Synaptic Plasticity and Cognitive Function in RASopathies

NCT03504501 | Terminated Phase 2 DMC

• 2 other identifiers: SYN-1748-MAL-0030-I2016-005022-10
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

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.

Conditions

Impaired Synaptic Plasticity; Impaired Cognition

Keywords

RASopathies, neurofibromatosis type 1, noonan syndrome, synaptic plasticity, transcranial magnetic stimulation

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• Difference between the neuropsychological testing of attention (Test of attentional performance) after placebo and after medication (LTG and LOV)

  12 months

• Differences in short interval cortical inhibition (SICI) after placebo and after medication (LTG and LOV)

  12 months

Other Outcomes (1)

• Assessment of safety: EMG recording during TMS evaluation

  12 months

Study Arms (3)

Exp. I: Noonan Syndrome - Lovastatin

EXPERIMENTAL

200 mg Lovastatin daily for four days / Lovastatin-placebo (cross-over) prior to transcranial magnetic stimulation and test of attentional performance

Drug: Lovastatin

Exp. II: Noonan Syndrome - Lamotrigine

EXPERIMENTAL

300 mg Lamotrigine single dose / Lamotrigine-placebo prior to transcranial magnetic stimulation and test of attentional performance

Drug: Lamotrigine

Exp. III: Neurofibromatosis Type 1 - Lamotrigine

EXPERIMENTAL

300 mg Lamotrigine single dose / Lamotrigine-placebo prior to transcranial magnetic stimulation and test of attentional performance

Drug: Lamotrigine

Interventions

Lovastatin DRUG

oral application prior to transcranial magnetic stimulation intervention

Exp. I: Noonan Syndrome - Lovastatin

Lamotrigine DRUG

oral application prior to transcranial magnetic stimulation intervention

Exp. II: Noonan Syndrome - Lamotrigine; Exp. III: Neurofibromatosis Type 1 - Lamotrigine

Eligibility Criteria

• Age: 16 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Group 1: NS, Group 2: NF1 (both genetically assured)
• Age ≥16 years
• 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.
• Signed informed consent if ≥ 16 years and legal guardian.
• 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.
• Signed informed consent if ≥ 18 years.
• 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.

You may not qualify if:

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

Sponsors & Collaborators

• Technical University of Munich: lead

Study Sites (1)

Technical University Munich

Munich, 81377, Germany

Location

Related Publications (2)

• 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.

  PMID: 24088225 BACKGROUND

• Jung NH, Egert-Schwender S, Schossow B, Kehl V, Wahllander U, Brich L, Janke V, Blankenstein C, Zenker M, Mall V. Improvement of synaptic plasticity and cognitive function in RASopathies-a monocentre, randomized, double-blind, parallel-group, placebo-controlled, cross-over clinical trial (SynCoRAS). Trials. 2023 Jun 6;24(1):383. doi: 10.1186/s13063-023-07392-z.

  PMID: 37280688 DERIVED

MeSH Terms

Conditions

Cognition Disorders; Neurofibromatosis 1; Noonan Syndrome

Interventions

Lovastatin; Lamotrigine

Condition Hierarchy (Ancestors)

Neurocognitive Disorders; Mental Disorders; Neurofibromatoses; Neurofibroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Nervous System Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Musculoskeletal Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Connective Tissue Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Triazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Monocenter, randomized, double-blind, parallel-group, placebo controlled, cross-over design with a series of three experiments (Noonan Syndrome: 2 experiments; Neurofibromatosis type 1 1 experiment) and n=14 participants per experiments

Study Record Dates

• First Submitted: April 11, 2018
• First Posted: April 20, 2018
• Study Start: March 22, 2019
• Primary Completion: February 9, 2023
• Study Completion: October 31, 2023
• Last Updated: November 30, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)