Clinical Trials Register

Summary
EudraCT Number:	2017-001031-39
Sponsor's Protocol Code Number:	69HCL17_0018
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-06-19
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

France - ANSM

A.2

EudraCT number

2017-001031-39

A.3

Full title of the trial

BABH Study: Efficacy and safety of bevacizumab on severe bleedings associated with Hemorrhagic Hereditary Telangiectasia (HHT). A National, randomized multicenter phase III study.

Etude BABH - Efficacité et tolérance du bévacizumab pour le traitement des hémorragies sévères chez les patients porteurs de la maladie de Rendu-Osler.
Etude nationale, randomisée, multicentrique de phase III.

A.3.1

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

BABH Study: Efficacy and safety of bevacizumab on severe bleedings associated with Hemorrhagic Hereditary Telangiectasia (HHT)

Etude BABH - Efficacité et tolérance du bévacizumab pour le traitement des hémorragies sévères chez les patients porteurs de la maladie de Rendu-Osler.

A.3.2

Name or abbreviated title of the trial where available

BABH

A.4.1

Sponsor's protocol code number

69HCL17_0018

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	Hospices Civils de Lyon
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	French Ministry of Health
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	Hospices Civils de Lyon
B.5.2	Functional name of contact point	Justine Bricout
B.5.3	Address:
B.5.3.1	Street Address	3 QUAIS DES CELESTINS
B.5.3.2	Town/ city	LYON
B.5.3.3	Post code	69002
B.5.3.4	Country	France
B.5.4	Telephone number	472406829+33
B.5.5	Fax number	472115190+33
B.5.6	E-mail	drci_promo@chu-lyon.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	AVASTIN
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/14/1390– EMA/OD/167/14
D.3 Description of the IMP
D.3.1	Product name	BEVACIZUMAB
D.3.4	Pharmaceutical form	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.3.9.4	EV Substance Code	SUB16402MIG
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	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.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

Hemorrhagic Hereditary Telangiectasia

Rendu-Osler

E.1.1.1

Medical condition in easily understood language

Hemorrhagic Hereditary Telangiectasia

Rendu-Osler

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

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	10031132
E.1.2	Term	Osler-Weber-Rendu disease
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate, 6 months after the beginning of the treatment, the efficacy of intraveinous bevacizumab (5 mg/kg/injection, administrated every 14 days, 6 times) on blood transfusions (number of units) in patients with HHT complicated by severe bleedings responsible for severe anemia.

Evaluer l’efficacité, d’une série de 6 injections intraveineuses de bévacizumab, 6 mois après le début du traitement sur le nombre d’unité de globules rouges transfusés chez des patients porteurs de la maladie de Rendu Osler présentant des hémorragies sévères responsables d’anémie.

E.2.2

Secondary objectives of the trial

1. To evaluate efficacy of treatment on hemoglobin levels 3 and 6 months after the beginning of the treatment.
2. To evaluate efficacy on the evolution of other clinical parameters: epistaxis (frequency, duration and ESS), quality of life 3 to 6 months after the beginning of treatment, hospitalizations.
3. To assess the safety of bevacizumab in HHT patients with severe hemorrhages.
4. To evaluate the efficacy of bevacizumab on associated digestive vascular malformations in HHT patients with digestive bleeding (Endoscopy).
5. To study the pharmacokinetics of bevacizumab in HHT patients with bleedings.

1. Evaluer l’efficacité sur le taux d’hémoglobine à 3 et à 6 mois après le début du traitement
2. Evaluer l’efficacité sur l’évolution d’autres paramètres cliniques : les épistaxis (fréquence, durée et score de sévérité « ESS »), la qualité de vie à 3 et à 6 mois après la fin du traitement (questionnaire SF-36) et le nombre d’hospitalisations
3. Evaluer la tolérance du bévacizumab chez les patients avec des hémorragies sévères
4. Evaluer l’efficacité du bévacizumab sur les MAV digestives par endoscopie chez des patients présentant des saignements digestifs extériorisés.
5. Etudier la pharmacocinétique du bévacizumab.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age ≥ 18 years.
- Patients who have given their free informed and signed consent.
- Patients affiliated to a social security scheme or similar.
- Patients monitored for clinically confirmed HHT (presence of at least three Curaçao criteria) and / or with molecular biology confirmation.
- Blood transfusions with the requirement for at least 3 units of blood in the 3-month period before study enrollment, related to epistaxis or digestive bleeding.

- Age ≥ 18 ans.
- Patient ayant donné leur consentement libre, éclairé et signé.
- Patient affilié à un régime de sécurité sociale ou assimilé.
- Patient suivi pour une maladie de Rendu-Osler confirmée cliniquement (présence d’au moins 3 critères de Curaçao) et/ou en biologie moléculaire.
- Transfusion d’un minimum de 3 culots de globules rouges en rapport avec des épistaxis ou des saignements digestifs dans les 3 mois précédant l’inclusion.

