Synaptic Plasticity and Cognitive Function in RASopathies

Phase 2

Terminated

• Conditions: Impaired Synaptic Plasticity; Impaired Cognition
• Interventions: Drug: Lovastatin; Drug: Lamotrigine

• Registration Number: NCT03504501
• Lead Sponsor: Technical University of Munich

Brief Summary

The project is targeting cognitive impairment, one of the main health problems of patients with RAS pathway disorders. The aim of this study is to translate findings of animal studies to humans. This has been done by the applicants successfully for Lovastatin in Nf1. This result will be transferred to patients with Noonan Syndrome. lamotrigine is most likely a more effective and promising substance improving synaptic plasticity and consecutive cognitive function. It is expected that both substances are improving synaptic plasticity as well as alertness and changes in alertness may be a precondition for improvement of cognition.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2018-04-11
• Study First Submitted QC: 2018-04-11
• Study First Posted: 2018-04-20
• Study Start: 2019-03-22
• Primary Completion: 2023-02-09
• Status Verified: 2023-05
• Study Completion: 2023-10-31
• Last Update Submitted: 2023-11-29
• Last Update Posted: 2023-11-30

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 16

Inclusion Criteria

1. Group 1: NS, Group 2: NF1 (both genetically assured)
2. Age ≥16 years
3. The adolescent (≥16) and legal guardian who are capable to give their consent and understand the aim and rationale of the study. In case of doubts, an independent medical practitioner will evaluate the capacity to consent.
4. Signed informed consent if ≥ 16 years and legal guardian.
5. Persons who are ≥ 18 years old and capable to give their consent and understand the aim and rationale of the study. In case of doubts, an independent medical practitioner will evaluate the capacity to consent.
6. Signed informed consent if ≥ 18 years.
7. Male participants and female participants who are not capable of bearing children or who use a method of contraception that is medically approved by the health authority of the respective country.

Exclusion Criteria

1. Epilepsy
2. Medication with known CNS effects
3. Severe mental retardation
4. Side effects during previous medication with and contraindications for LTG and/or LOV and/or TMS
5. Psychiatric diseases
6. Previous history of allergic reactions with LTG and LOV medications
7. Potentially unreliable patients
8. Patients who are not suitable for the study in the opinion of the investigator
9. Pregnancy (incl. positive urine pregnancy test)
10. Persons who are incapable of giving consent or do not understand the aim or rationale of the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Exp. I: Noonan Syndrome - Lovastatin	Lovastatin	200 mg Lovastatin daily for four days / Lovastatin-placebo (cross-over) prior to transcranial magnetic stimulation and test of attentional performance
Exp. II: Noonan Syndrome - Lamotrigine	Lamotrigine	300 mg Lamotrigine single dose / Lamotrigine-placebo prior to transcranial magnetic stimulation and test of attentional performance
Exp. III: Neurofibromatosis Type 1 - Lamotrigine	Lamotrigine	300 mg Lamotrigine single dose / Lamotrigine-placebo prior to transcranial magnetic stimulation and test of attentional performance

Primary Outcome Measures

Name	Time	Method
Long-term potentiation (LTP)-like plasticity measured with transcranial magnetic stimulation (TMS)	12 months	Changes in peak-to-peak amplitudes of motor evoked potentials (MEP)

Secondary Outcome Measures

Name	Time	Method
Difference between the neuropsychological testing of attention (Test of attentional performance) after placebo and after medication (LTG and LOV)	12 months	Response time (seconds) for alertness, visual scanning, Go/no Go, Incompatibility
Differences in short interval cortical inhibition (SICI) after placebo and after medication (LTG and LOV)	12 months	Changes in SICI

Trial Locations

Locations (1)

Technical University Munich; 🇩🇪 Munich, Germany