| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Osteoporosis is a disorder of impaired bone strength that results in skeletal fragility and increased fracture risk. It is a common and costly disorder, and is associated with significant morbidity and mortality. |
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| E.1.1.1 | Medical condition in easily understood language |
| Osteoporosis is a disease where bones deteriorate and become less dense, more porous, and brittle. The decrease in bone mass and strength leads to increased fragility and risk of fracture. |
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| 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 |
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| 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 |
To demonstrate the equivalence between EB1001 and EU-licensed Prolia in terms of change in BMD at the lumbar spine from baseline to Month 12 in postmenopausal women with osteoporosis.
To demonstrate the pharmacodynamic similarity between EB1001 and EU-licensed Prolia for the AUEC of s-CTX from baseline to Month 6 in postmenopausal women with osteoporosis. |
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| E.2.2 | Secondary objectives of the trial |
To compare the efficacy, PK, PD, safety, and immunogenicity profile of EB1001 and EU licensed Prolia in postmenopausal women with osteoporosis.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet all of the following criteria to be enrolled in this study:
1. Patient and/or their legally authorized representative must be able to understand and provide written informed consent prior to any study procedures.
2. Able to comply with all study procedures including requirements for supplementation.
3. Woman between the age of 55 and 85 years, inclusive.
4. Body weight between 40.0 and 99.9 kg, both inclusive, when rounded to the nearest tenth.
5. BMD absolute value consistent with a T-score ≤−2.5 SD and ≥−4.0 SD at the lumbar spine (L1 to L4) as assessed by DXA scan during the screening period. At least 2 lumbar vertebrae (from L1 to L4) must be evaluable by DXA scan.
6. At least one hip considered evaluable by DXA scan.
7. Postmenopausal, defined as at least 12 consecutive months since spontaneous amenorrhea with FSH level ≥40 mIU/mL, or at least 12 months postsurgical bilateral oophorectomy (with or without hysterectomy) at screening.
8. Albumin-adjusted total serum calcium ≥8.5 mg/dL (≥2.125 mmol/L) at screening.
9. Adequate hepatic function at screening, defined as having AST and ALT levels ≤3 × ULN in absence of evidence of viral hepatitis and total bilirubin ≤2 × ULN.
10. In good general health as determined by medical history, physical examination, and laboratory tests and able to walk without assistance. |
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| E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria will be excluded from the study:
1. Previously received denosumab (Prolia, Xgeva®, or biosimilar denosumab) or any other monoclonal antibody or fusion protein containing IgG.
2. Confirmed or suspected with infection with SARS-CoV-2 (COVID-19) at screening, or who has been diagnosed with COVID-19 or had contact with a COVID 19 patient within 14 days of screening.
3. Any severe or unresolved infection requiring hospitalization within 4 weeks prior to the first administration of the study drug, parenteral antibiotics within 4 weeks prior to the first administration of the study drug, or oral antibiotics within 2 weeks prior to the first administration of the study drug.
4. History of or current HIV or HCV infection.
5. Active HBV. Patients with past HBV infection will be allowed to participate if resolved.
6. Any disease that can affect bone metabolism except for osteoporosis, including osteomalacia, osteogenesis imperfecta, Paget’s disease, rheumatoid arthritis, fibrous dysplasia, ankylosing spondylitis, osteopetrosis, an unexplained elevation of ALP, Cushing’s disease, history of hyperprolactinemia, malabsorption syndrome, and advanced scoliosis or extensive lumbar fusion which will preclude vertebral fracture assessment.
7. History of hip fracture or 1 severe or >2 moderate vertebral fractures. Severe vertebral fracture (Grade 3) is defined as >40% vertebral height loss, and moderate vertebral fracture (Grade 2) is defined as 25% to 40% vertebral height loss, determined by lateral spine x ray.
8. Hypersensitivity to any component of denosumab or dry natural rubber (a derivative of latex).
9. Height, weight, or girth that may preclude accurate DXA measurements.
10. History of hyperparathyroidism or hypoparathyroidism.
11. Current hyperthyroidism or hypothyroidism, unless well-controlled on stable therapy for at least 3 months prior to baseline.
12. Malignancy (except fully resected cutaneous basal cell or squamous cell carcinoma, cervical or breast ductal carcinoma in situ) within 5 years of screening. Any history of bone metastases, implant radiation involving the skeleton or skeletal malignancies will be excluded.
13. New York Heart Association Class III or IV chronic heart failure, or any unstable cardiovascular disease, pulmonary disease, autoimmune disease, or ECG abnormalities that are judged to be significant at investigator’s discretion.
14. Serum 25-OH vitamin D level <20 ng/mL. Vitamin D repletion will be permitted at the investigator’s discretion and patients may be re-tested for 25-OH vitamin D. If vitamin D deficiency has been supplemented and 2 tests show the level >20 ng/mL within a month, the patient can be enrolled.
