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

  • STATUS
    Recruiting
  • End date
    Oct 25, 2022
  • participants needed
    62
  • sponsor
    University Hospital, Toulouse
Updated on 26 January 2021

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.

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.

Details
Condition Noonan Syndrome, CONNECTIVE TISSUE DISEASE, Congenital Heart Defect, Congenital Heart Disease, Dermatomyositis (Connective Tissue Disease), Connective Tissue Diseases, Heart Defect
Treatment Placebo, Simvastatin
Clinical Study IdentifierNCT02713945
SponsorUniversity Hospital, Toulouse
Last Modified on26 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age between 6 yrs and 16 yrs?
Gender: Male or Female
Do you have any of these conditions: Noonan Syndrome or CONNECTIVE TISSUE DISEASE or Congenital Heart Disease or Heart Defect or Dermatomyositis (Connective Tissue Disease) or Connective ...?
Do you have any of these conditions: Heart Defect or Connective Tissue Diseases or CONNECTIVE TISSUE DISEASE or Dermatomyositis (Connective Tissue Disease) or Noonan Syndrome or Congenita...?
Do you have any of these conditions: Noonan Syndrome or CONNECTIVE TISSUE DISEASE or Congenital Heart Defect or Dermatomyositis (Connective Tissue Disease) or Heart Defect or Connective T...?
Do you have any of these conditions: Heart Defect or Congenital Heart Defect or Connective Tissue Diseases or Congenital Heart Disease or CONNECTIVE TISSUE DISEASE or Noonan Syndrome or D...?
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
Clear my responses

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