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    Summary
    EudraCT Number:2005-000668-17
    Sponsor's Protocol Code Number:CZOL446H2301E1
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2006-03-14
    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 ConcernedItaly - Italian Medicines Agency
    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 post-menopausal women taking calcium and vitamin D
    Estensione della durata di 3 anni dello studio CZOL446H2301 per valutare la sicurezza e l'efficacia a lungo termine dell'acido zoledronico nel trattamento dell'osteoporosi in donne in postmenopausa che assumono calcio e vitamina D.
    A.4.1Sponsor's protocol code numberCZOL446H2301E1
    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 SponsorNOVARTIS FARMA
    B.1.3.4CountryItaly
    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.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNZoledronic acid
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 Yes
    D.3.11.13.1Other medicinal product typeNon Applicabile
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Post menopausal osteoporosis
    Osteoporosi post menopausale
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10031285
    E.1.2Term Osteoporosis postmenopausal
    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 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).
    Valutare le modificazioni percentuali della densita` minerale ossea (BMD) del collo del femore, misurata mediante DXA dopo 6 anni rispetto alla valutazione del terzo anno nelle pazienti trattate con acido zoledronico per un totale di 6 anni (3 anni nello studio principale CZOL446H2301 e 3 anni nella fase di estensione, Gruppo Z6) in confronto alle pazienti trattate con acido zoledronico per 3 anni nello studio principale CZOL446H2301 e successivamente con placebo per 3 anni nello studio di estensione (Gruppo Z3P3).
    E.2.2Secondary objectives of the trial
    Secondary efficacy objectives are: • 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 in Z6 patients compared to Z3P3 patients. • To assess the relative change in biochemical markers of bone turnover at Year 4.5 and 6 relative to Year 3 in Z6 patients compared to Z3P3 patients. • PLS see protocol
    modificazioni % della BMD del collo del femore,dell'anca e del trocantere nelle paz del gruppo Z6 in confr.a quelle del gruppo Z3P3: dopo 4.5 e 6 anni di tratt rispetto ai valori basali; dopo 4.5 anni di tratt rispetto ai valori al terzo anno di tratt; dopo 6 anni di tratt rispetto ai valori al terzo anno di tratt;• le modificazioni relative dei marker biochimici del turnover osseo nelle paz del gruppo Z6 in confr.a quelle del gruppo Z3P3: dopo 4.5 e 6 anni di tratt rispetto ai valori basali dopo 4.5 e 6 anni di tratt rispetto ai valori al terzo anno di tratt; dopo 3.5,4,4.5,5 e 6 anni di tratt rispetto ai valori basali in un sottogruppo di circa 200 paz appartenenti al gruppo Z6 e al gruppo Z3P3 che parteciperanno a questo studio ancillare; dopo 3.5,4,4.5,5 e 6 anni di tratt rispetto al terzo anno di tratt in un sottogruppo di circa 200 paz appartenenti al gruppo Z6 e al gruppo Z3P3 che parteciperanno a questo studio ancillare
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria • Women, 93 years of age and under, inclusive (at the time of randomization in extension study) and 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
    • Pazienti di eta` &#8804; 93 anni al tempo della randomizzazione nella fase di estensione che hanno ricevuto 3 infusioni del trattamento in studio; • Consenso informato scritto. • Pazienti deambulanti, anche con ausili (bastone, stampella, etc.). • Pazienti in trattamento con calcio e vitamina D come prescritto nel protocollo principale (1000- 1500 mg di calcio e 400-1200 IU di vitamina D al giorno) da almeno 3 mesi prima dell'ingresso nell'estensione e devono presentare, al basale, valori di calcemia nei limiti della norma. • DXA dell'anca eseguita alla Visita 7 (visita finale dello studio principale). • Le pazienti devono essere randomizzate allo studio di estensione alla Visita 8, tra i 10 e i 18 mesi successivi la somministrazione della terza dose del trattamento dello studio principale (Visita 6).
