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Neuroimaging GABA Physiology in Fragile X Syndrome

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ClinicalTrials.gov Identifier: NCT04308954
Recruitment Status : Recruiting
First Posted : March 16, 2020
Last Update Posted : May 22, 2020
Sponsor:
Information provided by (Responsible Party):
Frederick Chin, PhD, Stanford University

Brief Summary:
The investigators wish to compare the brain distribution of GABA(A) receptors and GABA levels in young adult males with Fragile X Syndrome compared to idiopathic intellectual developmental disorder. The radiopharmaceutical [18F]flumazenil has been used to study GABA(A) receptor distribution in other genetic syndromes with autistic features; however, despite overwhelming evidence supporting the importance of the GABAergic system in FXS, no clinical investigation of this system in human FXS has been reported in the literature. Therefore, this study will provide the first in vivo comprehensive examination of the GABAergic system in FXS using hybrid positron emission tomography/ magnetic resonance imaging (PET/MRI).

Condition or disease Intervention/treatment Phase
Fragile X Syndrome (FXS) Idiopathic Intellectual Developmental Disorder (IDD) Drug: [18F]flumazenil Phase 1

Detailed Description:
Fragile X syndrome (FXS) is the most common genetic cause of autism spectrum disorder (ASD). Converging evidence suggests that GABAergic dysfunction occurs in FXS. The investigators wish to examine brain distribution of GABA (A) receptors in young adult males with FXS using hybrid PET/MRI with [18F]flumazenil. This project will study the distribution of GABA(A) receptors in 15 young male adults with FXS (18-30 years old) compared to 15 age-matched male subjects with idiopathic intellectual developmental disorder (IDD) as controls. Simultaneous PET/MRI acquisition is an optimal technique to study in vivo GABAergic dysfunction and GABAa receptor distribution.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 15 male subjects with FXS will be compared to 15 subjects with idiopathic intellectual developmental disorder, who will be the control group. Young male adults with idiopathic intellectual developmental disorder will be (group) matched to FXS participants for mean age (and age range), handedness, socioeconomic status and ethnicity.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Cross-Species Multi-Modal Neuroimaging to Investigate GABA Physiology in Fragile X Syndrome
Actual Study Start Date : November 1, 2016
Estimated Primary Completion Date : November 1, 2021
Estimated Study Completion Date : November 1, 2022


Arm Intervention/treatment
Experimental: Fragile X Syndrome
Adult males aged 18-30 years diagnosed with FXS will undergo a non-invasive F18 FMZ PET/MRI scan to determine GABA(A) receptor density; developmental dynamics of GABA(A) receptor distribution, and structural neuroanatomy and connectional anatomy.
Drug: [18F]flumazenil
[18F]flumazenil is a PET radiopharmaceutical that can be used to determine gamma-aminobutyric acid (GABA(A)) receptor density.
Other Name: F18 FMZ

Experimental: Idiopathic Intellectual Developmental Disorder
Adult males aged 18-30 years diagnosed with idiopathic intellectual developmental disorder will undergo a non-invasive F18 FMZ PET/MRI scan to determine GABA(A) receptor density; developmental dynamics of GABA(A) receptor distribution, and structural neuroanatomy and connectional anatomy.
Drug: [18F]flumazenil
[18F]flumazenil is a PET radiopharmaceutical that can be used to determine gamma-aminobutyric acid (GABA(A)) receptor density.
Other Name: F18 FMZ




Primary Outcome Measures :
  1. Non-displaceable binding potential of [18F]flumazenil (F18 FMZ) [ Time Frame: Up to 2 hours per scan on a single study day ]

    Binding potential provides an estimate of the GABA (A) receptor distribution and affinity of [18F]flumazenil-PET to the GABA receptors. Binding potential will be measured in patients with fragile X syndrome and control group comprising individuals with idiopathic intellectual developmental disorder.

    Using imaging data obtained from PET that was corrected for attenuation and partial volume effects by MRI, nuclear medicine physicians will draw regions of interest (ROI's) around the areas of the brain listed below to estimate the F18 FMZ non-displaceable binding potential (BPnd) of F18 FMZ to GABA (A) receptors in FXS.


  2. GABA (A) receptor density in fragile X syndrome (FXS) patients relative to control group comprising individuals with idiopathic Intellectual Developmental Disorder (IDD) [ Time Frame: Up to 2 hours per scan on a single study day ]

    Binding potential measurements will be compared between participants with fragile X syndrome and control group with idiopathic intellectual developmental disorder(IDD) using the PET radiotracer [18F]flumazenil-PET.

    Binding Potential (BPnd) is estimated as the distribution volume ratio (DVR) -1.

    DVR's of tracers are used in PET receptor studies where the radiopharmaceutical can be specifically bound to receptors; nonspecifically bound to other macromolecular components, or free in tissue (FT). DVR is calculated using a Logan Plot, which uses the dynamic PET images obtained during imaging and compartment modeling to graphically analyze by linear regression pharmacokinetic data for radiopharmaceuticals that undergo 'reversible' uptake.

    PET scans of FXS patients will be compared to the PET scans of control group.




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Ages Eligible for Study:   18 Years to 30 Years   (Adult)
Sexes Eligible for Study:   Male
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Participants must be male adults with idiopathic intellectual developmental disorder (IDD) or fragile X-syndrome (FXS)
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria for participants with FXS:

  1. Have an established diagnosis of FXS (full mutation with aberrant FMR1 methylation) by genetic testing
  2. Diagnosis of intellectual disability
  3. Males who are physically healthy
  4. Age 18 to 30 years inclusive
  5. IQ between 40 and 80 points
  6. Ability to remain seated for more than 10 minutes
  7. Ability to travel to Stanford

Exclusion criteria for participants with FXS:

  1. Diagnosis of a known genetic disorder (other than FXS).
  2. Active medical problems such as unstable seizures, congenital heart disease, endocrine disorders.
  3. Significant sensory impairments such as blindness or deafness.
  4. DSM-5 diagnosis of other severe psychiatric disorder such as bipolar disorder or schizophrenia.
  5. Pre-term birth (<34 weeks' gestation) or low birth weight (<2000g).
  6. Current use of benzodiazepines.
  7. Contraindication for PET or MRI.

Inclusion criteria for participants with IDD:

  1. Age 18 to 30 years inclusive
  2. Adults who are physically healthy
  3. No significant recent changes in psychosocial stressors per history
  4. Diagnosis of intellectual disability
  5. IQ between 40 and 80 points
  6. Ability to remain seated for more than 10 minutes
  7. Ability to travel to Stanford

Exclusion Criteria for participants with IDD:

  1. Genetic diagnosis of FXS.
  2. Active medical problems such as unstable seizures, congenital heart disease, endocrine disorders.
  3. Significant sensory impairments such as blindness or deafness.
  4. DSM-5 diagnosis of other severe psychiatric disorder such as bipolar disorder or schizophrenia.
  5. Pre-term birth (<34 weeks' gestation) or low birth weight (<2000g).
  6. Current use of benzodiazepines.
  7. Contraindication for PET or MRI.

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): NCT04308954


Contacts
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Contact: Frederick T Chin, PhD 650-725-4182 chinf@stanford.edu
Contact: Rhea Lubrin Scott 650-721-3306 rheascott@stanford.edu

Locations
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United States, California
Stanford University Recruiting
Stanford, California, United States, 94305
Contact: Soujanya Gade    650-724-2951    sgade@stanford.edu   
Contact: MS         
Principal Investigator: Frederick Chin, PhD         
Sub-Investigator: Scott Hall, PhD         
Sub-Investigator: Guido Davidzon, MD         
Sub-Investigator: Lawrence Fung, MD, PhD         
Sponsors and Collaborators
Stanford University
Investigators
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Principal Investigator: Frederick T Chin, PhD Stanford University
Publications:
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Responsible Party: Frederick Chin, PhD, Assistant Professor (Research) of Radiology (General Radiology), Stanford University
ClinicalTrials.gov Identifier: NCT04308954    
Other Study ID Numbers: IRB 32149
First Posted: March 16, 2020    Key Record Dates
Last Update Posted: May 22, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Frederick Chin, PhD, Stanford University:
FXS, Intellectual Disability
Additional relevant MeSH terms:
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Fragile X Syndrome
Intellectual Disability
Syndrome
Developmental Disabilities
Disease
Pathologic Processes
Mental Retardation, X-Linked
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Sex Chromosome Disorders
Chromosome Disorders
Congenital Abnormalities
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Heredodegenerative Disorders, Nervous System
Neurodevelopmental Disorders
Mental Disorders
Flumazenil
Antidotes
Protective Agents
Physiological Effects of Drugs
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action