were imputed with the actual value for the LLOQ.
Time Frame	Baseline (pre-dose Day 1), Day 2, Day 4, Week 8, Week 18, Week 22, Week 26, Week 39 and Week 52

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		GP2411	EU-Prolia
Arm/Group Description:		Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed		228	213
Mean (Standard Deviation); Unit of Measure: ng/mL
Baseline	Number Analyzed	228 participants	213 participants
		60.3 (27.1)	62.2 (30.0)
Day 2	Number Analyzed	228 participants	213 participants
		58.5 (25.9)	60.2 (29.3)
Day 4	Number Analyzed	227 participants	213 participants
		56.8 (23.2)	58.8 (26.8)
Week 8	Number Analyzed	223 participants	207 participants
		21.2 (9.53)	21.0 (7.58)
Week 18	Number Analyzed	221 participants	200 participants
		12.1 (4.52)	12.6 (5.10)
Week 22	Number Analyzed	227 participants	212 participants
		13.5 (5.92)	13.3 (4.59)
Week 26	Number Analyzed	228 participants	213 participants
		15.4 (7.44)	15.9 (6.71)
Week 39	Number Analyzed	227 participants	208 participants
		10.5 (3.14)	10.7 (3.43)
Week 52	Number Analyzed	225 participants	207 participants
		15.0 (5.95)	15.7 (7.11)

18. Secondary Outcome

Title	PINP Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2
Description	PINP is a bone formation biomarker. Serum samples were analyzed for PINP concentrations. PINP serum concentrations were determined by a validated ligand-binding immunoassay. Values below the LLOQ were imputed with the actual value for the LLOQ.
Time Frame	Week 56, Week 65 and Week 78

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
Arm/Group Description:		Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Overall Number of Participants Analyzed		253	124	124
Mean (Standard Deviation); Unit of Measure: ng/mL
Week 56	Number Analyzed	252 participants	122 participants	124 participants
		13.7 (8.06)	13.9 (5.39)	14.4 (11.0)
Week 65	Number Analyzed	250 participants	123 participants	123 participants
		10.5 (3.40)	10.9 (3.43)	11.1 (3.85)
Week 78	Number Analyzed	252 participants	123 participants	124 participants
		17.5 (14.1)	20.3 (20.4)	17.1 (8.37)

19. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs up to Week 52 - Treatment Period 1
Description	Number of participants with TEAEs and serious TEAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs during Treatment Period 1. The number of participants in each category is reported in the table.
Time Frame	From first dose of study treatment on Day 1 up to pre-dose at Week 52

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GP2411	EU-Prolia
Arm/Group Description:	Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed	263	264
Measure Type: Count of Participants; Unit of Measure: Participants
TEAE	157 59.7%	181 68.6%
Treatment-related TEAE	36 13.7%	49 18.6%
Serious TEAE	12 4.6%	8 3.0%
Treatment-related serious TEAE	0 0.0%	0 0.0%

20. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs From Week 52 up to Week 78 - Treatment Period 2
Description	Number of participants with TEAEs and serious TEAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs during Treatment Period 2. The number of participants in each category is reported in the table.
Time Frame	From dosing of study treatment at Week 52 up to Week 78

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
Arm/Group Description:	Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Overall Number of Participants Analyzed	253	125	124
Measure Type: Count of Participants; Unit of Measure: Participants
TEAE	68 26.9%	47 37.6%	48 38.7%
Treatment-related TEAE	7 2.8%	7 5.6%	5 4.0%
Serious TEAE	4 1.6%	2 1.6%	0 0.0%
Treatment-related serious TEAE	0 0.0%	0 0.0%	0 0.0%

21. Secondary Outcome

Title	Number of Participants With Vertebral Fractures up to Week 52 - Treatment Period 1
Description	Vertebral fractures were assessed by independent radiologists at the central imaging vendor. The radiologists assessed lateral thoracic (vertebrae T4 to T12) and lumbar (vertebrae L1 to L4) spine radiographs for vertebral fractures. New and worsening vertebral fractures are defined as occurrence of new fracture (i.e. change in Genant score from 0 at baseline to 1 or higher at a later time point) or worsening fracture (i.e. increase in Genant score from baseline at a later time point) in any assessed vertebra. The Genant classification of vertebral fractures is based on the vertebral shape, with respect to vertebral height loss involving the anterior, posterior, and/or middle vertebral body and ranges between 0 (normal) and 3 (severe fracture, >40% loss of height). The number of participants in each category is reported in the table.
Time Frame	Baseline (screening) and Week 52

