| 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 |
| The primary objective of this prospective controlled study is to evaluate the efficacy and the safety of abaloparatide-SC 80 μg per day compared to placebo in men with osteoporosis. |
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The subject is a healthy ambulatory male from 40 to 85 years of age (inclusive) with primary osteoporosis or osteoporosis associated with hypogonadism.
2. The subject has a bone mineral density (BMD) T-score (based on the male reference range as assessed by the central imaging vendor) of
a. ≤ –2.5 at the lumbar spine (L1–L4) or hip (femoral neck or total hip) by DXA or
b. <–1.5 and with radiologic evidence of vertebral fracture or a documented (radiograph films or report) history of low-trauma nonvertebral fracture sustained in the past 5 years.
c. Men older than 65 years may be enrolled if they have a BMD T-score ≤ –2.0 even if they do not meet the fracture criteria.
3. The subject is in good general health as determined by medical history and physical examination (including vital signs), has a body mass index (BMI) of 18.5 to 33, inclusive, and is without evidence of a clinically significant abnormality in the opinion of the Investigator, or none for which there is a reasonable chance of interfering with the subject’s health and/or medical treatment during the study. The subject has a body mass index (BMI) of 18.5 to 33, inclusive. The body mass index is derived from the subject's height and weight. In the case where a subject's height cannot be adequately assessed (e.g., due to vertebral compression fractures or scoliosis), the subject's historical height (as documented in the subject's medical record) will be used to derive the BMI.
4. Hypogonadal subjects whose doses of androgens have been stable for at least twelve months before randomization are eligible and may continue therapy during the study.
5. The subject has serum calcium (albumin-corrected), PTH, serum phosphorus and 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 must have a normal bone-specific alkaline phosphatase to be enrolled. Any subject with a TSH value outside of the normal range must have central laboratory reported T3 and free T4 values within the normal ranges to be enrolled.
6. The subject has serum 25-hydroxyvitamin D values ≥ 20 ng/mL and within 3 times the upper normal range. Subjects with serum 25-hydroxyvitamin D levels < 20 ng/ml may be treated with vitamin D and re-tested once during the Screening Period.
7. The subject’s systolic blood pressure is ≥ 100 and ≤ 155 mmHg, diastolic blood pressure is ≥ 40 and ≤ 95 mmHg, and heart rate is ≥ 45 and ≤ 100 bpm (taken sitting or supine). Any recorded values outside of these ranges and assessed by the Investigator to be not clinically significant must be reviewed with the Sponsor Medical Monitor for approval prior to enrollment.
8. The subject has no clinically significant abnormality of serum hemoglobin, hematocrit, WBC and platelets, or usual serum biochemistry: 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.
9. In subjects who have partners of childbearing potential, the subject and his partner should abstain from sexual intercourse, or use highly effective contraceptive measures (e.g. oral contraceptive and condom, intrauterine device (IUD) and condom, or diaphragm with spermicide and condoms; other forms of contraception must be approved by the medical monitor) when engaging in sexual intercourse throughout the study, and for at least 90 days after the last dose of abaloparatide.
10. The subject has read, understood, and signed the written informed consent form. |
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| E.4 | Principal exclusion criteria |
General exclusion criteria
1. Presence of abnormalities of the lumbar spine that would prohibit assessment of spinal bone mineral density, defined as having at least 2 radiologically evaluable vertebrae within L1–L4 as assessed by the central imaging vendor.
Anatomically abnormal vertebrae are excluded if:
o They are clearly abnormal and non-assessable within the resolution of the system
or;
o There is a more than 1.0 T-score difference between the vertebra in question and adjacent vertebrae.
2. A BMD T-score of ≤ –3.5 at the total hip, femoral neck, or lumbar spine based upon the male reference range.
3. Unevaluable hip BMD or subjects who have undergone bilateral hip replacement (unilateral hip replacement is acceptable).
4. Fragility fracture within the prior twelve months.
5. History of severe vertebral fracture or > 2 moderate vertebral fractures.
6. History of bone disorders (e.g., Paget’s disease) other than osteoporosis.
7. Subjects with clinical signs of hypogonadism present at screening who plan to initiate testosterone replacement.
8. History of prior external beam or implant radiation therapy involving the skeleton other than radioiodine.
9. History of chronic or recurrent renal, hepatic, pulmonary, allergic, cardiovascular, gastrointestinal, endocrine, central nervous system, hematologic or metabolic diseases, or immunologic, emotional and/or psychiatric disturbances to a degree that would interfere with the interpretation of study data or compromise the safety of the subject.
10. History of Cushing’s disease, growth hormone deficiency or excess, hyperthyroidism, hypo- or hyperparathyroidism or malabsorptive syndromes within the past year.
11. History of significantly impaired renal function (serum creatinine >177 μmol/L or >2.0 mg/dL. If the serum creatinine is > 1.5 and ≤ 2.0 mg/dL, the calculated creatinine clearance (Cockcroft-Gault) must be ≥ 37 mL/min.
12. History of any cancer within the past 5 years (other than basal cell or squamous cancer of the skin).
13. History of osteosarcoma at any time.
14. Subjects with hereditary disorders predisposing them to osteosarcoma.
15. History of nephrolithiasis or urolithiasis within the past five years.
16. Subjects known to be positive for Hepatitis B, Hepatitis C, HIV-1 or HIV-2. Testing is not required in the absence of clinical signs and symptoms suggestive of HIV infection or acute or chronic hepatitis.
Medication-related exclusion criteria:
17. Known history of hypersensitivity to any of the test materials or related compounds.
18. Prior treatment with PTH- or PTHrP-derived drugs, including abaloparatide or teriparatide, or PTH(1-84).
19. Prior treatment with IV bisphosphonates at any time or oral bisphosphonates within the past three years. Subjects who had 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.
20. Treatment with fluoride or strontium in the past five years or prior treatment with gallium nitrate, or other bone-acting investigational agents at any time. Limited use of gallium citrate/nitrate for diagnostic purposes (i.e., a gallium scan) is not exclusionary.
21. Prior treatment with calcitonin or tibolone in the past 6 months.
22. Prior treatment with denosumab in the past 18 months.
23. 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.
24. Treatment with anabolic steroids or calcineurin inhibitors (cyclosporin, tacrolimus) within past 90 days
25. Daily treatment with oral, intranasal or inhaled corticosteroids within the 12 months prior to the Screening Period. Occasional use of all corticosteroids (for seasonal allergies or asthma) is not exclusionary.
26. Exposure to an investigational drug within the 12 months prior to the Screening Period.
Life-style related exclusion criteria:
27. Abnormal nutritional status (as assessed by the investigator), Vitamin D intake of ≥4,000 IU/day or Vitamin A intake of ≥ 10,000 IU/day1. Short term use of high doses of Vitamin D to increase endogenous Vitamin D levels for study entry is not exclusionary.
28. Subject is known to consume > 2 alcoholic drinks per day to use illegal drugs , or to abuse tobacco or marijuana (medicinally or recreationally where legal) within 12 months of the Screening Period. The Investigator must determine and document use vs. abuse of tobacco or marijuana. |
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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 bone mineral density (BMD) at 12 months. |
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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) |
The key secondary efficacy endpoints are:
- Percent change from baseline in total hip BMD at 12 months
- Percent change from baseline in femoral neck BMD at 12 months
Additional secondary efficacy endpoints are:
- Percent change in baseline in:
Lumbar spine BMD at 3 and 6 months
Total hip BMD at 3 and 6 months
Femoral neck BMD at 3 and 6 months
Ultra-distal radius BMD at 3, 6 and 12 months
Distal one-third radius BMD at 3, 6 and 12 months
- Log ratio of post-baseline over baseline in
Serum procollagen type I N-terminal propeptide (s-PINP) at 1, 3, 6, and 12 months
Serum Carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX) at 1, 3, 6, and 12 months
- Proportion of subjects experiencing BMD gains from baseline of >0%, >3%, and >6% at the lumbar spine, femoral neck, and total hip at 3, 6, and 12 months;
- Incidence of new clinical fractures at 12 months;
- Proportion of subjects converting from the categories of osteoporosis to osteopenia or to normal at 12 months, where:
• Osteoporosis is defined as lumbar spine or total hip BMD T-score ≤ -2.5
• Osteopenia is defined as one of the following:
Lumbar spine > -2.5 and total hip BMD T-score > -2.5 and < -1.0
Lumbar spine > -2.5 and < -1.0 and total hip BMD T-score > -2.5
•Normal is defined as lumbar spine and total hip BMD T-score ≥ -1.0
• The percent change in total hip and femoral neck volumetric BMD as measured by quantitative CT (QCT) from baseline to 12 months QTC will be performed in a subset of subjects in a selected number of study sites.
For those subjects who consent to PK sample collection, the PK endpoints are:
• The plasma concentration of abaloparatide based on sparse PK
sampling at the following visits:
- Month 6: postdose PK samples collected 45 minutes (±15 minutes)
and 2.5 hours (±0.5 hour) after abaloparatide-SC injection
- Month 9: postdose PK samples collected 20 minutes (±10 minutes)
and 4 hours (±0.5 hour) after abaloparatide-SC injection
- Month 12: a predose sample and a postdose sample collected 1.5 hours (±0.5 hour) after abaloparatide-SC injection.
Safety endpoints
- Overall safety and tolerability of abaloparatide-SC in men with osteoporosis as assessed by adverse events (AEs), vital signs, ECGs, laboratory tests of chemistry and hematology, urinalysis, local tolerance, and presence of antibodies.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
12 months
For those subjects who consent to PK sample collection, the PK endpoints are 6, 9 and 12 months.
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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