| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Osteoporosis in postmenopausal women |
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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 | 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 evaluate the non-inferiority of abaloparatide-sMTS 300 μg compared to abaloparatide-SC 80 μg based on lumbar spine BMD at 12 months.
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| E.2.2 | Secondary objectives of the trial |
Percent change from baseline in total hip BMD at 12 months
Percent change from baseline in femoral neck BMD at 12 months
Determine safety and tolerability of 12 months of dosing with abaloparatide-sMTS |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Healthy ambulatory female from 50 to 85 years of age (inclusive) with postmenopausal osteoporosis
2. Postmenopausal for at least 5 years as demonstrated by a history of amenorrhea for at least 5 years
3. BMD T-score based on the female reference range as assessed by the central imaging vendor of:
a. Less than or equal to -2.5 and greater than -5.0 at the lumbar spine (L1–L4) or hip (femoral neck or total hip) by dual energy X-ray absorptiometry (DXA) and: i) Radiological evidence of 2 or more mild or 1 or more moderate lumbar or thoracic vertebral fractures, or ii) History of fragility fracture to the forearm, humerus, sacrum, pelvis, hip, femur, or tibia within the past 5 years.
b. Postmenopausal women older than 65 years who meet the fracture criteria (i or ii) but have a T-score of ≤ -2.0 and > -5.0 may be enrolled
c. Postmenopausal women older than 65 years who do NOT meet the fracture criteria may be enrolled if they have a BMD T-score ≤ -3.0 and >-5 at the lumbar spine (L1-L4) or hip (femoral neck or total hip) by DXA
4. In good general health as determined by medical history and physical examination (including vital signs), has a body mass index of 18.5 to 33 kg/m2, inclusive, and is without evidence of clinically significant abnormality in the opinion of the Investigator.
5. Serum calcium (albumin-corrected), PTH (1-84), serum phosphorus, alkaline phosphatase, and thyroid stimulating hormone (TSH) values all within the normal range during the Screening Period. Any subject with an elevated alkaline phosphatase value and who meets all other entry criteria would be required to have a normal bone-specific alkaline phosphatase in order to be enrolled. Any subject with a TSH value outside of the normal range may be enrolled if their T3 and free T4 values are within the normal range
6. Serum 25-hydroxyvitamin D values must be ≥ 20 ng/mL
7. Resting 12-lead ECG at Screening shows no clinically significant abnormality
8. Systolic blood pressure is ≥ 100 and ≤ 155 mmHg, diastolic blood pressure is ≥ 40 and ≤ 95 mmHg, and pulse rate is ≥ 45 and ≤ 100 beats per minute (taken sitting or supine)
9. Has no clinically significant abnormality of serum hemoglobin, hematocrit, white blood cells, and platelets, or usual serum biochemistry, including electrolytes, renal function, liver function and serum proteins, that might be expected to interfere with the subject’s health and/or medical treatment during the study.
