<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03826940</url>
  </required_header>
  <id_info>
    <org_study_id>CRU2C-ICNAS-001</org_study_id>
    <secondary_id>FLAD Life Science 2020</secondary_id>
    <nct_id>NCT03826940</nct_id>
  </id_info>
  <brief_title>From Molecules to Cognition: Inhibitory Mechanisms in ASD and NF1</brief_title>
  <acronym>ASD/NF1inhib</acronym>
  <official_title>Linking Inhibition From Molecular to Systems and Cognitive Levels: a Preclinical and Clinical Approach in Autism Spectrum Disorders and Neurofibromatosis.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Coimbra</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Coimbra</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study aims to investigate synaptic physiology and behavioral inhibition in patients with&#xD;
      NF1 and ASD and to answer whether inhibitory deficits at these levels are modulated by&#xD;
      lovastatin.&#xD;
&#xD;
      Structure: (1) Visit 1: Baseline assessment- participant's characterization, baseline outcome&#xD;
      measures and additional evaluations, (2) 3 consecutive days of physiologically probing&#xD;
      drug/placebo intake, (3) Visit 2: Outcome measures and additional evaluations in the day&#xD;
      after the last drug/placebo intake, (4) Washout period of 4 to 6 weeks, (5) 3 consecutive&#xD;
      days of drug/placebo intake, (6) Visit 3: Outcome measures and additional evaluations in the&#xD;
      day after the last placebo/drug intake.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The literature has shown synaptic inhibitory dysfunction in both ASD and NF1. Here the&#xD;
      investigators aim to test whether a mechanistic link can be established between that synaptic&#xD;
      inhibitory dysfunction, systems levels changes in oscillatory synchrony and regulation of&#xD;
      inhibition and treatment with Lovastatin in these two neurodevelopmental disorders. The&#xD;
      investigators will explore this link through the application of complementary quantitative&#xD;
      measures (putative biomarkers), such as magnetic resonance spectroscopy (MRS) transcranial&#xD;
      magnetic stimulation (TMS) and electroencephalogram (EEG) applied to the same group of adult&#xD;
      patients before and after the lovastatin or placebo intake during three days.&#xD;
&#xD;
      The intervention comprehends three sessions: the first two visits will occur in the same week&#xD;
      and the third visit will take place 4 to 6 weeks later. In the first visit (baseline&#xD;
      assessment), participants will perform neuropsychological, EEG, MRS and TMS assessment. In&#xD;
      the other two visits participants will repeat EEG, MRS and TMS assessments to study possible&#xD;
      post- intervention effects. Participants will intake 60mg of Lovastatin or Placebo during&#xD;
      three consecutive days before the second and the third visits.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 19, 2019</start_date>
  <completion_date type="Actual">August 31, 2020</completion_date>
  <primary_completion_date type="Actual">March 31, 2020</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Neurochemical response changes to GABAergic stimulation</measure>
    <time_frame>Through study completion, an average of 1 year</time_frame>
    <description>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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Motor evoked potentials changes under motor cortical stimulation</measure>
    <time_frame>Through study completion, an average of 1 year</time_frame>
    <description>Amplitudes (mV) will be measured during stimulation of the primary motor cortex using transcranial magnetic stimulation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cortical excitability changes under motor cortical stimulation</measure>
    <time_frame>Through study completion, an average of 1 year</time_frame>
    <description>Periods (ms) will be measured during stimulation of the primary motor cortex using transcranial magnetic stimulation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brain oscillations changes under sensory stimulation</measure>
    <time_frame>Through study completion, an average of 1 year</time_frame>
    <description>Power (microV^2) will be recorded during sensory stimulation using high density electroencephalography.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Event-related potentials changes under sensory stimulation</measure>
    <time_frame>Through study completion, an average of 1 year</time_frame>
    <description>Amplitude (microV) will be recorded during sensory stimulation using high density electroencephalography.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Autism Spectrum Disorder</condition>
  <condition>Neurofibromatosis 1</condition>
  <arm_group>
    <arm_group_label>NF1 - experimental</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>NF1 - control</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>ASD - experimental</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>ASD - control</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lovastatin 60 MG</intervention_name>
    <description>60 MG Lovastatin per day for 3 consecutive days</description>
    <arm_group_label>ASD - experimental</arm_group_label>
    <arm_group_label>NF1 - experimental</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebos</intervention_name>
    <description>60 MG Placebo per day for 3 consecutive days</description>
    <arm_group_label>ASD - control</arm_group_label>
    <arm_group_label>NF1 - control</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Positive diagnostic results for ASD in:&#xD;
&#xD;
        The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria.&#xD;
&#xD;
          -  Positive diagnostic results for NF1:&#xD;
&#xD;
        Clinical diagnosis based on the well-established clinical criteria&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Global Intelligence Quotient &lt; 80&#xD;
&#xD;
          -  Associated medical condition such as epilepsy, neurologic conditions, genetic&#xD;
