Clinical trial NCT02713945: Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Noonan Syndrome
Keywords: Simvastatin
Ras
MAPK
Lead sponsor: University Hospital, Toulouse
Sponsor class: OTHER
First posted: 2016-03-21
Enrollment: 53
Sex: ALL
Minimum age (years): 6
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: 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
timeFrame: Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary outcomes:
measure: Effect of a 12-month simvastatin treatment on growth velocity as assessed by Height measurement.
timeFrame: Baseline, month 1, month 3, month 6, month 9 and month 12
measure: Effect of a 12-month simvastatin treatment on body mass index as assessed by height and weight measurement.
timeFrame: Baseline, month 1, month 3, month 6, month 9 and month 12
measure: Effect of a 12-month simvastatin treatment on waist circumference as assessed by clinical examination
timeFrame: Baseline, month 1, month 3, month 6, month 9 and month 12
measure: Effect of a 12-month simvastatin treatment on hormonal growth parameters as assessed by serum IGFBP-3 levels
timeFrame: Baseline, month 1, month 3, month 6, month 9 and month 12
measure: Effect of a 12-month simvastatin treatment on growth plates as assessed by serum C-type natriuretic peptide (CNP) levels
timeFrame: Baseline, month 1, month 3, month 6, month 9 and month 12
measure: Effect of a 12-month simvastatin treatment on growth plates as assessed by serum amino-terminal propeptide of CNP (NTproCNP) levels
timeFrame: Baseline, month 1, month 3, month 6, month 9 and month 12
measure: Effect of a 12-month simvastatin treatment on bone formation as assessed by serum bone alkaline phosphatase (BAP) levels
timeFrame: Baseline, month 1, month 3, month 6, month 9 and month 12
measure: Effect of a 12-month simvastatin treatment on bone resorption as assessed by serum carboxy-terminal collagen crosslinks (CTX) levels
timeFrame: Baseline, month 1, month 3, month 6, month 9 and month 12
measure: Effect of a 12-month simvastatin treatment on cardiac function as assessed by echocardiography
timeFrame: Baseline and month 12
measure: Effect of a 12-month simvastatin treatment on cognitive deficits as assessed by parent-rated child behaviour checklist (CBCL)
timeFrame: Baseline and month 12
measure: Effect of a 12-month simvastatin treatment on behavioural deficits as assessed by parent-rated child behaviour checklist (CBCL)
timeFrame: Baseline and month 12
measure: Effect of a 12-month simvastatin treatment on metabolism of lipids as assessed by lipids levels.
timeFrame: Baseline, month 1, month 3, month 6, month 9 and month 12
measure: Effect of a 12-month simvastatin treatment on metabolism of lipids as assessed by leptin levels.
timeFrame: Baseline, month 1, month 3, month 6, month 9 and month 12
measure: Effect of a 12-month simvastatin treatment on metabolism of lipids as assessed by adipokines levels.
timeFrame: Baseline, month 1, month 3, month 6, month 9 and month 12
measure: Effect of a 12-month simvastatin treatment on fat body mass as assessed by Dual-energy X-ray Absorptiometry (DXA).
timeFrame: Baseline and month 12
measure: Effect of a 12-month simvastatin treatment on insulin sensitivity indices as assessed by Homeostasis Model Assessment of Insulin Resistance (HOMA-IR).
timeFrame: Baseline, month 1, month 3, month 6, month 9 and month 12
measure: Effect of a 12-month simvastatin treatment on insulin sensitivity indices as assessed by Quantitative Insulin-Sensitivity Check Index (QUICKI)
timeFrame: Baseline, month 1, month 3, month 6, month 9 and month 12
Other outcomes:
Locations:
city: Angers
country: France
facility: CHU Angers Unité d'endocrinologie pédiatrique
city: Bordeaux
country: France
facility: CHU Bordeaux Unité de Génétique pédiatrique
city: Dijon
country: France
facility: Chu Dijon
city: Lille
country: France
facility: CHRU Lille Unité d'endocrinologie pédiatrique
city: Lyon
country: France
facility: CHU Lyon Unité d'endocrinologie pédiatrique
city: Marseille
country: France
facility: CHU Marseille La Timone Unité d'Endocrinologie pédiatrique
city: Montpellier
country: France
facility: Chu Montpellier
city: Nancy
country: France
facility: CHU Nancy Unité de Génétique pédiatrique
city: Paris
country: France
facility: Hôpital Robert Debré Unité de Génétique pédiatrique
city: Paris
country: France
facility: Hôpital Trousseau Unité d'endocrinologie pédiatrique
city: Rennes
country: France
facility: CHU Rennes Unité de Génétique pédiatrique
city: Toulouse
country: France
facility: CHU Toulouse Hôpital des Enfants
Study officials:
affiliation: Children's Hospital, Toulouse University Hospital
name: Thomas Edouard, MD, PHD
role: PRINCIPAL_INVESTIGATOR
References: