Clinical Trials Register

Summary
EudraCT Number:	2004-001786-18
Sponsor's Protocol Code Number:	CZOL446GDE08
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:	2007-05-15
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

2004-001786-18

A.3

Full title of the trial

Effectiveness of Zometa treatment for the prevention of bone metastases in high risk prostate cancer patients. A randomized, open-label, multicenter study of the European Association of Urology (EAU) in Cooperation with the Scandinavian Prostate Cancer Group (SPCG) and the Arbeitsgemeinschaft Urologische Onkologie (AUO)

Efficacia del trattamento con acido zoledronico nella prevenzione delle metastasi ossee in pazienti con tumore prostatico ad alto rischio. Studio randomizzato, in aperto, multicentrico della European Association of Urology (EAU) in cooperazione con lo Scandinavian Prostate Cancer Group (SPCG) e lo Arbeitsgemeinschaft Urologische Onkologie (AUO)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A.4.1

Sponsor's protocol code number

CZOL446GDE08

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	EAU EUROPEAN ASSOCIATION OF UROLOGY
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	EAU European Association of Urology
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Dario Draga`
B.5.2	Functional name of contact point	Clinical Research Associate
B.5.3	Address:
B.5.3.1	Street Address	Via Barozzi, 6
B.5.3.2	Town/ city	Bologna
B.5.3.3	Post code	40126
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 335 5611720
B.5.6	E-mail	dario.draga@iperbole.bologna.it

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	No
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.3.1	Product name	ZOLEDRONIC ACID
D.3.2	Product code	CGP42446
D.3.4	Pharmaceutical form	Concentrate for 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	4
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Prevention of bone metastasis in high risk prostate cancer patients.

Prevenzione delle metastasi ossee in pazienti con carcinoma prostatico ad alto rischio.

E.1.1.1

Medical condition in easily understood language

Prevention of bone metastasis in high risk prostate cancer patients.

Prevenzione delle metastasi ossee in pazienti con carcinoma prostatico ad alto rischio.

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

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	10060862
E.1.2	Term	Prostate cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 of this study is to show superiority of zoledronic acid as compared to control in the proportion of patients with at least one bone metastasis after 48 months of treatment.

Dimostrare la superiorita' dell'acido zoledronico rispetto al controllo nella proporzione di pazienti con almeno una metastasi ossea dopo 48 mesi di trattamento.

E.2.2

Secondary objectives of the trial

· to evaluate the effect of zoledronic acid on the time to the first bone metastasis irrespective whether symptomatic or not; · to evaluate the effect of zoledronic acid on overall survival; · to evaluate the effect of zoledronic acid on serum PSA doubling time; · to evaluate the effect of zoledronic acid on biochemical markers of bone turnover (selected centers only); · to evaluate the effect of zoledronic acid on bone mineral density at two and four years after randomization in patients receiving hormonal therapy at study entry (substudy in selected centers)

1)valutare l`effetto dell`acido zoledronico sul tempo di comparsa della prima metastasi ossea,sintomatica o asintomatica; 2)valutare l`effetto dell`acido zoledronico sulla sopravvivenza globale; 3) valutare l`effetto dell`acido zoledronico sul tempo di raddoppiamento del PSA sierico; 4) valutare l`effetto dell`acido zoledronico sui marcatori biochimici di metabolismo osseo (solo nei Centri selezionati).5)- valutare l effetto dell acido zoledronico sulla densita` minerale ossea a due e quattro anni dalla randomizzazione in pazienti in trattamento ormonale (sottostudio realizzato solo nei Centri selezionati).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

· Male patients aged 18+, ECOG = 0 (Karnofsky performance status > 90). · M0 prostate cancer patients who previously received local curative treatment (e.g. surgery, radiotherapy) or no local curative treatment. Duration between local curative treatment and starting of the study drug must not be longer than 6 months. · At least one of the following conditions must be present: Gleason Score 8-10; - pN+; - PSA ³ 20 at diagnosis. · Patients receiving androgen deprivation by orchiectomy or administration of GnRH analogue ± anti-androgens or no androgen deprivation. Hormone therapy regimen will depend on standard medical management of prostate cancer patients, i.e. when corresponding to standard medical management, patients on hormone treatment at study entry can later be withdrawn and patients not on hormone treatment at study entry can later start with androgen deprivation. Intermittent hormone treatment is allowed when corresponding to standard medical management. Patients should not be under hormonal ablation for longer than 6 months before the first study drug infusion. Neoadjuvant androgen deprivation is allowed as long as the duration between start of androgen deprivation and start of study drug is no longer than 6 months. · Life expectancy of > 6 months · Signed informed consent prior to initiation of any study procedure.

- Pazienti maschi di eta` ≥ 18 anni, ECOG=0 (indice di performance di Karnofsky ≥ 90); - Carcinoma prostatico senza metastasi, precedentemente trattato localmente (chirurgia, radioterapia) oppure senza trattamento locale. Fra l inizio dei trattamenti locali e quello del prodotto in studio non devono essere trascorsi piu` di 6 mesi; - Almeno una delle seguenti condizioni deve essere presente: Gleason score 8-10, pN+, PSA ≥ 20 alla diagnosi - Pazienti sottoposti a deprivazione androgenica mediante orchiectomia o somministrazione di analoghi del GnRH con o senza antiandrogeni, oppure non sottoposti a deprivazione androgenica. Il trattamento ormonale sara` scelto sulla base della normale pratica clinica del centro; se ritenuto opportuno, il trattamento ormonale presente al momento dell entrata in studio potra` essere successivamente sospeso; inoltre, i pazienti non in trattamento ormonale all entrata in studio potranno successivamente essere sottoposti a deprivazione androgenica. Il trattamento intermittente e` ammesso quando corrisponde al trattamento medico standard. I pazienti non devono essere in deprivazione ormonale da oltre 6 mesi prima della prima dose del farmaco in studio. La deprivazione androgenica neoadiuvante e` ammessa solo se la sua durata prima dell inizio del farmaco in studio non supera i 6 mesi; - Aspettativa di vita > 6 mesi; - Consenso informato scritto prima dell inizio di qualsiasi procedura di studio

E.4

Principal exclusion criteria

· Patients with known visceral metastasis or bone metastases in bone scan; · prior treatment with bisphosphonates; · chemotherapy to treat prostate carcinoma; · Anti-androgen monotherapy is not allowed; · use of other investigational drugs (drugs not marketed for any indication) within 6 months before start of study; · history of noncompliance to medical regimens and patients who are considered potentially unreliable or incapable of giving informed consent as judged by the investigator; · Abnormal renal function as evidenced by a calculated creatinine clearance < 30 ml/minute. Creatinine clearance (CrCl) is calculated using the Cockcroft-Gault formula. If serum creatinine is measured in micromol/l, the creatinine value in micromol/l should be multiplied with factor 0.0113 in order to obtain the creatinine value in mg/dL. For example: serum creatinine is 265 micromol/l x 0.0113 = 3 mg/dL. · Current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures; · Recent (within 6 weeks) or planned dental or jaw surgery (e.g.. extraction, implants); ·history of other malignant neoplasm within previous five years with exception of nonmelanomatous skin cancer which has been satisfactorily treated; · other known concurrent, severe medical disorder jeopardizing the life of the patient in the immediate future (myocardial infarction in previous six months, angina pectoris despite treatment, uncontrolled severe arterial hypertension, progressive cardiac or respiratory failure)

- Pazienti con metastasi viscerali o ossee alla scintigrafia; - Precedente trattamento con bisfosfonati; -Trattamento del carcinoma prostatico mediante chemioterapia; - Uso di altri farmaci sperimentali nei 6 mesi precedenti lo studio; - Storia di scarsa adesione a protocolli medici, oppure pazienti giudicati non affidabili o incapaci di fornire il consenso informato scritto, a giudizio dello sperimentatore; - Alterata funzionalita` renale evidenziata da una clearance della creatinina < 30 ml/minuto. La clearance della creatinina (CrCl) viene calcolata utilizzando la formula di Cockcroft-Gault. Se la creatinina sierica e` misurata in micromoli/l, il valore della creatinina in micromoli/l dovra` essere moltiplicato per il fattore di conversione 0.0113 in modo da ottenere il valore della creatinina in mg/dL. Ad esempio: creatinina sierica = 265 micromoli/litro x 0.0113 = 3 mg/dL; - Odontopatie attive comprese infezioni dei denti o della mascella o mandibola; trauma dentale o dell impianto, diagnosi di osteonecrosi della mascella o della mandibola, dell osso esposto, o di guarigione lenta dopo procedure odontoiatriche; - Chirurgia recente (entro 6 settimane) o programmata dei denti o della mascella o mandibola (ad es. estrazioni, impiantologia); -Storia di altre neoplasie maligne nei 5 anni precedenti, fatta eccezione per i tumori della cute non di tipo melanoma trattati con successo; - Altre gravi patologie che possano mettere a rischio la vita del paziente nel futuro immediato (infarto miocardico nei 6 mesi precedenti, angina pectoris incontrollata, ipertensione arteriosa grave non controllata, insufficienza cardiaca o respiratoria progressiva)

E.5 End points

E.5.1

Primary end point(s)

The absolute difference of T-score at the lumbar spine and total hip as evaluated at visit 1 and at visit 10 and visit 18 is the outcome variable for this study.

La differenza assoluta di T-score alla colonna lombare e all`anca in toto come valutato alle visite 1, 10 e 18.

E.5.1.1

Timepoint(s) of evaluation of this end point

Not applicable for amendment 8

Non applicabile per l`emendamento 8

E.5.2

Secondary end point(s)

Not applicable for amendment 8

Non applicabile per l`emendamento 8

E.5.2.1

Timepoint(s) of evaluation of this end point

Not applicable for amendment 8

Non applicabile per l`emendamento 8

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

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

NESSUN TRATTAMENTO

NO TREATMENT

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

129

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Switzerland

Turkey

E.8.7

Trial has a data monitoring committee

Yes

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.8.9.1

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

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

650

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

650

F.2 Gender

F.2.1

Female

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

200

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1190

F.4.2.2

In the whole clinical trial

1300

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)

See amendment 7

Vedi emendamento 7

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

2005-03-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2004-09-13

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-03-25

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