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

Tracking Information

• First Submitted Date: June 3, 2019
• First Posted Date: June 4, 2019
• Results First Submitted Date: February 7, 2023
• Results First Posted Date: March 8, 2023
• Last Update Posted Date: March 8, 2023
• Actual Study Start Date: July 2, 2019
• Actual Primary Completion Date: April 22, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 7, 2023)

• Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 52 - Per-Protocol Set [ Time Frame: Baseline (screening), 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.
• Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 52 - TP1 Full Analysis Set [ Time Frame: Baseline (screening), up to Week 52 ]
  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.
• Area Under the Effect-time Curve (AUEC) of Percentage Change From Baseline in Serum CTX Concentrations After First Dose - Pharmacodynamic Analysis Set [ Time Frame: Baseline (pre-dose Day 1), up to Week 26 ]
  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.
• Maximum Observed Serum Concentration (Cmax) of Denosumab After First Dose [ Time Frame: Baseline (pre-dose Day 1), up to Week 26 ]
  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.
• Area Under the Serum Concentration-time Curve From Time Zero to Infinity (AUCinf) of Denosumab After First Dose [ Time Frame: Baseline (pre-dose Day 1), up to Week 26 ]
  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.

Original Primary Outcome Measures (submitted: June 3, 2019)

• Percent change from baseline (%CfB) in lumbar spine Bone Mineral Density [ Time Frame: Baseline, Week 52 ]
  Treatment Period 1
• Area under the effect versus time curve (AUEC) after first dose, percent change from baseline in serum Collagen C-telopeptide (CTX) [ Time Frame: Baseline, Week 52 ]
  Treatment Period 1
• Serum PK parameter AUCinf after first dose [ Time Frame: Baseline, Week 52 ]
  Treatment Period 1
• Serum PK parameter Cmax after first dose [ Time Frame: Baseline, Week 52 ]
  Treatment Period 1

Current Secondary Outcome Measures (submitted: February 7, 2023)

• Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 26 - Treatment Period 1 (Per-Protocol Set) [ Time Frame: Baseline (screening), 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.
• Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 26 - Treatment Period 1 (TP1 Full Analysis Set) [ Time Frame: Baseline (screening), 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.
• Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set) [ Time Frame: Baseline (screening), Week 78 ]
  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.
• Percent Change From Baseline in Femoral Neck Bone Mineral Density (FN-BMD) at Week 26 and Week 52 - Treatment Period 1 (Per-Protocol Set) [ Time Frame: Baseline (screening), Week 26 and Week 52 ]
  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.
• 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) [ Time Frame: Baseline (screening), Week 26 and Week 52 ]
  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.
• Percent Change From Baseline in Femoral Neck Bone Mineral Density (FN-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set) [ Time Frame: Baseline (screening), 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.
• Percent Change From Baseline in Total Hip Bone Mineral Density (TH-BMD) at Week 26 and Week 52 - Treatment Period 1 (Per-Protocol Set) [ Time Frame: Baseline (screening), Week 26 and Week 52 ]
  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.
• 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) [ Time Frame: Baseline (screening), Week 26 and Week 52 ]
  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.
• Percent Change From Baseline in Total Hip Bone Mineral Density (TH-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set) [ Time Frame: Baseline (screening), 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.
• CTX Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 [ Time Frame: Baseline (pre-dose Day 1), Day 2, Day 4, Week 8, Week 18, Week 22, Week 26, Week 39 and Week 52 ]
  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.
• CTX Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2 [ Time Frame: Week 56, Week 65 and Week 78 ]
  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.
• PINP Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 [ Time Frame: Baseline (pre-dose Day 1), Day 2, Day 4, Week 8, Week 18, Week 22, Week 26, Week 39 and Week 52 ]
  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.
• PINP Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2 [ Time Frame: Week 56, Week 65 and Week 78 ]
  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.
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs up to Week 52 - Treatment Period 1 [ Time Frame: From first dose of study treatment on Day 1 up to pre-dose at Week 52 ]
  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.
• Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs From Week 52 up to Week 78 - Treatment Period 2 [ Time Frame: From dosing of study treatment at Week 52 up to Week 78 ]
  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.
• Number of Participants With Vertebral Fractures up to Week 52 - Treatment Period 1 [ Time Frame: Baseline (screening) and Week 52 ]
  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.
• Number of Participants With Vertebral Fractures From Week 52 up to Week 78 - Treatment Period 2 [ Time Frame: Week 52 and Week 78 ]
  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.
• Number of Participants With Nonvertebral Fractures up to Week 52 - Treatment Period 1 [ Time Frame: From first dose of study treatment on Day 1 up to pre-dose at Week 52 ]
  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.
• Number of Participants With Nonvertebral Fractures From Week 52 up to Week 78 - Treatment Period 2 [ Time Frame: From dosing of study treatment at Week 52 up to Week 78 ]
  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.
• Number of Participants With Injection Site Reactions (ISRs) up to Week 52 - Treatment Period 1 [ Time Frame: From first dose of study treatment on Day 1 up to pre-dose at Week 52 ]
  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.
• Number of Participants With Injection Site Reactions (ISRs) From Week 52 up to Week 78 - Treatment Period 2 [ Time Frame: From dosing of study treatment at Week 52 up to Week 78 ]
  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.
• Number of Participants With Anti-drug Antibodies (ADA) up to Week 52 - Treatment Period 1 [ Time Frame: From Week 2 up to Week 52 ]
  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.
• Number of Participants With Anti-drug Antibodies (ADA) From Week 52 up to Week 78 - Treatment Period 2 [ Time Frame: From Week 56 up to Week 78 ]
  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.
• Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1 [ 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 ]
  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.
• Denosumab Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2 [ Time Frame: Week 56, Week 65 and Week 78 ]
  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.

