| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Osteoporosis in postmenopausal women. |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10031285 |
| E.1.2 | Term | Osteoporosis postmenopausal |
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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 |
Determine the effects of six months of treatment with BA058 on:
- serum markers of bone formation and resorption;
- lumbar spine bone mineral density; and,
- hip and forearm bone mineral density, in otherwise healthy postmenopausal women with osteoporosis when compared with placebo.
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| E.2.2 | Secondary objectives of the trial |
| Determine the safety and tolerability of six months of dosing with BA058 in otherwise healthy postmenopausal women with osteoporosis. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The patient is a healthy ambulatory postmenopausal woman from 55 to 85 years of age (inclusive) with osteoporosis. Postmenopausal women younger than 55 years of age with known osteoporosis who meet all other entry criteria also may be considered for enrollment.
2. The patient has been postmenopausal for at least 5 years. Postmenopausal status will be established by a history of amenorrhea for at least 5 years and by an elevated serum follicle-stimulating hormone (FSH) value based on the postmenopausal range of the assay.
3. The patient has a bone mineral density T-score ≤ 2.5 at the lumbar spine or hip (femoral neck) by dual energy x-ray absorptiometry (DXA). Women with a bone mineral density T-score of 2.0 or lower and a prior low-trauma forearm, humerus, vertebral, sacral, pelvic, hip, femoral, or tibial fracture within the past 5 years, or who have an additional risk factor such as age 65 or greater or a strong maternal history of osteoporosis defined as a fracture related to osteoporosis or osteoporosis itself as determined by BMD criteria, are also study candidates.
4. The patient 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 clinically significant abnormality in the opinion of the Investigator (refer to Appendix 14.3).
5. Any required concomitant medications which are not excluded in Section 6.0 may be continued through the study. Every effort should be made to maintain the medication at a stable dose throughout the study, subject to the Investigator’s medical judgment.
6. The patient has serum total calcium, PTH(1-84), serum 25-hydroxy Vitamin D, serum phosphorus, and alkaline phosphatase values all within the normal range during the Screening Period.
7. The patient’s resting 12-lead electrocardiogram obtained during screening shows no clinically significant abnormality and a QTc ≤ 470 msec (Bazett’s correction).
8. The patient’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.
9. The patient has no clinically significant abnormality of serum hemoglobin, hematocrit, WBC and platelets, or usual serum biochemistry: electrolytes, renal function, liver function and serum proteins.
10. The patient has read, understood, and signed the written informed consent form.
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| E.4 | Principal exclusion criteria |
General exclusion criteria:
1. History of bone disorders (e.g., Paget’s disease) other than postmenopausal osteoporosis.
2. Unexplained elevation of serum alkaline phosphatase.
3. History of radiotherapy (radiation therapy).
4. 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 patient.
5. History of malabsorption or of significantly impaired renal function (serum creatinine >177 µmol/L or 1.5 mg/dL).
6. History of carcinoma, nephrolithiasis or urolithiasis within the past five years or osteosarcoma at any time.
7. Vitamin D deficiency, defined as a serum 25-hydroxy Vitamin D level of < 15 ng/mL. Patients with a normal serum 25-hydroxy Vitamin D level but less than 15 ng/mL may be considered for enrollment on a case by case basis.
8. 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 lying and 3 minutes standing) and/or any symptomatic hypotension (21,22).
9. Patients 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.
10. 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 L1-4.
11. Patients who have undergone bilateral hip replacement (unilateral hip replacement is acceptable).
12. Previously randomized and dosed in this study; patients cannot be entered into the study a second time.
Medication related exclusion criteria:
13. Known history of hypersensitivity to any of the test materials or related compounds.
14. Prior treatment with bisphosphonates or strontium in the past five years, or prior treatment with parathyroid hormone or its analogs, with fluoride, or with gallium nitrate, or with as yet unapproved bone-acting investigational agents such as denosumab at any time (23).
15. Prior treatment with calcitonin, estrogens, estrogen derivatives, SERMs (such as raloxifene or tamoxifen), tibolone, progestins or anabolic steroids in the past 6 months or current treatment with thiazide diuretics.
16. Daily treatment with oral, intranasal or inhaled corticosteroids within the 6 months prior to the Screening Period.
17. Exposure to general anesthesia within the 12 weeks prior to the Screening Period.
18. Exposure to an investigational drug within the 12 months prior to the Screening Period.
Lifestyle related exclusion criteria:
19. Abnormal nutritional status (abnormal diets, excessive or unusual vitamin or herbal intakes, malabsorption, significant recent weight change), Vitamin D intake of ≥ 1200 IU/day or Vitamin A intake of ≥ 10,000 IU/day.
20. Patient is known to abuse alcohol or use illegal drugs within 12 months of the Screening Period.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The pharmacodynamic endpoints to be assessed are:
• Change in serum levels of PINP over the course of treatment
• Change in BMD across 6 months of treatment
• Changes in serum PICP, bone specific alkaline phosphatase and osteocalcin across 6 months of treatment
Safety analyses will include the incidence and severity of adverse events by dose and cumulative dose and pathological changes in hematology, chemistry and urinalysis data. Changes in physical examination, vital signs, ECG and clinical laboratory tests will be descriptively summarized. Shift frequencies will be summarized for clinical laboratory tests.
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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 | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.2.3 | Other | No |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Information not present in EudraCT |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Information not present in EudraCT |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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 trail will be the last visit of the last patient undergoing treatment. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 4 |
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