Outcome Measure Data

Analysis Population Description

All participants in the TP1 Safety Analysis Set

Arm/Group Title	GP2411	EU-Prolia
Arm/Group Description:	Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed	263	264
Measure Type: Count of Participants; Unit of Measure: Participants
At least one vertebral fracture at baseline	123 46.8%	116 43.9%
New vertebral fractures at Week 52	15 5.7%	24 9.1%
Worsening vertebral fractures at Week 52	3 1.1%	3 1.1%

22. Secondary Outcome

Title	Number of Participants With Vertebral Fractures From Week 52 up to Week 78 - Treatment Period 2
Description	Vertebral fractures were assessed by independent radiologists at the central imaging vendor. The radiologists assessed lateral thoracic (vertebrae T4 to T12) and lumbar (vertebrae L1 to L4) spine radiographs for vertebral fractures. New and worsening vertebral fractures are defined as occurrence of new fracture (i.e. change in Genant score from 0 at Week 52 to 1 or higher at a later time point) or worsening fracture (i.e. increase in Genant score from Week 52 at a later time point) in any assessed vertebra. The Genant classification of vertebral fractures is based on the vertebral shape, with respect to vertebral height loss involving the anterior, posterior, and/or middle vertebral body and ranges between 0 (normal) and 3 (severe fracture, >40% loss of height). The number of participants in each category is reported in the table.
Time Frame	Week 52 and Week 78

Outcome Measure Data

Analysis Population Description

All participants in the TP2 Safety Analysis Set

Arm/Group Title	GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
Arm/Group Description:	Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Overall Number of Participants Analyzed	253	125	124
Measure Type: Count of Participants; Unit of Measure: Participants
At least one vertebral fracture at Week 52	126 49.8%	57 45.6%	65 52.4%
New vertebral fractures at Week 78	12 4.7%	3 2.4%	8 6.5%
Worsening vertebral fractures at Week 78	1 0.4%	0 0.0%	0 0.0%

23. Secondary Outcome

Title	Number of Participants With Nonvertebral Fractures up to Week 52 - Treatment Period 1
Description	Information about any nonvertebral fractures while on study were recorded as adverse events. The diagnosis of nonvertebral fractures did not require central X-ray reading and was based on local radiology reports. The number of participants in each category is reported in the table.
Time Frame	From first dose of study treatment on Day 1 up to pre-dose at Week 52

Outcome Measure Data

Analysis Population Description

All participants in the TP1 Safety Analysis Set

Arm/Group Title	GP2411	EU-Prolia
Arm/Group Description:	Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed	263	264
Measure Type: Count of Participants; Unit of Measure: Participants
Hip fracture	2 0.8%	0 0.0%
Femoral neck fracture	1 0.4%	0 0.0%
Femur fracture	0 0.0%	1 0.4%
Ankle fracture	1 0.4%	1 0.4%
Wrist fracture	1 0.4%	0 0.0%
Radius fracture	0 0.0%	1 0.4%

24. Secondary Outcome

Title	Number of Participants With Nonvertebral Fractures From Week 52 up to Week 78 - Treatment Period 2
Description	Information about any nonvertebral fractures while on study were recorded as adverse events. The diagnosis of nonvertebral fractures did not require central X-ray reading and was based on local radiology reports. The number of participants in each category is reported in the table.
Time Frame	From dosing of study treatment at Week 52 up to Week 78

Outcome Measure Data

Analysis Population Description

All participants in the TP2 Safety Analysis Set

Arm/Group Title	GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
Arm/Group Description:	Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Overall Number of Participants Analyzed	253	125	124
Measure Type: Count of Participants; Unit of Measure: Participants
Hip fracture	1 0.4%	0 0.0%	0 0.0%
Fibula fracture	1 0.4%	0 0.0%	0 0.0%
Hand fracture	0 0.0%	0 0.0%	1 0.8%

25. Secondary Outcome

Title	Number of Participants With Injection Site Reactions (ISRs) up to Week 52 - Treatment Period 1
Description	The injection site reaction (ISR) assessment was done by the investigator/designee. It consisted of grading the severity of each injection reaction based on criteria the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The ISR grading was defined as follows: Grade 1: Tenderness with or without associated symptoms (e.g., warmth, erythema, itching); Grade 2: Pain; lipodystrophy; edema; phlebitis; Grade 3: Ulceration or necrosis; severe tissue damage; operative intervention indicated; Grade 4: Life-threatening consequences; urgent intervention indicated The number of participants in each category is reported in the table.
Time Frame	From first dose of study treatment on Day 1 up to pre-dose at Week 52

Outcome Measure Data

Analysis Population Description

All participants in the TP1 Safety Analysis Set

Arm/Group Title	GP2411	EU-Prolia
Arm/Group Description:	Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed	263	264
Measure Type: Count of Participants; Unit of Measure: Participants
ISR Grade 1	6 2.3%	9 3.4%
ISR Grade 2	1 0.4%	1 0.4%
ISR Grade 3	0 0.0%	0 0.0%
ISR Grade 4	0 0.0%	0 0.0%

26. Secondary Outcome

Title	Number of Participants With Injection Site Reactions (ISRs) From Week 52 up to Week 78 - Treatment Period 2
Description	The injection site reaction (ISR) assessment was done by the investigator/designee. It consisted of grading the severity of each injection reaction based on criteria the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The ISR grading was defined as follows: Grade 1: Tenderness with or without associated symptoms (e.g., warmth, erythema, itching); Grade 2: Pain; lipodystrophy; edema; phlebitis; Grade 3: Ulceration or necrosis; severe tissue damage; operative intervention indicated; Grade 4: Life-threatening consequences; urgent intervention indicated The number of participants in each category is reported in the table.
Time Frame	From dosing of study treatment at Week 52 up to Week 78

Outcome Measure Data

Analysis Population Description

All participants in the TP2 Safety Analysis Set

Arm/Group Title	GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
Arm/Group Description:	Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Overall Number of Participants Analyzed	253	125	124
Measure Type: Count of Participants; Unit of Measure: Participants
ISR Grade 1	1 0.4%	0 0.0%	0 0.0%
ISR Grade 2	0 0.0%	0 0.0%	0 0.0%
ISR Grade 3	0 0.0%	0 0.0%	0 0.0%
ISR Grade 4	0 0.0%	0 0.0%	0 0.0%

27. Secondary Outcome

Title	Number of Participants With Anti-drug Antibodies (ADA) up to Week 52 - Treatment Period 1
Description	Immunogenicity was evaluated in serum. Samples were screened for potential anti-drug antibodies (ADA) and positive screen results were confirmed using a confirmatory assay. For confirmed ADA positive samples, titers were determined. Confirmed ADAs were also analyzed for their neutralization potential. Patient ADA status was defined as follows: ADA Positive: ADA-positive sample at any time point during TP1; ADA Positive, Persistent: 'Persistent' indicates a subject experiencing a positive ADA result at the final visit and with at least 2 consecutive positive ADA results; ADA Positive, Transient: 'Transient' indicates a subject experiencing positive ADA result but not qualifying as 'Persistent'; ADA titer positive: ADA-positive sample with a titer result ≥ 20 ng/mL; NAb Positive: ADA-positive sample with presence of neutralizing antibodies (NAb) The number of participants in each category is reported in the table.
Time Frame	From Week 2 up to Week 52

Outcome Measure Data

Analysis Population Description

All participants in the TP1 Safety Analysis Set

Arm/Group Title	GP2411	EU-Prolia
Arm/Group Description:	Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed	263	264
Measure Type: Count of Participants; Unit of Measure: Participants
ADA Positive	93 35.4%	108 40.9%
ADA Positive, Persistent	7 2.7%	4 1.5%
ADA Positive, Transient	86 32.7%	104 39.4%
ADA titer positive	2 0.8%	2 0.8%
NAb positive	3 1.1%	1 0.4%