Original Secondary Outcome Measures (submitted: June 3, 2019)

• Percent change from baseline in Bone Mineral Density at femoral neck and total hip by DXA [ Time Frame: Baseline, Week 52 ]
  Treatment Period 1
• CTX serum concentration [ Time Frame: Baseline, Week 52 ]
  Treatment Period 1
• Occurence of adverse events and serious adverse events [ Time Frame: Screening, Week 52 ]
  Treatment Period 1
• Anti-drug antibodies (ADAs) serum concentration [ Time Frame: Baseline, Week 52 ]
  Treatment Period 1
• Percent change from baseline of Bone Mineral density at lumbar spine, femoral neck and total hip by DXA [ Time Frame: Week 52, Week 78 ]
  Treatment Period 2
• CTX serum concentration [ Time Frame: Week 52, week 78 ]
  Treatment Period 2
• Adverse events and serious adverse events [ Time Frame: Week 52, Week 78 ]
  Treatment Period 2
• Progollagen 1 N-terminal propeptide (P1NP) serum concentration [ Time Frame: Week 52, Week 78 ]
  Treatment Period 2
• P1NP serum concentration [ Time Frame: Baseline, Week 52 ]
  Treatment Period 1
• Antidrug antibodies (ADAs) serum concentration [ Time Frame: Week 52, Week 78 ]
  Treatment Period 2

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study Investigating PK, PD, Efficacy, Safety, and Immunogenicity of Biosimilar Denosumab (GP2411) in Patients With Postmenopausal Osteoporosis
• Official Title: A Randomized, Double-blind, Multicenter Integrated Phase I/III Study in Postmenopausal Women With Osteoporosis to Compare the Pharmacokinetics, Pharmacodynamics, Efficacy, Safety and Immunogenicity of GP2411 (Proposed Biosimilar Denosumab) and Prolia® (EU-authorized)
• Brief Summary: This study was conducted to assess if there were any clinically meaningful differences in pharmacokinetics (PK), pharmacodynamics (PD), efficacy, safety, or immunogenicity between GP2411 (proposed biosimilar denosumab) and EU-authorized Prolia® (denosumab).

Detailed Description

This was an international, multicenter, randomized, double-blind, parallel-group study with a total duration of up to 83 weeks.

The study comprised a screening period of up to 5 weeks to assess a subject's eligibility and two treatment periods: Treatment Period 1 (TP1) from Day 1 to Week 52 and Treatment Period 2 (TP2) from Week 52 to Week 78.

Women with postmenopausal osteoporosis (PMO) were randomized on Day 1 in a 1:1 ratio to receive either two 60 mg subcutaneous (s.c.) doses at 26-week intervals of GP2411 (proposed biosimilar denosumab) or EU-Prolia (EU-authorized Prolia®) during TP1. At Week 52, participants in the EU-Prolia group were re-randomized 1:1 to either continue with a third dose of EU-Prolia or switch to GP2411 for TP2. Participants in the GP2411 group continued the treatment with a third dose of GP2411 in TP2. The End of Study was achieved at Week 78.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Masking Description:

double blind

Primary Purpose: Treatment

• Condition: Postmenopausal Women With Osteoporosis

Intervention

• Biological: GP2411
  60 mg /mL subcutaneous injection every 6 months
• Biological: EU-Prolia (EU-authorized Prolia®)
  60 mg /mL subcutaneous injection every 6 months

Study Arms

• Experimental: GP2411
  60 mg /mL subcutaneous injection every 6 months
  Intervention: Biological: GP2411
• Active Comparator: EU authorized Prolia
  60 mg /mL subcutaneous injection every 6 months
  Intervention: Biological: EU-Prolia (EU-authorized Prolia®)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 26, 2021): 527
• Original Estimated Enrollment (submitted: June 3, 2019): 522
• Actual Study Completion Date: April 22, 2022
• Actual Primary Completion Date: April 22, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Postmenopausal women, diagnosed with osteoporosis
• Aged ≥ 55 and ≤ 80 years at screening
• Body weight ≥ 50 kg and ≤ 90 kg at screening
• Absolute bone mineral density consistent with T-score ≤ -2.5 and ≥ -4.0 at the lumbar spine as measured by DXA
• At least two vertebrae in the L1-L4 region and at least one hip joint are evaluable by DXA

Exclusion Criteria:

• Previous exposure to denosumab (Prolia, Xgeva, or biosimilar denosumab)
• History and/or presence of one severe or more than two moderate vertebral fractures or hip fracture
• History and/or presence of bone metastases, bone disease or metabolic disease
• Ongoing use of any osteoporosis treatment or use of prohibited treatment
• Other bone active drugs
• History and/or current hypoparathyroidism or hyperparathyroidism, hypocalcemia or hypercalcemia

Sex/Gender

• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Postmenopausal women, diagnosed with osteoporosis

• Ages: 55 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Bulgaria, Czechia, Japan, Poland, Spain, United States

Administrative Information

• NCT Number: NCT03974100
• Other Study ID Numbers: CGP24112301; 2018-003523-11 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

• Current Responsible Party: Sandoz
• Original Responsible Party: Same as current
• Current Study Sponsor: Sandoz
• Original Study Sponsor: Same as current
• Collaborators: Hexal AG
• Investigators: Not Provided
• PRS Account: Sandoz
• Verification Date: February 2023