Postmenopausal Women With Osteoporosis
Conditions
Brief summary
This is a randomized, double-blind, multicenter, parallel-arm, Phase 3 study to compare the efficacy, PK (Pharmacokinetic), PD (Pharmacodynamic), safety, and immunogenicity of Bmab 1000 and Prolia® in postmenopausal women with osteoporosis
Detailed description
The study will consist of 3 study periods: Screening period; Part 1, double-blind active-controlled period; and Part 2, transition period. In the double-blind active-controlled period, eligible Patients will be randomized in a 1:1 ratio to receive either Bmab 1000 or Prolia®. Prior to dosing At Week 52, patients in Prolia® treatment group will be randomized again in a 1:1 ratio to either continue on Prolia® or be transitioned to Bmab 1000. To maintain the study blinding, the patients in the original Bmab 1000 arm will also go through the re-randomization procedure; however, they will continue to receive Bmab 1000. The interventions (Bmab 1000 or Prolia®) will be administered subcutaneously every 6 months. End-of-study visit will be at Week 78 post randomization (Month 18).
Interventions
Sponsors
Biocon Biologics UK Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Double-blind (Patient, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
55 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Postmenopausal women, aged ≥55 and \<80 years at screening. Postmenopausal is defined as 12 months of spontaneous amenorrhea with serum FSH (follicle-stimulating hormone) levels ≥40 mIU/mL at screening or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy. 2. Evidence of osteoporosis as assessed by lumbar spine (L1-L4) absolute BMD corresponding to a T-score classification ≤-2.5 and ≥-4.0. 3. At least 3 vertebrae in the L1-L4 region and at least one hip joint are evaluable by DXA at screening. 4. Patients with body weight ≥50 to \<90 kg at screening.
Exclusion criteria
1. Patients with T-score of \<-4.0 at the lumbar spine, total hip, or femoral neck. 2. Known history of previous exposure to denosumab (Prolia®, Xgeva®, or any biosimilar denosumab). 3. For prior or ongoing use of any osteoporosis treatment (other than calcium and vitamin D supplements) following points to be considered for the washout periods prior to the screening visit: a. Oral bisphosphonate i. Ineligible if used for 3 or more years cumulatively ii. If used for \<3 years, a gap of at least 1 year since the last dose is required at the screening visit b. Dose received any time 4. Systemic glucocorticosteroids 5. Patients with ongoing serious infections 6. Evidence of any of the following per the patient's history, DXA, or X-ray review and/or current disease: 1. Patient in bed rest for 2 or more weeks during the last 3 months prior to screening 2. Current hyperthyroidism or hypothyroidism 3. History and/or current hyperparathyroidism or hypoparathyroidism 4. Current hypocalcemia or hypercalcemia based on albumin-adjusted serum calcium 5. Any bone disease including bone metastasis or metabolic disease (except for osteoporosis), eg, osteomalacia or osteogenesis imperfecta, rheumatoid arthritis, Paget's disease, ALP (alkaline phosphatase) elevation (at investigator's discretion), Cushing's disease, clinically significant hyperprolactinemia (at investigator's discretion), fibrous dysplasia, malabsorption syndrome which may interfere with the interpretation of the results 6. History and/or presence of one severe or 3 or more moderate vertebral fractures 7. History and/or presence of hip fracture or bilateral hip replacement 8. Presence of an active healing fracture according to assessment of investigator 9. History of severe skeletal pain with bisphosphonates which, as per the investigator, is a risk to her participation in the trial 10. Oral/dental or periodontal conditions:
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Lumbar Spine BMD (Bone Mineral Density) | Baseline and Week 52 | To demonstrate equivalent efficacy between Bmab 1000 and Prolia® based on percentage change from baseline at Week 52 in lumbar spine BMD |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Lumbar Spine BMD | Baseline and Week 26 | To demonstrate equivalent efficacy between Bmab 1000 and Prolia® based on percentage change from baseline at Week 26 in lumbar spine BMD |
