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

Toulouse University Hospital

Status and phase: Completed; Phase 3

Conditions: Noonan Syndrome

Treatments: Drug: Simvastatin; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT02713945

RC31/15/7826

Details and patient eligibility

About

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.

Full 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.

Enrollment: 53 patients

Sex: All

Ages: 6 to 16 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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53 participants in 2 patient groups, including a placebo group

Simvastatin

Experimental group

Description:

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.

Treatment:

Drug: Simvastatin

Control

Placebo Comparator group

Description:

Placebo administrated orally once daily in the morning

Treatment:

Drug: Placebo