Clinical Trials Register

Summary
EudraCT Number:	2004-004131-57
Sponsor's Protocol Code Number:	CZOL446M2309
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:	2007-12-07
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

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2004-004131-57

A.3

Full title of the trial

A two year multicenter, randomized, double-blind, placebocontrolled, parallel group study to evaluate the fracture efficacy and safety of intravenous zoledronic acid 5 mg annually for the treatment of osteoporosis in men

Studio multicentrico, randomizzato, in doppio cieco, controllato verso placebo, a gruppi paralleli, per valutare l'efficacia sulle fratture e la sicurezza di acido zoledronico 5 mg somministrato una volta all'anno nel trattamento dell'osteoporosi maschile.

A.4.1

Sponsor's protocol code number

CZOL446M2309

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	NOVARTIS FARMA
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	ACLASTA
D.2.1.1.2	Name of the Marketing Authorisation holder	NOVARTIS FARMA SpA
D.2.1.2	Country which granted the Marketing Authorisation	Italy
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Zoledronic acid
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Non Applicabile

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

osteoporosis

osteoporosi

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10031282
E.1.2	Term	Osteoporosis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to demonstrate the superiority of treatment with zoledronic acid compared to placebo regarding the proportion of patients with at least one new morphometric vertebral fracture over 24 months.

• Dimostrare la superiorita' del trattamento con acido zoledronico in confronto a placebo valutando la percentuale di pazienti con almeno una nuova frattura vertebrale morfometrica nell'arco di 24 mesi.

E.2.2

Secondary objectives of the trial

• The secondary objectives include the evaluation of the following parameters in male osteoporotic patients treated with zoledronic acid compared to patients treated with placebo: • Time to first clinical vertebral fracture • Proportion of patients with at least one new morphometric vertebral fracture over 12 months. • Proportion of patients with at least one new moderate or severe morphometric vertebral fracture over 12 and 24 months • The change in height at Month 12 and Month 24. • The percent change of BMD at lumbar spine and total hip at Month 6, Month 12 and Month 24 relative to baseline as measured by DXA in a sub-set of at least 100 evaluable patients at selected sites. • The changes in biochemical markers of bone resorption and bone formation at all postbaseline time points relative to baseline in a sub-set of at least 100 evaluable patients at selected sites. • Time to first clinical fracture • Time to first non-vertebral fracture

valut nei paz con osteoporosi maschile tratt con acido zoledronico in confr.a placebo dei seguenti parametri:• T alla 1° frattura vertebrale clinica.• % di paz con almeno 1 nuova fratt vertebr morfometrica nell'arco di 12 mesi.• % di paz con almeno 1 nuova fratt vertebr morfometrica moderata o grave nell'arco di 12 mesi e di 24 mesi.• Modificazione dell'h al mese 12 e 24.• Modificazione % della BMD della colonna lombare e dell'anca totale,misurata mediante DXA,al mese 6, 12 e 24 rispetto al basale,in un sottogruppo di almeno 100 paz valutabili in centri selezionati.• Modificazione dei marker biochimici del riassorbimento osseo e della formazione dell'osso a tutti i tempi di valut risp al basale,in un sottogruppo di almeno 100 paz valutabili in centri selezionati (questo sottostudio non sarà condotto in centri italiani) • T alla 1° frattura clinica.• T alla 1° frattura non vertebrale.• Sicur.complessiva di acido zoledronico rispetto a placebo in paz di sesso maschile con osteoporosi

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Male patients between 50 and 85 years of age, inclusive • At least three readable L1-L4 vertebra, confirmed by the centralized expert readers prior to randomization: only applicable for patients qualifying via BMD at the lumbar spine and/or belonging to the subset of at least 100 patients at the selected sites. For details regarding the imaging assessments of the subset of patients at the selected sites, please see Section 7.4.3. • Bone mineral density T-score of less than or equal to -2.5 SD at the total hip or femoral neck OR less than or equal to -2.5 SD at the lumbar spine as confirmed by the central expert reader. Or • Bone mineral density T-score of less than or equal to -1.5 SD at the total hip or femoral neck as confirmed by the central expert reader, AND at least 1 up to a maximum of 3 prevalent vertebral fractures of mild or moderate grade as defined by the modified Genant method for males and confirmed by the central expert reader. As per Amendment 2, this inclusion criterion is not applicable in Finland. Important: The BMD T-score must be confirmed by the central expert reader prior to randomization. Additionally, vertebral x-rays (lateral thoracic and lumbar views) will be performed and must be submitted to the central imaging laboratory for confirmation of prevalent vertebral fractures prior to randomization. Please note: Patients with more than 3 mild to moderate vertebral fractures or any severe vertebral fracture, or patients with acute painful osteoporotic fractures requiring treatment with ... PLS SEE PROTOCOL

• Pazienti maschi di eta' compresa tra 50 85 anni (entrambi inclusi). • Almeno 3 vertebre valutabili nella regione L1-L4, confermate, prima della randomizzazione, dagli esperti che eseguiranno la lettura presso il laboratorio centralizzato. Questo criterio si applica solamente al sottogruppo di almeno 100 pazienti provenienti da centri selezionati per la valutazione della BMD della colonna lombare • BMD T-score dell'anca totale o del collo del femore o della colonna lombare minore o uguale a -2.5 SD, confermati dall'esperto che eseguira' la lettura presso il laboratorio centralizzato OPPURE • BMD T-score dell'anca totale o del collo del femore minore o uguale a -1.5 SD confermati dall'esperto, che eseguira' la lettura presso il laboratorio centralizzato, E con almeno 1 frattura vertebrale prevalente di grado lieve o moderato fino a un massimo di 3 fratture. Il grado di severita' delle fratture sara' definito in base al metodo di Genant modificato per i soggetti di sesso maschile e confermato dall'esperto che eseguira' la lettura presso il laboratorio centralizzato. Importante: Il BMD T-score deve essere confermato prima della randomizzazione dall'esperto che eseguira' la lettura presso il laboratorio centralizzato. Inoltre, saranno eseguite radiografie della colonna (proiezioni laterali a livello toracico e lombare) che dovranno essere inviate al laboratorio centralizzato per la conferma delle fratture vertebrali prevalenti prima della randomizzazione. Nota bene: i pazienti con piu' di 3 fratture vertebrali di grado lieve o moderato o con qualsiasi frattura vertebrale grave o i pazienti con fratture osteoporotiche acute dolorose che necessitano di trattamento con uno dei farmaci non consentiti dal protocollo non potranno partecipare allo studio.

E.4

Principal exclusion criteria

• Patients with 25-(OH) Vitamin D levels less than 15 ng/mL at Visit 1. If the vitamin D level is < 15 ng/ml the patient should receive a loading dose of 75,000-100,000 IU of vitamin D IM or orally once as soon as possible after visit 1 and have the vitamin D test repeated at visit 1A. This repeat test for vitamin D should be done after at least 3 weeks have passed since the loading dose was given. • Baseline renal insufficiency (calculated creatinine clearance less than 30.0 mL/min) at Visit 1 and/or Visit 1A or urine dipstick greater than or equal to 2+ protein without evidence of contamination or bacteriuria (may be repeated one time at least a week apart if there is suspicion of contamination). Patients with calculated creatinine clearance equal to or greater than 30.0 mL/min and less than 60.0 mL/min or serum creatinine greater than the upper limit of normal at Visit 1 must be verified at a second visit (Visit 1A). The average creatinine clearance of the two tests must be equal to or greater than 30.0 mL/min and the result of the creatinine retest must be below the upper limit of normal. (Patients with calculated creatinine clearance greater than 60.0 mL/min and serum creatinine within normal limits at Visit 1 do not require re-test.) In the United Kingdom, patients with a urine dipstick result greater than trace protein without evidence of contamination or bacteriuria cannot be included. • Patients who require re-test of creatinine clearance at Visit 1A will be excluded if there is an increase in serum creatinine greater than 0.5 mg/dL between Visit 1 and Visit 1A. Serum creatinine may be repeated once and the investigator may discuss with the Novartis Clinical Research Physician whether to consider the patient's entry into the trial based on the repeated serum creatinine result and the patient's overall renal status. • Hypercalcemia, defined as serum calcium greater than or equal to 2.75 mmol/L (11.0 mg/dL) at Visit 1 or Visit 1A. • Hypocalcemia, defined as serum calcium less than or equal to 2.0 mmol/L (8.0 mg/dL) at Visit 1 or Visit 1A. • AST or ALT greater than 3 times the upper limit of normal • Serum alkaline phosphatase greater than 1.5 times the upper limit of normal • Previous use of calcitonin except according to the following washout schedule, measured from randomization: - 6 months (if used for 12 weeks or longer) - 3 months (if used for greater than or equal to 4 weeks but less than 12 weeks) • Hypersensitivity to bisphosphonates • Prior treatment with i.v. bisphosphonates within the last 2 years prior to randomization • Use of oral bisphosphonates except according to the following washout schedule, measured from the date of randomization: PLS SEE PROTOCOL

