Clinical Trials Register

Summary
EudraCT Number:	2006-000341-19
Sponsor's Protocol Code Number:	20050103
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:	2006-12-15
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

2006-000341-19

A.3

Full title of the trial

A Randomized, Double-Blind, Multicenter Study of Denosumab Compared with Zoledronic Acid (Zometa) in the Treatment of Bone Metastases in Men with Hormone-Refractory Prostate Cancer

Studio Multicentrico, Randomizzato, in Doppio Cieco con Denosumab in Confronto all`Acido Zoledronico (Zometa) nel Trattamento delle Metastasi Ossee in Uomini affetti da Carcinoma Prostatico Ormono-Refrattario

A.4.1

Sponsor's protocol code number

20050103

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	Amgen Inc
B.1.3.4	Country	United States
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	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	Denosumab
D.3.2	Product code	AMG 162
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Denosumab
D.3.9.1	CAS number	615258-40-7
D.3.9.2	Current sponsor code	AMG 162
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	70
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	ZOMETA*IV 1FL 4MG+1F 5ML SOLV
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	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	.8
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	Concentrate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment of bone metastases in men with hormone- refractory prostate cancer

Trattamento delle metastasi ossee in uomini con carcinoma prostatico ormono-refrattario

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	10036909
E.1.2	Term	Prostate cancer metastatic
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

-To compare the treatment effect of denosumab with zoledronic acid on the first occurrence of either a skeletal-related event (SRE) in men with hormone-refractory prostate cancer and bone metastases

-Determinare se denosumab e' non-inferiore all'acido zoledronico (Zometa) in riferimento al primo evento correlato al sistema scheletrico (SRE) occorso durante lo studio in uomini con carcinoma prostatico ormono-refrattario e metastasi ossee

E.2.2

Secondary objectives of the trial

-To compare the treatment effect of denosumab with zoledronic acid on the first occurrence of an SRE or hypercalcemia of malignancy (HCM) -To compare the treatment effect of denosumab with zoledronic acid on the first use of radiation to bone -To compare the treatment effect of denosumab with zoledronic acid on first-and-subsequent SRE (multiple- event analysis) -To compare the treatment effect of denosumab with zoledronic acid on pain and analgesic use -To assess the safety and tolerability of denosumab compared with zoledronic acid

-Determinare se denosumab e' superiore all'acido zoledronico in riferimento al primo SRE occorso durante lo studio-Determinare se denosumab e' superiore all'acido zoledronico in riferimento al primo e ai successivi SRE occorsi durante lo studio (superiorita',utilizzando l'analisi per eventi multipli)-Stabilire la sicurezza e la tollerabilita' di denosumab in confronto all'acido zoledronico

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

 men with histologically or cytologically-confirmed prostate cancer  current or prior radiographic (x-ray, magnetic resonance imaging [MRI] or computer tomography [CT]) evidence of at least 1 bone metastasis  documented failure of at least one hormonal therapy as evidenced by a rising PSA (ie, 3 consecutive determinations, taken at least 2 weeks apart from one another, with the third measurement being  4.0 ng/dL and taken within 8 weeks prior to randomization)  serum testosterone level of < 50 ng/dL due to either surgical or chemical castration  administration of concurrent chemotherapy or hormonal therapy for metastatic prostate cancer is allowed during the study, however, the therapy must be initiated and remain unchanged 28 days or more before randomization to the study  life expectancy > 6 months  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2  adequate organ function as defined by the following criteria: - serum aspartate aminotransferase (AST)  5 x upper limit of normal (ULN) - serum alanine aminotransferase (ALT)  5 x ULN - serum total bilirubin  2 x ULN - creatinine clearance (Cockroft-Gault)  30 mL/min - albumin-adjusted serum calcium  2.0 mmol/L (8.0 mg/dL) and  2.9 mmol/L (11.5 mg/dL)  before any study-specific procedure, the appropriate written informed consent must be obtained

