Efficacy of Minoxidil in Children With Williams-Beuren Syndrome

• Sponsor: Hospices Civils de Lyon (Other)
• Overall Status: Completed
• CT.gov ID: NCT00876200
• Collaborator: (none)
• Enrollment: 21
• Locations: 18
• Arms: 2
• Duration (Months): 77
• Patients Per Site: 1.2
• Patients Per Site Per Month: 0

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Williams Beuren Syndrome	Drug: Minoxidil; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Efficacy of Minoxidil in Children With Williams-Beuren Syndrome: a Randomized Clinical Trial.
• Study Start Date: Mar 1, 2009
• Actual Primary Completion Date: Feb 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. Variation of Carotid Intima-media Thickness (IMT) Assessed by Vascular Echography [12 months]

Secondary Outcome Measures

1. Efficacy of Minoxidil on Humeral IMT Assessed by Vascular Echography [18 months]

2. Efficacy of Minoxidil on Arterial Stiffness (Pulse Wave Velocity and Vascular Compliance at J0, M12 and M18) [18 months]

3. Efficacy of Minoxidil on Supravalvular Stenosis, Pulmonary Stenosis, Aortic Stenosis and Renal Stenosis (Cardiac and Renal Echodoppler at J0, and M12) [12 months]

4. Efficacy of Minoxidil on Arterial Tension (24H-Holter at J0 and M12) [12 months]

5. Effect of Minoxidil on Neurohumoral Mechanisms of Cardiovascular Regulation and on Plasmatic Markers of the Extracellular Matrix. [12 months]

6. Genetic Study: Characterization of Deletions Responsible for WBS (Size Deletion, DNA Sample at Inclusion). [Day 0]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Service de Cardiologie Pédiatrique, CHU Angers	Angers		France	49033
2	Service de Cardiologie, Hôpital Saint-André, CHU Bordeaux	Bordeaux		France	33075
3	Service de Néphrologie Pédiatrique, Hôpital Pellegrin, CHU Bordeaux	Bordeaux		France	33076
4	Service de Génétique Médicale, Hôpital Pellegrin, CHU Bordeaux	Bordeaux		France
5	Département de Pédiatrie, Hôpital Femme Mère Enfant	Bron		France	69677
6	Service de Cardiologie Pédiatrique, Hôpital Cardiovasculaire L. Pradel	Bron		France	69677
7	Service Cardiologie, CHU St Jacques	Clermont-Ferrand		France	63000
8	Département de Pédiatrie- Service de Cardiologie, CHU Grenoble	Grenoble		France	38043
9	Service de Néphrologie Pédiatrique, CHRU de Lille	Lille		France	59000
10	Service des Maladies Cardiovasculaires Infantiles et Congénitales, CHRU Lille	Lille		France	59000
11	Service de Cardiologie Infantile, CHU Nancy	Nancy		France	54511
12	Service de Cardiologie Pédiatrique, Hôpital Necker Enfants Malades	Paris		France	75015
13	Service de Physiologie, Explorations Fonctionnelles, Hôpital Robert Debré	Paris		France	75019
14	Unité de Pharmacologie Clinique, Hôpital Robert Debré	Paris		France	75019
15	Service de Pathologie Cardiaque Congénitale du Fœtus, de l'Enfant et de l'Adulte, Hôpital Haut Lévêque, CHU de Bordeaux	Pessac		France	33604
16	Service de Génétique Médicale, CHU La Milétrie	Poitiers		France	86021
17	Service de Cardiologie - Hôpital des Enfants	Toulouse		France	31059
18	Service de Néphrologie Pédiatrique - Hôpital des Enfants, CHU Toulouse	Toulouse		France	31059

Sponsors and Collaborators

• Hospices Civils de Lyon

Investigators

• Principal Investigator: Behrouz KASSAI, MD, Hospices Civils de Lyon

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Hospices Civils de Lyon
• ClinicalTrials.gov Identifier: NCT00876200
• Other Study ID Numbers: 2006.437/30
• First Posted: Apr 6, 2009
• Last Update Posted: Jul 26, 2019
• Last Verified: Jan 1, 2016

• Keywords provided by Hospices Civils de Lyon: Williams Beuren syndrome; Cardiovascular abnormalities; Cardiovascular structure
• Additional relevant MeSH terms: Williams Syndrome; Syndrome; Minoxidil

Study Results

Participant Flow

Arm/Group Title	Minoxidil	Placebo
Arm/Group Description	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. 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 = lactose 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.
Period Title: Overall Study
STARTED	9	12
COMPLETED	8	9
NOT COMPLETED	1	3

Baseline Characteristics

Arm/Group Title	Minoxidil	Placebo	Total
Arm/Group Description	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. 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 = lactose 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.	Total of all reporting groups
Overall Participants	9	12	21
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.33 (4.42)	10.75 (3.77)	11.43 (4.03)
Sex: Female, Male (Count of Participants)
Female	5 55.6%	4 33.3%	9 42.9%
Male	4 44.4%	8 66.7%	12 57.1%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
History of hypertension (Count of Participants)
Count of Participants [Participants]	2 22.2%	2 16.7%	4 19%
History of cardiovascular disease (Count of Participants)
Count of Participants [Participants]	4 44.4%	6 50%	10 47.6%
Systolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	128.11 (16.78)	120.83 (12.68)	123.95 (14.65)
Diastolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	78.22 (15.58)	73.17 (8.97)	75.33 (12.16)
BMI (Kg/cm2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Kg/cm2]	17.93 (3.88)	17.54 (3.30)	17.71 (3.47)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Minoxidil	Placebo
Arm/Group Description	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. 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 = lactose 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.
Measure Participants	9	9
Mean (95% Confidence Interval) [mm]	0.028	0.012

2. Secondary Outcome

Title	Efficacy of Minoxidil on Humeral IMT Assessed by Vascular Echography
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Efficacy of Minoxidil on Arterial Stiffness (Pulse Wave Velocity and Vascular Compliance at J0, M12 and M18)
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Efficacy of Minoxidil on Supravalvular Stenosis, Pulmonary Stenosis, Aortic Stenosis and Renal Stenosis (Cardiac and Renal Echodoppler at J0, and M12)
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Efficacy of Minoxidil on Arterial Tension (24H-Holter at J0 and M12)
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Effect of Minoxidil on Neurohumoral Mechanisms of Cardiovascular Regulation and on Plasmatic Markers of the Extracellular Matrix.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Genetic Study: Characterization of Deletions Responsible for WBS (Size Deletion, DNA Sample at Inclusion).
Time Frame	Day 0

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Minoxidil		Placebo
Arm/Group Description	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. 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 = lactose 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.
All Cause Mortality
	Minoxidil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Minoxidil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/9 (11.1%)		1/12 (8.3%)
Musculoskeletal and connective tissue disorders
Flat foot	0/9 (0%)	0	1/12 (8.3%)	1
Surgical and medical procedures
Strabismus correction	1/9 (11.1%)	1	0/12 (0%)	0
Other (Not Including Serious) Adverse Events
	Minoxidil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/9 (55.6%)		0/12 (0%)
Skin and subcutaneous tissue disorders
Hypertrichosis	5/9 (55.6%)	5	0/12 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.