| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Postmenopausal women with osteoporosis at increased risk of falls. |
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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 |
In postmenopausal women with osteoporosis and at increased risk of falls:
1) To evaluate the proportion of patients with serum levels of 25(OH)D below 20 ng/mL after 26 weeks (primary objective of base study) and 52 weeks (one of the objectives of the extension study) of treatment with FOSAVANCE 5600 once weekly versus Referred-Care.
2) To assess the safety and tolerability of 26 weeks (primary objective of base study) and 52 weeks (one of the objectives of the extension study) of treatment with FOSAVANCE 5600.
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| E.2.2 | Secondary objectives of the trial |
In postmenopausal women with osteoporosis and at increased risk of falls:
To evaluate the effect of 26 weeks of treatment with FOSAVANCE 5600 once weekly versus Referred-Care, on percent change from baseline in serum and urine biochemical markers of bone turnover, including serum levels of BSAP and urine levels of NTx
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is a woman and is ≥ 65 years of age on the day of signing informed consent.
2. Patient meets one of the following BMD criteria:
a) Patient has BMD T-score ≤ -2.5 in at least one of the anatomic sites including lumbar spine, total hip, and femoral neck, OR
b) Patient has prior non-pathological fragility fracture (of hip, spine, wrist, humerus or clavicle) and BMD T-score ≤ -1.5 in at least one of the anatomic sites including lumbar spine, total hip, and femoral neck sites,
Note: Eligibility for this criterion is based on absolute BMD in g/cm2 as follows: Total hip T-scores of -1.5 and -2.5 correspond to 0.759 and 0.637 for Hologic machines; 0.820 and 0.694 for GE Lunar machines, and 0.736 and 0.614 for Norland machines. Femoral neck T-scores of -1.5 and -2.5 correspond to 0.678 and 0.558 for Hologic machines; 0.830 and 0.691 for GE Lunar machines, and 0.762 and 0.629 for Norland machines. Lumbar spine T-scores of -1.5 and -2.5 at L1 to L4 correspond to 0.882 and 0.772 for Hologic machines, 1.000 and 0.880 for GE Lunar machines, and 0.848 and 0.689 for Norland machines.
Note: A fragility fracture is defined as a fracture that occurred with minimal trauma that would be unlikely to cause fracture in a non-osteoporotic adult. This assessment is made by the study investigator.
3. Patient has been postmenopausal for at least one year. Postmenopause is defined as no menses for at least one year, OR 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL, OR at least 6 months after a surgical bilateral oophorectomy with or without hysterectomy.
4. Patient has increased risks of falls and meets all followings:
a) At least one or more falls within the past 12 months. The study investigators should determine the prior falls primarily based on patients' self-reporting or recall with or without medical records or documents.
b) Reduced lower extremity physical function. This is defined by having a summary score between 4 and 9 on SPPB at Screening (Visit 1).
c) Low level of serum 25(OH)D. Baseline level of 25(OH)D should be ≥ 8 ng/mL (20 nmol/L), but ≤ 20 ng/mL (50 nmol/L) at Screening (Visit 1).
5. Patient understands the study procedures, available alternative treatments and risks involved with the study, and voluntarily agrees to participate by signing a written informed consent.
6. Patient is mentally competent. This is defined by having a score ≥21 on the Folstein’s Min-mental State Examination (MMSE) at Screening (Visit 1), and in the opinion of the investigator, she is able to participate in all study required assessments and procedures.
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| E.4 | Principal exclusion criteria |
1. Patient has any contraindication to alendronate and vitamin D
2. Patient is not ambulatory. Patient needs assistance for walking and standing-up.
3. Patient has abnormal finding or test result in any of physical examination, 12-lead electrocardiogram (ECG) and routine clinical laboratory safety screening tests performed at Screening/Baseline (Visit 1).
