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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

16 Oct 2024 → ongoing

Decision date (initial)

2024-10-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

DGOS (Direction Générale de l'Offre de Soins), Ministry of Health, France

External identifiers

EU CT number

2024-516241-39-00

EudraCT number

2022-001174-54

ClinicalTrials.gov

NCT05424016

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Study the effectiveness of propranolol on the growth of central nervous system hemangioblastomas in patients with von Hippel-Lindau disease.

Secondary objectives 8

1. Compare the safety of use (tolerance) between the two treatment arms at 24 months post-randomization
2. Compare the growth rate of hemangioblastomas (HB) between the two treatment arms at 24 months post-randomization.
3. Compare the extent of peritumoral edema between the two treatment arms every 6 months.
4. Compare the occurrence of de novo lesions between the two treatment arms every 6 months.
5. Compare the angiogenic profile of HB between the two groups every 6 months.
6. Study the evolution of serum VEGF levels under treatment at 12 and 24 months.
7. Compare the number of patients requiring surgery between the two treatment arms.
8. Compare the autonomy and quality of life of patients at the end of the protocols between the two arms.

Conditions and MedDRA coding

Von Hippel-Lindau (VHL) disease

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Age ≥ 18 years
2. VHL patients with one or more central nervous system hemangioblastomas (HB) none of which require urgent surgical intervention (within 3 months)
3. Patients who have provided written consent to participate in the study
4. Affiliation with a social security scheme or dependent status

Exclusion criteria 16

1. Chronic obstructive pulmonary disease and asthma
2. Uncontrolled heart failure
3. Second- and third-degree atrioventricular blocks
4. Bradycardia (<50 beats/minute after 3 minutes of rest)
5. Raynaud's phenomenon and severe peripheral arterial disease
6. Hypotension
7. Hypersensitivity to propranolol
8. Cardiogenic shock
9. Prinzmetal angina
10. Sick sinus syndrome (including sinoatrial block)
11. Untreated pheochromocytoma
12. History of anaphylactic reaction
13. In the context of primary and secondary prevention of gastrointestinal hemorrhages in cirrhotics: advanced liver failure with hyperbilirubinemia, massive ascites, hepatic encephalopathy
14. Predisposition to hypoglycemia (such as after fasting or in case of abnormal response to hypoglycemia)
15. Metabolic acidosis
16. Contraindications for MRI: • Claustrophobia • Presence of a pacemaker and other stimulators/implants • Metallic foreign bodies in the eyes • Ferromagnetic cardiac valves or vascular clips • Patients already on propranolol or another beta-blocker • Patients under guardianship or conservatorship, or under judicial protection • Pregnant or breastfeeding women • Women planning a pregnancy in the medium term

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Effectiveness will be assessed using the proportion of patients responding to treatment with propranolol at 24 months post-randomization. The treatment response at 24 months will be a binary variable (responder/non-responder), evaluated by two neuroradiologists independently. They will be blinded to the randomization group.

Secondary endpoints 8

1. To study the safety of use (tolerance) at 24 months post-randomization: All adverse events related to the use of propranolol occurring during the study will be collected, analyzed, and compared between the two treatment arms.
2. To compare the growth rate of hemangioblastomas (HB) between the two treatment arms at 24 months post-randomization: The growth rate of HB will be measured on each MRI (every 6 months) by two neuroradiologists, blinded to the randomization arm. It will be calculated in mm³/month using the function available on the ITK-SNAP imaging software (www.itksnap.org), which allows for accurate measurement of tumor volume (in case of disagreement, a reconciliation session will be organized). The growth r
3. To compare the extent of peritumoral edema between the two treatment arms: The size of the peritumoral edema will be measured on each MRI (every 6 months) by two neuroradiologists, blinded to the randomization arm.
4. To compare the occurrence of de novo lesions between the two treatment arms: The number of de novo HB will be specified for each patient at each control MRI (every 6 months) by two neuroradiologists, blinded to the randomization arm. A de novo HB is defined as the appearance during follow-up of an HB that did not exist on the initial imaging (or the transition from a non-measurable HB to a measurable state).
5. To compare the angiogenic profile of HB between the two groups every 6 months through a perfusion sequence with r-CBV measurement for each measurable and perfusable lesion (> 1 cm).
6. To study the evolution of serum VEGF levels under treatment: Serum VEGF levels will be measured at the start of treatment, then at 12 and 24 months through a simple peripheral venous blood draw.
7. To compare the number of patients requiring surgery between the two treatment arms: The need for surgery will be recorded during patient follow-up (surgery/no surgery). The necessity for surgery will be left to the discretion of the physician responsible for the patient’s follow-up.
8. To compare the degree of autonomy and quality of life of patients between the two treatment arms: The degree of autonomy of each patient will be assessed using the Karnofsky index, mRS, ECOG Performance Status, and SF-36 every 6 months

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Nozar AGHAKHANI

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Malika Yahmi

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications