Synaptic Plasticity and Cognitive Function in RASopathies (SynCoRAS)

Improvement of Synaptic Plasticity and Cognitive Function in RAS Pathway Disorders

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.

Study Overview

• Status: Terminated
• Conditions: Impaired Cognition; Impaired Synaptic Plasticity
• Intervention / Treatment: Drug: Lovastatin; Drug: Lamotrigine

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Volker Mall, Prof.; Phone Number: +49 (0)89 71009-233; Email: volker.mall@kbo.de
• Study Contact Backup: Name: Nikolai Jung, Dr.; Phone Number: +49 (0)89 71009-236; Email: nikolai.jung@tum.de

Study Locations

• Germany
  • Munich, Germany, 81377
    • Technical University Munich

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of safety: EMG recording during TMS evaluation	Safety	12 months

Collaborators and Investigators

• Sponsor: Technical University of Munich

Publications and helpful links

General Publications

• Mainberger F, Jung NH, Zenker M, Wahllander U, Freudenberg L, Langer S, Berweck S, Winkler T, Straube A, Heinen F, Granstrom S, Mautner VF, Lidzba K, Mall V. Lovastatin improves impaired synaptic plasticity and phasic alertness in patients with neurofibromatosis type 1. BMC Neurol. 2013 Oct 2;13:131. doi: 10.1186/1471-2377-13-131.

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2019
• Primary Completion (Actual): February 9, 2023
• Study Completion (Actual): October 31, 2023

Study Registration Dates

• First Submitted: April 11, 2018
• First Submitted That Met QC Criteria: April 11, 2018
• First Posted (Actual): April 20, 2018

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: RASopathies, neurofibromatosis type 1, noonan syndrome, synaptic plasticity, transcranial magnetic stimulation
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Anticonvulsants; Sodium Channel Blockers; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Lamotrigine; Lovastatin; L 647318; Dihydromevinolin
• Other Study ID Numbers: SYN-1748-MAL-0030-I; 2016-005022-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No