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From Molecules to Cognition: Inhibitory Mechanisms in ASD and NF1 (ASD/NF1inhib)

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ClinicalTrials.gov Identifier: NCT03826940
Recruitment Status : Not yet recruiting
First Posted : February 1, 2019
Last Update Posted : February 1, 2019
Sponsor:
Information provided by (Responsible Party):
Miguel Castelo-Branco, University of Coimbra

Brief Summary:

This study aims to investigate synaptic physiology and behavioral inhibition in patients with NF1 and ASD and to answer whether inhibitory deficits at these levels are modulated by lovastatin.

Structure: (1) Visit 1: Baseline assessment- participant's characterization, baseline outcome measures and additional evaluations, (2) 3 consecutive days of physiologically probing drug/placebo intake, (3) Visit 2: Outcome measures and additional evaluations in the day after the last drug/placebo intake, (4) Washout period of 4 to 6 weeks, (5) 3 consecutive days of drug/placebo intake, (6) Visit 3: Outcome measures and additional evaluations in the day after the last placebo/drug intake.


Condition or disease Intervention/treatment Phase
Autism Spectrum Disorder Neurofibromatosis 1 Drug: Lovastatin 60 MG Drug: Placebos Not Applicable

Detailed Description:

The literature has shown synaptic inhibitory dysfunction in both ASD and NF1. Here the investigators aim to test whether a mechanistic link can be established between that synaptic inhibitory dysfunction, systems levels changes in oscillatory synchrony and regulation of inhibition and treatment with Lovastatin in these two neurodevelopmental disorders. The investigators will explore this link through the application of complementary quantitative measures (putative biomarkers), such as magnetic resonance spectroscopy (MRS) transcranial magnetic stimulation (TMS) and electroencephalogram (EEG) applied to the same group of adult patients before and after the lovastatin or placebo intake during three days.

The intervention comprehends three sessions: the first two visits will occur in the same week and the third visit will take place 4 to 6 weeks later. In the first visit (baseline assessment), participants will perform neuropsychological, EEG, MRS and TMS assessment. In the other two visits participants will repeat EEG, MRS and TMS assessments to study possible post- intervention effects. Participants will intake 60mg of Lovastatin or Placebo during three consecutive days before the second and the third visits.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Linking Inhibition From Molecular to Systems and Cognitive Levels: a Preclinical and Clinical Approach in Autism Spectrum Disorders and Neurofibromatosis.
Estimated Study Start Date : February 2019
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : January 2020


Arm Intervention/treatment
Experimental: NF1 - experimental Drug: Lovastatin 60 MG
60 MG Lovastatin per day for 3 consecutive days

Placebo Comparator: NF1 - control Drug: Placebos
60 MG Placebo per day for 3 consecutive days

Experimental: ASD - experimental Drug: Lovastatin 60 MG
60 MG Lovastatin per day for 3 consecutive days

Placebo Comparator: ASD - control Drug: Placebos
60 MG Placebo per day for 3 consecutive days




Primary Outcome Measures :
  1. Neurochemical response changes to GABAergic stimulation [ Time Frame: Through study completion, an average of 1 year ]
    Comparing changes in brain excitation-inhibition measures (i.e., glutamate and GABA) when the GABAergic system is activated by oral dose of the Lovastatin 60mg during 3 days versus the placebo condition.


Secondary Outcome Measures :
  1. Motor evoked potentials changes under motor cortical stimulation [ Time Frame: Through study completion, an average of 1 year ]
    Amplitudes (mV) will be measured during stimulation of the primary motor cortex using transcranial magnetic stimulation

  2. Cortical excitability changes under motor cortical stimulation [ Time Frame: Through study completion, an average of 1 year ]
    Periods (ms) will be measured during stimulation of the primary motor cortex using transcranial magnetic stimulation

  3. Brain oscillations changes under sensory stimulation [ Time Frame: Through study completion, an average of 1 year ]
    Power (microV^2) will be recorded during sensory stimulation using high density electroencephalography.

  4. Event-related potentials changes under sensory stimulation [ Time Frame: Through study completion, an average of 1 year ]
    Amplitude (microV) will be recorded during sensory stimulation using high density electroencephalography.



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Ages Eligible for Study:   16 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Positive diagnostic results for ASD in:

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria.

  • Positive diagnostic results for NF1:

Clinical diagnosis based on the well-established clinical criteria

Exclusion Criteria:

  • Global Intelligence Quotient < 80
  • Associated medical condition such as epilepsy, neurologic conditions, genetic syndromes, or other usual comorbidity in ASD and NF1 populations
  • Medication capable of interfering with the intervention and/or study results
  • Pregnancy
  • Drug use and/or alcohol abuse
  • Contra-indications to MR and TMS

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03826940


Contacts
Contact: Miguel S Castelo-Branco, MD, PhD +351 239488510 ext 518505 mcbranco@fmed.uc.pt
Contact: Sónia Pires +351 239488510 ext 518517 soniapires@uc.pt

Sponsors and Collaborators
University of Coimbra
Investigators
Principal Investigator: Miguel S Castelo-Branco, MD, PhD ICNAS - Institute of Nuclear Sciences Applied to Health

Publications:
Responsible Party: Miguel Castelo-Branco, Research Director of CIBIT-ICNAS, University of Coimbra
ClinicalTrials.gov Identifier: NCT03826940     History of Changes
Other Study ID Numbers: CRU2C-ICNAS-001
FLAD Life Science 2020 ( Other Grant/Funding Number: Luso-American Development Foundation )
First Posted: February 1, 2019    Key Record Dates
Last Update Posted: February 1, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Miguel Castelo-Branco, University of Coimbra:
Inhibition
GABA
molecular imaging
functional magnetic resonance imaging
Autism Spectrum Disorder
Neurofibromatosis 1

Additional relevant MeSH terms:
Molecular Mechanisms of Pharmacological Action
Autistic Disorder
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Neurofibromatoses
Neurofibromatosis 1
Neurofibroma
Neurodevelopmental Disorders
Mental Disorders
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
Genetic Diseases, Inborn
Peripheral Nervous System Diseases
Neuromuscular Diseases
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Lovastatin
L 647318
Dihydromevinolin
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Lipid Regulating Agents