| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Postmenopausal women diagnosed with osteoporosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Postmenopausal women diagnosed with osteoporosis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10031285 |
| E.1.2 | Term | Osteoporosis postmenopausal |
| E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
a. To demonstrate equivalent efficacy between Bmab 1000 and Prolia based on percentage change from baseline at Week 52 in lumbar spine BMD (Co-primary for EMA and Primary for US FDA)
b. To demonstrate pharmacodynamic equivalence between Bmab 1000 and Prolia based on AUEC of the bone resorption marker sCTX from baseline to week 26 (Co-primary for EMA and secondary US FDA) |
|
| E.2.2 | Secondary objectives of the trial |
Part 1:
- To compare other efficacy parameters between Bmab 1000 and Prolia
- To compare bone turnover between Bmab 1000 and Prolia
- To compare safety and tolerability of 2 admin of Bmab 1000 and Prolia
- To compare immunogenicity between Bmab 1000 and Prolia
- To assess denosumab serum concentrations following Bmab 1000 and Prolia administration
Part 2:
- To assess the risk of hypersensitivity and AE up to 6 months after the single transition from Prolia to Bmab 1000 compared with those on Prolia
- To assess the risk of immunogenicity after single transition from Prolia to Bmab 1000 compared with those continuing on Prolia
Other:
- To assess efficacy after single transition from Prolia to Bmab 1000 compared with those to continuing on Prolia
- To assess efficacy of 3 doses of Bmab 1000 compared to Prolia
- To assess PK & PD:
- To assess the AE on Bmab 1000 compared to Prolia
- To assess the risk of immunogenicity on Bmab 1000 throughout compared to Prolia throughout |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Willingness to sign the written ICF, ambulatory, able to follow study instructions and comply with the protocol requirements, and not visually impaired as per the
investigator’s opinion to participate in the trial.
2. Postmenopausal women, aged ≥55 and <80 years at screening. Postmenopausal is defined as 12 months of spontaneous amenorrhea with serum FSH levels ≥40 mIU/mL
at screening or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
3. Evidence of osteoporosis as assessed by lumbar spine (L1-L4) absolute BMD corresponding to a T-score classification ≤–2.5 and ≥–4.0. Bone mineral density measurements should be performed by DXA using Hologic or Lunar densitometers at
screening visit. All DXA scans will be assessed by a central imaging center for this purpose.
4. At least 3 vertebrae in the L1-L4 region and at least one hip joint are evaluable by DXA at screening.
5. Patients with body weight ≥50 to <90 kg at screening. |
|
| E.4 | Principal 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.
3. Use of any biologic drugs within 90 days or within five half-lives of the drug,
whichever is longer prior to the screening.
4. Known hypersensitivity to denosumab.
5. For prior or ongoing use of any osteoporosis treatment, specific washout periods consideration are added in the protocol
6. Systemic glucocorticosteroids within past 3 months before screening.
7. Other bone active drugs including but not limited to anticoagulants, antiplatelet, anticonvulsants, systemic ketoconazole, adrenocorticotropic hormone, lithium, gonadotropin releasing hormone agonists, and anabolic steroids within the last 3 months. Receipt of PPI for >1 year continuously will be allowed only after 3 months of washout prior to the screening. Patients receiving PPI for ≤1 year continuously are not allowed if they plan to continue the use of PPI during the study such that the continuous use of PPI will be >1 year.
8. Patients with ongoing serious infections, or infection requiring parenteral antibiotics within 4 weeks prior to the first administration of the study treatment, or oral antibiotics within 2 weeks prior to the first administration of the study treatment.
9. Evidence of any of the following:
a. Patient in bed rest for 2 or more weeks during the last 3 months prior to
screening
b. Current hyperthyroidism or hypothyroidism. Patients with subclinical hyperthyroidism or subclinical hypothyroidism will be excluded
c. History and/or current hyperparathyroidism or hypoparathyroidism
d. Patients who have had recurrent episode of hypocalcemia in the past
e. Current hypocalcemia or hypercalcemia
f. Any bone disease including bone metastasis or metabolic disease which may interfere with the interpretation of the results
g. Malignancy within the last 5 years from screening visit
h. Height, weight, and girth which may preclude accurate DXA measurements
i. Advanced scoliosis or extensive lumbar fusion
j. History and/or presence of one severe or 3 or more moderate vertebral
fractures
k. History and/or presence of hip fracture or bilateral hip replacement or history of atypical femoral fracture
l. Presence of an active healing fracture
m. History of severe skeletal pain with bisphosphonates
n. Oral/dental or periodontal specific conditions as per protocol details
o. Any organic or psychiatric disorder or laboratory abnormality or underlying
condition which will impact on the trial participation.
p. History of presence of a severe allergic reaction.
q. Personal/family history of prolonged QT interval syndrome or family history
of sudden death.
10. New York Heart Association Class III or IV chronic heart failure, any unstable
cardiovascular disease, pulmonary disease, autoimmune disease or ECG
abnormalities, which can be judged as clinically significant at the investigator’s
discretion.
11. Patient has a planned surgical intervention.
12. One of the specific laboratory test results at screening as per protocol details
13. Allergy to vitamin D or calcium supplements.
14. Participation in a drug study within 90 days or 5 half-lives of the previous drug.
15. Known case of active hepatitis B, hepatitis C or HIV infection.
16. Evidence of alcohol or substance-abuse within the last 12 months prior to screening.
17. Confirmed or suspected with infection with SARS-CoV-2 from screening to randomization, or who has been diagnosed with COVID-19 (as per site and/or local regulatory guidelines) or history of COVID-19 infection requiring oxygen supplementation in the last 8 weeks prior to screening or had contact with a COVID 19 patient 14 days prior to screening and within the screening period up to randomization.
18. Patient has received live virus vaccine within 4 weeks |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Co-primary endpoint: Percentage change from baseline at Week 52 in the lumbar spine BMD by DXA (Time Frame: Baseline and Week 52)
- Co-primary endpoint: AUEC of sCTX from baseline to 26 weeks (Time Frame: Baseline to Week 26) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Please see above: timepoints added to each end points |
|
| E.5.2 | Secondary end point(s) |
Part 1:
- Percentage change from baseline at Week 26 in lumbar spine BMD by DXA (Time Frame: Baseline
and Week 26)
- Percentage change from baseline at Weeks 26 and 52 in total hip BMD by DXA (Time Frame: Baseline,
Week 26, and Week 52)
- Percentage change from baseline at Weeks 26 and 52 in femoral neck BMD by DXA (Time Frame:
Baseline, Week 26, and Week 52)
- Incidence of fracture up to Week 52 (Time Frame: Baseline up to Week 52)
- Cmin of sCTX (Time Frame: Baseline up to Week 26)
- Serum concentrations of P1NP (Time Frame: Baseline up to Week 52)
- PD parameters of sCTX: Imax, TImax, AUIC (Time Frame: Baseline up to Week 52)
- Incidence of TEAEs up to 6 months after the second dose (Time Frame: Baseline up to Week 52
- Incidence of clinically significant changes in vital sign, physical examinations, laboratory safety tests,
and ECGs up to 6 months after the second dose (Time Frame: Baseline up to Week 52
- Incidence and titer of ADA, incidence of NAb up to
Week 52 (Time Frame: Baseline up to Week 52)
- Denosumab concentrations at Weeks 2, 4, 12, 26, 38, and 52 (Time Frame: Baseline up to Week 52)
Part 2:
- Incidence of TEAEs from the third dose at Week 52 and up to and including Week 78 (Time
Frame: from Week 52 up to Week 78)
- Incidence of clinically significant changes in physical examinations, laboratory safety tests, ECG and vital signs from the third dose at
Week 52 and up to and including Week 78 (Time Frame: from Week 52 up to Week 78)
- Incidence of deaths and SAEs from the third dose at Week 52 and up to and including Week 78
(Time Frame: from Week 52 up to Week 78)
- Incidence and titer of ADA, incidence of NAb at Week 78 split by serostatus at Week 52 (Time Frame: from Week 52 up to Week 78)
Other:
- Percentage change from Week 52 at Week 78 in lumbar spine BMD by DXA (Time Frame: from Week 52 up to Week 78)
- Percentage change from (original) baseline at Week 78 in lumbar spine, hip and femoral neck BMD by DXA (Time Frame: Day 1 up to
Week 78)
- Serum concentrations of denosumab at Week 56, 64, and 78 (PK) (Time Frame: from Week 56 up
to Week 78)
- Serum concentrations of CTX at Week 78 (PD) (Time Frame: Week 78)
- Incidence of TEAEs from the first dose up to and including Week 78 (Time Frame: Day 1 up to
Week 78)
- Incidence of clinically significant changes in physical examinations, laboratory safety tests, ECG and vital signs from the first dose up to and including Week 78 (Time Frame: Day 1 up to Week 78)
- Incidence of deaths and SAEs from the first dose up to and including Week 78 (Time Frame: Day 1 up to Week 78)
- Incidence and titer of ADA, incidence of NAb at any point from the first dose up to Week 78 (Time
Frame: Day 1 up to Week 78) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please see above: timepoints added to each end points |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Yes |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 34 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Ukraine |
| United States |
| Estonia |
| Latvia |
| Poland |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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