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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the percent change in BMD of the femoral neck as measured by DXA at Year 6 relative to Year 3 in patients treated with zoledronic acid for up to 6 years in the CZOL446H2301 core and extension studies (Group Z6) compared to patients treated with zoledronic acid for 3 years in the CZOL446H2301 core study followed by up to 3 years of placebo in the CZOL446H2301 extension study (Group Z3P3). |
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E.2.2 | Secondary objectives of the trial |
Assess % changes in BMD of femoral neck, total hip, and trochanter at Year 4.5, Year 6 relative to Year 0 in Z6 patients compared to Z3P3 patients. Assess % changes in BMD of the femoral neck, total hip, and trochanter at Year 4.5 relative to Year 3 in Z6 patients compared to Z3P3 patients. Assess % changes in BMD of total hip and trochanter at Year 6 relative to Year 3 in Z6 patients compared to Z3P3 patients. Assess the relative change in biochemical markers of bone turnover at Year 4.5, Year 6 relative to Year 0 and Year 3 in Z6 patients compared to Z3P3 patients. Assess the relative change in biochemical markers of bone turnover at Year 3.5, 4, 4.5, 5, and 6 relative to Year 0 and Year 3 in a subset of approximately 200 Z6 and Z3P3 patients who participated in this subset of core study. Assess % changes in BMD of spine and distal radius at Year 4.5 and Year 6 relative to Year 0 and Year 3 in a subset of approximately 200 and 300 Z6 (respectively) and Z3P3 patients.
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
•Women, 93 years of age and under, inclusive (at the time of randomization in extension study) who have received 3 infusions of study medication in the core study according to the guidelines and instructions provided. •Signed written informed consent to participate in the extension study •Patients must be considered ambulatory. Patients can be included who are ambulatory with an assistive device (cane, walker, etc) •Patients must have been taking the dosage of calcium and vitamin D required in the core study (1000 to 1500 mg of elemental calcium and 400 to 1200 IU of vitamin D daily) for at least 3 months prior to entry into the extension study •Patients must have DXA measurements of the hip performed at Visit 7 (final core study visit) •Patients must be randomized into the extension study at Visit 8 between 10 and 16 months after receiving their third dose of study medication on the core study at Visit 6.
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E.4 | Principal exclusion criteria |
•Patients who demonstrated a major protocol violation in the core study or patients for whom the investigator feels participation in the extension study is not appropriate
•Pregnant or nursing (lactating) women
•Women of child-bearing potential (WOCBP)
•Any prior use of iv bisphosphonate other than the study drug during the core study and during the period after completion of the core study but prior to randomization in the extension study
•Any use of oral bisphosphonates for more than 1 month total during the core study and during the period after completion of the core study but prior to randomization in the extension study
•Any prior use of PTH for more than 1 month during the core study and during the period after completion of the core study but prior to randomization in the extension study
•Use of systemic corticosteroids (oral or i.v.) at an average dose of greater than or equal to 7.5 mg per day of oral prednisone or equivalent for a period of three months just prior to entering the extension
•Any use of anabolic steroids or growth hormone for more than 3 months just prior to entering the extension
•Any prior use of strontium (all formulations)
•Any use of sodium fluoride for osteoporosis during the core study and during the period after completion of the core study but prior to randomization in the extension study
•Serum calcium less than 8 mg/dL (2.0 mmol/L) at Visit 7 (final core study visit) or at a subsequent pre-dose laboratory test prior to randomization in the extension study
•Serum calcium greater than 11.0 mg/dL (2.75 mmol/L) at Visit 7 (final core study visit) or at a subsequent pre-dose laboratory test prior to randomization in the extension study
•Active primary hyperparathyroidism
•Surgery to the thyroid or parathyroids resulting in partial or complete hypoparathyroidism
•Uncontrolled seizure disorders associated with falls
•Bilateral hip replacement or bilateral hip surgery with implantation of an appliance during the core study
•Cancer exclusions: •Patients with a new diagnosis or active treatment for cancer during the course of the core study. •Patients using tamoxifen or aromatase inhibitors for a recent or active cancer •Patients with metastases (or with a history of metastases) •Patients with a history of radiation therapy to the head or neck area •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, Ductal Carcinoma in-situ (DCIS) that has been surgically removed, and Carcinoma in-situ (CIS) of the uterine cervix that has been surgically removed.
•Multiple myeloma or Paget’s disease diagnosed or discovered during the core study
•Occurrence of iritis or uveitis except when secondary to trauma during the core study and during the period after completion of the core study but prior to randomization in the extension study
•History of diabetic nephropathy or retinopathy or uncontrolled diabetes (e.g. patients with a history of HbA1c > 10%).
•AST or ALT greater than twice the upper limit of normal at Visit 7 (final core study visit) or at a subsequent pre-dose laboratory test prior to randomization in the extension study
•Alkaline phosphatase greater than 1.5 times the upper limit of normal at Visit 7 (final core study visit) or at a subsequent pre-dose laboratory test prior to randomization in the extension study
•Renal insufficiency with a calculated creatinine clearance less than 30.0 mL/min (0.5 mL/sec) or urine dipstick greater than 2+ protein without evidence of contamination or bacteriuria at Visit 7 (final core study visit) or at a subsequent pre-dose laboratory test prior to randomization in the extension study
•Serum creatinine greater than 2.0 mg/dL (176.8 μmol/L) at Visit 7 (final core study visit) or at a subsequent pre-dose laboratory test prior to randomization in the extension study
•A sustained increase in serum creatinine between Visit 6 and Visit 7 in the core study of greater than 0.5 mg/dL (44.2 μmol/L)
•History of hypersensitivity to bisphosphonates or any serious adverse reaction to the study drug during the core study and during the period after completion of the core study but prior to randomization in the extension study
•Use of other investigational drugs within 3 months prior to randomization in the extension study
•Any medical or psychiatric condition which, in the Investigator’s opinion, would peclude the participant from adhering to the Protocol or completing the trial per protocol
•A life expectancy of less than 3 years
•Patients with a decrease in bone mineral density at the total hip of greater than 10% or an increase of greater than 15% from baseline in the core study to any post-randomisation DXA scan in the core study.
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E.5 End points |
E.5.1 | Primary end point(s) |
Percent change in BMD of the femoral neck at Year 6 relative to Year 3 in Z6 patients compared to Z3P3 patients. |
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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 | Information not present in EudraCT |
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 | Yes |
E.7.1.3.1 | Other trial type description |
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E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |