Neuroimaging GABA Physiology in Fragile X Syndrome

NCT04308954 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: IRB 32149
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

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).

Conditions

Fragile X Syndrome (FXS); Idiopathic Intellectual Developmental Disorder (IDD)

Keywords

FXS, Intellectual Disability

Outcome Measures

Primary Outcomes (2)

• Non-displaceable binding potential of [18F]flumazenil (F18 FMZ)

  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.

  Up to 2 hours per scan on a single study day

• GABA (A) receptor density in fragile X syndrome (FXS) patients relative to control group comprising individuals with idiopathic Intellectual Developmental Disorder (IDD)

  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.

  Up to 2 hours per scan on a single study day

Study Arms (2)

Fragile X Syndrome

EXPERIMENTAL

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

Idiopathic Intellectual Developmental Disorder

EXPERIMENTAL

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

Interventions

[18F]flumazenil DRUG

\[18F\]flumazenil is a PET radiopharmaceutical that can be used to determine gamma-aminobutyric acid (GABA(A)) receptor density.

Also known as: F18 FMZ

Fragile X Syndrome; Idiopathic Intellectual Developmental Disorder

Eligibility Criteria

• Age: 18 Years - 30 Years
• Gender Eligibility Details: Participants must be male adults with idiopathic intellectual developmental disorder (IDD) or fragile X-syndrome (FXS)
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• Diagnosis of a known genetic disorder (other than FXS).
• Active medical problems such as unstable seizures, congenital heart disease, endocrine disorders.
• Significant sensory impairments such as blindness or deafness.
• DSM-5 diagnosis of other severe psychiatric disorder such as bipolar disorder or schizophrenia.
• Pre-term birth (\<34 weeks' gestation) or low birth weight (\<2000g).
• Current use of benzodiazepines.
• Contraindication for PET or MRI.
• Age 18 to 30 years inclusive
• Adults who are physically healthy
• No significant recent changes in psychosocial stressors per history
• Diagnosis of intellectual disability
• IQ between 40 and 80 points
• Ability to remain seated for more than 10 minutes
• Ability to travel to Stanford
• Genetic diagnosis of FXS.

Sponsors & Collaborators

• Stanford University: lead

Study Sites (1)

Stanford University

Stanford, California, 94305, United States

Location

Related Publications (2)

• Lucignani G, Panzacchi A, Bosio L, Moresco RM, Ravasi L, Coppa I, Chiumello G, Frey K, Koeppe R, Fazio F. GABA A receptor abnormalities in Prader-Willi syndrome assessed with positron emission tomography and [11C]flumazenil. Neuroimage. 2004 May;22(1):22-8. doi: 10.1016/j.neuroimage.2003.10.050.

  PMID: 15109994 BACKGROUND

• Holopainen IE, Metsahonkala EL, Kokkonen H, Parkkola RK, Manner TE, Nagren K, Korpi ER. Decreased binding of [11C]flumazenil in Angelman syndrome patients with GABA(A) receptor beta3 subunit deletions. Ann Neurol. 2001 Jan;49(1):110-3. doi: 10.1002/1531-8249(200101)49:13.0.co;2-t.

  PMID: 11198279 BACKGROUND

MeSH Terms

Conditions

Fragile X Syndrome; Intellectual Disability

Interventions

5-(2'-fluoroethyl)flumazenil

Condition Hierarchy (Ancestors)

X-Linked Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Sex Chromosome Disorders; Chromosome Disorders; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Heredodegenerative Disorders, Nervous System; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurodevelopmental Disorders; Mental Disorders

Study Officials

• Frederick T Chin, PhD

  Stanford University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor (Research) of Radiology (General Radiology)

Model Details: 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.

Study Record Dates

• First Submitted: March 11, 2020
• First Posted: March 16, 2020
• Study Start: November 1, 2016
• Primary Completion: December 6, 2018
• Study Completion: December 6, 2018
• Last Updated: January 28, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)