28. Secondary Outcome

Title	Number of Participants With Anti-drug Antibodies (ADA) From Week 52 up to Week 78 - Treatment Period 2
Description	Immunogenicity was evaluated in serum. Samples were screened for potential anti-drug antibodies (ADA) and positive screen results were confirmed using a confirmatory assay. For confirmed ADA positive samples, titers were determined. Confirmed ADAs were also analyzed for their neutralization potential. Patient ADA status was defined as follows: ADA Positive: ADA-positive sample at any time point during TP1; ADA Positive, Persistent: 'Persistent' indicates a subject experiencing a positive ADA result at the final visit and with at least 2 consecutive positive ADA results; ADA Positive, Transient: 'Transient' indicates a subject experiencing positive ADA result but not qualifying as 'Persistent'; ADA titer positive: ADA-positive sample with a titer result ≥ 20 ng/mL; NAb Positive: ADA-positive sample with presence of neutralizing antibodies (NAb) The number of participants in each category is reported in the table.
Time Frame	From Week 56 up to Week 78

Outcome Measure Data

Analysis Population Description

All participants in the TP2 Safety Analysis Set

Arm/Group Title	GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
Arm/Group Description:	Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Overall Number of Participants Analyzed	253	125	124
Measure Type: Count of Participants; Unit of Measure: Participants
ADA Positive	42 16.6%	26 20.8%	26 21.0%
ADA Positive, Persistent	3 1.2%	3 2.4%	0 0.0%
ADA Positive, Transient	39 15.4%	23 18.4%	26 21.0%
ADA titer positive	0 0.0%	1 0.8%	0 0.0%
NAb positive	1 0.4%	0 0.0%	1 0.8%

29. Secondary Outcome

Title	Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1
Description	Serum samples were analyzed for concentrations of free denosumab by using a validated ligand binding assay. Briefly, the concentration of free denosumab was determined by binding to coated ligand molecules. Denosumab concentrations below the LLOQ were set to zero in order to calculate arithmetic means.
Time Frame	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		GP2411	EU-Prolia
Arm/Group Description:		Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1
Overall Number of Participants Analyzed		260	258
Mean (Standard Deviation); Unit of Measure: ng/mL
Day 1	Number Analyzed	256 participants	257 participants
		0.00 (0.00)	0.928 (14.9)
Day 4	Number Analyzed	258 participants	258 participants
		4930 (2530)	5250 (2660)
Week 1	Number Analyzed	259 participants	254 participants
		6820 (3220)	6890 (3320)
Week 2	Number Analyzed	259 participants	255 participants
		6940 (3040)	6760 (2890)
Week 8	Number Analyzed	253 participants	251 participants
		3160 (1500)	3070 (1510)
Week 14	Number Analyzed	250 participants	249 participants
		1130 (740)	1090 (797)
Week 18	Number Analyzed	248 participants	241 participants
		536 (516)	495 (487)
Week 22	Number Analyzed	256 participants	254 participants
		208 (277)	198 (392)
Week 26	Number Analyzed	252 participants	253 participants
		95.9 (415)	47.9 (114)
Week 39	Number Analyzed	250 participants	245 participants
		1490 (902)	1390 (787)
Week 52	Number Analyzed	250 participants	244 participants
		91.9 (186)	58.3 (126)

30. Secondary Outcome

Title	Denosumab Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2
Description	Serum samples were analyzed for concentrations of free denosumab by using a validated ligand binding assay. Briefly, the concentration of free denosumab was determined by binding to coated ligand molecules. Denosumab concentrations below the LLOQ were set to zero in order to calculate arithmetic means.
Time Frame	Week 56, Week 65 and Week 78

