Clinical Trials Register

Summary
EudraCT Number:	2020-003094-21
Sponsor's Protocol Code Number:	2831
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-05-24
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

2020-003094-21

A.3

Full title of the trial

Strategy Option in Combined locoregional treatment (Strategy CHemoEMbolization & Ablation) of patients with hepatocellular carcinoma: A Non-inferiority Randomized Multicenter Trial

Studio Prospettico Multicentrico Randomizzato Interventistico (SCHEMA)

A.3.1

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

Strategy Option in Combined locoregional treatment (Strategy CHemoEMbolization & Ablation) of patients with hepatocellular carcinoma: A Non-inferiority Randomized Multicenter Trial

Studio Prospettico Multicentrico Randomizzato Interventistico (SCHEMA)

A.3.2

Name or abbreviated title of the trial where available

SCHEMA

A.4.1

Sponsor's protocol code number

2831

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	FONDAZIONE POLICLINICO UNIVERSITARIO AGOSTINO GEMELLI IRCCS UNIVERSITA' CATTOLICA DEL SACRO CUORE
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	GUERBET
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione Policlinico Universitario A. Gemelli IRCCS
B.5.2	Functional name of contact point	Direzione Scientifica
B.5.3	Address:
B.5.3.1	Street Address	LARGO A. GEMELLI 8
B.5.3.2	Town/ city	ROMA
B.5.3.3	Post code	00168
B.5.3.4	Country	Italy
B.5.4	Telephone number	0630155701
B.5.5	Fax number	0630155701
B.5.6	E-mail	DIREZIONE.SCIENTIFICA@POLICLINICOGEMELLI.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
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	Doxorubicin
D.3.2	Product code	[Doxorubicin]
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection/infusion
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.3.9.2	Current sponsor code	23214-92-8
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	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	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

Uninodular or multinodular (maximum 3 nodules) HCC with target lesion(s) = 3 cm and < 7 cm in size, not suitable for surgery, with unilobar Disease, with liver cirrhosis classified as Child-Pugh score till B7

Pazienti con HCC uni o multinodulare (massimo 3 noduli) con lesione target di diametro compreso tra 3 e 7 cm, non candidabile a chirurgia, con malattia monolobare, con cirrosi epatica con Child-Pugh score inferiore o uguale a B7

E.1.1.1

Medical condition in easily understood language

Uninodular or multinodular (maximum 3 nodules) HCC with target lesion(s) = 3 cm and < 7 cm in size, not suitable for surgery in good clinical conditions

PPazienti con HCC uni o multinodulare (massimo 3 noduli) con lesione target di diametro compreso tra 3 e 7 cm, non candidabile a chirurgia, in buone condizioni cliniche

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10062040
E.1.2	Term	Liver operation
E.1.2	System Organ Class	10042613 - Surgical and medical procedures

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 main objective of the study is to compare the two combined options in terms of complete response of a target lesion obtained at MRI follow-up (performed after 4 weeks and within 3 months post-treatment) for the treatment of unresectable early-intermediate HCC patients, with maximum 3 nodules, with the target lesion greater than 3 cm and less than 7 cm in size.

Obiettivo primario: Comparare l’efficacia delle due opzioni di trattamento combinato su lesione di HCC in pazienti in stadio precoce o intermedio con lesione target di diametro compreso tra 3 e 7 cm e valutando la risposta al trattamento mediante esame RM con mezzo di contrasto eseguito ad 1/3 mesi e secondo i criteri mRECIST.

E.2.2

Secondary objectives of the trial

Secondary objectives:
The two combined treatments will be also compared in terms of:
- Feasibility, defined as the proportion of “technical success”;
- Safety Profile (periprocedural complications and overall adverse events);
- Fluoroscopy Time and Procedural Duration
- Overall Response (OR) and Overall Disease Control (ODC) at 1- 3- and 6-month follow-up;
- Progression-Free-Survival (PFS);
- Overall Survival (OS);
- QoL with a questionnaire (assessed before and after the treatment – day 1 and day 30).

Obiettivo secondario:
Le modalità di successione dei due trattamenti verranno anche comparate in termini di:

- Fattibilità definita come percentuale di successo tecnico
- Sicurezza valutata come incidenza di complicanze periprocedurali e di eventi avversi
- Tempo di fluoroscopia e durata procedurale
- Risposta complessiva ( Overall Response - OR) e controllo complessivo di malattia (Overall Disease Control - ODC) valutati con esami RM con mezzo di contrasto a 1/3 e 6 mesi
- Sopravvivenza libera da malattia ( Progression Free Survival - PFS);
- Sopravvivenza globale (Overall Survival - OS);
- Qualità di vita (QoL) valutata mediante questionario somministrato al Paziente, prima e dopo il trattamento, in particolare al giorno 1 e 30 .

