| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Osteoporosis is a systemic skeletal disease that is characterized by low bone mass and micro architectural deterioration of bone tissue, with a low bone mineral density (BMD) and consequent increase in bone fragility and susceptibility to fracture. The incidence of fractures varies greatly by country, but on average up to 50% of women > 50 years of age are at risk of fractures. Postmenopausal osteoporosis, resulting from estrogen deficiency, is the most common type of osteoporosis. |
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| E.1.1.1 | Medical condition in easily understood language |
| Osteoporosis is defined as a systemic skeletal disorder characterized by low bone mass and micro architectural deterioration of bone tissue. |
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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 of CT-P41 to US licensed Prolia in terms of efficacy in postmenopausal women with osteoporosis as determined by percent change from baseline in BMD for lumbar spine (L1 to L4) at Week 52
- To demonstrate the PD similarity in terms of area under the effect curve (AUEC) of serum carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX) over the initial 6 months (from Day 1 predose to Week 26 predose) between CT-P41 and US-licensed Prolia
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| E.2.2 | Secondary objectives of the trial |
| To evaluate the efficacy, PK, PD, and safety including immunogenicity of CT P41 and US licensed Prolia |
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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 randomized in this study:
1. Women, 50 to 80 years of age, both inclusive.
2. Body weight between 40.0 and 99.9 kg, both inclusive, when rounded to the nearest tenth.
3. Postmenopausal, as defined by:
a) No menstrual period for at least 12 consecutive months prior to the Screening visit with follicle-stimulating hormone (FSH) level ≥ 30 mIU/mL assessed by central laboratory at Screening visit, or
b) Surgical menopause (bilateral oophorectomy with or without hysterectomy) ≥ 12 months prior to the Screening visit
4. Bone mineral density T-score ≤ − 2.5 and ≥ − 4.0 at the lumbar spine (L1 to L4) as assessed by the central imaging vendor based on DXA scan at Screening.
5. Patient must have at least 3 vertebrae considered evaluable at the lumbar spine (L1 to L4) and at least 1 hip considered evaluable by DXA scan assessed by the central imaging vendor at Screening. Patient with unilateral metal in hips that would be allowed for the other side of 1 evaluable hip is included.
6. Patient with albumin-adjusted total serum calcium ≥ 8.5 mg/dL (≥ 2.125 mmol/L) at Screening.
7. Patient has adequate hepatic function at Screening as defined by the following clinical chemistry results:
a) Aspartate aminotransferase and alanine aminotransferase ≤ 3 × upper limit of normal (ULN)
b) Alkaline phosphatase ≤ 2 × ULN and total bilirubin ≤ 2 × ULN
8. In good general health as determined by medical history, physical examination, and laboratory tests and able to walk without assistance, at the Investigator’s discretion.
9. Patient and/or their legally authorized representative must be informed and given ample time and opportunity to read and/or understand the nature and purpose of this study including possible risks, side effects and requirements for supplementation, and must sign the informed consent form (ICF) before any study specific procedures. |
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| E.4 | Principal exclusion criteria |
1.Patient who has previously received denosumab (Prolia, Xgeva, or biosimilar denosumab) any other monoclonal antibodies (e.g. romosozumab),or biologic agents for osteoporosis 2.Patient with hypersensitivity to any component of denosumab or dry natural rubber (a derivative of latex) 3.Patient who is confirmed or suspected with infection of COVID-19 at Screening or has contact with COVID-19 patient within 14 days from Screening.
4.Patient who currently has, or has history of, any of the following inf. a) Known inf. with active hepatitis B,C,or HIV. Patient with past hepatitis B virus allowed if resolved (b)Any severe/active inf. or history of inf. requiring hospitalization, parenteral antibiotics (Ab)within 4weeks prior to first study drug adm or oral Ab within 2 weeks prior to first study drug adm. 5. Patient who has a med. history of and/or current disease incl.:(a)One severe or>2 moderate vertebral fractures (severe fracture is defined as >40% vertebral height loss and moderate fracture is defined as 25% to 40% vertebral height loss as determined by central reading of lateral spine X-ray; (b)Hip fracture;(c)Hyperparathyroidism or hypoparathyroidism;(d)(e) Current hyperthyroidism /Current hypothyroidism (unless both well controlled);(f)Bone disease and metabolic disease(except for osteoporosis) that may interfere with the interpretation of the results including osteomalacia, osteogenesis imperfecta, Paget's disease,rheumatoid arthritis, ankylosing spondylitis,osteopetrosis, fibrous dysplasia, an elevation of ALP at the PI's discretion, Cushing's disease, hyperprolactinemia, malabsorption syndrome, advanced scoliosis or extensive lumbar fusion; (g)History of severe skeletal pain with bisphosphonates; (h)History and/or current oral or dental conditions including osteomyelitis or osteonecrosis of the jaw; active dental or jaw condition which requires oral surgery; planned invasive dental procedure (e.g., tooth extr., dental implants, oral surgery); unhealed dental oral surgery; (i) History of any malignancy within 5 years prior to first study drug adm except adequately treated squamous or basal cell carcinoma of the skin or cervical carcinoma in situ. Any history of bone metastases, implant radiation involving the skeleton, or skeletal malignancies are exclusionary; (J) New York Heart Association (NYHA) Class III or IV chronic heart failure,unstable cardiovascular disease, pulmonary disease, autoimmune disease or electrocardiogram (ECG) abnormalities which can be judged as clinically significant at PI's discretion 6. Patient has one of the following laboratory test result at Screening (a) Serum 25-OH vitamin D < 20 ng/mL (if vitamin D deficiency has been supplemented at PI’s discretion, and retest result shows the level above 20 ng/mL within Screening period, the patient can be enrolled in the study. The retest is limited up to twice within the Screening period); b) Estimated glomerular filtration rate <30 mL/min/1.73 m2; c) Hemoglobin <10 g/dL 7. Patient who has a history of and/or concurrent use of medications incl. any of the following:
