Clinical Trials Register

Summary
EudraCT Number:	2018-004105-85
Sponsor's Protocol Code Number:	D910DC00001
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2020-11-30
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2018-004105-85

A.3

Full title of the trial

A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study of Durvalumab Monotherapy or in Combination With Bevacizumab as Adjuvant Therapy in Patients With Hepatocellular Carcinoma Who Are at High Risk of Recurrence After Curative Hepatic Resection or Ablation (EMERALD-2)

Randomizowane, wieloośrodkowe badanie fazy III prowadzone metodą podwójnie ślepej próby z kontrolą placebo, oceniające durwalumab w monoterapii lub w połączeniu z bewacyzumabem jako terapię adjuwantową u pacjentów z rakiem wątrobowokomórkowym o wysokim ryzyku nawrotu po zabiegu chirurgicznym lub ablacji, wykonanych z intencją wyleczenia (EMERALD-2)

A.3.1

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

A global study to assess the efficacy and safety of durvalumab in combination with bevacizumab or durvalumab alone in patients with hepatocellular carcinoma who are at high risk of recurrence

Globalne badanie oceniające skuteczność i bezpieczeństwo durwalumabu w połączeniu z bewacyzumabem lub durwalumabu stosowanego samodzielnie u pacjentów z rakiem wątrobowokomórkowym o wysokim ryzyku nawrotu

A.3.2

Name or abbreviated title of the trial where available

EMERALD-2

A.4.1

Sponsor's protocol code number

D910DC00001

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	AstraZeneca AB
B.1.3.4	Country	Sweden
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	AstraZeneca AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AstraZeneca Clinical
B.5.2	Functional name of contact point	Study Information Center
B.5.3	Address:
B.5.3.1	Street Address	NA
B.5.3.2	Town/ city	NA
B.5.3.3	Post code	NA
B.5.3.4	Country	United States
B.5.4	Telephone number	1877240-9479
B.5.6	E-mail	information.center@astrazeneca.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	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	Durvalumab
D.3.2	Product code	MEDI4736
D.3.4	Pharmaceutical form	Concentrate 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	durvalumab
D.3.9.1	CAS number	1428935-60-7
D.3.9.2	Current sponsor code	MEDI4736
D.3.9.3	Other descriptive name	MEDI4736
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
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	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	Yes
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	AVASTIN
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Bevacizumab
D.3.2	Product code	RO487-6646/F02
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	Bevacizumab
D.3.9.1	CAS number	216974-75-3
D.3.9.2	Current sponsor code	RO487-6646
D.3.9.3	Other descriptive name	rhuMAb VEGF, anti-VEGF
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
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	No

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	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Histologically or cytologically (or radiologically for patients undergoing curative ablation) confirmed Hepatocellular Carcinoma (HCC), newly diagnosed, and successfully completed curative therapy (resection or
ablation).

Histologicznie lub cytologicznie (lub radiologicznie u pacjentów poddawanych ablacji leczniczej) potwierdzony, nowo rozpoznany, lokoregionalny rak wątrobowokomórkowy (HCC), z pomyślnie zakończonym leczeniem radykalnym (resekcja lub ablacja).

E.1.1.1

Medical condition in easily understood language

Early stage HCC patients

Wczesne stadium raka wątrobowokomórkowego

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10077746
E.1.2	Term	Hepatocellular carcinoma stage I
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 assess the efficacy of durvalumab in combination with bevacizumab compared to placebo in terms of Recurrence-free survival (RFS).

Ocena skuteczności durwalumabu w skojarzeniu z bewacizumabem w porównaniu z placebo pod względem przeżycie bez nawrotu choroby (RFS).

E.2.2

Secondary objectives of the trial

Arm A: Durvalumab + bevacizumab
Arm B: Durvalumab + placebo
Arm C: Placebo

-To compare the efficacy of Arm A versus Arm C in terms of RFS
-To assess the efficacy of Arm A vs Arm C and Arm B vs Arm C in terms of other efficacy endpoints (i.e. RFS24, RFS36, TTR, RFS2/PFS2, OS)

Grupa A: durwalumab + bewacizumab
Grupa B: duralumab + placebo
Grupa C: placebo

- Ocena skuteczności w grupie A w porównaniu z grupą C pod względem RFS
- Ocena skuteczności w grupie A w porównaniu z grupą C i w grupie B w porównaniu z grupą C pod kątem innych punktów skuteczności (t.j. przeżycie bez nawrotu choroby po 24 miesiącach (RFS24), przeżycie bez nawrotu choroby po 36 miesiącach (RFS36), czas do wystąpienia nawrotu (TTR), nawrót podczas kolejnego leczenia / progresja podczas kolejnego leczenia (RFS2/PFS2), przeżycie całkowite (OS)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Histologically or cytologically (or radiologically for patients undergoing curative ablation), newly diagnosed, confirmed HCC and successfully completed curative therapy (resection or ablation)
2.Imaging to confirm disease-free status within 28 days prior to randomization
3.ECOG 0-1 at enrolment
4.Child-Pugh score of 5 or 6
5.Patients with HBV infection must receive antiviral therapy at least after enrollment per institutional practice to ensure adequate viral suppression prior to randomization. Patients must remain on antiviral therapy for the study duration and for 6 months after the last dose of study treatment.
6.Patients with HCV infection must be managed per local institutional practice for the study and for 6 months after the last dose of study treatment.
7.Adequate organ and marrow function, as defined by the CSP