| Percentage Change in Total Hip BMD by DXA (Dual-energy X-ray Absorptiometry) | Baseline upto week 26 | To demonstrate equivalent efficacy between Bmab 1000 and Prolia® based on percentage change from baseline, at Week 26 and Week 52 in lumbar spine BMD |
| Serum Concentrations of P1NP (Procollagen Type 1 N-terminal Propeptide) | Baseline up to Week 52 | To compare bone turnover between Bmab 1000 and Prolia® based on P1NP after the first dose |
| Incidence of TEAEs (Treatment-emergent Adverse Events) up to 6 Months After the Second Dose | Baseline up to Week 78 | To compare safety and tolerability of 2 administrations of Bmab 1000 and Prolia® 6 months apart |
| Incidence of ADA (Anti-drug Antibody) | Week 78 (Transition Period) | To compare immunogenicity between Bmab 1000 and Prolia® |
| Incidence of NAb (Neutralizing Antibody) up to Week 52 | Baseline up to Week 52 (Double-blind Active-controlled Period) | To compare immunogenicity between Bmab 1000 and Prolia® |
| AUEC (Area Under the Effect Curve) of the Bone Resorption Marker sCTX (Serum C-terminal Telopeptide of Type 1 Collagen) | Baseline to Week 26 | To demonstrate pharmacodynamic equivalence between Bmab 1000 and Prolia® based on AUEC of the bone resorption marker sCTX from baseline to week 26 |
| Percentage Change From Baseline in Femoral BMD | Week 78 | To demonstrate equivalent efficacy between Bmab 1000 and Prolia® based on percentage change from baseline at Week 78 in Femoral BMD |
| Minimum Concentration (Cmin) of sCTX | baseline to Week 26 | To compare minimum Concentration (Cmin) of sCTX between Bmab 1000 and Prolia® |
| Denosumab Concentrations at Weeks 26 | Weeks 26 | Serum Concentrations of Denosumab |
| Denosumab Concentrations at Weeks 52 | Weeks 52 | Serum Concentrations of Denosumab |
| Denosumab Concentrations at Weeks 78 | Weeks 78 | Serum Concentrations of Denosumab |
| Percentage Change From Baseline in Hip BMD | Week 78 | To demonstrate equivalent efficacy between Bmab 1000 and Prolia® based on percentage change from baseline at Week 78 in Hip BMD |
Countries
United Kingdom
Participant flow
Recruitment details
The study was conducted at 42 sites across 4 countries, and enrolled 479 subjects
Participants by arm
| Arm | Count |
|---|---|
| Bmab 1000 Bmab 1000: 60 mg administered as a single subcutaneous (SC) injection once every 6 months. | 238 |
| Prolia®: Prolia®: 60 mg administered as a single SC injection once every 6 months | 241 |
| Total | 479 |
Baseline characteristics
| Characteristic | Bmab 1000 | Prolia®: | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 154 Participants | 153 Participants | 307 Participants |
| Age, Categorical Between 18 and 65 years | 84 Participants | 88 Participants | 172 Participants |
| Age, Continuous | 66.7 years STANDARD_DEVIATION 5.55 | 66.5 years STANDARD_DEVIATION 5.77 | 66.6 years STANDARD_DEVIATION 5.66 |
| Race/Ethnicity, Customized Japanese | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 237 participants | 241 participants | 478 participants |
| Region of Enrollment Europe | 235 participants | 238 participants | 473 participants |
| Region of Enrollment United Kingdom | 3 participants | 3 participants | 6 participants |
| Sex: Female, Male Female | 238 Participants | 241 Participants | 479 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 342 | 1 / 240 |
| other Total, other adverse events | 144 / 218 | 72 / 104 |
| serious Total, serious adverse events | 15 / 218 | 2 / 104 |
Outcome results
Primary
Percentage Change in Lumbar Spine BMD (Bone Mineral Density)
To demonstrate equivalent efficacy between Bmab 1000 and Prolia® based on percentage change from baseline at Week 52 in lumbar spine BMD
Time frame: Baseline and Week 52
Population: Full analysis set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bmab 1000 and Prolia | Percentage Change in Lumbar Spine BMD (Bone Mineral Density) | 1.698 Percent change | Standard Error 0.5115 |
| Prolia® | Percentage Change in Lumbar Spine BMD (Bone Mineral Density) | 1.440 Percent change | Standard Error 0.5089 |
Secondary
AUEC (Area Under the Effect Curve) of the Bone Resorption Marker sCTX (Serum C-terminal Telopeptide of Type 1 Collagen)
To demonstrate pharmacodynamic equivalence between Bmab 1000 and Prolia® based on AUEC of the bone resorption marker sCTX from baseline to week 26
Time frame: Baseline to Week 26
Population: Modified Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bmab 1000 and Prolia | AUEC (Area Under the Effect Curve) of the Bone Resorption Marker sCTX (Serum C-terminal Telopeptide of Type 1 Collagen) | 127 day*pg/mL | Standard Deviation 85.2 |
| Prolia® | AUEC (Area Under the Effect Curve) of the Bone Resorption Marker sCTX (Serum C-terminal Telopeptide of Type 1 Collagen) | 123 day*pg/mL | Standard Deviation 77.3 |
Secondary
Denosumab Concentrations at Weeks 26
Serum Concentrations of Denosumab
Time frame: Weeks 26
Population: Modified Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bmab 1000 and Prolia | Denosumab Concentrations at Weeks 26 | 53.6 ng/mL | Standard Deviation 119 |
| Prolia® | Denosumab Concentrations at Weeks 26 | 40.7 ng/mL | Standard Deviation 88.1 |
Secondary
Denosumab Concentrations at Weeks 52
Serum Concentrations of Denosumab
Time frame: Weeks 52
Population: Modified Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bmab 1000 and Prolia | Denosumab Concentrations at Weeks 52 | 69.4 ng/mL | Standard Deviation 161 |
| Prolia® | Denosumab Concentrations at Weeks 52 | 42.9 ng/mL | Standard Deviation 94 |
Secondary
Denosumab Concentrations at Weeks 78
Serum Concentrations of Denosumab
Time frame: Weeks 78
Population: Modified Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bmab 1000 and Prolia | Denosumab Concentrations at Weeks 78 | 87.6 ng/mL | Standard Deviation 223 |
| Prolia® | Denosumab Concentrations at Weeks 78 | 72.1 ng/mL | Standard Deviation 174 |
| Prolia®:-Prolia | Denosumab Concentrations at Weeks 78 | 66.2 ng/mL | Standard Deviation 111 |
Secondary
Incidence of ADA (Anti-drug Antibody)
To compare immunogenicity between Bmab 1000 and Prolia®
Time frame: Baseline up to Week 52 (Double-blind Active-controlled Period)
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bmab 1000 and Prolia | Incidence of ADA (Anti-drug Antibody) | 215 Participants |
| Prolia® | Incidence of ADA (Anti-drug Antibody) | 205 Participants |
Secondary
Incidence of ADA (Anti-drug Antibody)
To compare immunogenicity between Bmab 1000 and Prolia®
Time frame: Week 78 (Transition Period)
Population: Safety Analysis Set for Transition Period
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bmab 1000 and Prolia | Incidence of ADA (Anti-drug Antibody) | 46 Participants |
| Prolia® | Incidence of ADA (Anti-drug Antibody) | 13 Participants |
| Prolia®:-Prolia | Incidence of ADA (Anti-drug Antibody) | 14 Participants |
Secondary
Incidence of NAb (Neutralizing Antibody) up to Week 52
To compare immunogenicity between Bmab 1000 and Prolia®
Time frame: Week 78 (Transition Period)
Population: Safety Analysis Set for Transition Period
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bmab 1000 and Prolia | Incidence of NAb (Neutralizing Antibody) up to Week 52 | 3 Participants |
| Prolia® | Incidence of NAb (Neutralizing Antibody) up to Week 52 | 0 Participants |
| Prolia®:-Prolia | Incidence of NAb (Neutralizing Antibody) up to Week 52 | 0 Participants |
Secondary
Incidence of NAb (Neutralizing Antibody) up to Week 52
To compare immunogenicity between Bmab 1000 and Prolia®
Time frame: Baseline up to Week 52 (Double-blind Active-controlled Period)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bmab 1000 and Prolia | Incidence of NAb (Neutralizing Antibody) up to Week 52 | 7 Participants |
| Prolia® | Incidence of NAb (Neutralizing Antibody) up to Week 52 | 5 Participants |
Secondary
Incidence of TEAEs (Treatment-emergent Adverse Events) up to 6 Months After the Second Dose
To compare safety and tolerability of 2 administrations of Bmab 1000 and Prolia® 6 months apart
Time frame: Baseline up to Week 78
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bmab 1000 and Prolia | Incidence of TEAEs (Treatment-emergent Adverse Events) up to 6 Months After the Second Dose | 55 Participants |
| Prolia® | Incidence of TEAEs (Treatment-emergent Adverse Events) up to 6 Months After the Second Dose | 29 Participants |
| Prolia®:-Prolia | Incidence of TEAEs (Treatment-emergent Adverse Events) up to 6 Months After the Second Dose | 27 Participants |
Secondary
Minimum Concentration (Cmin) of sCTX
To compare minimum Concentration (Cmin) of sCTX between Bmab 1000 and Prolia®
Time frame: baseline to Week 26
