| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | Postmenopausal osteoporosis
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| E.1.1.1 | Medical condition in easily understood language | Osteoporosis in women after menopause
| |
| E.1.1.2 | Therapeutic area | Body processes [G] - Bones and nerves physological processes [G11] |
| 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 | - All regions: To demonstrate equivalent efficacy between LY06006 and EU-Prolia, in terms of BMD in female participants with postmenopausal osteoporosis.
- EU filing only: To demonstrate similar PD between LY06006 and EU-Prolia, in terms of the bone resorption marker sCTX in female participants with postmenopausal osteoporosis
| |
| E.2.2 | Secondary objectives of the trial | - To provide additional comparative efficacy data of LY06006 with EU-Prolia in female participants with postmenopausal osteoporosis
- To provide additional comparative PD data on LY06006 with EU-Prolia in female participants with postmenopausal osteoporosis
- To evaluate the safety of LY06006 compared to EU-Prolia in female participants with postmenopausal osteoporosis
- To evaluate the PK profile of LY06006 compared to EU-Prolia in female participants with postmenopausal osteoporosis
- To evaluate the immunogenicity of LY06006 compared to EU-Prolia in female participants with postmenopausal osteoporosis
| |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | Participants are eligible to be included in the study only if all of the following criteria are met:
1. Participant is ≥ 55 to ≤ 90 years of age inclusive (upper age limit of 75 years inclusive, for participants in Czech Republic only), at the time of signing the informed consent.
2. Participant is an ambulatory postmenopausal woman (defined as lack of menstrual period for at least 12 months prior to Screening Visit, for which there is no other obvious pathological or physiological cause).
- Serum FSH test can be done at the Screening Visit in case of uncertainty
- Female participants who underwent bilateral oophorectomy (with or without hysterectomy) at least 6 weeks prior to the Screening Period are eligible to participate.
3. Participant is diagnosed with osteoporosis, with absolute BMD consistent with a T-score of ≤ -2.5 and ≥ -4.0 at the lumbar spine (L1-L4 region) as measured by DXA at the Screening Visit.
4. Participant has at least two lumbar vertebrae in L1-L4 region and one hip evaluable by DXA for BMD measurement at the Screening Visit.
5. Participant has body weight ≥ 50 kg and ≤ 90 kg at Screening.
6. Participant is able to read and understand, and willing to provide signed informed consent as described in Appendix 1, Section 10.1.3 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
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| E.4 | Principal exclusion criteria | Participants are excluded from the study if any of the following criteria are met:
1. Participant has a history of any severe or more than two moderate vertebral fractures as determined by central reading of lateral spine X-ray at Screening Visit.
2. Participant has a history and/or presence of hip fracture.
3. Participant has a history and/or presence of atypical femur fracture.
4. Participant presents with any active healing fracture, per assessment of the Investigator.
5. Participant has a history of bilateral hip replacement (unilateral is allowed if the other hip is evaluable by DXA).
6. Participant has history and/or presence of osteonecrosis of the external auditory canal.
7. Evidence of any of the following conditions which may affect BMD or interfere with the interpretation of the findings:
a. Participant has a history of bone disease e.g., osteomalacia, osteopetrosis, Paget’s disease, or osteogenesis imperfecta.
b. Participant has a history of metabolic or other endocrinologic diseases such as Cushing’s disease, hyperprolactinemia, hypopituitarism, acromegaly, malabsorption syndrome (or any gastrointestinal disorders associated with malabsorption, e.g., Crohn’s disease and chronic pancreatitis).
c. Participant has a history of chronic inflammatory diseases, obvious sclerosis, osteophytosis, severe scoliosis, or other degenerative changes due to other co-morbidities.
d. Participant has a history or current hyperparathyroidism or hypoparathyroidism. Note: Mild non-clinically significant secondary hyperparathyroidism may be acceptable upon discussion with the Medical Monitor.
e. Participant has current uncontrolled hyperthyroidism or hypothyroidism. Note: Participants with hypothyroidism who are on stable thyroid hormone replacement therapy may be allowed per the following criteria:
• If TSH level is within normal range, the participant is eligible.
• If TSH level is elevated (> upper limit of normal and ≤ 10.0 µIU/mL) and serum free T4 is within normal range, the participant is eligible.
