Clinical Trials Register

Summary
EudraCT Number:	2011-005327-41
Sponsor's Protocol Code Number:	INT0211
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2012-03-07
Trial 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

2011-005327-41

A.3

Full title of the trial

Clinical trial randomized and controlled to compare the analgesic efficacy of the association zoledronic acid and 153Sm-lexidronam vs zoledronic acid in patients with skeletal metastases from hormono-refractory prostatic neoplasia and moderate-severe bone pain associated

Studio clinico randomizzato e controllato per comparare l'™efficacia analgesica dell'™associazione acido zoledronico e 153Sm-lexidronam verso acido zoledronico in pazienti affetti da metastasi ossee da neoplasia prostatica ormono-refrattaria con dolore associato a cancro di intensita' moderata-severa

A.3.1

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

Study of the analgesic efficacy of the association zoledronic acid and 153Sm-lexidronam in patients with skeletal metastases from prostatic cancer

Studio dell'efficacia analgesica dell'associazione acido zoledronico e 153Sm-lexidronam in pazienti con metastasi ossee da tumore della prostata

A.3.2

Name or abbreviated title of the trial where available

Zoledronic acid and 153Sm-lexidronam association

Associazione acido zoledronico e 153Sm-lexidronam

A.4.1

Sponsor's protocol code number

INT0211

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	ISTITUTO NAZIONALE PER LA CURA TUMORI
B.1.3.4	Country	Italy
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	Fondazione IRCCS Istituto Nzionale dei Tumori
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione IRCCS Istituto Nazionale dei Tumori
B.5.2	Functional name of contact point	Terapia del dolore
B.5.3	Address:
B.5.3.1	Street Address	Via Venezian 1
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.4	Telephone number	02 23902792
B.5.5	Fax number	02 23903393
B.5.6	E-mail	augusto.caraceni@istitutotumori.mi.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	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	Powder and solvent 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.3.9.1	CAS number	118072-93-8
D.3.9.4	EV Substance Code	SUB00176MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
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	No
D.IMP: 2
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	QUADRAMET*EV 1F 1,3GBQ/ML
D.2.1.1.2	Name of the Marketing Authorisation holder	CIS BIO 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 injection
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	SAMARIUM SM 153 LEXIDRONAM PENTASODIUM
D.3.9.1	CAS number	160369-78-8
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB15188MIG
D.3.10	Strength
D.3.10.1	Concentration unit	MBq/µg megabecquerel(s)/microgram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	28 to 65
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	Yes
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	No

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

Population enrolled in the study is represented by patients bearing advanced prostatic cancer with skeletal metastases and bone pain cancer-associated and treated with analgesic drugs

La popolazione in studio è rappresentata da pazienti con dolore osseo da cancro della prostata in fase avanzata con presenza accertata di metastasi ossee e in trattamento con farmaci analgesici.

E.1.1.1

Medical condition in easily understood language

Patients with advanced prostatic cancer and bone pain associated to the skeletal lesions

Pazienti con cancro della prostata in stadio avanzato e dolore associato alle metastasi ossee

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	LLT
E.1.2	Classification code	10005993
E.1.2	Term	Bone metastases
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

Main objective is the comparison of the analgesic efficacy of the association zoledronic acid and 153Sm-lexidronam versus zoledronic acid for the treatment of bone pain associated to prostatic cancer.

Obiettivo primario dello studio è quello di comparare l’efficacia analgesica dell’associazione tra acido zoledronico e [153Sm]Samario-Lexidronam verso acido zoledronico nel trattamento del dolore osseo da neoplasia prostatica con intensità del dolore al movimento, riferita alle precedenti 24 ore, ≥ 5.

E.2.2

Secondary objectives of the trial

Secondary objectives are: a) the performance of the two drugs in study by means of indicators that describe actions applied by the physician as variations of opioid dosage, switch of drugs, resort to rescue therapies, prescription of other analgesic drugs, interruption of the therapy or exit the protocol; b) incidence of correlates skeletal events; c) correlation between response and bone metabolism markers and PSA; d) safety and tolerability of the treatment observing adverse reactions to drugs, adverse events, adverse serious events and evaluating bone marrow adsorbed doses.

