Noonan SyndromePhase 3RASTATNCT02713945
Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
A Phase 3 study testing Simvastatin in people with Noonan Syndrome, run by University Hospital, Toulouse at 12 sites in France.
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. Read more about this study
- Who is it for?
- Ages 6 to 16 years
- Conditions the study is for
- Noonan Syndrome
- What is being tested?
- Simvastatin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 53 participants
- Where
- 12 sitesFrance
- Study dates
- 25 Jan 2017to 3 Mar 2023
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 to 16 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
12 sites in 1 country.
12 sites in 1 country
France12 sites
CHU Angers Unité d'endocrinologie pédiatrique
Angers
CHU Bordeaux Unité de Génétique pédiatrique
Bordeaux
Chu Dijon
Dijon
CHRU Lille Unité d'endocrinologie pédiatrique
Lille
CHU Lyon Unité d'endocrinologie pédiatrique
Lyon
CHU Marseille La Timone Unité d'Endocrinologie pédiatrique
Marseille
Chu Montpellier
Montpellier
CHU Nancy Unité de Génétique pédiatrique
Nancy
Hôpital Robert Debré Unité de Génétique pédiatrique
Paris
Hôpital Trousseau Unité d'endocrinologie pédiatrique
Paris
CHU Rennes Unité de Génétique pédiatrique
Rennes
CHU Toulouse Hôpital des Enfants
Toulouse
About this study
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
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.
Read the 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.
- Conditions
- Noonan Syndrome
- Being tested
- Simvastatin, Placebo
- Keywords
- Simvastatin, Ras, MAPK
- Medical subject headings
- Noonan Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SimvastatinDrug
Experimental drug administrated orally
PlaceboDrug
Treatment for the control group
| Study group | Role | What they receive |
|---|---|---|
| Simvastatin | Experimental | 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. Receives: Drug: Simvastatin |
| Control | Placebo comparator | Placebo administrated orally once daily in the morning Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: Baseline, month 1, month 3, month 6, month 9 and month 12
Secondary outcomes (17)
Effect of a 12-month simvastatin treatment on growth velocity as assessed by Height measurement.
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: 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
Measured: Baseline and month 12
Effect of a 12-month simvastatin treatment on cognitive deficits as assessed by parent-rated child behaviour checklist (CBCL)
Measured: Baseline and month 12
Effect of a 12-month simvastatin treatment on behavioural deficits as assessed by parent-rated child behaviour checklist (CBCL)
Measured: Baseline and month 12
Effect of a 12-month simvastatin treatment on metabolism of lipids as assessed by lipids levels.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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)
Measured: Baseline, month 1, month 3, month 6, month 9 and month 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Mar 2016 (estimated)
- Study start25 Jan 2017
- Primary completion3 Mar 2023
- Study completion3 Mar 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Noonan SyndromeStudies of the same condition, open and under way.
- More trials run by University Hospital, ToulouseThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 53 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Toulouse
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Thomas Edouard, MD, PHD, Principal investigator, Children's Hospital, Toulouse University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02713945
- Sponsor's protocol ID
- RC31/15/7826
- Acronym
- RASTAT
- Status last verified
- May 2023
- First submitted
- 9 Mar 2016
- Last updated
- 11 May 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Edouard T, Capri Y, Verloes A, Amouroux C, Bournez M, Bretones P, Coutant R, Houang M, Amsellem Jager J, de Kerdanet M, Lacombe D, Lefevre C, Netchine I, Nicolino M, Pigeon Kherchiche P, Reynaud R, Rossi M, Berot A, Van Gils J, Willems M, Kieffer I, Dulac Y, Prickett T, Espiner E, Gennero I, Auriol F, Lepage B, Yart A. RAS/MAPK pathway modulation with simvastatin in children with Noonan syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. EClinicalMedicine. 2026 Aug 11;99:104114. doi: 10.1016/j.eclinm.2026.104114. eCollection 2026 Sep.
PubMed 42621140
Study at a glance
From the registry record, last updated by the sponsor on 11 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02713945
- Acronym / sponsor ID
- RASTAT / RC31/15/7826
- Conditions
- Noonan Syndrome
- Keywords
- Simvastatin, Ras, MAPK
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 53 participants (actual)
- Lead sponsor
- University Hospital, ToulouseUniversity, hospital or other
- Study start
- 25 Jan 2017 (actual)
- Primary completion
- 3 Mar 2023 (actual)
- Study completion
- 3 Mar 2023 (actual)
- First posted
- 21 Mar 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Simvastatin | Experimental | Drug: SimvastatinSimvastatin 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. |
| Control | Placebo comparator | Drug: PlaceboPlacebo administrated orally once daily in the morning |
Who may qualify
- Ages
- 6 to 16 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (6 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SimvastatinExperimental drug administrated orally | Drug | Simvastatin |
| PlaceboTreatment for the control group | Drug | Control |
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
17 secondary outcomes
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 May 2023.
- Derived from this study: PubMed 42621140Edouard T, Capri Y, Verloes A, Amouroux C, Bournez M, Bretones P, Coutant R, Houang M, Amsellem Jager J, de Kerdanet M, Lacombe D, Lefevre C, Netchine I, Nicolino M, Pigeon Kherchiche P, Reynaud R, Rossi M, Berot A, Van Gils J, Willems M, Kieffer I, Dulac Y, Prickett T, Espiner E, Gennero I, Auriol F, Lepage B, Yart A. RAS/MAPK pathway modulation with simvastatin in children with Noonan syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. EClinicalMedicine. 2026 Aug 11;99:104114. doi: 10.1016/j.eclinm.2026.104114. eCollection 2026 Sep.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Thomas Edouard, MD, PHD principal investigator
Children's Hospital, Toulouse University Hospital
12 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Simvastatin in people with Noonan Syndrome, run by University Hospital, Toulouse at 12 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 May 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 12 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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 (time frame: Baseline, month 1, month 3, month 6, month 9 and month 12). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02713945, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 May 2023.