Clinical Trials Register

Summary
EudraCT Number:	2011-001477-14
Sponsor's Protocol Code Number:	HCC-P3-11-01
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:	2012-05-16
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

2011-001477-14

A.3

Full title of the trial

Phase 3 Prospective,Randomized, blinded and controlled investigation of Hepasphere/Quadrasphere microspheres for delivery of doxorubicin for the treatment of hepatocellular cancer. This Study is Phase IV in the European community.

Questo studio e' la fase IV, post-marketing studio nell'Unione europea. Studio prospettico, randomizzato, in cieco e controllato indagine di Hepasphere / Quadrasphere microsfere per la consegna della doxorubicina per il trattamento del carcinoma epatocellulare

A.3.1

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

Prospectived, Randomized, Blinded and Controlled investigation of Hepasphere/Quadrasphere microspheres for delivery of doxorubicin for the treatment of hepatocellular cancer.

Prospettico, randomizzato, indagine Accecato e controllata di Hepasphere / Quadrasphere microsfere per la consegna della doxorubicina per il trattamento del carcinoma epatocellulare

A.3.2

Name or abbreviated title of the trial where available

HiQuality Study Protocol HCC-P3-11-001

A.4.1

Sponsor's protocol code number

HCC-P3-11-01

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01387932

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	MERIT MEDICAL SYSTEMS, 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	Merit Medical
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Olivier Raclot
B.5.2	Functional name of contact point	Clinical Manager
B.5.3	Address:
B.5.3.1	Street Address	34 rue Pierre Baratin
B.5.3.2	Town/ city	Villeurbanne
B.5.3.3	Post code	69100
B.5.3.4	Country	France
B.5.4	Telephone number	+33 6 71 17 38 21
B.5.6	E-mail	oraclot@merit.com

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	DOXORUBICINA ESP*INIET 1FL50MG
D.2.1.1.2	Name of the Marketing Authorisation holder	ESP PHARMA LIMITED
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 injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarterial use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DOXORUBICIN
D.3.9.1	CAS number	23214-92-8
D.3.9.4	EV Substance Code	SUB06391MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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	Yes
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	LIPIODOL ULTRAFLUIDO*F 10ML
D.2.1.1.2	Name of the Marketing Authorisation holder	GUERBET 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 intravesical use
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Other use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IODINATED (I 131) ETHYL ESTERS OF THE FATTY ACIDS OF POPPY-SEED OIL
D.3.9.4	EV Substance Code	SUB23259
D.3.10	Strength
D.3.10.1	Concentration unit	ml millilitre(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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)	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.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

Liver Cancer

Hepatocellular cancer

E.1.1.1

Medical condition in easily understood language

Liver Cancer

cancro al fegato

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	10024722
E.1.2	Term	Liver, cancer of, primary
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

Evaluate overall survival in patients treated with HepaSphere/QuadraSphere compared to conventional transarterial chemoembolization with particle PVA

Valutare la sopravvivenza complessiva nei pazienti trattati con HepaSphere / QuadraSphere Rispetto ai tradizionali particelle transarteriosa con chemioembolizzazione PVA

E.2.2

Secondary objectives of the trial

Evaluate adverse events in patients treated with HepaSphere/QuadraSphere compared to those treated with conventional transarterial chemoembolization with particle PVA

Valutare gli eventi avversi nei pazienti trattati con HepaSphere / QuadraSphere rispetto a quelli trattati con i tradizionali chemioembolizzazione transarteriosa con particelle PVA.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

a. Age 18 or older b. Patient has signed informed consent c. Patient must have a diagnosist of hepatocellular cancer confirmed by at least one of the following: -histological confirmation -MRI result consistent with cirrhosis AND at least one solid liver lesion >2 cm with early enhancement and delayed enhancement washout, regardless of apha fetoprotein level -Alpha fetoprotein level >400 ng/mL AND evidence of at least one solid lesion >2 cm, regardless of specific imaging characteristics on MRI d. Patient must not be suitable for treatment by resection or percutaneous albation at time of study entry. Patients not suitable for ablation due to lesion location may be enrolled e. Patient MUST meet at least ONE of the following criteria: -Stage Child-Pugh B 7 -Recurrent HCC -Performance status ECOG 1 f. Patient has a life expectancy of at least 6 months g. Absence of occlusive thrombus to the main portal trunk

uno. Eta' 18 anni b. Il paziente ha firmato c consenso informato. Il paziente deve avere una diagnosi di tumore epatocellulare confermata da almeno uno dei seguenti:-la conferma istologica-MRI risultato coerente con cirrosi e almeno una lesione solida al fegato> 2 centimetri, con la valorizzazione precoce e washout delayed enhancement, a prescindere dal livello di alphafetoprotein-alfa fetoproteina livello> 400 ng / mL e la prova di almeno una lesione epatica solido> 2 cm, indipendentemente dalle caratteristiche specifiche di imaging in risonanza magnetica d. Il paziente non deve essere adatto per la resezione o ablazione percutanea al momento dell'ingresso nello studio. I pazienti non adatti per l'ablazione a causa della posizione della lesione e possono essere iscritti. Il paziente deve soddisfare almeno uno dei seguenti criteri: - Stage Pugh B 7 - HCC Recurrent - performance status ECOG 1 f. Il paziente ha un'aspettativa di vita di almeno 6 g mesi. Assenza di trombo occlusvie al tronco portale principaleUndo edits