 uomini ≥ 18 anni di eta' con carcinoma prostatico confermato da esame istologico  Evidenza radiografica (ossia raggi X, tomografia assiale computerizzata [TAC], o risonanza magnetica nucleare [RMN]) corrente o pregressa di almeno 1 metastasi ossea  fallimento documentato di almeno una terapia ormonale evidenziato dall'aumento del PSA (ossia 3 determinazioni consecutive, prese ad almeno 2 settimane di distanza l'una dall'altra. La terza misurazione deve essere ≥ 0.4 ng/ml e deve essere effettuata entro 8 settimane prima della randomizzazione)  Livelli di testosterone sierici < 50 ng/dl dovuti a castrazione chirurgica oppure chimica  Stato di disabilita' secondo l'Eastern Cooperative Oncology Group (ECOG) pari a 0, 1, o 2  Adeguata funzionalita' degli organi definita dai seguenti criteri:  aspartato aminotransferasi (AST)  5 x il limite massimo normale (ULN)  alanina aminotransferasi (ALT)  5 x ULN  bilirubina totale  2 x ULN  clearance della creatinina (Cockcroft-Gault)  30 mL/min  calcio sierico corretto sull'albumina  2.0 mmol/L (8.0 mg/dL) e  2.9 mmol/L (11.5 mg/dL)  Prima di eseguire qualsiasi procedura specifica per lo studio deve essere ottenuto un appropriato consenso informato scritto

E.4

Principal exclusion criteria

 current or prior IV bisphosphonate administration. Prior administration of oral bisphosphonates is allowed, but they must be discontinued prior to randomization to the study.  prior administration of denosumab  known brain metastases  known impending fracture in the hip region, defined as evidence of osteolytic lesions with cortical bone destruction exceeding 50% in the femur  history or current evidence of osteomyelitis or osteonecrosis of the jaw  active dental or jaw condition that requires oral surgery  Non healed dental/oral surgery  planned invasive dental procedures (eg, tooth extraction) for the course of the study  evidence of any of the following conditions per subject self report or medical chart review: - history of, or concurrent malignancy (other than prostate cancer, superficial bladder cancer (ie, stage < T1G3), or basal cell carcinoma) if active disease is <3 years before date of randomization - unstable systemic disease including active infection, uncontrolled hypertension, unstable angina, congestive heart failure, or myocardial infarction within 6 months before randomization - major surgery (including surgery to bone), or significant traumatic injury occurring within 4 weeks before randomization - known infection with human immunodeficiency virus - active infection with Hepatitis B virus or Hepatitis C virus  any organic or psychiatric disorder that, in the opinion of the investigator, might prevent the subject from completing the study or interfere with the interpretation of the study results  thirty days or less since receiving an unapproved (ie, no marketing authorization has been granted in that country) product or device in another clinical trial  known sensitivity to any of the products to be administered during the study (eg,zoledronic acid, mammalian derived products, calcium or vitamin D)

 Somministrazione EV corrente o precedente di bisfosfonati per qualsiasi motivo  Somministrazione orale corrente o precedente di bisfosfonati per il trattamento delle metastasi ossee  Radioterapia o intervento chirurgico all'osso pianificato  Precedente somministrazione di denosumab  Metastasi al cervello note  Aspettativa di vita inferiore a 6 mesi  Storia pregressa o evidenza corrente di osteonecrosi/osteomielite della mascella  Condizioni attive della dentizione o della mascella tali da richiedere intervento chirurgico al cavo orale  Intervento chirurgico dentale/orale non curativo  Procedura dentale invasiva pianificata durante lo studio  Evidenza di una qualsiasi delle seguenti condizioni, in base a quanto riportato dal soggetto stesso o alla revisione della cartella clinica:  Anamnesi nota di un secondo tumore maligno nei tre anni precedenti, ad esclusione del carcinoma delle cellule basali  Infezione nota da virus dell'immunodeficienza umana  Infezione attiva da virus dell'Epatite B o da virus dell'Epatite C  Qualsiasi disturbo che, a parere dello sperimentatore, possa impedire al soggetto di completare lo studio o possa interferire con l'interpretazione dei risultati dello studio  Trenta giorni o meno dalla somministrazione di un prodotto o dispositivo sperimentale (ossia privo di autorizzazione all'immissione in commercio) in un'altra sperimentazione clinica  Soggetti potenzialmente fertili che non accettino di utilizzare mezzi di contraccezione efficaci (come definiti dallo sperimentatore principale o personale designato)  Sensibilita' nota a uno qualsiasi dei prodotti da somministrare durante lo studio (per esempio acido zoledronico, prodotti derivati da mammiferi, calcio o vitamina D)

E.5 End points

E.5.1

Primary end point(s)

 time to the first on-study SRE (ie, fracture [vertebral and nonvertebral], radiation therapy to bone [including use of radioisotopes], surgery to bone, or spinal cord compression) or HCM

 Tempo di comparsa del primo SRE durante lo studio (non-inferiorita')

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

Yes

E.6.7

Pharmacodynamic

Yes

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

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)

Yes

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	26
F.4.2	For a multinational trial
F.4.2.1	In the EEA	387
F.4.2.2	In the whole clinical trial	1700

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

2006-09-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2006-07-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-02-24

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