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

Noonan Syndrome Clinical Trial

— RASTAT  

Official title:

Treatment With HMG-COA Reductase Inhibitor (Simvastatin) of Growth and Bone Abnormalities in Children With Noonan Syndrome: A Phase III Randomised, Double Blind, Placebo-controlled Therapeutic Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02713945
• Other study ID #: RC31/15/7826
• Status: Completed
• Phase: Phase 3
• Start date: January 25, 2017
• Est. completion date: March 3, 2023

Study information

• Verified date: May 2023
• Source: University Hospital, Toulouse
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 53
• Est. completion date: March 3, 2023
• Est. primary completion date: March 3, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years to 16 Years

Eligibility

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

Related Conditions & MeSH terms

• Noonan Syndrome
• Syndrome

Intervention

Drug:
• Simvastatin
Experimental drug administrated orally
• Placebo
Treatment for the control group

Locations

Country	Name	City	State
France	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

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Toulouse

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Effect of a 12-month simvastatin treatment on growth in NS children as assessed by change in Insulin-like Growth Factor-1 (IGF-1) levels converted to age and sex specific z-scores		Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary	Effect of a 12-month simvastatin treatment on growth velocity as assessed by Height measurement.		Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary	Effect of a 12-month simvastatin treatment on body mass index as assessed by height and weight measurement.		Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary	Effect of a 12-month simvastatin treatment on waist circumference as assessed by clinical examination		Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary	Effect of a 12-month simvastatin treatment on hormonal growth parameters as assessed by serum IGFBP-3 levels		Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary	Effect of a 12-month simvastatin treatment on growth plates as assessed by serum C-type natriuretic peptide (CNP) levels		Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary	Effect of a 12-month simvastatin treatment on growth plates as assessed by serum amino-terminal propeptide of CNP (NTproCNP) levels		Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary	Effect of a 12-month simvastatin treatment on bone formation as assessed by serum bone alkaline phosphatase (BAP) levels		Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary	Effect of a 12-month simvastatin treatment on bone resorption as assessed by serum carboxy-terminal collagen crosslinks (CTX) levels		Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary	Effect of a 12-month simvastatin treatment on cardiac function as assessed by echocardiography		Baseline and month 12
Secondary	Effect of a 12-month simvastatin treatment on cognitive deficits as assessed by parent-rated child behaviour checklist (CBCL)		Baseline and month 12
Secondary	Effect of a 12-month simvastatin treatment on behavioural deficits as assessed by parent-rated child behaviour checklist (CBCL)		Baseline and month 12
Secondary	Effect of a 12-month simvastatin treatment on metabolism of lipids as assessed by lipids levels.		Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary	Effect of a 12-month simvastatin treatment on metabolism of lipids as assessed by leptin levels.		Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary	Effect of a 12-month simvastatin treatment on metabolism of lipids as assessed by adipokines levels.		Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary	Effect of a 12-month simvastatin treatment on fat body mass as assessed by Dual-energy X-ray Absorptiometry (DXA).		Baseline and month 12
Secondary	Effect of a 12-month simvastatin treatment on insulin sensitivity indices as assessed by Homeostasis Model Assessment of Insulin Resistance (HOMA-IR).		Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary	Effect of a 12-month simvastatin treatment on insulin sensitivity indices as assessed by Quantitative Insulin-Sensitivity Check Index (QUICKI)		Baseline, month 1, month 3, month 6, month 9 and month 12