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title		GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
Arm/Group Description:		Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
Overall Number of Participants Analyzed		253	124	124
Mean (Standard Deviation); Unit of Measure: ng/mL
Week 56	Number Analyzed	252 participants	122 participants	124 participants
		6010 (2200)	5550 (1900)	6220 (2130)
Week 65	Number Analyzed	250 participants	123 participants	122 participants
		1540 (880)	1330 (753)	1640 (962)
Week 78	Number Analyzed	251 participants	123 participants	124 participants
		122 (406)	53.2 (133)	147 (652)

Adverse Events

Time Frame	From first dose of study treatment on Day 1 up to Week 78.
Adverse Event Reporting Description	Any sign or symptom that occurs from first dose of study treatment up to 26 weeks after last dose in each treatment period.
Arm/Group Title	GP2411	EU-Prolia	GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
Arm/Group Description	Two 60 mg s.c. doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) in TP1	Two 60 mg s.c. doses at 26-week intervals of EU-Prolia (denosumab) in TP1	Participants treated with GP2411 in TP1 continued with a third dose of GP2411 in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to continue with a third dose of EU-Prolia in TP2	Participants treated with EU-Prolia in TP1 were re-randomized to switch to GP2411 in TP2
All-Cause Mortality
	GP2411	EU-Prolia	GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1/263 (0.38%)	0/264 (0.00%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Serious Adverse Events
	GP2411	EU-Prolia	GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	12/263 (4.56%)	8/264 (3.03%)	4/253 (1.58%)	2/125 (1.60%)	0/124 (0.00%)
Eye disorders
Epiretinal membrane † 1	0/263 (0.00%)	1/264 (0.38%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Gastrointestinal disorders
Chronic gastritis † 1	1/263 (0.38%)	0/264 (0.00%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Gastritis erosive † 1	1/263 (0.38%)	0/264 (0.00%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Gastrointestinal inflammation † 1	0/263 (0.00%)	0/264 (0.00%)	0/253 (0.00%)	1/125 (0.80%)	0/124 (0.00%)
Intestinal ischaemia † 1	0/263 (0.00%)	0/264 (0.00%)	1/253 (0.40%)	0/125 (0.00%)	0/124 (0.00%)
Pancreatic fistula † 1	0/263 (0.00%)	0/264 (0.00%)	1/253 (0.40%)	0/125 (0.00%)	0/124 (0.00%)
General disorders
Sudden death † 1	1/263 (0.38%)	0/264 (0.00%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Hepatobiliary disorders
Cholecystitis † 1	0/263 (0.00%)	1/264 (0.38%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Infections and infestations
COVID-19 † 1	1/263 (0.38%)	1/264 (0.38%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Gastroenteritis clostridial † 1	0/263 (0.00%)	0/264 (0.00%)	0/253 (0.00%)	1/125 (0.80%)	0/124 (0.00%)
Gastrointestinal candidiasis † 1	0/263 (0.00%)	0/264 (0.00%)	0/253 (0.00%)	1/125 (0.80%)	0/124 (0.00%)
Pneumonia † 1	0/263 (0.00%)	1/264 (0.38%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Injury, poisoning and procedural complications
Ankle fracture † 1	1/263 (0.38%)	0/264 (0.00%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Femoral neck fracture † 1	1/263 (0.38%)	0/264 (0.00%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Hip fracture † 1	2/263 (0.76%)	0/264 (0.00%)	1/253 (0.40%)	0/125 (0.00%)	0/124 (0.00%)
Musculoskeletal and connective tissue disorders