4. Patient has received treatment with any agent listed below, including:
a) any anabolic steroid agent within the past 12 months
b) systemic glucocorticoids (> 5 mg/day of prednisone or equivalent) for more than 2 weeks in the past 6 months. The exception is over-the-counter topical preparations and inhaled glucocorticoid for the short term treatment of asthma
c) oral bisphosphonates (including alendronate, risedronate, etidronate, ibandronate or tiludronate) more than 3 months within the past 2 years; and any lifetime use of an intravenous administration (IV) of zoledronate. The exception is one dose of IV pamidronate or IV ibandronate in more than one year prior to Screening
d) immunosuppressant (e.g. cyclosporin, azathioprine). The exception is methotrexate for the treatment of rheumatoid arthritis
e) fluoride treatment at a dose greater than 1 mg/day for more than 2 weeks within the past 3 months
f) strontium-containing products (more than 200 mg elemental strontium daily, including over-the-counter preparations such as OSTEOVALIN™) for more than 2 weeks within the past 6 months
g) Parathyroid hormone [PTH (1-34 or 1-84)] for more than 2 weeks within the past 3 months
h) current use of chemotherapy, or heparin
i) growth hormone for more than 2 weeks within the past 6 months
j) active hormonal vitamin D analogs (e.g., alphacalcidol, calcitriol) in the past 2 months
k) current use of vitamin A (excluding beta carotene) >10,000 IU daily, unless willing to discontinue this dose during the study
l) current use of, lithium, or anti-convulsants including barbiturates, hydantoins, and carbamazepine
m) current use of calcium supplement in amount excess of 1,500 mg daily, unless willing to discontinue this dose during the study
5. Patient has a history of malignancy <5 years prior to signing informed consent.
6. Patient has one or more of the following concomitant conditions:
a) upper gastrointestinal (GI) disorders not adequately controlled
b) myocardial infarction, unstable angina, stroke and revascularization condition within 3 months
c) malabsorption syndrome
d) primary or secondary hyperparathyroidism not adequately controlled
e) thyroid disease not adequately controlled
f) renal insufficiency not adequately controlled. This is defined as serum-creatinine >1.6 mg/dL and calculated* creatinine clearance ≤ 30 mL/min (Cockroft and Gault method)
g) uncontrolled genitourinary, cardiovascular, hepatic, renal, endocrine, hematologic, neurological, psychiatric, or pulmonary diseases; unexplained laboratory test abnormality or other conditions that, in the opinion of the investigator, may suggest a high risk to the patient, impair the patient’s ability to complete the trial or confound study results
h) uncontrolled hypertension
i) new onset diabetes (within 3 months), poorly controlled hyperglycemia (e.g. Hb A1c >8.5%), hypoglycemia for any cause (e.g. blood glucose < 50 mg/dL)
j) history of, or evidence for metabolic bone disease other than osteoporosis (e.g. Paget’s disease or osteomalacia)
k) abnormal indices of calcium metabolism
l) active renal stone disease when a calcium supplement is contraindicated
m) mentally or legally incapacitated, or has significant emotional problems or has a significant history of psychiatric disorders at the time of Screening (Visit 1)
n) currently participating in or has participated in a study with an investigational compound or device within 30 days prior to signing informed consent (Visit 1)
7. Patient is a user of recreational or illicit drugs or has had a recent history (within the last year) of drug or alcohol abuse or dependence at the time of signing informed consent (Visit 1).
8. Patient heavily consumes alcohol or alcohol containing products. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be the proportion of patients with serum 25(OH)D below 20 ng/ml at week 26. The comparison will be assessed using a logistic regression model with terms for treatment, baseline covariates such as baseline 25(OH)D level stratum (≤ 15 ng/mL vs. > 15 ng/mL), age (a categorical variable ≤ 75 vs. > 75), and region (North America, Europe, Asia, or rest of the world (ROW)). Odds ratio and 95% confidence interval for the between-group comparison of FOSAVANCE 5600 to referred care will be obtained from the logistic model. No missing data will be estimated as every effort will be made to follow patients for the collection of the primary endpoint. |
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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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | 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 | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Referred-care arm will take whatever osteoporosis treatment their PCP will deem necessary. |
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| 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 | 40 |
| 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 | Information not present in EudraCT |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | 34 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 34 |
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