| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 10031282 |
| E.1.2 | Term | Osteoporosis |
| 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 clinical similarity of AVT03 and United States-licensed Prolia® (US-Prolia, generic name: denosumab, hereafter referred to as Prolia) in terms of percent change from Baseline in bone mineral density (BMD) at 12 months
•To demonstrate clinical similarity of AVT03 and Prolia in terms of area under the percent change from Baseline in serum C telopeptide of type 1 collagen up to 6 months (AUEC0 6months of %Cfb sCTX 1). Note: This objective will be considered as primary for European Medicines Agency (EMA) submission only; for all other agencies, this objective will be considered as secondary.
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| E.2.2 | Secondary objectives of the trial |
•To further compare clinical similarity of AVT03 and Prolia
•To assess and compare the safety of AVT03 with Prolia
•To assess and compare immunogenicity of AVT03 with Prolia
•To compare pharmacokinetic (PK) biosimilarity between AVT03 and Prolia
•To compare pharmacodynamic (PD) parameters between AVT03 and Prolia
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Postmenopausal women with osteoporosis willing to sign an informed consent form and able to undergo protocol related procedures.
2.Age: ≥50 years.
3.Female subject is postmenopausal according to 1 of the following criteria:
a.Spontaneous amenorrhea for ≥12 consecutive months
b.Biochemical criteria of menopause, follicle-stimulating hormone, >40 IU/L except surgically sterile
c.Having had bilateral oophorectomy ≥6 weeks prior to Screening
4.Body Mass Index: 18.5-32.0 kg/m2
5.A baseline dual-energy x-ray absorptiometry scan with a T-score ≤-2.5 and ≥ -4.0 at the lumbar spine (LS) (L1 to L4) and/or total hip and/or femoral neck.
A subject must have a T score within the stated range of ≤ -2.5 and ≥ -4.0 in at least 1 of the 3 areas: - Lumbar spine (L1 to L4) - Total hip - Femoral neck. On the contrary, subjects will be excluded from the trial if the T score is less than -4.0 in at least 1 of the 3 areas (ie, at the LS [L1 to L4], or total hip, or femoral neck).
Note: The left hip should be scanned for the calculation of total hip T score. If the left hip cannot be scanned (eg, due to left hip replacement, etc), the right hip can be scanned instead. The same hip should be used for all dual-energy x-ray absorptiometry scans.
6.At least 2 consecutive evaluable lumbar vertebrae and at least 1 evaluable hip.
7.Willing to receive calcium plus vitamin D supplements.
8.No history or evidence of a clinically significant disorder, condition, or disease that, in the opinion of the Investigator, would pose a risk to subject safety.
9.Resting supine systolic blood pressure of ≤150 mmHg and diastolic blood pressure of ≤90 mmHg. Other vital signs showing no clinically relevant deviations according to the Investigator’s judgment.
10.12-lead electrocardiogram (ECG) recording without signs of clinically relevant pathology or showing no clinically relevant deviations as judged by the Investigator.
11.Subject smokes <10 cigarettes per day within 3 months of Screening. Note: It is strongly recommended that subjects do not smoke during their participation in the study.
12.Recommended to abstain from alcohol from 48 hours prior to study drug administration, and 24 hours prior to study visits.
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| E.4 | Principal exclusion criteria |
1.Evidence of clinically relevant pathology, especially prior diagnosis of bone disease, or any uncontrolled condition that will affect bone metabolism such as, but not limited to: osteogenesis imperfecta, hyperparathyroidism, non-controlled hyperthyroidism (thyroid stimulating hormone(TSH)<0.5mIU/L), non controlled hypothyroidism(TSH≥5.0mIU/L), osteomalacia, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, current flare-up of osteoarthritis and/or gout, active malignancy, renal disease (defined as creatinine clearance<50mL/min as calculated by Cockcroft-Gault formula), Paget's disease of the bone, recent bone fracture(within 6 months), and malabsorption syndrome
2.History and/or presence of 1 severe or more than 1 moderate vertebral fractures confirmed by x-ray(according to Genant semiquantitative method).