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patients older than 18 years of age
• Uninodular or multinodular (maximum 3 nodules) HCC with target lesion(s) = 3 cm and < 7 cm in size, not suitable for surgery
• Unilobar Disease
• Adequate information and subsequent written informed consent
• Tumor volume = 50% of liver volume
• Liver cirrhosis classified as Child-Pugh score A or B7
• normalized ratio (INR) < 1.5; if a patient was on anticoagulants, they had to be able to stop medication temporarily prior to transarterial chemoembolization and have INR < 1.5 at the time of the procedure
• Adequate liver function, defined by total bilirubin < 2.0 mg/dl, alanine aminotransferase, aspartate aminotransferase was more than five times upper limit of normal range, and albumin > 2.5 g/dl
• Adequate renal function, defined by serum creatinine < 2.0 mg/dl
• No confirmed extrahepatic metastases, except for limited extra-hepatic spread defined as portal or mesenteric lymph nodes at imaging up to 2.5 cm each based on measurement of the short axis, focal lung lesion single < 1.5 cm or multiple lesions for a total diameter < 2 cm
• Performance status (ECOG) classified as 0-1 category

• Pazienti con età maggiore di 18 anni
• HCC uni o multinodulare (massimo 3 noduli) con lesione target di diametro compreso tra 3 e 7 cm, non candidabile a chirurgia
• Malattia monolobare
• Firma di un consenso informato
•Volume della lesione = 50% del volume complessivo del fegato
• Cirrosi epatica con Child-Pugh score tra A e B7
• International normalized ratio (INR) < 1.5; nel caso in cui il Paziente sia sotto terapia anticoagulante, questa dovrà essere sospesa per tempo prima del trattamento, secondo linee guida e l’INR al momento della procedura dovrà essere INR < 1.5
• Funzionalità epatica conservata e definita come bilirubina totale < 2.0 mg/dl, alanina aminotransferasi, aspartato aminotransferasi almeno 5 volte nei limiti e albumina > 2.5 g/dl
• Funzionalità renale conservata, definite come creatinina sierica < 2.0 mg/dl
• Assenza di metastasi extra-epatiche ad eccezione di una solo limitata estensione extra-epatica con presenza di linfonodi portali o mesenterici con asse corto fino a 2.5cm o la presenza di lesione singola polmonare <1.5 cm o multiple lesioni con diametro complessivo di 2 cm
• Performance status (ECOG) 0-1

E.4

Principal exclusion criteria

• Known hypersensitivity reactions towards components of the study drugs
• Child-Pugh score > B7
• Performance status (ECOG) = 2,
• Macrovascular invasion, only if assessed on pre-procedural imaging
• Platelet count < 40,000/µL and/or international normalized ratio >1.5,
• Severe renal impairment or serum creatinine levels = 2 mg/dl
• Family, psychological, social or geographical circumstances preventing the patients from undergoing follow-up and from complying with protocol procedures

Nota allergia alle sostanze/farmaci utilizzati
nello studio
• Child-Pugh score > B7
• Performance status (ECOG) = 2,
• Invasione macrovascolare documentata
all’imaging preprocedurale
• Conta piastrinica < 40,000/µL e/o INR >1.5,
• Insufficienza renale severa o livelli di creatinina
= 2 mg/dl
• Condizioni familiari, psicologiche, sociali, geografiche che non garantiscano l’adesione ad adeguati programmi di follow-up o comunque una adeguata compliance alle procedure previste all’interno del protocollo

E.5 End points

E.5.1

Primary end point(s)

Primary Endopoint: Early Complete Response Rate (within 3 months)

- END POINT PRIMARIO: tasso di risposta completa locale precoce (entro 3 mesi dal trattamento)
-

E.5.1.1

Timepoint(s) of evaluation of this end point

3 months

tre mesi

E.5.2

Secondary end point(s)

END POINT SECONDARI:
- PFS (progression free survival)
- OS: overall survival 1 year
- ORR (overall response rate)
- ODC (Overall disease control)

E.5.2.1

Timepoint(s) of evaluation of this end point

LVLS

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

stessa dose e stessa procedura

Not differences in terms of drug dosage and treatment procedure

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

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

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

120

F.4.2

For a multinational trial

F.4.2.1

In the EEA

160

F.4.2.2

In the whole clinical trial

160

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)

BEST CLINICAL PRACTICE

PRATICA 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

2021-02-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-02-11

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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