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)
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Sandoz
- 入组人数
- 527
- 试验地点
- 43
- 主要终点
- Area Under the Effect-time Curve (AUEC) of Percentage Change From Baseline in Serum CTX Concentrations After First Dose - Pharmacodynamic Analysis Set
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
double blind
入排标准
- 年龄范围
- 55 Years 至 80 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
结局指标
主要结局
Area Under the Effect-time Curve (AUEC) of Percentage Change From Baseline in Serum CTX Concentrations After First Dose - Pharmacodynamic Analysis Set
时间窗: 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.
Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 52 - Per-Protocol Set
时间窗: 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
时间窗: 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.
Maximum Observed Serum Concentration (Cmax) of Denosumab After First Dose
时间窗: 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
时间窗: 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.
次要结局
- Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set)(Baseline (screening), Week 78)
- Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 26 - Treatment Period 1 (Per-Protocol Set)(Baseline (screening), Week 26)
- CTX Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1(Baseline (pre-dose Day 1), Day 2, Day 4, Week 8, Week 18, Week 22, Week 26, Week 39 and Week 52)
- Percent Change From Baseline in Femoral Neck Bone Mineral Density (FN-BMD) at Week 26 and Week 52 - Treatment Period 1 (Per-Protocol Set)(Baseline (screening), Week 26 and Week 52)
- PINP Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1(Baseline (pre-dose Day 1), Day 2, Day 4, Week 8, Week 18, Week 22, Week 26, Week 39 and Week 52)
- PINP Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2(Week 56, Week 65 and Week 78)
- 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)(Baseline (screening), Week 26 and Week 52)
- Percent Change From Baseline in Total Hip Bone Mineral Density (TH-BMD) at Week 26 and Week 52 - Treatment Period 1 (Per-Protocol Set)(Baseline (screening), Week 26 and Week 52)
- 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)(Baseline (screening), Week 26 and Week 52)
- Percent Change From Baseline in Total Hip Bone Mineral Density (TH-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set)(Baseline (screening), Week 78)
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs up to Week 52 - Treatment Period 1(From first dose of study treatment on Day 1 up to pre-dose at Week 52)
- Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs From Week 52 up to Week 78 - Treatment Period 2(From dosing of study treatment at Week 52 up to Week 78)
- Percent Change From Baseline in Lumbar Spine Bone Mineral Density (LS-BMD) at Week 26 - Treatment Period 1 (TP1 Full Analysis Set)(Baseline (screening), Week 26)
- Number of Participants With Vertebral Fractures From Week 52 up to Week 78 - Treatment Period 2(Week 52 and Week 78)
- Percent Change From Baseline in Femoral Neck Bone Mineral Density (FN-BMD) at Week 78 - Treatment Period 2 (TP2 Full Analysis Set)(Baseline (screening), Week 78)
- Number of Participants With Nonvertebral Fractures From Week 52 up to Week 78 - Treatment Period 2(From dosing of study treatment at Week 52 up to Week 78)
- Number of Participants With Injection Site Reactions (ISRs) From Week 52 up to Week 78 - Treatment Period 2(From dosing of study treatment at Week 52 up to Week 78)
- CTX Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2(Week 56, Week 65 and Week 78)
- Number of Participants With Vertebral Fractures up to Week 52 - Treatment Period 1(Baseline (screening) and Week 52)
- Number of Participants With Injection Site Reactions (ISRs) up to Week 52 - Treatment Period 1(From first dose of study treatment on Day 1 up to pre-dose at Week 52)
- Denosumab Serum Concentrations as Per Visit Schedule up to Week 52 - Treatment Period 1(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)
- Denosumab Serum Concentrations as Per Visit Schedule From Week 52 up to Week 78 - Treatment Period 2(Week 56, Week 65 and Week 78)
- Number of Participants With Nonvertebral Fractures up to Week 52 - Treatment Period 1(From first dose of study treatment on Day 1 up to pre-dose at Week 52)
- Number of Participants With Anti-drug Antibodies (ADA) From Week 52 up to Week 78 - Treatment Period 2(From Week 56 up to Week 78)
- Number of Participants With Anti-drug Antibodies (ADA) up to Week 52 - Treatment Period 1(From Week 2 up to Week 52)