Obiettivi secondari sono: a) la performance dei 2 farmaci in studio utilizzando indicatori che descrivono alcune azioni messe in atto dal medico quali le variazioni del dosaggio del farmaco oppioide, il ricorso a cambiamenti del farmaco, l’utilizzo di una terapia aggiuntiva e di salvataggio, la prescrizione di farmaci adiuvanti analgesici, l’interruzione della terapia (inefficacia/tossicità assoluta) e/o l’uscita dallo studio; b) l’ incidenza degli eventi scheletrici correlati (SREs); c) la correlazione tra la risposta analgesica ai trattamenti in studio ed i markers del metabolismo osseo e della malattia prostatica (PSA); d) la sicurezza e la tollerabilità del trattamento osservando le reazioni avverse da farmaci, con valutazione della irradiazione al midollo osseo nei pazienti in trattamento con 153Smlexidronam, gli eventi avversi e gli eventi avversi seri.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- patient bearing hormono-refractory prostatic cancer with aching skeletal localizations positive to bone scintigraphy; - patient in therapy with opioid but that hasn't an adequate control of the painful symptomatology during the last 24 hours; - signed informed consent; - life expectancy of at least 3 months; - Karnofsky Performance Status (KPS) > 50; - Hormonal treatment stable from 2 months at least; - No dental contraindication.

•Paziente portatore di carcinoma della prostata ormono-refrattario con localizzazioni scheletriche dolenti ipercaptanti alla scintigrafia ossea eseguita non meno di 60 giorni prima della fase di screening; •Paziente in terapia stabile con oppioidi maggiori che non ha un controllo adeguato della sintomatologia dolorosa al movimento nelle ultime 24 ore (per controllo inadeguato si intende un dolore di intensità ≥ 5 su una scala di valutazione numerica di 11 livelli (0-10) malgrado un incremento della dose di oppioide, a dosaggio stabile in corso; •Paziente che ha dato consenso informato scritto; •Paziente per il quale la previsione clinica di sopravvivenza sia >3 mesi; •Paziente con Karnofsky Performance Status (KPS) > 50; •Trattamento ormonale stabile da più di due mesi; •Non controindicazioni odontoiatrica alla somministrazione del difosfonato.

E.4

Principal exclusion criteria

- Poor compliance to the protocol; - Inadequate medullar reserve; - Kidney failure; - Allergy to biphosphonates; - Medullar compression or epidural metastases; -Bone pain due to nervous pressure of nearby soft tissues by tumoral mass; - Chemotherapy or external radiotherapy within 6 weeks; -High risk of pathological fractures; - Contemporaneous treatment with aminoglycosides.

-Scarsa compliance di adesione al protocollo; -Ridotta riserva ematopoietica; -Insufficienza renale; -Allergia a composti contenenti bisfosfonati; -Presenza o sospetto di compressione midollare; Presenza di metastasi epidurali; -Presenza di dolore osseo riferito causato da compressione nervosa da massa tumorale dei tessuti molli adiacenti; -Chemioterapia e/o RT con fasci esterni conclusa da meno di sei settimane; -Rischio elevato di fratture patologiche; -Trattamento contemporaneo con aminoglicosidi.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint is represented by patients ratio that will be classified as non-responders to the therapies in study

L’endpoint primario di efficacia è rappresentato dalla proporzione di pazienti che saranno classificati come non rispondenti alle terapie oggetto dello studio (non-responders).

E.5.1.1

Timepoint(s) of evaluation of this end point

60 days

60 giorni

E.5.2

Secondary end point(s)

1) Evaluation of the first impact of the treatment in controlling bone pain; 2) Subject ratio that needed an increase of the opioid dosage >=5%; 3) Subject ratio that needed an additional treatment; 4) Subject ratio that needed adjuvant analgesic drugs; 5) Subject ratio that needed switch of opioid; 6) Subject ratio that exit protocol because of the treatment.

1) Valutazione del primo impatto sul dolore dei farmaci assegnati; 2) Proporzione di soggetti con un incremento di dose dell’oppioide ≥ al 5%; 3)Proporzione di soggetti che hanno richiesto il ricorso a un trattamento “aggiuntivo; 4)Proporzione di soggetti che hanno richiesto il ricorso a farmaci analgesici adiuvanti; 5) Proporzione di soggetti che hanno richiesto il cambio dell’oppioide come terapia analgesica; 6)Proporzione di pazienti che abbandonano lo studio per cause attribuibili al trattamento.

E.5.2.1

Timepoint(s) of evaluation of this end point

1) 15 days 2-6) 60 days

1) 15 giorni 2-6) 60 giorni

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

E.6.5

Efficacy

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

Yes

E.6.13.1

Other scope of the trial description

control of bone pain

controllo sintomatologia dolorosa

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

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

uno solo dei due farmaci in studio

only one of the two drugs in study

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

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)

Subject will continue follow-up also after the protocol study end.

I soggetti continueranno ad essere seguiti anche dopo la fine dello studio

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

2012-04-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-14

P. End of Trial
P.	End of Trial Status	Ongoing

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