| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Postmenopausal Osteoporosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Postmenopausal Bone thinning |
|
| 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 |
The primary objective of the study is to demonstrate that there are no clinically meaningful differences in efficacy between TVB-009P and PROLIA US administered
subcutaneously in patients with postmenopausal osteoporosis. |
|
| E.2.2 | Secondary objectives of the trial |
A secondary objective is to compare:
- further efficacy and pharmacodynamic parameters between TVB-009P and PROLIA US.
- efficacy and pharmacodynamic parameters between TVB-009P and PROLIA US after a single transition from PROLIA US to TVB-009P.
- the safety and tolerability, including device-related events, between TVB-009P and PROLIA US throughout the study.
- the safety and tolerability between TVB-009P and PROLIA US after a single transition from PROLIA US to TVB-009P, including device-related events.
A secondary objective of this study is to assess the immunogenicity of TVB-009P:
- in comparison with PROLIA US throughout the study.
- in comparison with PROLIA US after a single transition from PROLIA US to TVB-009P.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients may be included in this study only if they meet all of the following criteria:
a. The patient provides a signed and dated written informed consent.
b. The patient is a clinically stable, ambulatory, female postmenopausal adult (≥60 and ≤90 years) with a diagnosis of osteoporosis.
c. The patient is of postmenopausal status, defined as: Spontaneous amenorrhea for >12 months, or Spontaneous amenorrhea >6 months and serum follicle stimulating hormone
(FSH) and estradiol (E2) in menopausal range, or
Surgical menopause at least 6 weeks before the start of screening.
d. The patient has a body weight ≥50 kg and ≤90 kg (≥110 lb and ≤198 lb) at screening.
e. The patient agrees to be supplemented with 1000 mg calcium and at least 400 IU vitamin D daily from screening until the last visit.
f. The patient has a BMD-measurement T-score of less than -2.5 but not less than -4.0 by dual energy X-ray absorptiometry (DXA) at the lumbar spine at screening based on central reader assessment.
g. The patient has at least three (3) vertebrae in the L1-L4 region that are evaluable by DXA.
h. The patient has serum 25 (OH) vitamin D level >20 ng/mL at screening and no current hyper- or hypocalcemia, defined as albumin-adjusted serum calcium outside the normal range, as assessed by the central laboratory. Vitamin D and calcium supplements will be provided and patients may be rescreened once to re-evaluate calcium and/or vitamin D level post repletion.
i. The patient must be willing and able to comply with study restrictions and to remain
at the investigational center for the required duration during the study period, and willing to return to the investigational center for further visits, as applicable, and the follow-up procedures and assessments as specified in this protocol. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from participating in this study if they meet any of the following
criteria:
a. The patient has a known malabsorption of calcium or vitamin D supplements.
b. The patient has a metabolic or bone disease (except osteoporosis) such as Paget’s disease, Cushing’s disease, rheumatoid arthritis, sclerosteosis, osteomalacia, osteogenesis imperfecta, osteopetrosis, ankylosing spondylitis, hyperprolactinemia, malabsorption syndrome, osteomyelitis, multiple myeloma or related lymphoproliferative disorder, or bone metastases.
c. The patient has a current, uncontrolled hyperthyroidism or hypothyroidism, per
patient report or chart review.
d. The patient has hypoparathyroidism or hyperparathyroidism (irrespective of current
controlled or uncontrolled status).
e. The patient has a history and/or presence of risk factors of osteonecrosis of the jaw, as
determined by the principal investigator, (eg, unhealed open soft tissue lesions in the mouth, poor oral hygiene, periodontal disease, poorly fitting dentures, history of dental disease, recent or planned invasive dental procedures such as tooth extractions within the next 18 months), presence of anemia or coagulopathy at screening, and/or inability to maintain oral hygiene during the study.
f. The patient has a history and/or presence of 1 severe or more than 2 moderate vertebral fractures (as determined by central reading of lateral spine X-ray during the screening period).
g. The patient has a history and/or presence of hip fracture or atypical femur fracture.
h. The patient has participated in another study of an IMP (or a medical device) within
the previous 30 days or 5 half-lives of the IMP (whichever is longer) or longer if required by local regulations, or is currently participating in another study of an IMP (or a medical device).
i. The patient has a known hypersensitivity to any components of the IMPs stated in this
protocol or to calcium or vitamin D.
j. The patient has a renal impairment manifested with an estimated glomerular filtration rate (eGFR) <45 mL/min.
k. The patient has cardiac disease as per investigator's discretion, including electrocardiogram (ECG) abnormalities at screening indicating significant risk of safety for patients participating in the study.
l. The patient has a malignancy or past malignancy (except for local non-melanoma
skin cancer fully resected).
m. The patient has a current skin infection(s).
n. The patient has infectious disease:
- Acute infection and/or antibiotic treatment must be resolved 28 days prior to the first dose of IMP.
- Any relevant chronic infection. Ongoing hepatitis B, hepatitis C, human immunodeficiency virus (HIV) Types 1 or 2 infection.
- Positive test for coronavirus disease 2019 (COVID-19) during screening or patient reporting a recent history of confirmed COVID-19 which had not fully recovered more than 14 days before screening.
o. The patient has any medical condition that (treated or untreated), in the opinion of the
investigator, could jeopardize or would compromise the patient’s safety or ability to
participate in this study.
p. The patient has had any prior treatment with denosumab (PROLIA or XGEVA or biosimilars of denosumab products).
q. The patient has used intravenous bisphosphonates within less than 5 years prior to screening.
r. The patient has used oral bisphosphonates within the 12 months prior to start of screening and/or cumulative use >3 years before the start of screening.
s. The patient has ongoing use of any osteoporosis treatment (other than calcium and vitamin D supplements). The following rules for prior use of osteoporosis treatments
have to be adhered to:
- Drugs being investigated for osteoporosis, eg romosozumab: dose received at any time.
- Strontium or fluoride (for osteoporosis): dose received at any time.
- Teriparatide or any parathyroid hormone (PTH) analogs: dose received within 12 months before the start of screening.
- Calcitonin: dose received within 6 months before the start of screening.
- Cinacalcet: dose received within 3 months before the start of screening.
t. The patient has ongoing use of any bone active drugs which can affect BMD including:
- Heparin (except topical), anti-convulsives (with the exception of benzodiazepines), systemic ketoconazole, adrenocorticotropic hormone, lithium, gonadotropin releasing hormone agonists, or anabolic steroids; dose received within 3 months before the start of screening.
- Systemic glucocorticosteroids: total cumulative dose of ≥50 mg within 3 months
prior to randomization.
- Systemic oral or transdermal estrogen, or selective estrogen receptor modulators:
more than 1 month of cumulative use within 6 months prior to randomization.
v. The patient has a history of chronic alcohol or drug abuse within the previous 6 months.
w. The patient is vulnerable (eg, people kept in detention). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is:
- the percent change from baseline in lumbar spine-bone mineral density (LS-BMD) at week 52 based on centrally assessed dual-energy X-ray absorptiometry (DXA) measurements
- The co-primary efficacy endpoint for the European Union (EU) submission is the percent change from baseline in serum C-telopeptide cross-link of type 1 collagen (sCTX-1) at week 26. For the EU submission, this endpoint is regarded as co-primary. For the United States (US) submission, this endpoint is regarded as secondary |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy and pharmacodynamic endpoints are:
- percent change from baseline in LS-BMD at week 26 based on centrally assessed DXA measurements
- percent change from baseline in femoral neck bone mineral density (BMD) by DXA at week 26 and at week 52
- percent change from baseline in total hip BMD by DXA at week 26 and at week 52
- percent change from baseline in sCTX-1 at all time points
- sCTX-1 suppression at week 4
- percent change from baseline in procollagen type 1 N propeptide (P1NP) at week 26 and week 52
- incidence of fractures up to week 52
The pharmacodynamic/efficacy endpoints in the transition period are:
- percent change from week 52 in LS-BMD by DXA at week 78
- difference between percent change from baseline in sCTX-1 between week 52 and week 78
- percent change from week 52 in femoral neck BMD by DXA at week 78
- percent change from week 52 in total hip BMD by DXA at week 78
- difference between percent change from baseline in P1NP between week 52 and week 78
- incidence of fractures up to week 78
The safety and tolerability endpoints are:
- adverse events (and the number of patients who withdraw from the study due to adverse events)
- vital signs
- laboratory tests (hematology, serum chemistry, and urinalysis)
- electrocardiogram (ECG)
- local tolerability at injection site
- use of concomitant medications
- device-related adverse events and malfunctions
The immunogenicity endpoint is:
- incidence of patients with confirmed positive anti-drug antibody (ADA) sample
For confirmed positive samples, the ADA titer and the neutralizing potential will be tested.
The effect of positive immunogenicity findings on pharmacokinetics, efficacy, and safety will be assessed if applicable. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 | 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| 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 |
| United States |
| Poland |
| Bulgaria |
| Czechia |
| Germany |
| Georgia |
| Hungary |
| Russian Federation |
| Slovakia |
| Ukraine |
|
| 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
|
|
| 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 | 3 |
| 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 | 5 |
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