Efficacy of Minoxidil in Children With Williams-Beuren Syndrome (Williams)

The Efficacy of Minoxidil in Children With Williams-Beuren Syndrome: a Randomized Clinical Trial.

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

Study Overview

• Status: Completed
• Conditions: Williams Beuren Syndrome
• Intervention / Treatment: Drug: Minoxidil; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Angers, France, 49033
    • Service de Cardiologie Pédiatrique, CHU Angers
  • Bordeaux, France, 33075
    • Service de Cardiologie, Hôpital Saint-André, CHU Bordeaux
  • Bordeaux, France, 33076
    • Service de Néphrologie Pédiatrique, Hôpital Pellegrin, CHU Bordeaux
  • Bordeaux, France
    • Service de Génétique Médicale, Hôpital Pellegrin, CHU Bordeaux
  • Bron, France, 69677
    • Département de Pédiatrie, Hôpital Femme Mère Enfant
  • Bron, France, 69677
    • Service de Cardiologie Pédiatrique, Hôpital Cardiovasculaire L. Pradel
  • Clermont-Ferrand, France, 63000
    • Service Cardiologie, CHU St Jacques
  • Grenoble, France, 38043
    • Département de Pédiatrie- Service de Cardiologie, CHU Grenoble
  • Lille, France, 59000
    • Service de Néphrologie Pédiatrique, CHRU de Lille
  • Lille, France, 59000
    • Service des Maladies Cardiovasculaires Infantiles et Congénitales, CHRU Lille
  • Nancy, France, 54511
    • Service de Cardiologie Infantile, CHU Nancy
  • Paris, France, 75015
    • Service de Cardiologie Pédiatrique, Hôpital Necker Enfants Malades
  • Paris, France, 75019
    • Service de Physiologie, Explorations Fonctionnelles, Hôpital Robert Debré
  • Paris, France, 75019
    • Unité de Pharmacologie Clinique, Hôpital Robert Debré
  • Pessac, France, 33604
    • Service de Pathologie Cardiaque Congénitale du Fœtus, de l'Enfant et de l'Adulte, Hôpital Haut Lévêque, CHU de Bordeaux
  • Poitiers, France, 86021
    • Service de Génétique Médicale, CHU La Milétrie
  • Toulouse, France, 31059
    • Service de Cardiologie - Hôpital des Enfants
  • Toulouse, France, 31059
    • Service de Néphrologie Pédiatrique - Hôpital des Enfants, CHU Toulouse

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 16 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Minoxidil; Normotension: 0.2mg/kg/day for children under 12 and 5mg/day for children aged 12 or more. Hypertension: 0.2mg/kg/day, increasing up to a maximal dosage of 1 mg/kg) for children under 12. 5mg/day, increasing as needed of 0.1 mg/kg/day (up to a maximal dosage of 40 mg/day) for children aged 12 or more.	Drug: Minoxidil; Normotension: 0.2mg/kg/day for children under 12 and 5mg/day for children aged 12 or more. Hypertension: 0.2mg/kg/day, increasing up to a maximal dosage of 1 mg/kg) for children under 12. 5mg/day, increasing as needed of 0.1 mg/kg/day (up to a maximal dosage of 40 mg/day) for children aged 12 or more.
Placebo Comparator: Placebo; Placebo = lactose	Drug: Placebo; Normotension: 0.2mg/kg/day for children under 12 and 5mg/day for children aged 12 or more. Hypertension: 0.2mg/kg/day, increasing up to a maximal dosage of 1 mg/kg) for children under 12. 5mg/day, increasing as needed of 0.1 mg/kg/day (up to a maximal dosage of 40 mg/day) for children aged 12 or more.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Variation of Carotid Intima-media Thickness (IMT) Assessed by Vascular Echography	12 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Efficacy of Minoxidil on Humeral IMT Assessed by Vascular Echography	18 months
Efficacy of Minoxidil on Arterial Stiffness (Pulse Wave Velocity and Vascular Compliance at J0, M12 and M18)	18 months
Efficacy of Minoxidil on Supravalvular Stenosis, Pulmonary Stenosis, Aortic Stenosis and Renal Stenosis (Cardiac and Renal Echodoppler at J0, and M12)	12 months
Efficacy of Minoxidil on Arterial Tension (24H-Holter at J0 and M12)	12 months
Effect of Minoxidil on Neurohumoral Mechanisms of Cardiovascular Regulation and on Plasmatic Markers of the Extracellular Matrix.	12 months
Genetic Study: Characterization of Deletions Responsible for WBS (Size Deletion, DNA Sample at Inclusion).	Day 0

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Publications and helpful links

General Publications

• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): August 1, 2015

Study Registration Dates

• First Submitted: April 3, 2009
• First Submitted That Met QC Criteria: April 3, 2009
• First Posted (Estimate): April 6, 2009

Study Record Updates

• Last Update Posted (Actual): July 26, 2019
• Last Update Submitted That Met QC Criteria: May 29, 2019
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: Williams Beuren syndrome; Cardiovascular abnormalities; Cardiovascular structure
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Disease; Congenital Abnormalities; Genetic Diseases, Inborn; Aortic Valve Disease; Heart Valve Diseases; Intellectual Disability; Chromosome Disorders; Aortic Valve Stenosis; Aortic Stenosis, Supravalvular; Syndrome; Williams Syndrome; Antihypertensive Agents; Vasodilator Agents; Minoxidil
• Other Study ID Numbers: 2006.437/30