3.History of hip fracture
4.Presence of active healing fractures
5.Previous treatment with denosumab and use of the following medications:
a.Intravenous bisphosphonates, fluoride, or strontium ranelate at any dose within 5 years prior to Screening(Scr)
b.Oral bisphosphonates used for>3 years cumulative use, and any dose within 12 months of Scr
c.Parathyroid hormone or PTH derivatives(eg, teriparatide, abaloparatide), and selective estrogen receptor modulators(eg, raloxifene) within 1year of Scr
d.Romozosumab within 30days prior to Scr
e.Calcitonin within 6months of Scr
f.Other bone metabolism drugs: administration of any of the following treatments within the last 3 months,
i.anabolic steroids or testosterone
ii.glucocorticoids(>5mg/day prednisone or equivalent for>10days)
iii.systemic hormone replacement therapy
iv.tibolone
v.calcitriol
vi.anticonvulsants(except benzodiazepines and pregabalin)
vii.heparin
viii.systemic use of ketoconazole, androgens, adrenocorticotropic hormone, cinacalcet or any cathepsin K inhib.(eg, odanacatib), aluminium, lithium, protease inhib., methotrexate, gonadotropin releasing hormone agonists
6.Osteonecrosis of the jaw or risk factors for ONJ such as invasive dental procedures(eg, tooth extraction, dental implants, oral surgery in the past 6months), periodontal, and/or pre-existing dental disease
7.Evidence of hypo/hypercalcemia at Scr defined as <8.6 or >10. mg/dL
Note: If hypocalcaemia can be excluded based on calcium, corrected calcium, albumin, PTH, vitamin D3 values but ionized calcium is pending, the subject may be randomized, as per PI assessment and confirmation that exclusion criterion 7 has not been met. This needs to be recorded on source documents
8.Known vitamin D deficiency (25-hydroxy vitamin D level <20ng/mL[50nmol/L]) after supplementation at Screening
9.Known intolerance to Ca or vitamin D
10.Any current active infections, including localized infections, or any recent history(within 1 week prior to study drug administration) of active infections or a history of recurrent or chronic infections
11.Presence of known current infection with hepatitis B or presence of positive serology – ie, hepatitis B surface antigen(HBsAg) and/or hepatitis B core antibody(anti HBc)(hepatitis B core antigen test can be performed to conclude patient status), hepatitis C virus(HCV) antibody or human immunodeficiency virus(HIV) at Scr
Note: Any subject with positive anti-HBc at Scr should be reviewed and evaluated by the PI to exclude active infection. It is at the PI’s discretion whether to extend diagnostics to exclude current infection of hepatitis B. A local HBV quantitative DNA by PCR test may be performed within the Scr window visit
12.Hematology and chemistry lab. results outside the reference ranges, clinically significant, and, in the opinion of the PI or designee, could cause this study to be detrimental to the subject
13.Donation of more than 500mL of blood within the 8 weeks prior to study drug administration
14.Hypersensitivity to denosumab or its constituents
15.A recent history of major surgery including spine surgery due to disc herniation, spinal stenosis, or similar condition within 3months prior to randomization
16.History or presence of malignancy within 5years(with the exception of successfully treated basal cell carcinoma)
17.Inability to communicate or cooperate with the PI
18.A history or evidence of alcohol or drug abuse (including soft drugs like cannabis products)
19.Vaccination with a live vaccine with the exception of flu vaccine within the previous month. Coronavirus disease vaccination is not an exclusion criterion.
20.Any other condition which in the view of the PI is likely to interfere with the study or put the subject at risk
21.Current participation or history of participation in an investigational trial in the last 30 days or period less than 5-half-lives of the IMP under investigation - whichever is longer. For IMPs or drugs for which PD effect lasts longer than 5 half-lives, the wash-out period may be extended
22.A compromised immune system or treatment with immunosuppressants
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Percent change from Baseline in LS BMD at 12 months
Area under the percent change from Baseline in serum C-telopeptide of type 1 collagen up to 6 months (AUEC0 6months of %Cfb sCTX 1). Note: This endpoint will be considered as primary for EMA submission only; for all other agencies, this endpoint will be considered as secondary.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Efficacy endpoint
•Percent change from Baseline in LS BMD at 6 and 18 months
•Percent change from Baseline in hip and femoral neck BMD at 6, 12, and 18 months
•Incidence of new morphometric vertebral fractures at 12 and 18 months
Pharmacodynamic endpoints
•Percent change from Baseline in sCTX-1 at 3, 6, 9, 12, and 18 months
Safety endpoints
•Incidence, nature, and severity of adverse events including adverse drug reactions
•Frequency and severity of injection site reactions
•Frequency and severity of findings in routine safety parameters, including clinical laboratory assessments (hematology, clinical biochemistry, coagulation, urinalysis, and urine microscopy), vital signs, ECG, and physical examination
Immunogenicity endpoint
•Frequency and titer of anti-drug antibodies and frequency of neutralizing antibodies against AVT03 and Prolia at predose and Day 1, Day 2, Day 12, Day 30, Day 60, Day 90, Day 180, Day 270, Day 365 (Month 12), Day 365 (Month 12) +2 weeks, Month 15, and Month 18 (EoS) after treatment.
Pharmacokinetic endpoint
•Serum trough concentration of AVT03 and Prolia
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy endpoint - 6, 12 and 18 months.
Pharmakodynamic endpoint - 3, 6, 9, 12 and 18 months.
Immunogenicity endpoint - day 1, day 2, day 12, day 30, day 60, day 90, day 180, day 270, day 365, Day 365 (Month 12) +2 weeks, month 15, month 18. |
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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 |
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| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Georgia |
| South Africa |
| Bulgaria |
| Czechia |
| Poland |
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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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| 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 | 2 |
| 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 | 4 |
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