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    Summary
    EudraCT Number:2010-019415-38
    Sponsor's Protocol Code Number:CZOL446HDE38T
    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:2010-11-04
    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 number2010-019415-38
    A.3Full title of the trial
    A prospective, bicentric, randomised, primarily double blind, placebo-controlled study to evaluate the efficacy of zoledronic acid for the treatment of bone marrow syndrome
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A prospective, bicentric, randomised, primarily double blind, placebo-controlled study to evaluate the efficacy of zoledronic acid for the treatment of bone marrow syndrome
    A.3.2Name or abbreviated title of the trial where available
    ZoMARS
    A.4.1Sponsor's protocol code numberCZOL446HDE38T
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversitätsklinikum Würzburg
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportUniversitätsklinikum Würzburg
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCROLLL GmbH
    B.5.2Functional name of contact pointDr. Sabine Hoefling
    B.5.3 Address:
    B.5.3.1Street AddressWoernitzstr. 115a
    B.5.3.2Town/ cityNuremberg
    B.5.3.3Post code90449
    B.5.3.4CountryGermany
    B.5.4Telephone number004991125268847
    B.5.5Fax number004991125268840
    B.5.6E-mailsabine.hoefling@crolll.de
    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.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNZOLEDRONIC ACID
    D.3.9.1CAS number 118072-93-8
    D.3.9.2Current sponsor codeZOL446
    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) No
    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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    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 No
    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 placeboInfusion
    D.8.4Route of administration of the placeboIntravenous drip use (Noncurrent)
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Determination of efficacy of Zoledronic Acid on the treatment of bone marrow edema syndrome.
    E.1.1.1Medical condition in easily understood language
    Determination of efficacy of Zoledronic Acid on the treatment of bone marrow edema syndrome.
    E.1.1.2Therapeutic area Body processes [G] - Bones and nerves physological processes [G11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10064277
    E.1.2Term Bone marrow edema syndrome
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary aim is to test the reduction of bone marrow edema syndrome after a singular intravenous treatment with Zoledronic Acid within 6 weeks compared to placebo. The volume of the edema is defined as biometric data measured by the use of MRT before and six weeks after treatment. The hypothesis has to be checked whether Zoledronic Acid is efficient in the treatment of painfull bone marrow edema. A statistically significant reduction of the edema in the MRT is considered as evidence for efficacy.
    E.2.2Secondary objectives of the trial
    Secondary objectives are to assess safety and tolerance of the study medication compared to placebo as well as changes in the following parameters:
    Reduction of pain (VAS)
    Quality of life (Qualeffo-41 questionnaire)
    Subjective estimation of medical condition (PDI)
    Number of additional medicinal visits
    Number of days of illness
    Descriptive analysis of side effects and changes of the parameter concerning the osteologic values
    Number of aseptic bone necrosis and fatigue fractures
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Men: age over ≥ 18 years or women: age over ≥ 18 years with finished reproductivity according to the following definition:
    - ≥ 12 month persistent natural (spontaneous) amenorrhoea (women aged <50: additionally: FSH >40MIE/ml and estrogen deficiency of <30pg/ml or a negative estrogentest)
    - status post hysterectomy and / or bilateral oophorectomy
    - finished reproduction planning
    - secure diagnosis of bone marrow edema using MRT
    - current osteologic basic laboratory values (≤ 4 weeks before V2) according to DVO criteria
    - presence of an personally signed informed consent for the participation in the study
    E.4Principal exclusion criteria
    - subchondral bone loss or already occurred cartilage damage due to the bone marrow edema
    - reactive bone marrow edema with advanced arthrotic changes in the adjacent joint (grade III and IV according to Kellgren and Lawrence)
    - patients with edematous changes in bone marrow due to the diagnosis of M. Sudeck / algodystrophy / Complex Regional Pain Syndrome (CRPS)
    - patients with known hypo- and hyperparathyreoidism, osteogenesis imperfecta, osteomalacia, M. Paget or another systemic skeletal diseases, except osteoporosis
    - patients with bone necrosis in the painful skeletal region
    - patients with infectious process at the affected bone or the adjacent joint and adjacent soft parts, respectively
    - patients with diagnosed or assumed rheumatoid arthritis, Lupus erythematodes, collagenosis or vasculitides
    - patients with advanced renal insufficiency (GFR according to Cockcroft / Gault ≤ 40 ml/min/KO)
    - patients with malignant diseases with osseous manifestation in anamnesis/history
    - status post malignant basic/primary disease with large dosed chemotherapy
    - current or massive dose therapy completed before less than 6 weeks (>7.5mg prednisolon equivalent) with glucocorticoids
    - patients with a malignant tumor disease within the past 5 years, independent from the affected organ system and independent from the implemented treatment, the presence of a relapse or metastatic invasion, except basal cell carcinoma and squamous-cell carcinoma of the skin
    Current treatment due to uveitis
    - vague/ambiguous hyper- or hypocalcemia, hyper- or hypophosphatemia
    - etiological vague/ambiguous AP-increase
    - symptomatic renal calculus or nephrocalcinosis within 2 years before V2
    - recent fracture within the last 3 months independent of the localisation
    - non consolidated fractures
    - previous treatment with i.v. bisphosphonates within the last 12 months
    - previous treatment with oral bisphosphonates within the last 12 months and longer than 3 months
    - pre-treatment with prostacyclin analogs (Ilomedin / Iloprost) within the past 6 months
    - Current treatment due to inflammatory diseases of the jaw area as well as planned tooth extractions or tooth extractions less than 6 months ago or oral surgery implant treatment
    - pregnancy or nursing period
    - patients immediately involved in the conduction of the trial and relatives
    - patients with current proceedings related to the bone marrow edema
    - patients for which the participation in the study carries an increased risk under consideration of the health condition due to the assessment of the investigator
    - participation in another clinical trial within 30 days before study start or during the trial
    - participation of patient who might be dependent on the investigator, also the spouse, parents or children
    E.5 End points
    E.5.1Primary end point(s)
    The primary aim is to test the reduction of bone marrow edema syndrome after a singular intravenous treatment with Zoledronic Acid within 6 weeks compared to placebo. The volume of the edema is defined as biometric data measured by use of MRT before and 6 weeks after treatment.The hypothesis has to be checked whether Zoledronic Acid is efficient in the treatment of painfull bone marrow edema. A statistically significant reduction of the edema in the MRT is considered as evidence for efficacy.
    Primary endpoints:
    -Reduction of the Edema area
    -Assessment of pain
    E.5.1.1Timepoint(s) of evaluation of this end point
    -Reduction of the Edema area: Week 6 after study start
    -Assessment of pain: Week 0, 3, 6 after study start
    E.5.2Secondary end point(s)
    Secondary objectives are to assess safety and tolerance of the study medication compared to placebo as well as changes in the following parameters:
    Reduction of pain (VAS)
    Quality of life (Qualeffo-41 questionnaire)
    Subjective estimation of medical condition (PDI)
    Number of additional medicinal visits
    Number of days of illness
    Descriptive analysis of side effects and changes of the parameter concerning the osteologic values
    Number of aseptic bone necrosis and fatigue fractures
    E.5.2.1Timepoint(s) of evaluation of this end point
    Reduction of pain (VAS)
    Quality of life (Qualeffo-41 questionnaire): Week 0, 3, 6
    Subjective estimation of medical condition (PDI): Week 0, 3, 6
    Number of additional medicinal visits: Week 0, 3, 6
    Number of days of illness: Week 0, 3, 6
    Descriptive analysis of side effects and changes of the parameter concerning the osteologic values: Week 3, 6
    Number of aseptic bone necrosis and fatigue fractures: Optional
    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 Yes
    E.8.1.7.1Other trial design description
    primary double blind, unblinding after visit 4 (week 6)
    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.8.2.4Number of treatment arms in the trial2
    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 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 No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    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.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 24
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 24
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state48
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Further therapeutical options are discussed with the patient, if necessary. This includes surgical treatment to release pressure of the bone marrow area as well as application of medication to increase blood circulation (Iloprost, Ilomedin).
    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 Decision2011-03-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-03-14
    P. End of Trial
    P.End of Trial StatusCompleted
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