15. Estimated glomerular filtration rate <30 mL/min/1.73 m2.
16. Anemia (hemoglobin <10 g/dL).
17. Osteomyelitis or osteonecrosis of the jaw, or risk factors for osteonecrosis of the jaw including active dental or jaw condition which requires oral surgery, planned invasive dental procedure, or open soft tissue lesions in mouth.
18. History of and/or concomitant use of medications, including:
a. Intravenous bisphosphonate, fluoride, or strontium within 5 years of screening.
b. Oral bisphosphonates ≥3 years cumulatively prior to screening. If used for <3 years cumulatively and the last dose was ≥1 year before screening, patient can be enrolled.
c. Parathyroid hormone or PTH derivatives, systemic hormone-replacement therapy, SERMs, tibolone, calcitonin, or calcitriol within 1 year of screening.
d. Any of these medications within 3 months of screening: heparin, anticonvulsives (except benzodiazepines), systemic ketoconazole, anabolic steroids, testosterone, androgens, adrenocorticotropic hormone, cinacalcet, aluminum, lithium, protease inhibitors, methotrexate, or gonadotropin-releasing hormone agonists.
e. Oral or parenteral glucocorticosteroids (>5 mg prednisone equivalent per day for more than 10 days) within 3 months of screening.
f. Receipt of any investigational medication within 30 days or 5 half-lives of screening, whichever is longer.
19. History of severe skeletal pain with bisphosphonates.
20. Evidence of alcohol or substance-abuse within the last 12 months prior to screening.
21. Any evidence of any other co-existing disease or medical or psychological condition, metabolic dysfunction, physical examination finding, or clinical laboratory finding which, in the opinion of the investigator, will prevent the patient from completing the study or interfere with the interpretation of the study results. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Estimand 1a (Primary): Comparison of percent change in BMD at the lumbar spine (L1 to L4) by DXA from baseline to Month 12 in postmenopausal women with osteoporosis treated with EB1001 or EU licensed Prolia who adhere to treatment regimen regardless of discontinuation of study for reasons related to study drug (lack of efficacy/tolerability), and assuming patients have not died and prohibited medications were not used. Principle stratum strategy will be used to address intercurrent event of treatment adherence. Treatment policy strategy will be used to address intercurrent events of discontinuation for reasons related to study drug. Hypothetical strategy will be used to address intercurrent events of death and prohibited medications.
Primary Efficacy Endpoint: Percent change in BMD at the lumbar spine (L1 to L4) by DXA from baseline to Month 12.
Estimand 1b: Comparison of the AUEC of s-CTX from Day 1 predose to Month 6 predose in postmenopausal women with osteoporosis treated with EB1001 or EU-licensed Prolia regardless of discontinuation of study for reasons related to study drug (lack of efficacy/tolerability), and assuming patients have not died and prohibited medications were not used. Treatment policy strategy will be used to address intercurrent events of discontinuation for reasons related to study drug. Hypothetical strategy will be used to address intercurrent events of death and prohibited medications.
Primary PD Endpoint: The AUEC of s-CTX from Day 1 predose to Month 6 predose.
|
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy Endpoint: Month 12.
PD Endpoint: Month 6 predose. |
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints
• Percent change in BMD at the lumbar spine (L1 to L4) by DXA from baseline to Month 6
• Percent change in BMD at the femoral neck by DXA from baseline to Month 6 and Month 12
• Percent change in BMD at the total hip by DXA from baseline to Month 6 and Month 12
Safety Endpoints
• Incidence and grade of AEs from Screening through the EoS
• Incidence and grade of SAEs from screening through the EoS
• Incidence and grade of TEAEs from baseline through the EoS
• Incidence and grade of AESI including injection site reaction, drug-related hypersensitivity/allergic reaction, infection, hypocalcemia, osteonecrosis of the jaw, cellulitis, and other dermatologic reactions from baseline through the EoS
• Injection site pain as measured by VAS scores
• Incidence of ADA and neutralizing antibodies (NAb) at baseline, Week 2, and Months 1, 2, 3, 6, 9, and 12
• Number of patients with abnormal findings in physical examinations, vital signs, clinical safety labs, or ECGs from baseline (Day 1) through the EoS
Secondary PD Endpoints
• The AUEC of PINP from Day 1 predose to Month 6 predose between EB1001 and EU-licensed Prolia
• Percent change in s-CTX and PINP from baseline to Months 1, 3, 6 (predose) and 12 between EB1001 and EU-licensed Prolia
PK Endpoints
• PK of EB1001 and EU-licensed Prolia as assessed by serum concentration for potential population PK modeling analyses |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Efficacy Endpoints: Month 6, 12
Safety Endpoints: from Screening through the EoS
Secondary PD Endpoints: Month 1, 3, 6 (predose), 12
PK Endpoints: Day 1, Month 6 |
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| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
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| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Estonia |
| Bulgaria |
| Hungary |
| Poland |
| Ukraine |
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| 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
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| The end of the study is defined as the date on which the last patient completes the last visit (includes follow-up visit). |
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| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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