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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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-c

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 Summary:

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 at
Sponsor: University Hospital, Toulouse

Current Primary Outcome: 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 ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • Effect of a 12-month simvastatin treatment on cardiac function as assessed by echocardiography [ Time Frame: Baseline and month 12 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • 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 ]


Original Secondary Outcome: Same as current

Information By: University Hospital, Toulouse

Dates:
Date Received: March 9, 2016
Date Started: January 2017
Date Completion: October 2018
Last Updated: April 24, 2017
Last Verified: April 2017