Clinical Trials Register

Summary
EudraCT Number:	2018-000740-25
Sponsor's Protocol Code Number:	RAD-18-TAcE
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:	2021-09-07
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

2018-000740-25

A.3

Full title of the trial

“TRANSARTERIAL EMBOLIZATION ALONE VERSUS DRUG-ELUTING BEADS CHEMOEMBOLIZATION FOR HEPATOCELLULAR CARCINOMA. A RANDOMIZED CONTROLLED TRIAL”

"EMBOLIZZAZIONE TRANSARTERIOSA VERSUS CHEMIOEMBOLIZZAZIONE CON MICROSFERE CARICATE CON FARMACO NEL TRATTAMENTO DELL’EPATOCARCINOMA: TRIAL RANDOMIZZATO CONTROLLATO"

A.3.1

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

“TRANSARTERIAL EMBOLIZATION ALONE VERSUS DRUG-ELUTING BEADS CHEMOEMBOLIZATION FOR HEPATOCELLULAR CARCINOMA. A RANDOMIZED CONTROLLED TRIAL”

"EMBOLIZZAZIONE TRANSARTERIOSA VERSUS CHEMIOEMBOLIZZAZIONE CON MICROSFERE CARICATE CON FARMACO NEL TRATTAMENTO DELL’EPATOCARCINOMA: TRIAL RANDOMIZZATO CONTROLLATO"

A.3.2

Name or abbreviated title of the trial where available

RAD-18-TAcE

A.4.1

Sponsor's protocol code number

RAD-18-TAcE

A.5.4

Other Identifiers

Name:

RAD-18-TAcE

Number:

RAD-18-TAcE

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	AOU DI BOLOGNA POLICLINICO S.ORSOLA-MALPIGHI
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	Ministero della Salute (RF-2016)
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	AOU di Bologna
B.5.2	Functional name of contact point	U.O. Radiologia (Golfieri)
B.5.3	Address:
B.5.3.1	Street Address	Via Albertoni 15
B.5.3.2	Town/ city	Bologna
B.5.3.3	Post code	40138
B.5.3.4	Country	Italy
B.5.4	Telephone number	051214307
B.5.5	Fax number	0516362699
B.5.6	E-mail	rita.golfieri@aosp.bo.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	ADRIBLASTINA - 50 MG POLVERE PER SOLUZIONE INIETTABILE 1 FLACONE POLVERE
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER ITALIA S.R.L.
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.3.1	Product name	Doxorubicina
D.3.2	Product code	[Doxorubicina]
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	DOXORUBICINA CLORIDRATO
D.3.9.2	Current sponsor code	Doxorubicina
D.3.9.3	Other descriptive name	Doxorubicina
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	150
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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.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

Hepatocellular carcinoma

Epatocarcinoma

E.1.1.1

Medical condition in easily understood language

Hepatocellular carcinoma

Epatocarcinoma

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10024662
E.1.2	Term	Liver cell carcinoma non-resectable
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Compare TTP since randomization, as recommended from expert panel opinion [26] after TAE and DEB-TACE in a
homogeneous HCC patients population and using small size beads in both arms.

Lo studio è stato progettato, in relazione all'endpoint primario, come un trial di equivalenza tra le due metodiche di trattamento intraarterioso dell’HCC, ovvero la DEB-TACE e la TAE. Il TTP considerato come valore di riferimento per il braccio di paziente sottoposti alla DEB-TACE è di 9 mesi, sulla base dei risultati della nostra precedente esperienza multicentrica [6]. Si prevede che la deviazione standard del TTP non superi i 6 mesi, previa accurata selezione dei pazienti. Il limite di equivalenza è fissato a non più di 5 mesi tra i due bracci. Quindi, usando le formule appropriate, ogni braccio sarà formato da 69 pazienti (alfa: 0,05; beta: 0,80). Tenendo conto di un 10% di drop-out, la dimensione finale del campione per ciascun braccio sarà di 77 pazienti (154 totali).

E.2.2

Secondary objectives of the trial

Compare safety -Severe adverse events (SAE)-,radiologic tumor response (mRECIST) and OS in the two arms. To date,
no evidence exists that TAE can ameliorate patient survival in regards to TACE but literature suggests a reduction in the
SAE occurrence in patients submitted to TAE.
Compare cost-effectiveness of TACE vs TAE after the entire follow-up, because, if oncologic outcomes for these two
procedures are equivalent, cost containment alone should be a strong reason to support a shift from TACE to TAE.
Experimental Design

