|E.1 Medical condition or disease under investigation |
|E.1.1||Medical condition(s) being investigated || |
|E.1.1.1||Medical condition in easily understood language || |
|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 |
|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, 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.
|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 parameters between AVT03 and Prolia
|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 less than or equal to -2.5 and greater than or equal to -4.0 at the lumbar spine (LS) (L1 to L4), total hip, and/or femoral neck.
Note: If the left hip cannot be scanned (eg, due to left hip replacement, etc), right hip can be scanned instead. However, it is required to always scan the same hip.
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.
|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, hyperthyroidism, hypothyroidism, osteomalacia, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, current flare-up of osteoarthritis and/or gout, active malignancy, renal disease (defined as creatinine clearance <50 mL/min as calculated by Cockcroft-Gault formula), Paget's disease of the bone, recent bone fracture (within 6 months), and malabsorption syndrome. For causes of secondary osteoporosis, please see Appendix 14.2. |
2.History and/or presence of 1 severe or more than 1 moderate vertebral fractures confirmed by x-ray.
3.History of hip fracture.
4.Presence of active healing fractures.
5.Previous treatment with denosumab and previous use of the following medications:
a.Intravenous bisphosphonates, fluoride, or strontium ranelate within 5 years prior to Screening
b.Oral bisphosphonates used for >3 years cumulative use, and any dose within 12 months of Screening
c.Parathyroid hormone (PTH) or PTH derivatives, eg, teriparatide and selective estrogen receptor modulators eg, raloxifene within 1 year of Screening
d.Calcitonin within 6 months of Screening
e.Other bone metabolism drugs: administration of any of the following treatments within the last 3 months,
i.anabolic steroids or testosterone
ii.glucocorticoids (>5 mg/day prednisone or equivalent for >10 days)
iii.systemic hormone replacement therapy
vi.anticonvulsants (except benzodiazepines)
viii.systemic use of ketoconazole, androgens, adrenocorticotropic hormone (ACTH), cinacalcet or any cathepsin K inhibitor (eg, odanacatib), aluminium, lithium, protease inhibitors, methotrexate, gonadotropin releasing hormone agonists
6.Osteonecrosis of the jaw (ONJ) or risk factors for ONJ such as invasive dental procedures (eg, tooth extraction, dental implants, oral surgery in the past 6 months), periodontal, and/or pre-existing dental disease requiring therapy.
7.Evidence of hypo/hypercalcemia at Screening.
8.Known vitamin D deficiency (25-hydroxy vitamin D level <20 ng/mL [50 nmol/L]) after supplementation at Screening.
9.Known intolerance to calcium or vitamin D supplement.
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 and or core antigen, hepatitis C virus antibody or human immunodeficiency virus at Screening.
12.Haematology and chemistry laboratory results outside the reference ranges, which are clinically significant, and, in the opinion of the Investigator or designee, could cause this study to be detrimental to the subject.
13.Donation of more than 500 mL 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 3 months prior to randomization.
16.History or presence of malignancy within 5 years (with the exception of successfully treated basal cell carcinoma).
17.Inability to communicate or cooperate with the Investigator because of language difficulties or poor mental development or incapacitation.
18.A history (within the previous 3 years) 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 2019 vaccination is not considered an exclusion criterion.
20.Any other condition which in the view of the Investigator 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 5 half-lives - whichever is longer.
|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.
|E.5.1.1||Timepoint(s) of evaluation of this end point|| |
|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
•Percent change from Baseline in sCTX-1 at 3, 6, 9, 12, and 18 months
•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
•Frequency and titer of anti-drug antibodies and frequency of neutralizing antibodies against AVT03 and Prolia at predose and Day 30, Day 90, Day 180, Day 270, Day 365 (Month 12), Month 15, and Month 18 (EoS) after treatment.
•Serum trough concentration of AVT03 and Prolia
|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 30, day 90, day 180, day 270, day 365, month 15, month 18.
|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.22.214.171.124||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.126.96.36.199||Comparator description|| |
|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||3 |
|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|| |
|South Africa |
|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||4 |
|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 |