             syndromes, or other usual comorbidity in ASD and NF1 populations&#xD;
&#xD;
          -  Medication capable of interfering with the intervention and/or study results&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Drug use and/or alcohol abuse&#xD;
&#xD;
          -  Contra-indications to MR and TMS&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Miguel S Castelo-Branco, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>ICNAS - Institute of Nuclear Sciences Applied to Health</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>ICNAS</name>
      <address>
        <city>Coimbra</city>
        <zip>3000-043</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Portugal</country>
  </location_countries>
  <reference>
    <citation>Pizzarelli R, Cherubini E. Alterations of GABAergic signaling in autism spectrum disorders. Neural Plast. 2011;2011:297153. doi: 10.1155/2011/297153. Epub 2011 Jun 23.</citation>
    <PMID>21766041</PMID>
  </reference>
  <reference>
    <citation>Violante IR, Ribeiro MJ, Edden RA, Guimaraes P, Bernardino I, Rebola J, Cunha G, Silva E, Castelo-Branco M. GABA deficit in the visual cortex of patients with neurofibromatosis type 1: genotype-phenotype correlations and functional impact. Brain. 2013 Mar;136(Pt 3):918-25. doi: 10.1093/brain/aws368. Epub 2013 Feb 11.</citation>
    <PMID>23404336</PMID>
  </reference>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>January 23, 2019</study_first_submitted>
  <study_first_submitted_qc>January 31, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 1, 2019</study_first_posted>
  <last_update_submitted>April 1, 2021</last_update_submitted>
  <last_update_submitted_qc>April 1, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 2, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Coimbra</investigator_affiliation>
    <investigator_full_name>Miguel Castelo-Branco</investigator_full_name>
    <investigator_title>Research Director of CIBIT-ICNAS</investigator_title>
  </responsible_party>
  <keyword>Inhibition</keyword>
  <keyword>GABA</keyword>
  <keyword>molecular imaging</keyword>
  <keyword>functional magnetic resonance imaging</keyword>
  <keyword>Autism Spectrum Disorder</keyword>
  <keyword>Neurofibromatosis 1</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neurofibromatoses</mesh_term>
    <mesh_term>Neurofibromatosis 1</mesh_term>
    <mesh_term>Neurofibroma</mesh_term>
    <mesh_term>Autistic Disorder</mesh_term>
    <mesh_term>Autism Spectrum Disorder</mesh_term>
    <mesh_term>Child Development Disorders, Pervasive</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lovastatin</mesh_term>
    <mesh_term>L 647318</mesh_term>
    <mesh_term>Dihydromevinolin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03826940
org study id: CRU2C-ICNAS-001
secondary id: FLAD Life Science 2020
nct id: NCT03826940
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
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.
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.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Neurochemical response changes to GABAergic stimulation
time frame: Through study completion, an average of 1 year
description: 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.
measure: Motor evoked potentials changes under motor cortical stimulation
time frame: Through study completion, an average of 1 year
description: Amplitudes (mV) will be measured during stimulation of the primary motor cortex using transcranial magnetic stimulation
measure: Cortical excitability changes under motor cortical stimulation
time frame: Through study completion, an average of 1 year
description: Periods (ms) will be measured during stimulation of the primary motor cortex using transcranial magnetic stimulation
measure: Brain oscillations changes under sensory stimulation
time frame: Through study completion, an average of 1 year
description: Power (microV^2) will be recorded during sensory stimulation using high density electroencephalography.
measure: Event-related potentials changes under sensory stimulation
time frame: Through study completion, an average of 1 year
description: Amplitude (microV) will be recorded during sensory stimulation using high density electroencephalography.
arm group label: NF1 - experimental
arm group type: Experimental
arm group label: NF1 - control
arm group type: Placebo Comparator
arm group label: ASD - experimental
arm group type: Experimental
arm group label: ASD - control
arm group type: Placebo Comparator
intervention type: Drug
intervention name: Lovastatin 60 MG
description: 60 MG Lovastatin per day for 3 consecutive days
arm group label: ASD - experimental
arm group label: NF1 - experimental
intervention type: Drug
intervention name: Placebos
description: 60 MG Placebo per day for 3 consecutive days
arm group label: ASD - control
arm group label: NF1 - control
criteria: 
gender: All
minimum age: 16 Years
maximum age: 65 Years
healthy volunteers: No
last name: Miguel S Castelo-Branco, MD, PhD
role: Principal Investigator
affiliation: ICNAS - Institute of Nuclear Sciences Applied to Health
facility: 
country: Portugal
citation: Pizzarelli R, Cherubini E. Alterations of GABAergic signaling in autism spectrum disorders. Neural Plast. 2011;2011:297153. doi: 10.1155/2011/297153. Epub 2011 Jun 23.
PMID: 21766041
citation: Violante IR, Ribeiro MJ, Edden RA, Guimaraes P, Bernardino I, Rebola J, Cunha G, Silva E, Castelo-Branco M. GABA deficit in the visual cortex of patients with neurofibromatosis type 1: genotype-phenotype correlations and functional impact. Brain. 2013 Mar;136(Pt 3):918-25. doi: 10.1093/brain/aws368. Epub 2013 Feb 11.
PMID: 23404336
responsible party type: Principal Investigator
investigator affiliation: University of Coimbra
investigator full name: Miguel Castelo-Branco
investigator title: Research Director of CIBIT-ICNAS
mesh term: Neurofibromatoses
mesh term: Neurofibromatosis 1
mesh term: Neurofibroma
mesh term: Autistic Disorder
mesh term: Autism Spectrum Disorder
mesh term: Child Development Disorders, Pervasive
mesh term: Lovastatin
mesh term: L 647318
mesh term: Dihydromevinolin
sharing ipd: Undecided