• Livelli di vitamina D inferiori a 15 ng/mL alla Visita 1.Se i livelli di vitamina D sono inferiori a 15 ng/mL al paziente sara' somministrata, appena possibile dopo la Visita 1, a una dose di carico pari a 75.000-100.000 IU di vitamina D i.m.o per via orale, e si dovra' ripetere la valutazione dei valori di vitamina D alla visita 1A.La misurazione della vitamina D deve essere ripetuta ad almeno 3 settimane di distanza dalla somministrazione della dose da carico. • Insufficienza renale basale (clearance della creatinina calcolata < 30.0 mL/min) alla Visita 1 e/o alla Visita 1A o dipstick delle urine ≥ 2+ di proteinuria senza evidenza di contaminazione o batteriuria (con possibilita' di una sola ripetizione del test a distanza di almeno una settimana in caso di sospetto di contaminazione).Valori di clearance della creatinina calcolata ≥ 30.0 mL/min e < 60.0 mL/min o creatinina sierica maggiore del limite superiore della norma alla Visita 1 devono essere confermati alla seconda visita di screening (Visita 1A).I valori medi della clearance della creatinina nelle due misurazioni devono essere ≥ 30.0 mL/min e i risultati del test di conferma devono essere inferiori al limite inferiore di normalita'.I pazienti con valori di clearance della creatinina calcolata ≥ 60.0 mL/min e di creatinina sierica entro i limiti della norma alla Visita 1 non necessitano di conferma. • I pazienti che devono effettuare il re-test della clearance della creatinina alla visita 1A, dovranno essere esclusi in caso di aumento della creatinina sierica tra la Visita 1 e la Visita 1A superiore a 0.5 mg/dl.La valutazione della creatinina sierica deve essere ripetuta una sola volta e lo sperimentatore deve valutare con il personale responsabile di Novartis l'ingresso del paziente nello studio sulla base dei risultati dell'esame ripetuto della creatinina sierica e delle condizioni generali della funzionalita' renale. • Ipercalcemia, definita da livelli di calcio sierico ≥ 2.75 mmol/L (11.0 mg/dL) alla Visita 1 o alla Visita 1A. • Ipocalcemia, definita da livelli di calcio sierico ≤2.0 mmol/L (8.0 mg/dL), alla Visita 1 o alla Visita 1A. • AST o ALT maggiori di 3 volte il limite superiore della norma o fosfatasi alcalina maggiore di 1.5 volte il limite superiore della norma • Impiego precedente di calcitonina a meno che non sia stato rispettato il seguente schema di sospensione del trattamento (il periodo di washout deve essere calcolato a partire dalla data di randomizzazione): - 6 mesi (se impiegata per un periodo pari o superiore a 12 settimane) - 3 mesi (se impiegata per un periodo pari o superiore a 4 settimane ma inferiore a 12 settimane) • Ipersensibilita' ai bisfosfonati. • Impiego di bisfosfonati per via endovenosa negli ultimi 2 anni prima della randomizzazione. • Impiego di bisfosfonati orali, a meno che non sia stato rispettato il seguente schema di sospensione del trattamento (il periodo di washout deve essere calcolato a partire dalla data di randomizzazione): - 2 anni (se impiego per un periodo pari o superiore a 48 settimane) - 1 anno (se impiego per un periodo superiore a 8 settimane, ma inferiore a 48 settimane) - 6 mesi (se impiego per un periodo superiore a 2 settimane, ma inferiore o pari a 8 settimane). • Impiego di PTH per piu' di 1 settimana; se impiego inferiore o pari a 1 settimana, il periodo di washout dovra' essere di 3 mesi prima della randomizzazione. • Impiego precedente di stronzio ranelato o fluoruro di sodio. • Impiego di testosterone nell'anno precedente la randomizzazione. • Impiego cronico di corticosteroidi sistemici (per os oppure ev) nell'ultimo anno Nota: l'impiego di corticosteroidi sotto forma di creme topiche, formulazioni nasali o inalatorie o iniettate localmente (intrarticolari) non sono motivo di esclusione. • Impiego di steroidi anabolizzanti od ormone della crescita nei 6 mesi precedenti la randomizzazione. • PER FAVORE VED.PROT.

E.5 End points

E.5.1

Primary end point(s)

The primary objective is to demonstrate the superiority of treatment with zoledronic acid relative to placebo in reducing the incidence of vertebral fractures in men with osteoporosis. The incidence of new morphometric vertebral fractures will be evaluated based on the proportion of new morphometric vertebral fractures over 24 months.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

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

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects
F.1 Age Range
F.1.1	Trial has subjects under 18	No
F.1.1	Number of subjects for this age range:	0
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	Yes
F.2 Gender
F.2.1	Female	No
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	No
F.3.3.1	Women of childbearing potential not using contraception	No
F.3.3.2	Women of child-bearing potential using contraception	No
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	24
F.4.2	For a multinational trial
F.4.2.1	In the EEA	950
F.4.2.2	In the whole clinical trial	1072

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2008-04-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2007-11-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2010-10-14

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