10. Read, understood, and signed the written Informed Consent Form (ICF)
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| E.4 | Principal exclusion criteria |
1. History of more than 4 spine fractures, mild or moderate, or any severe fractures based on Genant Semi-quantitative Scoring method on radiographic findings
2. Presence of abnormalities of the lumbar spine that would prohibit assessment of spinal BMD, defined as having at least 2 radiologically-evaluable vertebrae within L1–L4 as assessed by the central imaging review of the DXA images
Anatomically abnormal vertebrae are excluded if:
- They are clearly abnormal and non-assessable within the resolution of the system; or
- There is a more than 1.0 T-score difference between the vertebra in question and adjacent vertebrae
3. Unevaluable hip BMD or subjects who have undergone bilateral hip replacement (unilateral hip replacement is acceptable)
4. History of bone disorders (eg, Paget’s disease) other than postmenopausal osteoporosis
5. History of prior external beam or implant radiation therapy involving the skeleton, other than radioiodine
6. History of Cushing’s disease, hyperthyroidism, hypo- or hyperparathyroidism, or malabsorptive syndromes within the past year
7. History of significantly impaired renal function (serum creatinine > 177 μmol/L or > 2.0 mg/dL). If serum creatinine is > 1.5 and ≤ 2.0 mg/dL, the calculated creatinine clearance (Cockcroft-Gault) must be ≥ 37 mL/minute
8. History of any cancer within the past 5 years (other than basal cell or squamous cancer of the skin)
9. History of osteosarcoma at any time
10. Hereditary disorders predisposing to osteosarcoma
11. History of nephrolithiasis or urolithiasis within the past 5 years
12. Decrease of 20 mmHg or more in systolic blood pressure or 10 mmHg or more in diastolic blood pressure from supine to standing (5 minutes laying and 3 minutes standing) or any symptomatic hypotension at Screening
13. Application site is compromised by scars, inflammation, or skin conditions that may compromise uniformity of patch application or drug delivery (nevi, plaques, tattoos, scars, piercing, etc)
14. Any other medical condition, that, in the opinion of the Investigator, renders the subject unable or unlikely to complete the study, would interfere with the interpretation of study data, or produce significant risk to the subject
15. Known history of hypersensitivity to any of the test materials or related compounds
16. Prior treatment with PTH- or PTHrP-derived drugs or bone anabolic drugs including abaloparatide, teriparatide, or PTH (1-84)
17. Prior treatment with intravenous bisphosphonates at any time or oral bisphosphonates within the past 3 years. Subjects who have received a short course of oral bisphosphonate therapy (3 months or less) may be enrolled as long as the treatment occurred 6 or more months prior to enrollment
18. Prior treatment with selective estrogen receptor modulators (such as raloxifene or tamoxifen) in the past 6 months. Estrogens administered as hormone replacement therapy, with or without progestins, are not exclusionary
19. Treatment with fluoride or strontium in the past 5 years or prior treatment with gallium nitrate or bone-acting investigational agents at any time
20. Prior treatment with calcitonin or tibolone in the past 6 months
21. Treatment with denosumab within the past 18 months
22. Treatment with anticonvulsants that affect vitamin D metabolism (phenobarbital, phenytoin, carbamazepine, or primidone) or with chronic heparin within the 6 months prior to the Screening Period
23. Treated with anabolic steroids or calcineurin inhibitors (cyclosporin, tacrolimus) in the past 90 days
24. Daily treatment with corticosteroids within the 12 months prior to the Screening Period. Occasional use of low dose corticosteroids (for seasonal allergies or asthma) is not exclusionary. Use of low dose oral corticosteroids (eg, ≤ 5 mg/day of prednisone or the relative equivalent dose of another corticosteroid) is also not exclusionary
25. Participation in another clinical trial with any investigational drug or device within 90 days or 5 half-lives of the investigational drug (if known), whichever is longer, of study drug administration
26. Abnormal nutritional status as assessed by the Investigator, vitamin D intake of
≥ 4,000 IU/day, or vitamin A intake of ≥ 10,000 IU/day. Short-term use of high doses of vitamin D to bolster endogenous vitamin D levels for study entry during the Screening Period is not exclusionary
27. Subject is known to have used illegal drugs or abused alcohol, tobacco, or marijuana within 12 months of the Screening Period. Medicinal or recreational use of marijuana, where legal, is permitted. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the percent change from baseline in lumbar spine BMD.
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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) |
- Percent change from baseline in total hip BMD
- Percent change from baseline in femoral neck BMD
- Treatment-emergent AEs (TEAEs), AEs of special interest (AESI), vital signs (orthostatic blood pressure, pulse rate, body temperature, and respiration rate), electrocardiograms (ECGs), laboratory tests (chemistry, hematology, coagulation, and urinalysis), local tolerance, and presence of anti-drug antibodies (ADAs) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Belgium |
| Bulgaria |
| Denmark |
| Hungary |
| Poland |
| Czechia |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 7 |
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