E.4

Principal exclusion criteria

- Pregnant or nursing (lactating) women or likely to become so in the course of the study.
- Patients who are protected adults under the terms of the law (French Public Health Code).
- Refusal to consent.
- Patients for whom the diagnosis of HHT has not been confirmed clinically and / or by molecular biology study.
- Active infection and/or fever>38°C
- Participation in another clinical trial within 28 days prior to inclusion.
- Hypersensitivity to the active substance or to any of the excipients.
- Known hypersensitivity to products of Chinese hamster ovary cells (CHO) or other recombinant human or humanized antibodies.
- Patients who have taken Avastin ® intravenously in the 6 months prior to inclusion.
- Patients who have had a therapeutic endoscopy for gastrointestinal bleeding or ENT surgery for epistaxis will have to wait at least 3 months less after treatment to be included if bleeding persists.
- Patients who had a surgery in the month prior inclusion or planned surgery within 6 months
- Severe peripheral arterial disease with ulcerations
- Unhealed wound

- Femmes enceintes ou susceptibles de l’être pendant l’étude, ou en cours d’allaitement.
-Patient majeur protégé selon les termes de la loi (Code de la santé Publique).
-Refus de consentement.
-Patient pour lequel le diagnostic de maladie de Rendu-Osler n’a pas été confirmé cliniquement ou/et en biologie moléculaire.
-Fièvre > 38°C et/ou infection en cours.
- Participation à un autre essai thérapeutique dans les 28 jours précédant l’inclusion.
- Hypersensibilité connue au bévacizumab, à l’un des excipients de la solution d’Avastin ®, aux produits des cellules ovariennes de hamster chinois ou aux anticorps recombinant ou humanisés.
- Patient ayant reçus une perfusion intraveineuse d’Avastin ® dans les 6 mois avant l’inclusion.
- Patient ayant eu une endoscopie digestive curatrice pour des saignements digestifs.
- Patient n’ayant plus d’épistaxis 3 mois après une intervention chirurgicale ORL pour des épistaxis.
- Patient ayant eu une chirurgie dans le mois précédant l’inclusion ou une chirurgie planifiée dans les 6 mois après l’inclusion.
- Maladie artérielle périphérique avec ulcération.
- Plaie non cicatrisée.

E.5 End points

E.5.1

Primary end point(s)

The percentage of patients successful in both groups will be compared. Efficacy will be considered for a patient if the number of red blood cell transfusions is decreased by at least 50% between the 3 months-period (N1) before treatment and the period from the 3rd to 6th months (N2) after the beginning of treatment.

Le pourcentage de patients ayant répondu au traitement dans chacun des groupes sera comparé. L’efficacité du bévacizumab est définie par une diminution de 50% des transfusions entre la période de 3 mois immédiatement avant le traitement et la période entre 3 et 6 mois après le début du traitement.

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

6 mois

E.5.2

Secondary end point(s)

1.Hemoglobin levels measured before treatment (M0) and at 3 and 6 months.
2. Criteria for clinical efficacy :
- Evolution of the mean monthly epistaxis duration and frequency (number / month) before treatment, at 3 months and 6 months after the beginning of treatment. This criterion will be assessed on the basis of monitoring of epistaxis grids completed by the patient 3 months before treatment and for 6 months after starting treatment.
- Changing the scores on the SF-36 quality of life and ESS questionnaire, between the start of treatment, 3 months and 6 months after starting treatment.
3.Adverse events observed with repeated administration of bevacizumab: evaluation by collecting data at each visit, monitoring nosebleeds, bleeding throughout the study.
4.Presence of gastrointestinal bleeding will be evaluated by digestive endoscopy for patients who have gastrointestinal bleeding externalized before treatment (follow-up endoscopy) and 6 months after starting treatment.
5.Pharmacokinetics study is carried on by a dosage of bevacizumab before each injection (residual) and 2 hours after the first injection.

1.Taux d’hémoglobine mesuré avant (M0), à 3 mois et à 6 mois après le début du traitement.
2.Critères d’efficacité clinique :
- Evolution de la durée mensuelle des épistaxis et de la fréquence des épisodes à 3 et à 6 mois après l’initiation du traitement. Des grilles d’évaluation des saignements seront complétées par le patient 3 mois avant le début du traitement et pendant toute la durée de l’étude (6 mois).
- Evolution des scores obtenus au questionnaire de qualité de vie, SF36 et de sévérité des épistaxis (score ESS) complétés à l’inclusion (M0), à la fin du traitement (M3) et à la fin de l’étude (M6).
3. Tolérance des perfusions répétées de bévacizumab avec l’observation des évènements indésirables à chaque visite.
4.La présence de saignements digestifs 6 mois après le début du traitement chez les patients qui en avaient avant l’inclusion, critère évaluée par endoscopie digestive (vidéocapsule).
5.Etude pharmacocinétique grâce au dosage du bévacizumab résiduel avant chaque nouvelle perfusion et deux heures après la première perfusion.

E.5.2.1

Timepoint(s) of evaluation of this end point

3 months, 6 months

3 mois, 6 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

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

LVLP

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

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

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)

In case of a non response of a patient, evaluated at the visit at 6 months, investigator could lift the blind on request to the Anti-Poison Center in Lyon. If patient received placebo, a bevacizumab treatment will be propose apart from clinical trial. If patient received bevacizumab an alternative medical care will be implemented.

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

2017-05-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-05-19

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2020-05-15

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