Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome

NCT ID: NCT02713945

Last Updated: 2023-05-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 53 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-25
• Study Completion Date: 2023-03-03

Brief Summary

This study evaluate the efficacy of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-COA) reductase inhibitors, also known as "statins" in the treatment of growth and skeletal abnormalities in children with Noonan syndrome. Half of patients will receive simvastatin while the other half will receive a placebo.

Detailed Description

Noonan syndrome (NS) is a relatively frequent autosomal dominant disorder characterised by facial dysmorphic features, heart defects, developmental delay, and short stature. This syndrome is mostly caused by gain-of-function mutations in the PTPN11 gene, encoding tyrosine phosphatase. The best-defined consequence of NS-causing mutants is an enhancement of Ras/MAPK activation that is responsible for the different NS features. Mutations in several genes encoding other components of the Ras/Mitogen Activated Protein Kinase (MAPK) pathway, resulting in hyperactivation, are also found in syndromes close to NS.

Short stature caused by growth hormone insensitivity and skeletal abnormalities are major concerns in NS. To date there is no effective specific therapy for affected patients. Given the role of Ras/Mitogen Activated Protein Kinase (MAPK) activation in NS pathophysiology, therapeutic strategies aiming to reduce this activation seem to be very promising.

Recently, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-COA) reductase inhibitors, also known as "statins" have been suggested as a potential therapy by decreasing Ras activity.

The efficacy of statins for treating cognitive deficits have been reported in mouse models of NS. Statins (simvastatin) have been assessed in mouse models and clinical studies for the treatment of cognitive deficits in children with discordant results but good tolerance. Recently, it has been demonstrated that statins may also correct bone growth abnormality in a mouse model for achondroplasia.

As growth is usually normal at birth in NS patients and thereafter progressively worsens throughout childhood, the investigators expect that precocious modulation of Ras/MAPK activation by statins may attenuate growth retardation. To achieve this goal, the present study is the first prospective randomised placebo-controlled therapeutic trial using statins in children with NS.

Marketing authorisation for statins is already accepted for the treatment of children with familial hypercholesterolemia and worldwide marketing authorisation of statins.

Conditions

Noonan Syndrome

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Simvastatin

Simvastatin administrated orally at 10 mg once a day in the morning during the first month Simvastatin administrated orally at 20 mg once a day in the morning during the second month During months 3 to 12, the dose will be fixed at 20 mg per day for children aged 12 years and younger and 40 mg for adolescent older than 12 years.

Group Type: EXPERIMENTAL

Simvastatin

Intervention Type: DRUG

Experimental drug administrated orally

Control

Placebo administrated orally once daily in the morning

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Treatment for the control group

Interventions

Simvastatin

Experimental drug administrated orally

Intervention Type: DRUG

Placebo

Treatment for the control group

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Genetically confirmed Noonan syndrome
• Female child between 6 to 15 years, without menses, with bone age < 13 years
• Male child between 6 to 16 years, with bone age < 14 years
• Decreased growth velocity (< -1 SDS) and/or short stature (height < -2 SDS or -1,5 SDS under target height)
• Informed consent obtained from child and parents

Exclusion Criteria

• Contraindication to simvastatin treatment :
• Progressive liver disease, increased serum levels of alanine aminotransferase (ALT) (> 1,5 uper limit of normal (ULN)), aspartate aminotransferase (> 1,5 ULN)
• Known hypersensitivity to simvastatin
• Pregnancy
• Treatment with CYP3A4 inhibitors (erythromycin, clarithromycin, ketoconazole, or itraconazole)
• Growth promoting therapies such as recombinant human Growth Hormone (GH) or IGF-1 treatment

• Minimum Eligible Age: 6 Years
• Maximum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Toulouse

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Thomas Edouard, MD, PHD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital, Toulouse University Hospital

Locations

CHU Angers Unité d'endocrinologie pédiatrique

Angers, , France

CHU Bordeaux Unité de Génétique pédiatrique

Bordeaux, , France

Chu Dijon

Dijon, , France

CHRU Lille Unité d'endocrinologie pédiatrique

Lille, , France

CHU Lyon Unité d'endocrinologie pédiatrique

Lyon, , France

CHU Marseille La Timone Unité d'Endocrinologie pédiatrique

Marseille, , France

Chu Montpellier

Montpellier, , France

CHU Nancy Unité de Génétique pédiatrique

Nancy, , France

Hôpital Robert Debré Unité de Génétique pédiatrique

Paris, , France

Hôpital Trousseau Unité d'endocrinologie pédiatrique

Paris, , France

CHU Rennes Unité de Génétique pédiatrique

Rennes, , France

CHU Toulouse Hôpital des Enfants

Toulouse, , France

Countries

France

Other Identifiers

RC31/15/7826

Identifier Type: -

Identifier Source: org_study_id