Clinical Trials Register

Summary
EudraCT Number:	2014-002536-13
Sponsor's Protocol Code Number:	2014_05
National Competent Authority:	Belgium - FPS Health-DGM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2016-06-16
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Belgium - FPS Health-DGM

A.2

EudraCT number

2014-002536-13

A.3

Full title of the trial

Evaluation of the efficacy of antibiotic therapy combined with corticosteroids in severe alcoholic hepatitis

Evaluation de l’efficacité d’une thérapie antibiotique combinée aux corticostéroïdes dans l’hépatite alcoolique aigue

A.3.1

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

Evaluation of the efficacy of an antibiotic combined with standard treatment in severe alcoholic hepatitis

Evaluation de l’efficacité d’une thérapie antibiotique combinée au traitement standard dans l’hépatite alcoolique aigue

A.3.2

Name or abbreviated title of the trial where available

AntibioCOR- HAA

A.4.1

Sponsor's protocol code number

2014_05

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	Centre Hospitalier Régional et Universitaire de Lille
B.1.3.4	Country	France
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	Direction Générale de l'Offre de Soin
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	Délégation à la Recherche Clinique et à l’Innovation
B.5.2	Functional name of contact point	Secretary (file followed by THYOT)
B.5.3	Address:
B.5.3.1	Street Address	2 av Oscar Lambret
B.5.3.2	Town/ city	Lille
B.5.3.3	Post code	59037
B.5.3.4	Country	France
B.5.4	Telephone number	33320 44 41 45
B.5.5	Fax number	33320 44 57 11
B.5.6	E-mail	FRC@chru-lille.fr

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	AUGMENTIN
D.2.1.1.2	Name of the Marketing Authorisation holder	GSK
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Augmentin
D.3.2	Product code	0029-6085
D.3.4	Pharmaceutical form	Oral suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	AMOXICILLIN TRIHYDRATE
D.3.9.4	EV Substance Code	SUB00504MIG
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	POTASSIUM CLAVULANATE
D.3.9.4	EV Substance Code	SUB12232MIG
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	125
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	SOLUPRED
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi Adventis
D.2.1.2	Country which granted the Marketing Authorisation	France
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	Solupred
D.3.4	Pharmaceutical form	Pillules
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.3	Other descriptive name	PREDNISOLONE
D.3.9.4	EV Substance Code	SUB10018MIG
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	20
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.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	Oral suspension in sachet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

K70.1 (Severe Alcoholic hepatisis)

K70.1 (Hépatite alcoolique aigue)

E.1.1.1

Medical condition in easily understood language

Severe Alcoholic hepatisis

Hepatite Alcoolique Aigue

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10001624
E.1.2	Term	Alcoholic hepatitis
E.1.2	System Organ Class	100000004871

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 of the study is to demonstrate that a combination of corticosteroids and antibiotics improve 2-month survival more than corticosteroids alone in the subgroup of patients with severe alcoholic hepatitis who have a high short-term risk of death (MELD score≥21). This time-point was chosen because most deaths occur in patients with severe alcoholic hepatitis within the first two months (e.g. mean time until death 49.7 days in the most recent multicentre study).

L’objectif principal de l’étude est de démontrer qu’une combinaison de corticostéroïdes et d’antibiotiques améliore la survie à 2 mois plus que les corticostéroïdes seuls dans la sous population de patients atteints d’hépatite alcoolique aigue et ayant un haut risque de décès à court terme (score de MELD ≥21). Cette période a été déterminée du fait que la majeure partie des décès surviennent dans les 2 premiers mois chez les patients atteints d’hépatite alcoolique aigue. (le temps moyen de survie étant de 49.7 jours au vu des plus récentes études multicentriques).

E.2.2

Secondary objectives of the trial

Secondary objectives are :
- to show that patients treated with antibiotics and corticosteroids develop fewer infections than patients treated with corticosteroids alone
- to show that patients treated with antibiotics and corticosteroids develop hepatorenal syndrome less frequently than patients treated with corticosteroids alone
- to show that patients treated with antibiotics and corticosteroids have a greater improvement in liver function than patients treated with corticosteroids alone, assessed by the MELD score <17 at two months
- and to show that the probability of response assessed by the Lille model is higher in patients treated with an association of antibiotics and corticosteroids than corticosteroids alone.

Les objectifs secondaires sont :
- de démontrer que les patients traités avec la combinaison d’antibiotiques et de corticostéroïdes développent moins d’infections que les patient traités aux corticostéroïdes seuls.
- de démontrer que les patients traités avec la combinaison d’antibiotiques et de corticostéroïdes développent des syndromes hépatorénaux à une fréquence moindre par rapport aux patients traités par corticostéroïdes seuls
- de démontrer que les patients traités avec la combinaison d’antibiotiques et de corticostéroïdes ont une meilleure amélioration des fonctions hépatiques par rapport aux patients traités par corticostéroïdes seuls, estimées par un score de MELD <17 à 2 mois
- et de démontrer que la probabilité de réponse estimée par le model de Lille est meilleur chez le patient traité par une association d’antibiotiques et de corticostéroïdes.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients aged 18-75
- Recent onset of jaundice (<3 months)
- Biopsy proven alcoholic hepatitis (transjugular liver biopsy)
- Maddrey’s discriminant function above 32, defining severe alcoholic hepatitis
- MELD score ≥21
- Alcohol consumption of more than 40g/day (women) and 50g/day (men)
- Written informed consent

- Hommes et femmes âgés de 18 à 75ans
- Ictère récent (<3 mois)
- ponction biopsie hépatique par voie trans-jugulaire documentant une Hépatite alcoolique
- Score de Maddrey > à 32, documentant une hépatite alcoolique aigue
- score de MELD ≥21
- Une consommation moyenne quotidienne en alcool ≥40g/jour (femme) et 50g/jour (homme)
- Malades ayant donné un consentement libre, éclairé et par écrit en l’absence d’encéphalopathie sévère ou obtention d’un consentement par un membre de la famille pouvant le représenter

E.4

Principal exclusion criteria

Previous severe allergy or hypersensitivity to amoxicillin or clavulanic acid (anaphylactic shock, Quincke edema, severe urticaria)
- Hypersensitivity to any component of the medication
- History of liver injury to amoxicillin and/or clavulanic acid
- Phenylketonuria, because of the presence of aspartame in the powder for the oral suspension
- Type 1 hepatorenal syndrome before the initiation of treatment
- Severe extrahepatic disease
- Any malignant tumor < 2 years
- Uncontrolled gastrointestinal bleeding
- Ongoing viral or parasitic infection
- Untreated bacterial infection.
- Withdrawal from any antibiotic treatment less than 7 days. Patients who are currently being treated or were previously treated with antibiotics* for diagnosed infection or after a positive screening for infection may be included after wash-out period of 7 days (time from withdrawal of antibiotics to randomization).
- Tuberculosis < 5 years
- Positive blood PCR in patients with positive antibodies against HCV
- Patient carrying HBV or HIV
- Treatment with corticosteroids, immunosuppression therapy or budesonide within 6 months before the study
-pregnant/nursing woman
*use of beta-lactams is preferred, when considering a low accumulation in the body

- Antécédent d’Allergie ou d’hypersensibilité à l’amoxilline ou à l’acide clavulanique (choc anaphylactique, œdème de Quincke, urticaire aigu)
- Hypersensibilité à un des composants du traitement
- Antécédent de lésion du foie due à l’amoxicilline et/ou à l’acide clavulanique
- Phenylketonurie, en raison de la présence d’aspartame dans la poudre pour suspension orale
- Syndrome hépatorénal de type 1 avant initiation du traitement
- Maladie extra hépatique grave
- Toute tumeur maligne < 2 ans
- saignement gastro-intestinal non contrôlé
- Infection virale, fongique ou parasitaire
- Infection bactérienne non traitée.
- Arrêt d’un traitement par antibiotique depuis moins de 7 jours. Les patients en cours de traitement, ou qui ont précédemment été traité par antibiotiques pour tout infect ion diagnostiqué peuvent être inclus après une période de wash-out de 7 jour temps de sevrage de tout traitement antibiotique jusqu’à randomisation).
- Tuberculose < 5 ans
- PCR positive chez les patients porteurs d’anticorps anti HCV
- Patient porteur du HBV ou HIV
- Thérapie immunosuppressive, traitement aux corticostéroïdes ou au budesonide dans les 6 mois précèdent l’étude
- Femmes enceintes ou alaitantes
*l’utilisation de la beta-lactamine est préférée, en raison de sa faible accumulation dans le corps

E.5 End points

E.5.1

Primary end point(s)

Primary end point is the survival rate at 2 months

Le critère d’évaluation de l’objectif principal sera la survie à 2 mois.

E.5.1.1

Timepoint(s) of evaluation of this end point

2 months

2 mois

E.5.2

Secondary end point(s)

Evaluation criteria regarding the secondary objectives will be:
-Incidence of infection during follow-up
-Incidence of hepatorenal syndrome during follow-up
-Percentage of patients who have a greater improvement in liver function, assessed by the MELD score and the Lille model
-Prediction of outcome by the Lille model

Les critères d’évaluation des l’objectifs secondaire seront:
-La survenue d’une infection au cours du suivi
-La survenue d’un syndrome hépatorénal au cours du suivi
-Le pourcentage de patient ayant une meilleure amélioration des fonctions hépatiques, estimée par le score de MELD et le model de Lille
-Prédiction des conséquences par le model de Lille

E.5.2.1

Timepoint(s) of evaluation of this end point

2 months

2 mois

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

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS

Dernière Visite du Dernier Patient

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:

240

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Some of the subjects will suffer from hepatysis encephalitis. It may lead to mental confusion, mental desorder. Therefore, those subjects will not be able to receive and understand the information

Certains patients souffriront d’encéphalites hépatiques. Celles-ci entraînent une confusion mentale ainsi que des troubles de la conscience et du comportement. Par conséquent, ces patients ne seront pas aptes à recevoir et à comprendre l’information.

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

280

F.4.2.2

In the whole clinical trial

280

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)

Same as usual treatment of Severe Alcoholic Hepatisis

Identique au traîtement habituel de l'Heptatite Alcoolique Aigue

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

2016-07-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-21

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

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials