Von Hippel-Lindau Disease Clinical Trial
— PRO-HEBOfficial title:
Efficacy of Propranolol for the Treatment of Central Nervous System Hemangioblastomas in Von Hippel-Lindau Disease: a Randomized Controlled Clinical Trial
Propranolol (beta-blocker), is successfully used for the treatment of infantile hemangiomas, the most common vascular tumor of newborns. The mechanism is related to its anti-angiogenetic and pro-apoptotic effects. Recently, in vitro studies demonstrated that propranolol decreased the expression of target genes of the HIF (hypoxia-inducible factor, of which the VHL gene is the main regulator) pathway in hemangioblastoma cells and affected their viability. The efficacy of propranolol (stabilization of all HB and decrease in serum VEGF levels) was demonstrated in a phase III study, but only in retinal BHs . The only study that evaluated the effect of propranolol on CNS HB was retrospective and involved a limited number of patients. Nevertheless, it showed a decrease in the growth rate of HBs. The investigator therefore propose to carry out a randomized controlled trial to study the effect of propranolol on the growth of CNS HB in patients with VHL disease (von Hippel-Lindau). The hypothesis of the present work is the following: the use of propranolol in VHL patients with CNS HB allows to decrease and/or slow down the tumor growth.
Status | Recruiting |
Enrollment | 85 |
Est. completion date | November 1, 2026 |
Est. primary completion date | November 1, 2026 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | Inclusion Criteria: - Age = 18 - VHL patient with one or more hemangioblastomas of the central nervous system, none of which require urgent surgery (within 3 months) - Patient with written consent to participate in the study - Enrolled in a social security plan or beneficiary Exclusion Criteria: - Contraindication to the use of propranolol: - chronic obstructive pulmonary disease and asthma, - uncontrolled heart failure, - 2nd and 3rd degree atrioventricular blocks, - bradycardia (<50 beats/minute after 3 minutes of rest), - Raynaud's phenomenon and peripheral arterial disorders, - arterial hypotension, - hypersensitivity to propranolol - cardiogenic shock, - Prinzmetal's angina, - sinus disease (including sino-auricular block) - untreated pheochromocytoma, - history of anaphylactic reaction, - in the context of primary and secondary prevention of digestive bleeding in cirrhotics: advanced liver failure with hyperbilirubinemia, massive ascites, hepatic encephalopathy - predisposition to hypoglycemia (as after fasting or in case of abnormal response to hypoglycemia) - metabolic acidosis - Contraindication to MRI: - claustrophobia, - presence of a pace maker and other stimulators/implants - ocular metallic foreign bodies, - heart valves or ferromagnetic metal vascular clips - Patients already on Propranolol or other beta blockers - Patients under guardianship or conservatorship - Pregnant or breastfeeding women - Woman with a medium-term pregnancy project |
Country | Name | City | State |
---|---|---|---|
France | AP-HP, Bicêtre Hospital | Le Kremlin Bicêtre |
Lead Sponsor | Collaborator |
---|---|
Assistance Publique - Hôpitaux de Paris | Agence Générale des Equipements et Produits de Santé |
France,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | total and individual hemangioblastomas' volume measured by MRI | Response to treatment at 24 months will be a binary variable (responder/non responder) using initial imaging data and 24-month post-randomization, assessed by two neuroradiologists, independently.
On baseline imaging two types of CNS BHs will be defined and measured: "measurable" BHs whose largest diameter is = 5 mm "Non-measurable" BHs whose largest diameter is < 5 mm For each patient the sum of the volumes of all measurable BHs in mm3 will be calculated initially and compared to this same sum at 24 months post-randomization. A patient will be as "responder" : The sum at 24 months remains stable Or regresses No HB identified as "non-measurable" initially has reached the "measurable" criterion No de novo HBs have appeared A patient will be as "non-responder": The sum at 24 months increases At least one HB identified as "non-measurable" initially has reached the "measurable" criterion At least one de novo HB appears The patient has required surgery during follow-up |
24 months | |
Secondary | To compare the safety (tolerance) between the two treatment arms at 24 months post-randomization | To study safety (tolerability) of propranolol in VHL patients: All adverse events related to the use of Propanolol that occurred during the study will be collected, analyzed and compared between the two treatment arms | 24 months | |
Secondary | To Compare the growth rate of HB between the two treatment arms at 24 months post-randomization | To compare HB growth rate between the two treatment arms at 24 months post-randomization: HB growth rate will be measured on each MRI 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 an accurate measurement of the tumor volume (In case of disagreement a conciliation session will be organized). The growth rate is therefore obtained by dividing the change in volume by the number of months between the two MRIs | 24 months | |
Secondary | Compare the extent of peritumoral edema between the two treatment arms | To compare the extent of peritumoral edema between the two treatment arms: The size of peritumoral edema will be measured on each MRI by two neuroradiologists, blinded to the randomization arm | 24 months | |
Secondary | Compare the development of de novo lesions between the two treatment arms every 6 months | To compare the occurrence of de novo lesions between the two treatment arms: the number of de novo HBs will be specified for each patient at each follow-up MRI by two neuroradiologists, blinded to the randomization arm. A de novo HB is defined as the appearance during follow-up of a HB that did not exist on the initial imaging (or the transition from a non-measurable HB to a measurable state | 24 months | |
Secondary | Compare the angiogenic profile of BHs between the two groups every 6 months | To compare the angiogenic profile of BHs between the two groups by perfusion sequence with r-CBV measurement for each measurable and perfusion-studyable lesion (> 1cm) | 24 months | |
Secondary | Study the evolution of serum VEGF level under treatment at 12 and 24 months | To study the evolution of serum VEGF level under treatment: Determination of serum VEGF level at the beginning of the treatment and then at 12 and 24 months by a simple peripheral venous blood sample. (pg/ml) | 24 months | |
Secondary | Compare the number of patients requiring surgery between the two treatment arms | To compare the number of patients requiring surgery between the two treatment arms: The use of surgery will be recorded during patient follow-up (use/non-use). The need for surgery will be left to the discretion of the physician responsible for the patient's follow-up | 24 months |
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