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

First-level eligibility criteria include:
1) diagnosis of HCC according to the AASLD criteria [26];
2) patients =18 years;
2) HCC unsuitable for curative treatment or for failure / recurrence after resection / ablation and diagnosed according to the AASLD criteria [26];
3) no previous treatment of target lesions (previous treatments include surgical resections on non-target lesions);
4) Child-Pugh Class A or B (maximum score 7);
5) ECOG Performance Status (PS) <2;
6) measurable target lesion according to mRECIST [24].
Second-level eligibility criteria include:
1) the prognostic score "modified hepatoma arterial-embolization prognostic score" (m-HAP-II) [27], based on bilirubin, albumin, alpha-fetoprotein, number of lesions and tumor size, which divides patients into 4 classes (A, B, C, D) with different survivals and is useful for stratifying the prognosis [28]. The first selection criteria will be the fulfillment of class B or C of m-HAP-II;
2) UNOS / TNM stage: patients with T1, T2, T3 and T4a will be included.
These two main criteria will be used for the stratification of patients before randomization in order to obtain an identical prevalence of the m-HAP-II B / C classes and of the UNO / TNM stages from T1 to T4a.
3) obtaining informed consent.

I criteri di eleggibilità di primo livello includono:
1) diagnosi di HCC secondo i criteri AASLD [26];
2) pazienti =18 anni;
2) HCC inadatto al trattamento curativo o per fallimento/recidiva dopo resezione/ablazione e diagnosticato secondo i criteri AASLD [26];
3) nessun precedente trattamento delle lesioni target (precedenti trattamenti includono resezioni chirurgiche su lesioni non target);
4) Classe A o B di Child-Pugh (punteggio massimo 7);
5) ECOG Performance Status (PS) <2;
6) lesione target misurabile secondo mRECIST [24].
I criteri di idoneità di secondo livello includono:
1) il punteggio prognostico “modified hepatoma arterial-embolization prognostic score” (m-HAP-II) [27], basato su bilirubina, albumina, alfa-fetoproteina, numero di lesioni e dimensione del tumore, che divide i pazienti in 4 classi (A, B, C, D) con diverse sopravvivenze ed è utile per la stratificazione della prognosi [28]. I primi criteri di selezione saranno l'adempimento delle classi B o C del m-HAP-II;
2) stadio UNOS/TNM: saranno inclusi pazienti con T1, T2, T3 e T4a.
Questi due criteri principali saranno utilizzati per la stratificazione dei pazienti prima della randomizzazione al fine di ottenere una prevalenza identica delle classi m-HAP-II B/C e degli stadi UNO/TNM da T1 a T4a.
3) ottenimento consenso informato.

E.4

Principal exclusion criteria

1) HCC infiltrative;
2) neoplastic invasion of a portal branch and of the common portal trunk;
3) equivocal liver injury;
4) advanced liver disease (bilirubin levels> 2.5 mg dl-1, albumin <30 g l-1, platelets <50 x 109 / L, INR> 1.5);
5) ascites and / or esophageal varices F3;
6) other tumors in the previous 5 years;
7) technical contraindications to arteriography or TACE.

1) HCC infiltrativo;
2) invasione neoplastica di un ramo portale e del tronco portale comune;
3) lesione epatica equivoca;
4) malattia epatica avanzata (livelli di bilirubina >2.5 mg dl-1, albumina <30 g l-1, piastrine <50 x 109/L, INR >1,5);
5) ascite e/o varici esofagee F3;
6) altri tumori nei precedenti 5 anni;
7) controindicazioni tecniche all'arteriografia o alla TACE.

E.5 End points

E.5.1

Primary end point(s)

The study was designed, in relation to the primary endpoint, as an equivalence trial between the two methods of intra-arterial HCC treatment, ie DEB-TACE and TAE. The TTP considered as the reference value for the patient arm submitted to DEB-TACE is 9 months, based on the results of our previous multicentric experience [6]. The TTP standard deviation is not expected to exceed 6 months, after careful patient selection. The limit of equivalence is set at no more than 5 months between the two arms. Then, using the appropriate formulas, each arm will be made up of 69 patients (alpha: 0.05; beta: 0.80). Taking into account a 10% drop-out, the final sample size for each arm will be 77 patients (154 total).

E.5.1.1

Timepoint(s) of evaluation of this end point

24 months

24 mesi

E.5.2

Secondary end point(s)

- Security. AEs and SAEs will be monitored and registered. Each AE will be assessed during and after each treatment and at all check-ups and classified according to the NCIs Common Terminology Criteria for AE (CTCAE) version 3.0. AEs occurring within 4 weeks of each intra-arterial procedure will be considered related to treatment. The incidence of SAEs in both treatment embers will be ascertained by hypothesizing a reduction in SAE of 25% after DEB-TACE and by 19% after TAE. This hypothesis would require 607 patients per arm to be confirmed. To evaluate this hypothesis, the O'Brien-Fleming stopping boundaries will be used by performing the concluded enrollment analysis of the 69 patients for each arm and with the follow-up completed. A nominal p value <0.001 (z score: 3.15) will be required to confirm the hypothesis. If the p value is higher than this threshold (even if <0.05) the null hypothesis will not be rejected.
- Effectiveness. The response will be evaluated by CT or MRI as a local response (per lesion) and global response (per patient), applying mRECIST [24], 1 month after each TACE and thereafter every 3 months for at least 2 years.
-Survival. Through proper patient selection, we expect a standard deviation of average survival of no more than 10 months. To draw this equivalence study we expect a difference in mean survival of not more than 5 months (equivalence limit) between the two treatment groups, DEB-TACE and TAE. Using the formulas proposed by Julious et al [25], each arm will be made up of 69 patients (alpha: 0.05; beta: 0.80). To obtain more reliable estimates and accounting for any drop-out from the study, 10% of patients will be added to the initial sample size, resulting in 77 patients for each arm.
- Costs. Cost effectiveness will be assessed from a third-party perspective, thus including only direct costs of procedures and related costs (hospitalization, imaging, etc.). The effectiveness will be assessed by measuring life expectancy. The incremental cost-effectiveness ratio (Incremental Cost Effectiveness Ratio, ICER) will be used to evaluate the cost-effectiveness of one treatment over another.

- Sicurezza. Gli AE e i SAE saranno monitorati e registrati. Sarà valutato ciascun AE durante e dopo ogni trattamento e in tutte le visite di controllo e classificato secondo i NCI Common Terminology Criteria for AE (CTCAE) versione 3.0. Gli AE che si verificano entro 4 settimane da ciascuna procedura intraarteriosa saranno considerati correlati al trattamento. L'incidenza dei SAE in entrambi i braci di trattamento sarà accertata ipotizzando una riduzione dei SAE del 25% dopo DEB-TACE e del 19% dopo TAE. Tale ipotesi richiederebbe 607 pazienti per braccio per essere confermata. Per valutare questa ipotesi, saranno utilizzati gli O'Brien-Fleming stopping boundaries eseguendo l’analisi ad arruolamento concluso dei 69 pazienti per ciascun braccio e con follow-up terminato. Sarà necessario un valore p nominale <0,001 (punteggio z: 3,15) per confermare l'ipotesi. Se il valore p sarà superiore a questa soglia (anche se <0.05) l'ipotesi nulla non sarà rifiutata.
- Efficacia. La risposta sarà valutata mediante TC o RM come risposta locale (per lesione) e risposta globale (per paziente), applicando gli mRECIST [24], a 1 mese dopo ogni TACE e, successivamente, ogni 3 mesi, per almeno 2 anni.
-Sopravvivenza. Attraverso una corretta selezione dei pazienti, ci aspettiamo una deviazione standard della sopravvivenza media di non più di 10 mesi. Per disegnare questo studio di equivalenza ci aspettiamo una differenza nella sopravvivenza media non superiore a 5 mesi (limite di equivalenza) tra i due gruppi di trattamento, DEB-TACE e TAE. Usando le formule proposte da Julious et al [25], ogni braccio sarà formato da 69 pazienti (alfa: 0,05; beta: 0,80). Per ottenere stime più attendibili e la contabilizzazione dell'eventuale drop-out dallo studio, un 10% dei pazienti verrà aggiunto alla dimensione del campione iniziale, risultando in 77 pazienti per ciascun braccio.
- Costi. L'efficacia in termini di costi verrà valutata da una prospettiva di terzo pagante, quindi includendo solo i costi diretti delle procedure e i costi relativi (ospedalizzazione, imaging, ecc.). L'efficacia sarà valutata misurando l'aspettativa di vita. Il rapporto costo-efficacia incrementale (Incremental Cost Effectiveness Ratio, ICER) sarà utilizzato per valutare il rapporto costo-efficacia di un trattamento rispetto all’altro.

E.5.2.1

Timepoint(s) of evaluation of this end point

24 months

24 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

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

Braccio A: microsfere (dispositivo) con Doxorubicina
Braccio B: microsfere embolizzanti (dispositivo

Arm A: microspheres (device) with Doxorubicin
Arm B: embolizing microspheres (device) without a medi

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.8.5.1

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

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.1.1.1

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

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2021-09-07.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

Yes

F.3.3.4

Nursing women

Yes

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

154

F.4.2

For a multinational trial

F.4.2.1

In the EEA

154

F.4.2.2

In the whole clinical trial

154

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)

Normal patient care

Normale prattica clinica

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

2018-09-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-04-18

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

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