Clinical trial NCT00876200: Efficacy of Minoxidil in Children With Williams-Beuren Syndrome
Official title: The Efficacy of Minoxidil in Children With Williams-Beuren Syndrome: a Randomized Clinical Trial.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Williams Beuren Syndrome
Keywords: Williams Beuren syndrome
Cardiovascular abnormalities
Cardiovascular structure
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2009-04-06
Enrollment: 21
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The Williams-Beuren syndrome (WBS) is a sporadic congenital disorder characterized by a multisystem developmental impairment. This syndrome is caused by a microdeletion in chromosome 7q11.23 that encompasses loss of the elastin locus.

Elastin, which is part of the extracellular matrix, controls proliferation of vascular smooth muscle cells (VSMCs) and stabilizes arterial structure. Loss of elastin gene in WBS patients has been claimed to provide a biological basis for the abnormal elastic fibre properties leading to cardiovascular abnormalities like supravalvular aortic stenosis (SVAS), hypertension, arteriosclerosis and stenosis in more than 50% of WBS children.

These cardiovascular pathologies result in important consequences and neither curative nor preventive medicinal treatments exist at this time. Surgery is needed in more than half cases, while it is often leading to complications.

Minoxidil is a well-known antihypertensive drug used in adults and children. Furthermore, according to animal studies, minoxidil seems to increase arterial elastin content by decreasing elastase activity in these tissues. Other data demonstrate that minoxidil specifically stimulate elastin synthesis.

Working Hypothesis:If insufficient elastin synthesis leads to vascular complications and arterial hypertension in children with WBS, restoration of sufficient quantity of elastin should then result in prevention or inhibition of vascular malformations and improvement in arterial tension. Therefore, as a pharmacological agent capable to stimulate elastin expression, minoxidil might be a useful drug for the treatment of abnormal elastin metabolism in WBS children.

Objective:To evaluate the efficacy of minoxidil on cardiovascular structure in children with Williams Beuren syndrome.

Methodology: randomized controlled trial on two parallel group (23 patients in each arm) Main criterion:variation of carotid Intima-media thickness (IMT) before and after 12 months of treatment with Minoxidil versus placebo Secondary intermediate criteria of the vascular properties are arterial stiffness, cardiac and renal stenosis, arterial tension.

Total study duration:30 months including a 12 month-recruitment period


Eligibility criteria: Inclusion Criteria:

* proven diagnosis of Williams Beuren syndrome (genetic test)
* normotension or hypertension, treated or not
* male or female,
* 6\< age \<18,
* negative pregnancy test for childbearing potential female
* effective birth control for sexually active female
* signed consent form collected from parents or legal guardian

Exclusion Criteria:

* pulmonary hypertension secondary to mitral stenosis
* myocardial infarction within 1 month prior randomization
* known allergies to minoxidil or any of the components of Lonoten.
* asthma
* renal failure (creatinine clearance \<40ml/min)
* no affiliation to a national health insurance program (social security)
* intolerance to lactose
* current vasodilator anti hypertensive treatment

Primary outcomes:
measure: Variation of Carotid Intima-media Thickness (IMT) Assessed by Vascular Echography
timeFrame: 12 months
Secondary outcomes:
measure: Efficacy of Minoxidil on Humeral IMT Assessed by Vascular Echography
timeFrame: 18 months
measure: Efficacy of Minoxidil on Arterial Stiffness (Pulse Wave Velocity and Vascular Compliance at J0, M12 and M18)
timeFrame: 18 months
measure: Efficacy of Minoxidil on Supravalvular Stenosis, Pulmonary Stenosis, Aortic Stenosis and Renal Stenosis (Cardiac and Renal Echodoppler at J0, and M12)
timeFrame: 12 months
measure: Efficacy of Minoxidil on Arterial Tension (24H-Holter at J0 and M12)
timeFrame: 12 months
measure: Effect of Minoxidil on Neurohumoral Mechanisms of Cardiovascular Regulation and on Plasmatic Markers of the Extracellular Matrix.
timeFrame: 12 months
measure: Genetic Study: Characterization of Deletions Responsible for WBS (Size Deletion, DNA Sample at Inclusion).
timeFrame: Day 0
Other outcomes:
Locations:
city: Angers
country: France
facility: Service de Cardiologie Pédiatrique, CHU Angers
city: Bordeaux
country: France
facility: Service de Cardiologie, Hôpital Saint-André, CHU Bordeaux
city: Bordeaux
country: France
facility: Service de Néphrologie Pédiatrique, Hôpital Pellegrin, CHU Bordeaux
city: Bordeaux
country: France
facility: Service de Génétique Médicale, Hôpital Pellegrin, CHU Bordeaux
city: Bron
country: France
facility: Département de Pédiatrie, Hôpital Femme Mère Enfant
city: Bron
country: France
facility: Service de Cardiologie Pédiatrique, Hôpital Cardiovasculaire L. Pradel
city: Clermont-Ferrand
country: France
facility: Service Cardiologie, CHU St Jacques
city: Grenoble
country: France
facility: Département de Pédiatrie- Service de Cardiologie, CHU Grenoble
city: Lille
country: France
facility: Service de Néphrologie Pédiatrique, CHRU de Lille
city: Lille
country: France
facility: Service des Maladies Cardiovasculaires Infantiles et Congénitales, CHRU Lille
city: Nancy
country: France
facility: Service de Cardiologie Infantile, CHU Nancy
city: Paris
country: France
facility: Service de Cardiologie Pédiatrique, Hôpital Necker Enfants Malades
city: Paris
country: France
facility: Service de Physiologie, Explorations Fonctionnelles, Hôpital Robert Debré
city: Paris
country: France
facility: Unité de Pharmacologie Clinique, Hôpital Robert Debré
city: Pessac
country: France
facility: Service de Pathologie Cardiaque Congénitale du Fœtus, de l'Enfant et de l'Adulte, Hôpital Haut Lévêque, CHU de Bordeaux
city: Poitiers
country: France
facility: Service de Génétique Médicale, CHU La Milétrie
city: Toulouse
country: France
facility: Service de Cardiologie - Hôpital des Enfants
city: Toulouse
country: France
facility: Service de Néphrologie Pédiatrique - Hôpital des Enfants, CHU Toulouse
Study officials:
affiliation: Hospices Civils de Lyon
name: Behrouz KASSAI, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kassai B, Bouye P, Gilbert-Dussardier B, Godart F, Thambo JB, Rossi M, Cochat P, Chirossel P, Luong S, Serusclat A, Canterino I, Mercier C, Rabilloud M, Pivot C, Pirot F, Ginhoux T, Coopman S, Grenet G, Gueyffier F, Di-Fillippo S, Bertholet-Thomas A. Minoxidil versus placebo in the treatment of arterial wall hypertrophy in children with Williams Beuren Syndrome: a randomized controlled trial. BMC Pediatr. 2019 May 28;19(1):170. doi: 10.1186/s12887-019-1544-1.