If a marginally low TSH level results from the therapy, the participant may be enrolled after discussion with the Medical Monitor. Note: 2) If TSH is marginally out of normal range, serum free T4 is within normal range, and there are no plausible medical conditions resulting in abnormal TSH level, the participant may be enrolled with the
approval from the Medical Monitor.
f. Participant has other disease conditions where there is bone/joint involvement (e.g., rheumatoid arthritis, ankylosing spondylitis, gout, multiple myeloma, achondroplasia, bone metastases, renal osteodystrophy, osteomyelitis).
8. Participant has hypocalcemia (defined as albumin adjusted serum calcium level < 2.0 mmol/L [8.0 mg/dL] or hypercalcemia (defined as albumin adjusted serum calcium levels > 2.62 mmol/L [10.50 mg/dL]).
9. Participant has vitamin D deficiency (defined as 25-hydroxy vitamin D level < 20 ng/mL
[< 50 nmol/L]).
Note: Oral replenishment of vitamin D is permitted at the discretion of the Investigator and in accordance with local standard of care during the Screening Period. Participants can be enrolled if a repeat test (post supplementation) prior to enrollment shows corrected 25-hydroxy vitamin D level ≥ 20 ng/mL (≥ 50 nmol/L).
10. Participant has any malignancy (except fully resected cutaneous basal cell or squamous cell carcinoma, cervical or breast ductal carcinoma in situ) within the last 5 years.
11. Participant has known history of liver cirrhosis.
12. Participant has known history of hepatitis B, hepatitis C, or HIV infection, or an active infection including, but not limited to SARS-CoV-2, tests positive for hepatitis B (positive HBsAg, positive anti-HBc with negative anti-HBs), hepatitis C (hepatitis C antibody), or HIV antibody during the Screening Period.
13. Participant has oral or dental conditions:
a. Prior history or current evidence of osteomyelitis or osteonecrosis of the jaw.
b. Active dental or jaw condition which requires oral surgery.
c. Invasive dental procedure planned during the study or within the past 6 months (e.g., tooth extraction, dental implants, oral surgery).
d. Non-healed dental or oral surgery.
e. Active periodontal disease.
f. Poor oral hygiene.
14. Participant has a history of major surgery within 8 weeks prior to the Screening Period or planned, anticipated major surgery during the study.
15. Participant has a history and/or presence of significant cardiac disease or ECG abnormalities indicating significant risk for participating in the study as judged by the Investigator.
16. Participant shows contraindications to denosumab therapy (e.g., hypocalcemia), or calcium or vitamin D supplementation before starting study intervention administration.
17. Participant requires ongoing use of any osteoporosis treatment (other than calcium and vitamin D supplements).
Further exclusion criteria are listed in the study protocol.
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| E.5 End points |
| E.5.1 | Primary end point(s) | Primary endpoint:
- %CfB in lumbar spine BMD at Month 12
- Co-primary endpoint for the EU filing only: standardized AUEC0-6m (post first dose) of -%CfB in bone resorption marker sCTX over 6 months
| |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | • %CfB in lumbar spine BMD at Month 6
• %CfB in total hip BMD at Months 6 and 12
• %CfB in femoral neck BMD at Months 6 and 12
• %CfB in sCTX at Months 0.5, 1, 2, 3, 6, and 12
• %CfB in sP1NP at Months 1, 6, and 12.
• AEs, including SAEs
• Vital signs
• Physical and dental examination
• Clinical laboratory tests (hematology, clinical chemistry, and urinalysis)
• 12-lead ECG
• Injection site reaction assessment
• Serum drug concentrations at baseline and at Months 0.5, 1, 2, 3, 6, 9, and 12
• Incidence of ADAs at baseline and at Months 0.5, 1, 2, 3, 6, 9, and 12
• Incidence of NAbs at baseline and at Months 0.5, 1, 2, 3, 6, 9, and 12
• Serum drug concentrations, incidence of ADAs, incidence of NAbs at baseline (Month 12) and Months 15 and 18 | |
| 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 | 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 | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 | | Japan | | United States | | Bulgaria | | Czechia | | Poland | |
| 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 | The end of the clinical trial is defined as the date of the last visit (Vis.11/Month18 or early termination) of the last participant in the study globally or last scheduled procedure shown in the SoA(Prot.Table 1-1) for the last participant in the study globally.
The EoS of a participant is considered to have completed the study if she has completed all periods of the study including the last visit (Vis.11/Month18 or early termination) or the last scheduled procedure shown in the SoA(Table 1-1) | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 27 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 8 |
