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    The EU Clinical Trials Register currently displays   42567   clinical trials with a EudraCT protocol, of which   7008   are clinical trials conducted with subjects less than 18 years old.
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    Summary
    EudraCT Number:2009-011888-37
    Sponsor's Protocol Code Number:CZOL446HDE40
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-03-26
    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 ConcernedGermany - BfArM
    A.2EudraCT number2009-011888-37
    A.3Full title of the trial
    A 1-year, multicenter, double-blind, randomized, placebo-controlled, parallel group study to evaluate the efficacy of zoledronic acid 5 mg (Aclasta®) on bone mineral density in patients with multiple sclerosis followed by a 1-year open-label treatment phase
    A.3.2Name or abbreviated title of the trial where available
    EXALT
    A.4.1Sponsor's protocol code numberCZOL446HDE40
    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 GmbH
    B.1.3.4CountryGermany
    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 supportNovartis Pharma GmbH
    B.4.2CountryGermany
    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 5 mg Infusionslösung
    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.3.9.1CAS number 165800-06-6
    D.3.9.3Other descriptive nameZOLEDRONIC ACID MONOHYDRATE
    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 patients with multiple sclerosis
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10049088
    E.1.2Term Osteopenia
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10031282
    E.1.2Term Osteoporosis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate that zoledronic acid has superior efficacy compared with placebo on the percent change of bone mineral density (BMD) as assessed by the T-score at lumbar spine and total hip region at month 12 relative to screening as measured by Dual X-ray Absorptiometry (DXA) in MS patients suffering from osteoporosis.
    E.2.2Secondary objectives of the trial
    To further explore efficacy of zoledronic acid the following secondary outcomes will be evaluated
    •change from baseline to month 6 of BMD at lumbar spine,total hip, and femoral neck as measured by DXA
    •change from baseline to month 12 of BMD at femoral neck as measured by DXA
    •change from baseline to end of study of BMD at lumbar spine, total hip, and femoral neck as measured by DXA
    •To evaluate the effect of zoledronic acid vs. placebo on the course of disease in MS-
    patients; the Expanded Disability Status Scale (EDSS) will be used at month 12
    •To evaluate the effect of zoledronic acid vs. placebo on the number of new clinically evident fractures at month 12 and at the end of the additional 1 year open label phase
    •To evaluate safety and tolerability of zoledronic acid versus placebo in MS-patients
    •To evaluate safety and tolerability of zoledronic acid in MS patients at the end of the additional 1 year open label phase
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Written informed consent to participate in the trial
    2) Males and Females between 18 and 75 years of age
    3) Definite diagnosis of multiple sclerosis as defined by 2005 revised McDonald criteria (Appendix 3)
    4) MS-subtype: RRMS, SPMS, PPMS
    5) EDSS score between 2.5 to 6.5 (including)
    6) No immunomodulatory treatment for MS within the last 30 days or stable and well tolerated therapy with any beta-interferon formulation, glatirameracetate or fingolimod for at least 30 days immediately prior to baseline.
    7) BMD T-score of less or equal to -2.0 but not less or equal to -4.0 at the lumbar spine (L1-L4 with at least 2 evaluable vertebrae) and/or total hip region and/or femoral neck in recent DXA-scan (≤ 3 months). The DXA-scans for all assessments need to be performed with the same DXA-machine.
    8) Previous participation in CZOL446HDE39
    9) 25-OH vitamin D level greater or equal to 15 ng/ml
    10) Sufficient ability to read, write and communicate comprehensibly and comply to study procedures
    E.4Principal exclusion criteria
    1) Contraindications against Calcium and Vitamin D according to the summary product characteristics
    2) Contraindications against zoledronic acid according to the summary of product characteristics
    3) Hypersensitivity to bisphosphonates, Calcium and Vitamin D or to drugs with similar chemical structures
    4) More than one osteoporotic fracture
    5) Severe disability or any clinical impairment that can prevent the patient to meet all study requirements
    6) Concomitant medication with influence on bone mineral density (eg. enzyme-inducing antiepileptics like Carbamazepin, Phenytoin, Phenobarbital, Primidon)
    7) Any neurological disorder other than MS which is known to affect bone mineral density (e.g. muscular dystrophy, severe paresis due to other reasons than MS, degenerative nervous disorder, stroke)
    8) Any bone disorder other than osteoporosis known to affect bone mineral density (e.g. paget´s disease, osteogenesis imperfecta, multiple myeloma)
    9) Study personnel or first degree relatives of investigator(s) must not be included in the study.
    10) Women who are
    - pregnant or breast feeding (pregnancy defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mlU/ml)).
    - menstruating and capable of becoming pregnant* and not practicing two medically approved methods of contraception (Pearl Index < 1**) during and up to at least one year after the end of treatment. A negative pregnancy test (serum) for all women is required with sufficient lead time before inclusion.
    *definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH level > 40 mlU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy
    **examples of particularly reliable methods with Pearl Index (PI) < 1, according to guidelines of Deutsche Gesellschaft für Gynäkologie und Geburtshilfe:
    • Combination pill with estrogen and gestagen (no minipill, PI=0.1-0.9)
    • Vaginal ring (NuvaRing®, PI=0.65 uncorr.; 0.4 corr.)
    • Contraceptive patch (EVRA®, PI=0.72 uncorr.; 0.9 corr.)
    • Estrogen-free ovulation inhibitors (Cerazette®, PI=0.14)
    • Progestin-containing contraceptives (Implanon®, PI=0-0.08)
    • Injectable 3-month depot progestins (PI=0.3-1.4; 0.88 corr.)
    • Intra-uterine progestine device (Mirena®, PI=0.16)
    11) Baseline renal insufficiency (calculated creatinine clearance less than 35.0 mL/min); Urine dipstick greater than or equal to 2+ protein at Visit 1 without evidence of contamination or bacteriuria (may be repeated one time at least a week apart if there is suspicion of contamination).
    12) Pre-existing hypocalcemia ≤ 2.0 mmol/L (8.0 mg/dL) not adequately treated by intake of calcium and vitamin D before baseline
    13) Use of testosterone therapy within one year prior to randomization
    14) Use of systemic corticosteroids (oral or i.v.) in the last year with more than 7.5 mg/day prednisolone (or equivalent) continuously for more than four weeks.
    NOTE: Use of corticosteroids in forms such as topical creams, nasal or inhaled formulations or those injected locally (eg. intra-articularly, ocular, intrsthecal) or pulsed therapy for MS-relapses are NOT exclusionary.
    15) Prior exposure to anabolic steroids or growth hormone within 6 months prior to randomization
    16) Treatment with any investigational drug(s) and/or devices within 30 days prior to randomization.
    17) Treatment with any other immunomodulatory drug(s) than beta-interferon formulations within 3 months prior to randomization.
    18) Active history of iritis, uveitis or episcleritis
    19) History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases with the exception of localized basal cell carcinoma of the skin.
    20) Any disease of the spine that would preclude the proper acquisition of the spine DXA-scans (L1-L4) e.g., implantable devices, scoliosis, ankylosing spondylitis. Patients with less than 2 evaluable vertebrae in the region of interest (ROI) L1-L4 will not be considered eligible for this study.
    21) Spine (L1-L4) and bilateral hip surgery, that interfere with the DXA measurements (e.g. bilateral hip replacement)
    22) History of nephrocalcinosis
    23) Any kind of tooth extraction during the last 3 months or surgery of the jaw during the last 6 month before inclusion in the study
    24) Any kind of jaw bone disease or infection, that may necessitate oral surgery during the course of the study
    E.5 End points
    E.5.1Primary end point(s)
    The co-primary endpoints are the change in bone mineral density as measured by the T-score from the DXA of lumbar spine and total hip total region (baseline to week 53). The DXA is a widely used measure of bone mineral density.
    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 Yes
    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 No
    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 No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    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 concerned13
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    E.8.7Trial 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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state29
    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 Decision2010-04-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-07-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2012-06-20
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