(a)Receipt of i.v bisphosphonates, fluoride, and strontium for osteoporosis within the last 5 years prior to first adm of study drug; (b)Receipt of oral bisphosphonates ≥3 yrs cumulatively prior to Screening or receipt of any dose of oral bisphosphonates within 12months prior to Screening;(c)Use of parathyroid hormone (PTH) or its derivatives, systemic hormone-replacement therapy, (estrogen with or without progestogen), selective estrogen-receptor modulator, tibolone, calcitonin, or calcitriol within 12months prior to first adm. of study drug; (d)Use of other bone active drugs incl. heparin, anticonvulsives (except benzodiazepines), systemic ketoconazole, anabolic steroids, testosterone, androgens, adrenocorticotropic hormone, cinacalcet, aluminum, lithium, protease inhibitors, methotrexate, or gonadotropin-releasing hormone agonists within 3months prior to first adm of study drug; (e)Use of oral or parenteral glucocorticosteroids (>5 mg/prednisone daily or equi. for > 10 days) within 3months prior to the first adm. of the study drug;(f) Receipt of any investigational drug within 4 weeks or five half-lives (whichever is longer) prior to the first adm. of the study drug (g) Receipt of any authorized COVID-19 vaccines within 2 weeks prior and after the first adm. of the study drug (total of 4 weeks) 8. Patient who currently abuses alcohol/ drugs or has a history of alcohol/drug abuse within 12months prior to first study drug adm. 9. Patient who has evidence of any other coexisting disease or medical or psychological condition, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational product or could have interfere with the interpretation of study results, or patient is at high risk for treatment complication in the opinion of the Investigator. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy endpoint:
• Percent change from baseline in BMD for lumbar spine (L1 to L4) by DXA at Week 52
Primary Pharmacodinamic endpoint:
• Area under the effect curve of s-CTX over the initial 6 months (from Day 1 predose to Week 26 predose)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy Endpoint: Week 52
Pharmacodinamic Endpoint: Week 26 |
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoint:
• Percent change from baseline in BMD for lumbar spine (L1 to L4), total hip, and femoral neck by DXA at Weeks 26, 52, and 78
• The incidences of new vertebral, nonvertebral, and hip fractures during the study
• Change from baseline in health-related quality of life at Weeks 26, 52, and 78
Secondary Pharmacokinetic Endpoint:
• Serum concentration (up to Week 78)
• Trough serum concentration (Ctrough) (concentration prior to the next study drug administration)
• Maximum serum concentration (Cmax) after the first administration of study drug
• Truncated area under the concentration-time curve from zero to Week 26 (AUC0-t)
• Time of observed maximum serum concentration (Tmax) of denosumab after the first administration of the study drug
• Volume of distribution (Vd)
• Terminal elimination half-life (T1/2)
Secondary Pharmacodynamic Endpoint:
• Area under the effect curve of P1NP over the initial 6 months (from Day 1 predose to Week 26 predose)
• Percent change from baseline of s-CTX and P1NP at Weeks 26, 52, and 78
Secondary Safety endpoints:
• Adverse events (including SAEs)
• Adverse events of special interest (AESI; injection site reaction, drug-related hypersensitivity/allergic reaction, infection, hypocalcaemia, ONJ, atypical femoral fracture and dermatologic reactions)
• Hypersensitivity/allergic reaction assessments by vital sign monitoring (including systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature)
• Local site pain using 100 mm VAS
• Vital sign measurements, weight, height, and BMI
• Physical examination
• Clinical laboratory tests
• 12-lead electrocardiogram
• Prior and concomitant medication
• Immunogenicity (incidence of ADA and NAb)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Efficacy Endpoint: Weeks 26, 52, and 78
Secondary Pharmacokinetic Endpoint: 1st and 2nd (week 78); rest of endpoints at week 26
Secondary Pharmacodynamic Endpoint: Weeks 26, 52, and 78
Secondary Safety Endpoint: throughout the study |
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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 | 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 | 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 | 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 | No |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Latvia |
| Poland |
| Ukraine |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 completion of the study is defined as the date of final database lock with no further database change for the final CSR. |
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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 | 5 |
| E.8.9.1 | In the Member State concerned days | 1 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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