1 Osoby z histologicznie lub cytologicznie (lub radiologicznie u pacjentów poddawanych ablacji leczniczej) potwierdzonym, nowo rozpoznanym HCC, które pomyślnie zakończyły leczenie radykalne (resekcja lub ablacja)
2 Badania obrazowe do potwierdzenia statusu bez nawrotu choroby w ciągu 28 dni przed randomizacją.
3 Stan sprawności wg ECOG (Eastern Cooperative Oncology Group) 0 lub 1 przy włączeniu do badania.
4 Ocena wg klasyfikacji Childa-Pugha: 5 lub 6.
5 Pacjenci z zakażeniem HBV muszą otrzymać leczenie przeciwwirusowe co najmniej po włączeniu do badania, zgodnie z praktyką stosowaną w danym ośrodku, aby można było zapewnić u nich właściwą supresję wirusa przed randomizacją. Pacjenci muszą kontynuować leczenie przeciwwirusowe w trakcie badania oraz przez 6 miesięcy po przyjęciu ostatniej dawki badanego leczenia.
6 Pacjenci zakażeni wirusem HCV muszą być leczeni zgodnie z lokalną praktyką stosowaną w danym ośrodku w trakcie badania oraz przez 6 miesięcy po przyjęciu ostatniej dawki badanego leczenia
7 Wydolna czynność narządów i szpiku kostnego, zgodnie z opisem przedstawionym w Protokole Badania

E.4

Principal exclusion criteria

1.Known fibrolamellar HCC, sarcomatoid HCC or mixed cholangiocarcinoma and HCC
2.Evidence of metastasis, macrovascular invasion or co-existing malignant disease on baseline imaging
3.History of hepatic encephalopathy within 12 months prior to randomization
4.Evidence, by Investigator assessment, of varices at risk of bleeding on upper endoscopy or contrast-enhanced cross-sectional imaging
5.Patients with Vp1 to Vp4 portal vein thrombosis on baseline imaging are excluded
6.Active co-infection with HBV and HDV
7.Receipt of prior systemic anticancer therapy for HCC
8.Those on a waiting list for liver transplantation

1 Rozpoznana postać włóknisto-blaszkowa HCC, postać mięsakowata HCC lub mieszany rak przewodów żółciowych i HCC
2 Cechy przerzutów odległych, współistniejącego nowotworu złośliwego lub inwazji makronaczyń w wyjściowym badaniu obrazowym
3 Encefalopatia wątrobowa w wywiadzie w okresie 12 miesięcy przed randomizacją
4 Obecność (w ocenie badacza) cech żylaków z ryzykiem krwawienia podczas gastroskopii lub przekrojowego badania obrazowego z kontrastem
5 Pacjenci z Vp1 do Vp4 zakrzepicy żyły wrotnej podczas badania obrazowego w ocenie wyjściowej
6 Aktywne współistniejące zakażenie wirusem HBV oraz HDV
7 Wcześniejsze ogólnoustrojowe leczenie przeciwnowotworowe z powodu HCC
8 Osoby znajdujące się na liście oczekujących na przeszczepienie wątroby

E.5 End points

E.5.1

Primary end point(s)

RFS

Przeżycie bez nawrotu choroby (RFS)

E.5.1.1

Timepoint(s) of evaluation of this end point

Assessments for RFS will be collected regularly at predefined time points until disease recurrence or death

Analiza RFS będzie przeprowadzana regularnie, w określonych przedziałach czasowych do wystąpienia nawrotu choroby lub zgonu

E.5.2

Secondary end point(s)

Overall survival (OS)
Time to recurrence (TTR)
RFS at 24 months (RFS24)
Time from randomization to recurrence/progression on next therapy (RFS2/PFS2)

Przeżycie całkowite (OS)
Czas do wystąpienia nawrotu (TTR),
Przeżycie bez nawrotu choroby po 24 miesiącach (RFS24)
Przeżycie bez nawrotu choroby/ progresja podczas kolejnego leczenia (RFS/PFS2)

E.5.2.1

Timepoint(s) of evaluation of this end point

Assessments will be made regularly until disease recurrence, death, or until the end of the study

Ocena będzie przeprowadzana regularnie, do wystąpienia nawrotu choroby, zgonu lub zakończenia badania

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

Yes

E.6.4

Safety

Yes

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

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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)

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

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

Egypt

Peru

Philippines

Singapore

Hong Kong

Taiwan

Australia

Brazil

Canada

China

India

Japan

Korea, Republic of

Russian Federation

Thailand

Turkey

United States

Viet Nam

Austria

France

Germany

Italy

Poland

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

Last expected visit/contact of last patient undergoing the study

Ostatnia spodziewana wizyta/kontakt ostatniego pacjenta uczestniczącego w badaniu

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

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:

533

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

355

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

F.4.2.2

In the whole clinical trial

888

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)

The study has a maximum treatment period of 12 months. All patients are expected to have completed treatment prior to the end of the study. Thereafter, future treatment decisions will be at the investigator's and patient's discretion.

Maksymalny okres leczenia wynosi 12 miesięcy. Oczekuje się, że wszyscy pacjenci ukończą leczenie przed zakończeniem badania. Następnie, decyzje dotyczące przyszłego leczenia będą podejmowane według uznania badacza i pacjenta.

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

2021-02-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-01-21

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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IMP with orphan designation in the indication
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