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

Sponsor

University Hospital, Toulouse (Other)

Overall Status

Recruiting

CT.gov ID

NCT02713945

Collaborator

(none)

Enrollment

Locations

Arms

68.2

Anticipated Duration (Months)

5.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Noonan Syndrome	Drug: Simvastatin Drug: Placebo	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

62 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jan 25, 2017

Anticipated Primary Completion Date :

Sep 1, 2021

Anticipated Study Completion Date :

Oct 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Simvastatin Experimental drug administrated orally
Placebo Comparator: Control Placebo administrated orally once daily in the morning	Drug: Placebo Treatment for the control group

Arm

Intervention/Treatment

Experimental: 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.

Drug: Simvastatin

Experimental drug administrated orally

Placebo Comparator: Control

Placebo administrated orally once daily in the morning

Drug: Placebo

Treatment for the control group

Outcome Measures

Primary Outcome Measures

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 Outcome Measures

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]
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]
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]
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]
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]
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]
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]
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]
Effect of a 12-month simvastatin treatment on cardiac function as assessed by echocardiography [Baseline and month 12]
Effect of a 12-month simvastatin treatment on cognitive deficits as assessed by parent-rated child behaviour checklist (CBCL) [Baseline and month 12]
Effect of a 12-month simvastatin treatment on behavioural deficits as assessed by parent-rated child behaviour checklist (CBCL) [Baseline and month 12]
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]
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]
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]
Effect of a 12-month simvastatin treatment on fat body mass as assessed by Dual-energy X-ray Absorptiometry (DXA). [Baseline and month 12]
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]
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Years to 16 Years

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	Country
1	CHU Angers Unité d'endocrinologie pédiatrique	Angers	France
2	CHU Bordeaux Unité de Génétique pédiatrique	Bordeaux	France
3	Chu Dijon	Dijon	France
4	CHRU Lille Unité d'endocrinologie pédiatrique	Lille	France
5	CHU Lyon Unité d'endocrinologie pédiatrique	Lyon	France
6	CHU Marseille La Timone Unité d'Endocrinologie pédiatrique	Marseille	France
7	Chu Montpellier	Montpellier	France
8	CHU Nancy Unité de Génétique pédiatrique	Nancy	France
9	Hôpital Robert Debré Unité de Génétique pédiatrique	Paris	France
10	Hôpital Trousseau Unité d'endocrinologie pédiatrique	Paris	France
11	CHU Rennes Unité de Génétique pédiatrique	Rennes	France
12	CHU Toulouse Hôpital des Enfants	Toulouse	France