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    Summary
    EudraCT Number:2005-000668-17
    Sponsor's Protocol Code Number:CZOL446H2301 E1
    National Competent Authority:Finland - Fimea
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2006-02-07
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFinland - Fimea
    A.2EudraCT number2005-000668-17
    A.3Full title of the trial
    A 3 year, double-blind extension to CZOL446H2301 to evaluate the long term safety and efficacy of zoledronic acid in the treatment of osteoporosis in postmenopausal women taking calcium and vitamin D.
    A.3.2Name or abbreviated title of the trial where available
    2301 E1
    A.4.1Sponsor's protocol code numberCZOL446H2301 E1
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNovartis Pharma Services AG
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Aclasta
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameAclasta
    D.3.2Product code ZOL446H
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNzoledronic acid
    D.3.9.2Current sponsor codeZOL446H
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Information not present in EudraCT
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Osteoporosis in postmenopausal women
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10031282
    E.1.2Term Osteoporosis
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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).
    E.2.2Secondary objectives of the trial
    •To assess the percent changes in BMD of the femoral neck, total hip, and trochanter at Year 4.5 and Year 6 relative to Year 0 in Z6 patients compared to Z3P3 patients.

    •To assess the percent 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.

    •To assess the percent changes in BMD of the total hip and trochanter at Year 6 relative to Year 3 in Z6 patients compared to Z3P3 patients.

    •To assess the relative change in biochemical markers of bone turnover at Year 4.5 and Year 6 relative to Year 0 and Year 3 in Z6 patients compared to Z3P3 patients.

    •To 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 in the core study.
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal 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 and have a serum calcium within the normal range at baseline

    •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 18 months after receiving their third dose of study medication in the core study at Visit 6

    Additional Inclusion Criteria for Bone Biopsy Subset (up to 60
    patients)

    • Patients must have received three doses of study drug in this extension study to be eligible
    • Signed written informed consent to participate in the bone biopsy subset
    E.4Principal 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 postrandomization DXA scan in the core study


    • deletion of the following exclusion criteria for bone biopsy subset: "Any curent use of a cardiac pacemaker"
    E.5 End points
    E.5.1Primary 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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Information not present in EudraCT
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    extension trial
    E.7.2Therapeutic exploratory (Phase II) Information not present in EudraCT
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) Information not present in EudraCT
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other 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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Information not present in EudraCT
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Information not present in EudraCT
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Information not present in EudraCT
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state52
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2006-02-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-02-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2009-11-23
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