Clinical Trials Register

Summary
EudraCT Number:	2022-001174-54
Sponsor's Protocol Code Number:	APHP210075
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2022-04-05
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

2022-001174-54

A.3

Full title of the trial

Efficacy of Propranolol for the treatment of central nervous system hemangioblastomas in von Hippel-Lindau disease: a randomized controlled clinical trial

Efficacité du Propranolol pour le traitement des hémangioblastomes du système nerveux central dans le cadre de la maladie de von Hippel-Lindau : un essai clinique randomisé contrôlé

A.3.1

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

Efficacy of Propranolol for the treatment of central nervous system hemangioblastomas in von Hippel-Lindau disease: a randomized controlled clinical trial

Efficacité du Propranolol pour le traitement des hémangioblastomes du système nerveux central dans le cadre de la maladie de von Hippel-Lindau : un essai clinique randomisé contrôlé

A.3.2

Name or abbreviated title of the trial where available

PRO-HEB

A.4.1

Sponsor's protocol code number

APHP210075

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	Assistance Publique – Hôpitaux de Paris (AP-HP)
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	ministère de la santé (DGOS)
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	Assistance Publique – Hôpitaux de Paris (AP-HP)
B.5.2	Functional name of contact point	YAHMI MALIKA
B.5.3	Address:
B.5.3.1	Street Address	1 avenue Claude Vellefaux, hopital Saint-Louis
B.5.3.2	Town/ city	PARIS
B.5.3.3	Post code	75010
B.5.3.4	Country	France
B.5.4	Telephone number	330144 84 17 45
B.5.5	Fax number	330144 84 17 01
B.5.6	E-mail	malika.yahmi@aphp.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	PROPRANOLOL 40 mg, comprimé sécable
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	PROPRANOLOL
D.3.4	Pharmaceutical form	Tablet
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.3.8	INN - Proposed INN	Propranolol
D.3.9.1	CAS number	525-66-6
D.3.9.4	EV Substance Code	SUB10119MIG
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	40
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

von Hippel-Lindau desease

maladie de von Hippel-Lindau (VHL)

E.1.1.1

Medical condition in easily understood language

maladie de von Hippel-Lindau (VHL)

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

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

Étudier l’efficacité du propranolol sur la croissance des hémangioblastomes du système nerveux central, chez des patients atteints par la maladie de von Hippel-Lindau.

E.2.2

Secondary objectives of the trial

Étudier l’efficacité du propranolol sur la croissance des hémangioblastomes du système nerveux central, chez des patients atteints par la maladie de von Hippel-Lindau

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Âge ≥ 18 ans
- Patients VHL avec un ou plusieurs HB du SNC dont aucun ne nécessite une intervention chirurgicale urgente (dans 3 mois)
- Patient ayant donné son consentement écrit pour participer à l’étude
- Affiliation à un régime de sécurité sociale ou ayant-droit
- Contraception efficace durant toute la participation à l’étude pour les patientes en âge de procréer

E.4

Principal exclusion criteria

- Contre-indication à la prise de propranolol :
- bronchopneumopathie chronique obstructive et asthme,
- insuffisance cardiaque non contrôlée,
- blocs auriculo-ventriculaires des 2nd et 3ème degrés ,
- bradycardie (<50 battements/minute après 3 min de repos),
- phénomène de Raynaud et trouble artériels périphériques sévère,
- hypotension artérielle,
- hypersensibilité au propranolol)
- choc cardiogénique,
- angor de Prinzmeta
- maladie du sinus (y compris bloc sino-auriculaire),
- phéochromocytome non traité,
- antécédent de réaction anaphylactique,
- dans le cadre de la prévention primaire et secondaire des hémorragies digestives chez le cirrhotique : insuffisance hépatique évoluée avec hyperbilirubinémie, ascite massive, encéphalopathie hépatique,
- prédisposition à l'hypoglycémie (comme après un jeûne ou en cas d'anomalie de réponse aux hypoglycémies).
- acidose métabolique
- Contre -indication à la réalisation d’une IRM :
- claustrophobie,
- présence d’un pace maker et autres stimulateurs/implants,
- corps étrangers métalliques oculaires,
- valves cardiaques ou clips vasculaires métalliques ferromagnétiques)
- Patients déjà sous Propranolol ou un autre béta bloquant
- Patient sous tutelle ou curatelle ou sous sauvegarde de justice
- Femme enceinte ou allaitante

E.5 End points

E.5.1

Primary end point(s)

Étudier l’efficacité du propranolol sur la croissance des hémangioblastomes du système nerveux central, chez des patients atteints par la maladie de von Hippel-Lindau

E.5.1.1

Timepoint(s) of evaluation of this end point

24 mois

E.5.2

Secondary end point(s)

• Comparer la sécurité d’utilisation (tolérance) entre les deux bras de traitement à 24 mois post-randomisation
• Comparer la vitesse de croissance des HB entre les deux bras de traitement à 24 mois post-randomisation
• Comparer l’étendue de l’œdème péritumoral entre les deux bras de traitement tous le 6 mois (à 6, 12, 18 et 24 mois)
• Comparer l’apparition de lésions de novo entre les deux bras de traitement tous le 6 mois
• Comparer le profil angiogénique des HB entre les deux groupes tous les 6 mois
• Etudier l’évolution du taux sérique de VEGF sous traitement à 12 et 24 mois
• Comparer le nombre de patient ayant eu besoin de chirurgie entre les deux bras de traitement
• Comparer l’autonomie et la qualité de vie des patients en fin de protocole entre les deux bras

E.5.2.1

Timepoint(s) of evaluation of this end point

6mois, 12 mois, 24 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

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

suivi habituel

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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

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 suivi du 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

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

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.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)

Prise en charge habituelle dans le cadre du soin

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-05-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-05-19

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

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