    E.4Principal exclusion criteria
    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, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/ml) • Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy • 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 • Note: Use of corticosteroids in forms such as topical creams, nasal or inhaled formulations or those injected locally (intra-articularly) are NOT exclusionary • 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
    Criteri di esclusione principali: • Pazienti violatori di protocollo nello studio principale o pazienti per i quali lo sperimentatore non ritenga opportuna la partecipazione allo studio di estensione. • Gravidanza e allattamento. La gravidanza e` definita dal momento del concepimento al termine della gestazione, confermata da un test hCG positivo (&gt; 5 mIU/ml). • Donne in eta` fertile a meno che siano in amenorrea da almeno 12 mesi o da 6 mesi se accompagnata da livelli di FSH sierici &gt; 40 mIU/m o ovariectomia bilaterale da almeno 6 settimane con o senza isterectomia. • Uso di bisfosfonati per via endovenosa, ad eccezione del farmaco in studio, durante lo studio principale o durante il periodo compreso tra il termine dello studio principale e la randomizzazione allo studio di estensione. • Uso di bisfosfonati orali per un periodo superiore a 1 mese durante lo studio principale o durante il periodo compreso tra il termine dello studio principale e la randomizzazione allo studio di estensione. • Uso di PTH per piu` di 1 mese durante lo studio principale o durante il periodo compreso tra il termine dello studio principale e la randomizzazione allo studio di estensione. • Assunzione di corticosteroidi sistemici (per os oppure i.v.) a una dose media superiore o uguale a 7.5 mg al giorno per os di prednisone o equivalente per un periodo di tre mesi prima dell'inizio dello studio di estensione. - Nota: l'impiego di corticosteroidi sotto forma di creme topiche, formulazioni nasali o inalate o iniettate localmente (intrarticolari) NON sono criterio di esclusione. • Qualsiasi uso di steroidi anabolizzanti o di ormone della crescita per piu` di 3 mesi immediatamente prima dell'inizio dello studio di estensione. • Qualsiasi uso precedente di stronzio (tutte le formulazioni) • Qualsiasi uso di fluoruro di sodio per l'osteoporosi durante lo studio principale o durante il periodo compreso tra il termine dello studio principale e la randomizzazione allo studio di estensione. • Calcio sierico minore di 8 mg/dL o 2.0 mmol/L) alla Visita 7 dello studio principale o agli esami di laboratorio eseguiti prima della randomizzazione allo studio di estensione. • Calcio sierico maggiore di 11 mg/dL o 2.75 mmol/L) alla Visita 7 dello studio principale o agli esami di laboratorio eseguiti prima della randomizzazione allo studio di estensione. • Iperparatiroidismo primario in fase attiva. • Intervento chirurgico alla tiroide o alle paratiroidi con conseguente ipoparatiroidismo parziale o completo. • Crisi epilettiche non controllate associate a cadute. • Protesi d'anca bilaterale o chirurgia d'anca bilaterale con inserimento di mezzi di sintesi durante lo studio principale.
    E.5 End points
    E.5.1Primary end point(s)
    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).
    Valutare le modificazioni percentuali della densita` minerale ossea (BMD) del collo del femore, misurata mediante DXA dopo 6 anni rispetto alla valutazione del terzo anno nelle pazienti trattate con acido zoledronico per un totale di 6 anni (3 anni nello studio principale CZOL446H2301 e 3 anni nella fase di estensione, Gruppo Z6) in confronto alle pazienti trattate con acido zoledronico per 3 anni nello studio principale CZOL446H2301 e successivamente con placebo per 3 anni nello studio di estensione (Gruppo Z3P3).
    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 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.8.2.4Number of treatment arms in the trial3
    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 concerned9
    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
    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.1.1Number of subjects for this age range: 0
    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) No
    F.1.3Elderly (>=65 years) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    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 state170
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1072
    F.4.2.2In the whole clinical trial 2480
    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 Decision2005-05-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2005-05-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2009-11-26
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