E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of osteoporosis in men |
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MedDRA Classification |
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 is to demonstrate the superiority of treatment with zoledronic acid relative to placebo in reducing the incidence of vertebral fractures in men with osteoporosis. The incidence of new morphometric vertebral fractures will be evaluated based on the proportion of new morphometric vertebral fractures over 24 months. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives include the evaluation of the following parameters: • Time to first clinical vertebral fracture • Proportion of patients with at least one new vertebral fracture over 12 months. • Proportion of patients with at least one new moderate or severe morphometric vertebral fracture over 12 and 24 months • The change in height at Month 12 and Month 24. • The percent change of BMD at lumbar spine and total hip at Month 6, Month 12 and Month 24 relative to baseline as measured by DXA in a sub-set of at least 100 evaluable patients at selected sites. • The changes in biochemical markers of bone resorption and bone formation at all post-baseline time points relative to baseline in a sub-set of at least 100 evaluable patients at selected sites. • Time to first clinical fracture • Time to first non-vertebral fracture • The overall safety of zoledronic acid compared to placebo in osteoporotic men.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Male patients between 50 and 85 years of age, inclusive • At least three readable L1-L4 vertebra, confirmed by the centralized expert readers prior to randomization: only applicable for patients qualifying via BMD at the lumbar spine and/or belonging to the subset of at least 100 patients at the selected sites. For details regarding the imaging assessments of the subset of patients at the selected sites, please se Section 7.4.3 • Bone mineral density T-score of less than or equal to -2.5 SD at the total hip or femoral neck OR less than or equal to -2.5 SD at the lumbar spine as confirmed by the central expert reader. OR • Bone mineral density T-score of less than or equal to -1.5 SD at the total hip or femoral neck as confirmed by the central expert reader, AND at least 1 up to a maximum of 3 prevalent vertebral fractures of mild or moderate grade as defined by the modified Genant method for males and confirmed by the central expert reader. As per Amendment 2, this inclusion criterion is not applicable in Finland.
Important: The BMD T-score must be confirmed by the central expert reader prior to randomization. Additionally, vertebral x-rays (lateral thoracic and lumbar views) will be performed and must be submitted to the central imaging laboratory for confirmation of prevalent vertebral fractures prior to randomization.
Please note: Patients with more than 3 mild to moderate vertebral fracture or any severe vertebral fracture, or patients with acute painful osteoporotic fractures requiring treatment with any of the prohibited medications can not be included in the trial. In Denmark, patients with a BMD T-score below -3 cannot be included if they have any moderate vertebral fractures OR if they have more than 1 moderate vertebral fracture despite the T-score level. |
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E.4 | Principal exclusion criteria |
• Patients with 25-(OH) Vitamin D levels < 15 ng/mL at Visit 1. If the vitamin D level is < 15 ng/ml the patient should receive a loading dose of 75,000-100,000 IU of vitamin D IM or orally once at visit 1 and have the vitamin D test repeated at visit 1A. This repeat test for vitamin D should be done after at least 3 weeks have passed since the loading dose was given. • Baseline renal insufficiency (calculated creatinine clearance < 30.0 mL/min) at Visit 1 and/or Visit 1A or urine dipstick greater than or equal to 2+ protein without evidence of contamination or bacteriuria (may be repeated one time at least a week apart if there is suspicion of contamination). Patients with calculated creatinine clearance equal to or greater than 30.0 mL/min and < 60.0 mL/min or serum creatinine greater than the upper limit of normal at Visit 1 must be verified at a second visit (Visit 1A). The average creatinine clearance of the two tests must be equal to or > 30.0 mL/min and the result of the creatinine retest must be below the upper limit of normal. (Patients with calculated creatinine clearance > 60.0 mL/min and serum creatinine equal to or less than 2.0 mg/dL do not require re-test) In the UK patients with a urine dipstick result greater than trace protein without evidence of contamination or bacteriuria cannot be included. • Patients who require re-test of creatinine clearance at Visit 1A will be excluded if there is an increase in serum creatinine > 0.5 mg/dL between Visit 1 and Visit 1A. • Hypercalcemia, defined as serum calcium > or equal to 2.75 mmol/L (11.0 mg/dL) at Visit 1 or Visit 1A. • Hypocalcemia, defined as serum calcium < or equal to 2.0 mmol/L (8.0 mg/dL) at Visit 1 or Visit 1A. • AST or ALT > 3 times the upper limit of normal • Serum alkaline phosphatase > 1.5 times the upper limit of normal • Previous use of calcitonin except according to the following washout schedule, measured from randomization: - 6 months (if used for 12 weeks or longer) - 3 months (if used for > or equal to 4 weeks but < or equal to 12 weeks) • Hypersensitivity to bisphosphonates • Prior treatment with i.v. bisphosphonates within the last 2 years prior to randomization • Use of oral bisphosphonates except according to the following washout schedule, measured from the date of randomization: - 2 years (if used for 48 weeks or longer) - 1 year (if used for > 8 weeks but < 48 weeks) - 6 months (if used for > 2 weeks but < or equal to 8 weeks) • Any prior use of PTH for more than 1 week; if used for less than or equal to 1 week, the washout period for PTH is 3 months prior to randomization. • Any prior use of strontium ranelate or sodium fluoride • Use of testosterone therapy within one year prior to randomization. • Chronic use of systemic corticosteroids (oral or i.v.) within the last year: NOTE: Use of corticosteroids in forms such as topical creams, nasal or inhaled formulations or those injected locally (intra-articularly) are NOT exclusionary. • Prior exposure to anabolic steroids or growth hormone within 6 months prior to randomization • Treatment with any investigational drug(s) and/or devices within 30 days prior to randomization. • History of iritis or uveitis, except when secondary to trauma, and must have resolved for more than 2 years prior to randomization. • Cancer exclusions: - Patients with evidence of any cancer or metastases on or prior to randomization, or with a history of cancer within the last 5 years - Patients with evidence of paraneoplastic syndrome, especially those characterized by hypercalcemia during screening or by history - Patients with the following may be included: basal cell or squamous cell carcinoma of the skin, colonic polyps with non-invasive malignancy which have been removed, and Carcinoma in-situ (CIS) of the prostate (Stage I only) that has been surgically removed. • Previous major solid organ or bone marrow transplant recipient or on a transplant waiting list • For those patients qualifying via BMD at the lumbar spine and/or belonging to the subset of 100 patients at the selected sites: Any disease of the spine that would preclude the proper acquisition of a lumbar spine DXA (L1-L4) e.g., implantable devices, scoliosis (Cobb angle ≤15: acceptable; Cobb angle >15-≤20: follow up with protocol physician), ankylosing spondylitis. In this group of patients menthioned above those individuals with less than 3 evaluable vertebrae in the region of interest (ROI) L1-L4 will not be considered eligible for this study. • History of osteogenesis imperfecta, multiple myeloma, or Paget’s disease, or any other metabolic bone disease, except osteoporosis. • Bilateral hip replacements
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the proportion of patients with at least one new morphometric vertebral fracture over 24 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 | Yes |
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 | 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) | No |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 80 |
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 | 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
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The trial ends when the last patient has his final visit scheduled at month 24 |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 4 |