Population: Modified Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bmab 1000 and Prolia | Minimum Concentration (Cmin) of sCTX | 41.5 pg/mL | Standard Deviation 18.2 |
| Prolia® | Minimum Concentration (Cmin) of sCTX | 41.1 pg/mL | Standard Deviation 17.8 |
Secondary
Percentage Change From Baseline in Femoral BMD
To demonstrate equivalent efficacy between Bmab 1000 and Prolia® based on percentage change from baseline at Week 52 in Femoral BMD
Time frame: Week 52
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bmab 1000 and Prolia | Percentage Change From Baseline in Femoral BMD | 2.138 Percent change | Standard Error 0.8042 |
| Prolia® | Percentage Change From Baseline in Femoral BMD | 1.767 Percent change | Standard Error 0.7999 |
Secondary
Percentage Change From Baseline in Femoral BMD
To demonstrate equivalent efficacy between Bmab 1000 and Prolia® based on percentage change from baseline at Week 78 in Femoral BMD
Time frame: Week 78
Population: Full Analysis Set for Transition Period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bmab 1000 and Prolia | Percentage Change From Baseline in Femoral BMD | 3.666 Percent change | Standard Deviation 3.664 |
| Prolia® | Percentage Change From Baseline in Femoral BMD | 3.333 Percent change | Standard Deviation 3.5021 |
| Prolia®:-Prolia | Percentage Change From Baseline in Femoral BMD | 2.834 Percent change | Standard Deviation 3.9551 |
Secondary
Percentage Change From Baseline in Hip BMD
To demonstrate equivalent efficacy between Bmab 1000 and Prolia® based on percentage change from baseline at Week 78 in Hip BMD
Time frame: Week 78
Population: Full Analysis Set for Transition Period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bmab 1000 and Prolia | Percentage Change From Baseline in Hip BMD | 4.011 Percent change | Standard Deviation 2.7744 |
| Prolia® | Percentage Change From Baseline in Hip BMD | 4.052 Percent change | Standard Deviation 3.43 |
| Prolia®:-Prolia | Percentage Change From Baseline in Hip BMD | 3.483 Percent change | Standard Deviation 2.6155 |
Secondary
Percentage Change in Lumbar Spine BMD
To demonstrate equivalent efficacy between Bmab 1000 and Prolia® based on percentage change from baseline at Week 26 in lumbar spine BMD
Time frame: Baseline and Week 26
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bmab 1000 and Prolia | Percentage Change in Lumbar Spine BMD | 3.872 Percent change | Standard Error 0.7885 |
| Prolia® | Percentage Change in Lumbar Spine BMD | 3.699 Percent change | Standard Error 0.786 |
Secondary
Percentage Change in Total Hip BMD by DXA (Dual-energy X-ray Absorptiometry)
To demonstrate equivalent efficacy between Bmab 1000 and Prolia® based on percentage change from baseline, at Week 26 and Week 52 in lumbar spine BMD
Time frame: Week 52
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bmab 1000 and Prolia | Percentage Change in Total Hip BMD by DXA (Dual-energy X-ray Absorptiometry) | 2.224 Percent change | Standard Error 0.5532 |
| Prolia® | Percentage Change in Total Hip BMD by DXA (Dual-energy X-ray Absorptiometry) | 2.132 Percent change | Standard Error 0.5513 |
Secondary
Percentage Change in Total Hip BMD by DXA (Dual-energy X-ray Absorptiometry)
To demonstrate equivalent efficacy between Bmab 1000 and Prolia® based on percentage change from baseline, at Week 26 and Week 52 in lumbar spine BMD
Time frame: Baseline upto week 26
Population: Full Analysis Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bmab 1000 and Prolia | Percentage Change in Total Hip BMD by DXA (Dual-energy X-ray Absorptiometry) | 1.698 Percent change | Standard Error 0.5115 |
| Prolia® | Percentage Change in Total Hip BMD by DXA (Dual-energy X-ray Absorptiometry) | 1.440 Percent change | Standard Error 0.5089 |
Secondary
Serum Concentrations of P1NP (Procollagen Type 1 N-terminal Propeptide)
To compare bone turnover between Bmab 1000 and Prolia® based on P1NP after the first dose
Time frame: Baseline up to Week 52
Population: Modified Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bmab 1000 and Prolia | Serum Concentrations of P1NP (Procollagen Type 1 N-terminal Propeptide) | 69.4 ng/ml | Standard Deviation 161 |
| Prolia® | Serum Concentrations of P1NP (Procollagen Type 1 N-terminal Propeptide) | 42.9 ng/ml | Standard Deviation 94 |