Osteoarthritis † 1	0/263 (0.00%)	1/264 (0.38%)	0/253 (0.00%)	1/125 (0.80%)	0/124 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer † 1	1/263 (0.38%)	1/264 (0.38%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Colon cancer † 1	0/263 (0.00%)	0/264 (0.00%)	1/253 (0.40%)	0/125 (0.00%)	0/124 (0.00%)
Malignant neoplasm of ampulla of Vater † 1	1/263 (0.38%)	0/264 (0.00%)	1/253 (0.40%)	0/125 (0.00%)	0/124 (0.00%)
Metastatic neoplasm † 1	0/263 (0.00%)	1/264 (0.38%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Ovarian cancer † 1	0/263 (0.00%)	1/264 (0.38%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Nervous system disorders
Syncope † 1	1/263 (0.38%)	0/264 (0.00%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax spontaneous † 1	0/263 (0.00%)	0/264 (0.00%)	1/253 (0.40%)	0/125 (0.00%)	0/124 (0.00%)
Pulmonary embolism † 1	1/263 (0.38%)	0/264 (0.00%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
Vascular disorders
Thrombophlebitis † 1	0/263 (0.00%)	1/264 (0.38%)	0/253 (0.00%)	0/125 (0.00%)	0/124 (0.00%)
1 Term from vocabulary, MedDRA (25.0); † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	3%
	GP2411	EU-Prolia	GP2411/GP2411	EU-Prolia/EU-Prolia	EU-Prolia/GP2411
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	89/263 (33.84%)	119/264 (45.08%)	33/253 (13.04%)	29/125 (23.20%)	24/124 (19.35%)
Gastrointestinal disorders
Diarrhoea † 1	3/263 (1.14%)	7/264 (2.65%)	1/253 (0.40%)	4/125 (3.20%)	0/124 (0.00%)
General disorders
Injection site reaction † 1	7/263 (2.66%)	10/264 (3.79%)	1/253 (0.40%)	0/125 (0.00%)	0/124 (0.00%)
Infections and infestations
COVID-19 † 1	9/263 (3.42%)	13/264 (4.92%)	6/253 (2.37%)	7/125 (5.60%)	2/124 (1.61%)
Cystitis † 1	1/263 (0.38%)	9/264 (3.41%)	1/253 (0.40%)	0/125 (0.00%)	0/124 (0.00%)
Nasopharyngitis † 1	23/263 (8.75%)	16/264 (6.06%)	5/253 (1.98%)	4/125 (3.20%)	6/124 (4.84%)
Upper respiratory tract infection † 1	4/263 (1.52%)	8/264 (3.03%)	1/253 (0.40%)	2/125 (1.60%)	2/124 (1.61%)
Urinary tract infection † 1	5/263 (1.90%)	10/264 (3.79%)	2/253 (0.79%)	2/125 (1.60%)	0/124 (0.00%)
Injury, poisoning and procedural complications
Contusion † 1	3/263 (1.14%)	6/264 (2.27%)	1/253 (0.40%)	1/125 (0.80%)	4/124 (3.23%)
Spinal compression fracture † 1	1/263 (0.38%)	5/264 (1.89%)	2/253 (0.79%)	2/125 (1.60%)	4/124 (3.23%)
Metabolism and nutrition disorders
Hypocalcaemia † 1	28/263 (10.65%)	26/264 (9.85%)	1/253 (0.40%)	0/125 (0.00%)	0/124 (0.00%)
Vitamin D deficiency † 1	7/263 (2.66%)	12/264 (4.55%)	2/253 (0.79%)	3/125 (2.40%)	3/124 (2.42%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	12/263 (4.56%)	8/264 (3.03%)	7/253 (2.77%)	5/125 (4.00%)	2/124 (1.61%)
Back pain † 1	10/263 (3.80%)	9/264 (3.41%)	2/253 (0.79%)	2/125 (1.60%)	1/124 (0.81%)
Spinal osteoarthritis † 1	4/263 (1.52%)	9/264 (3.41%)	0/253 (0.00%)	2/125 (1.60%)	1/124 (0.81%)
Nervous system disorders
Headache † 1	6/263 (2.28%)	13/264 (4.92%)	1/253 (0.40%)	2/125 (1.60%)	3/124 (2.42%)
1 Term from vocabulary, MedDRA (25.0); † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Study Director
• Organization: Novartis Pharmaceuticals
• Phone: 862-778-8300
• EMail: Novartis.email@novartis.com

• Responsible Party: Sandoz
• ClinicalTrials.gov Identifier: NCT03974100
• Obsolete Identifiers: NCT03991338
• Other Study ID Numbers: CGP24112301; 2018-003523-11 ( EudraCT Number )
• First Submitted: June 3, 2019
• First Posted: June 4, 2019
• Results First Submitted: February 7, 2023
• Results First Posted: March 8, 2023
• Last Update Posted: March 8, 2023