E.4

Principal exclusion criteria

a. Current or previous treatment with chemo or radiation therapy or sorafenib b. Previous treatment with any form of transarterial embolization for HCC c. Patients with current or history of any other cancer except nonmelanomatous skin cancer d. Female patients who are pregnant, breastfeeding, or premenopausal and not using an effective method of contraceptive e. Performance status ECOG>2 f. Child-Pugh score >7 g. Active gastroinstestinal bleeding h. Evidence of uncorrectable bleeding diathesis i. Extrahepatice spread of the HCC j. Total Bilirubin >3mg/dL k. >50% tumor involvement of the liver l. Infiltrative or diffuse HCC m. Encephalopathy not adequately controlled medically. n. Prescence of ascites not controlled medically. o. Presence of medically relevant localized or systemic infection,other than hepatitis B,C,D,E or G p. Any contraindication for MRI q. Allergy to contrast media that cannot be managed with prophylaxis r. Allergy to iodized oit s. Any contraindication to arteriography t. Any contraindication for doxorubicin administration, including the following: -White blood cell count <3000 cells/mm -Absolute Neutrophil <1500 cells/mm -Cardiac ejection fraction <50% -Other condition deemed exclusionary by physician u. Any contraindication for hepatic embolization, including the following: -Porto-systemic shunt, or an arteriovenous shunt that cannot be adequately closed prior to chemoembolization -Hepatofugal blood flow -Serum creatinine >2mg/dL -Uncorrectable impaired clotting 1. Platelet <50000/mm 2. International Normalized Ratio (INR)>1.4 3. aPTT outside normal limits - AST >5x upper limit of normal for lab - ALT >5x upper limt of normal for lab -Severe peripheral vascular disease -Other condition demmed exclusionary by physician

uno. Il trattamento attuale o precedente con la terapia chemio o radioterapia o b sorafenib. Un precedente trattamento con qualsiasi forma di embolizzazione transarteriosa per HCC c. Pazienti con storia di corrente o qualsiasi altro cancro, tranne d nonmelanomatous cancro della pelle. Pazienti di sesso femminile che sono in stato di gravidanza, l'allattamento o in premenopausa e non utilizzando un metodo efficace e contraccettivi. Performance status ECOG> 2 f. Child-Pugh score> 7 g. Attivo gastroinstestinal sanguinamento h. La prova di non correggibile diatesi emorragica i. Extrahepatice diffusione del j HCC. Bilirubina totale> 3mg/dL k. > Tumorale 50% della L fegato. Infiltrativa o diffusa HCC m. Encefalopatia non adeguatamente controllati medico. n. Prescence di ascite non controllata medico. o. Presenza di clinicamente rilevante infezione localizzata o sistemica, oltre epatite B, C, D, E o G p. Qualsiasi controindicazione per MRI q. Allergia ai mezzi di contrasto che non possono essere gestiti con la profilassi r. Allergia al iodato oit s. Eventuali controindicazioni alla t arteriografia. Alcuna controindicazione per la somministrazione doxorubicina, tra cui le seguenti:-numero dei globuli bianchi <3000 cellule / mm assoluta dei neutrofili <1500 cellule / mm-Cardiac frazione di eiezione <50%-Other condizioni ritenute di esclusione da u medico. Qualsiasi controindicazione per embolizzazione epatica, inclusi i seguenti:-Porto-shunt sistemico, o un shunt artero-che non puo' essere adeguatamente chiusa prima chemioembolizzazione-Hepatofugal il flusso di sangue-La creatinina sierica> 2mg/dL-non correggibile compromessa 1 coagulazione. Piastrinica <50000/mm 2. International Normalized Ratio (INR)> 1.4 3. aPTT al di fuori dei limiti normali - AST> 5 volte il limite superiore del valore normale per il laboratorio - LIMT ALT> 5 volte superiore del valore normale per i lab-grave della malattia vascolare periferica-Altro dannata condizione di esclusione dal medico

E.5 End points

E.5.1

Primary end point(s)

The primary study endpoint will be overall survival.

L'endpoint primario dello studio sara' la sopravvivenza globale.

E.5.1.1

Timepoint(s) of evaluation of this end point

2 years

2 anni

E.5.2

Secondary end point(s)

Tumor response by mRECIST criteria Overall tumor response Treatment related to adverse events

La risposta tumorale da mRECIST trattamento criteri generali risposta del tumore in rapporto ad eventi avversi

E.5.2.1

Timepoint(s) of evaluation of this end point

6 months

6 mesi

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

Yes

E.6.6

Pharmacokinetic

Yes

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)

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

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

lipiodol and doxorubicin

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

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

European Union

United States

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

Patients will be followed from date of first embolization cycle to date of death is obtained or patient is lost to followup. Survival attempts will be attempted every 3 months after completion or final protocol specified study visit. End of trial will be when last patient dies.

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:

400

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

120

F.2 Gender

F.2.1

Female

Yes

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.4.2

For a multinational trial

F.4.2.1

In the EEA

210

F.4.2.2

In the whole clinical trial

520

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)

Patients will be followed up every 3 monts after treatment until survival. Patient may have any treatment deemed necessary by physician after completion in trial.

Patients will be followed up every 3 monts after treatment until survival. Patient may have any treatment deemed necessary by physician after completion in trial

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

2012-06-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-03-23

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

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