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

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ClinicalTrials.gov Identifier: NCT02713945
Recruitment Status : Recruiting
First Posted : March 21, 2016
Last Update Posted : November 9, 2020
Sponsor:
Information provided by (Responsible Party):
University Hospital, Toulouse

Study Description
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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
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Study Type : Interventional  (Clinical Trial)
Estimated 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 : January 25, 2017
Estimated Primary Completion Date : September 2021
Estimated Study Completion Date : October 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Simvastatin

Arms and Interventions
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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
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Primary Outcome Measures :
  1. 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 [ Time Frame: Baseline, month 1, month 3, month 6, month 9 and month 12 ]

Secondary Outcome Measures :
  1. Effect of a 12-month simvastatin treatment on growth velocity as assessed by Height measurement. [ Time Frame: Baseline, month 1, month 3, month 6, month 9 and month 12 ]
  2. Effect of a 12-month simvastatin treatment on body mass index as assessed by height and weight measurement. [ Time Frame: Baseline, month 1, month 3, month 6, month 9 and month 12 ]
  3. Effect of a 12-month simvastatin treatment on waist circumference as assessed by clinical examination [ Time Frame: Baseline, month 1, month 3, month 6, month 9 and month 12 ]
  4. Effect of a 12-month simvastatin treatment on hormonal growth parameters as assessed by serum IGFBP-3 levels [ Time Frame: Baseline, month 1, month 3, month 6, month 9 and month 12 ]
  5. Effect of a 12-month simvastatin treatment on growth plates as assessed by serum C-type natriuretic peptide (CNP) levels [ Time Frame: Baseline, month 1, month 3, month 6, month 9 and month 12 ]
  6. Effect of a 12-month simvastatin treatment on growth plates as assessed by serum amino-terminal propeptide of CNP (NTproCNP) levels [ Time Frame: Baseline, month 1, month 3, month 6, month 9 and month 12 ]
  7. Effect of a 12-month simvastatin treatment on bone formation as assessed by serum bone alkaline phosphatase (BAP) levels [ Time Frame: Baseline, month 1, month 3, month 6, month 9 and month 12 ]
  8. Effect of a 12-month simvastatin treatment on bone resorption as assessed by serum carboxy-terminal collagen crosslinks (CTX) levels [ Time Frame: Baseline, month 1, month 3, month 6, month 9 and month 12 ]
  9. Effect of a 12-month simvastatin treatment on cardiac function as assessed by echocardiography [ Time Frame: Baseline and month 12 ]
  10. Effect of a 12-month simvastatin treatment on cognitive deficits as assessed by parent-rated child behaviour checklist (CBCL) [ Time Frame: Baseline and month 12 ]
  11. Effect of a 12-month simvastatin treatment on behavioural deficits as assessed by parent-rated child behaviour checklist (CBCL) [ Time Frame: Baseline and month 12 ]
  12. Effect of a 12-month simvastatin treatment on metabolism of lipids as assessed by lipids levels. [ Time Frame: Baseline, month 1, month 3, month 6, month 9 and month 12 ]
  13. Effect of a 12-month simvastatin treatment on metabolism of lipids as assessed by leptin levels. [ Time Frame: Baseline, month 1, month 3, month 6, month 9 and month 12 ]
  14. Effect of a 12-month simvastatin treatment on metabolism of lipids as assessed by adipokines levels. [ Time Frame: Baseline, month 1, month 3, month 6, month 9 and month 12 ]
  15. Effect of a 12-month simvastatin treatment on fat body mass as assessed by Dual-energy X-ray Absorptiometry (DXA). [ Time Frame: Baseline and month 12 ]
  16. Effect of a 12-month simvastatin treatment on insulin sensitivity indices as assessed by Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). [ Time Frame: Baseline, month 1, month 3, month 6, month 9 and month 12 ]
  17. Effect of a 12-month simvastatin treatment on insulin sensitivity indices as assessed by Quantitative Insulin-Sensitivity Check Index (QUICKI) [ Time Frame: Baseline, month 1, month 3, month 6, month 9 and month 12 ]

Eligibility Criteria
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Ages Eligible for Study:   6 Years to 16 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02713945


Contacts
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Contact: Thomas Edouard, MD, PHD +33 (0)5 34 55 85 55 edouard.t@chu-toulouse.fr

Locations
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France
CHU Angers Unité d'endocrinologie pédiatrique Recruiting
Angers, France
Contact: Régis COUTANT, MD         
CHU Bordeaux Unité de Génétique pédiatrique Recruiting
Bordeaux, France
Contact: Didier LACOMBE, MD         
Chu Dijon Recruiting
Dijon, France
Contact: Sébastien MOUTTON         
CHRU Lille Unité d'endocrinologie pédiatrique Recruiting
Lille, France
Contact: Jacques WEILL, MD         
CHU Lyon Unité d'endocrinologie pédiatrique Recruiting
Lyon, France
Contact: Marc NICOLINO, MD         
CHU Marseille La Timone Unité d'Endocrinologie pédiatrique Recruiting
Marseille, France
Contact: Rachel REYNAUD, MD         
Chu Montpellier Recruiting
Montpellier, France
Contact: David GENEVIEVE         
CHU Nancy Unité de Génétique pédiatrique Recruiting
Nancy, France
Contact: Bruno LEHEUP, MD         
Hôpital Robert Debré Unité de Génétique pédiatrique Recruiting
Paris, France
Contact: Hélène CAVE, MD         
Hôpital Trousseau Unité d'endocrinologie pédiatrique Recruiting
Paris, France
Contact: Irène NETCHINE, MD         
CHU Rennes Unité de Génétique pédiatrique Recruiting
Rennes, France
Contact: Sylvie ODENT, MD         
CHU Toulouse Hôpital des Enfants Recruiting
Toulouse, France
Contact: Thomas EDOUARD, MD       edouard.t@chu-toulouse.fr   
Sponsors and Collaborators
University Hospital, Toulouse
Investigators
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Principal Investigator: Thomas Edouard, MD, PHD Children's Hospital, Toulouse University Hospital
More Information
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Responsible Party: University Hospital, Toulouse
ClinicalTrials.gov Identifier: NCT02713945    
Other Study ID Numbers: RC31/15/7826
First Posted: March 21, 2016    Key Record Dates
Last Update Posted: November 9, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University Hospital, Toulouse:
Simvastatin
Ras
MAPK
Additional relevant MeSH terms:
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Noonan Syndrome
Syndrome
Disease
Pathologic Processes
Congenital Abnormalities
Craniofacial Abnormalities
Musculoskeletal Abnormalities
Musculoskeletal Diseases
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
 Heart Diseases
Connective Tissue Diseases
Simvastatin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Enzyme Inhibitors