Clinical trial NCT04314856: Novel Clinical Target in Fragile X Syndrome
Official title: Sigma-1 Receptors: A Novel Clinical Target in Fragile X Syndrome
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
Conditions: Fragile X Syndrome (FXS)
Keywords: FXS
Lead sponsor: Stanford University
Sponsor class: OTHER
First posted: 2020-03-19
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 15 male subjects with FXS will be compared to 5 healthy volunteers who will be the control group.
Primary purpose: OTHER

Brief summary: Fragile X syndrome (FXS) is the most common genetic cause of autism spectrum disorder (ASD). The investigators wish to examine brain distribution of sigma-1 receptors in young adult males with FXS using 18F-FTC-146 PET. This project will study the distribution of sigma-1 receptors in 15 young (18-30 years) male adults with FXS compared to 5 healthy adult volunteers.

Detailed description: In this study, we measured sigma-1 receptor density in the regions of interest in brain known to be involved in executive functioning and cognition using 18F-FTC-146 PET. We then compared S1R density in areas ROIs not involved in executive functioning and cognition. This provided a framework for predicting functional impairment based on brain-behavior relationships.

The study had two aims. The first aim was to evaluate the reliability of 18F-FTC-146 brain uptake in healthy controls under test and retest conditions to establish a baseline measure of S1R density and quantify regional brain uptake of radiotracer in five healthy adults. The second aim was to characterize S1R density in brains of young adult males with FXS which will then be compared to healthy volunteers.

This was the very first PET study to image sigma-1 receptor density in participants with fragile X syndrome, thereby testing whether altered receptor density is present in brain in fragile X syndrome patients when compared to healthy volunteers. If confirmed, the current study would have provided compelling clinical-translational support for an important pathophysiological mechanism of cognition and executive function. The study had considerable potential for advancing the neurobiological understanding of fragile X syndrome in humans.

Eligibility criteria: INCLUSION CRITERIA

Inclusion criteria for healthy volunteers:

1. Ages 18-65
2. Either gender and all ethno-racial categories
3. Capacity to provide informed consent
4. Female participants are expected to use an effective method of birth control throughout the study which includes: hormonal methods (birth control pills, patches, injections, vaginal ring or implants), barrier method (condom or diaphragm) used with spermicide, intrauterine device (IUD), or abstinence (no sex)
5. Can travel to Stanford for 2 scan days.

Inclusion criteria for individuals with FXS:

1. Males who are physically healthy
2. Aged between 18 and 30 years inclusive
3. Can travel to Stanford for a 2-day visit.
4. IQ between 40 and 80 points.
5. Ability to remain seated for more than 10 minutes.
6. Have an established genetic diagnosis of FXS (full mutation with evidence of aberrant methylation of the FMR1 gene, confirmed by genetic testing).

EXCLUSION CRITERIA

Exclusion criteria for healthy volunteers:

1. Any current or lifetime psychiatric diagnosis
2. Current or past use of psychotropic medication for purposes of treating a mental illness
3. Pregnant or nursing females
4. Major medical or neurological problem, including anemia (Hb , 12 g/dl in women and \<14 g/dl in men) (e.g., unstable hypertension, seizure disorder, head trauma)
5. Current diagnosis of vasculopathy or Raynouds
6. Participant is unable to tolerate being off of anticoagulant medication during study
7. Positive urine screen for illicit drugs
8. Presence of metal in the body that is contraindicated for MRI scans
9. Current exposure to radiation in the workplace, or history of participation in nuclear medicine procedures does not exceed defined annual limits
10. Stanford University student status (i.e., we will exclude students such as undergrads, grad students and postdocs that currently attend at Stanford University)

Exclusion criteria for individuals with FXS:

1. Any contraindication for MRI scanning procedures (metal in body, braces, claustrophobia, etc.)
2. No history of with substance abuse, traumatic brain injury and
3. BMI greater than 18.5
4. Diagnosis of a known genetic disorder (other than FXS).
5. Active medical problems such as unstable seizures, congenital heart disease, endocrine disorders.
6. Significant sensory impairments such as blindness or deafness.
7. DSM-5 diagnosis of other severe psychiatric disorder such as bipolar disorder or schizophrenia.
8. Pre-term birth (\<34 weeks' gestation) or low birth weight (\<2000g).
9. Current use of benzodiazepines. Individuals who are taking concomitant psychoactive medications will be tracked and examined in post-hoc analyses, given that it is extremely difficult to recruit individuals who are medication-free or who are willing to go off those medications prior to entering the study.
10. Current exposure to radiation in the workplace, or history of participation in nuclear medicine procedures does not exceed defined annual limits

Primary outcomes:
measure: Number of concordant readings of regional brain uptake of radiotracer [18F]FTC-146 as a measure of reliability under test-retest conditions
timeFrame: Up to 6 hours per scan performed on Day 0 (Test) and Day 7 (Retest)
measure: Difference in Non-displaceable Binding Potential (BPND) of [18F]FTC-146 in fragile X syndrome (FXS) patients relative to healthy volunteers
timeFrame: Up to 6 hours per scan performed on Day 0 (both groups) and Day 7 (healthy volunteers)
Secondary outcomes:
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University
state: California
Study officials:
affiliation: Stanford University
name: Guido Davidzon, MD SM
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cipriano PW, Lee SW, Yoon D, Shen B, Tawfik VL, Curtin CM, Dragoo JL, James ML, McCurdy CR, Chin FT, Biswal S. Successful treatment of chronic knee pain following localization by a sigma-1 receptor radioligand and PET/MRI: a case report. J Pain Res. 2018 Oct 12;11:2353-2357. doi: 10.2147/JPR.S167839. eCollection 2018.
citation: Shen B, Park JH, Hjornevik T, Cipriano PW, Yoon D, Gulaka PK, Holly D, Behera D, Avery BA, Gambhir SS, McCurdy CR, Biswal S, Chin FT. Radiosynthesis and First-In-Human PET/MRI Evaluation with Clinical-Grade [18F]FTC-146. Mol Imaging Biol. 2017 Oct;19(5):779-786. doi: 10.1007/s11307-017-1064-z.
citation: Hjornevik T, Cipriano PW, Shen B, Park JH, Gulaka P, Holley D, Gandhi H, Yoon D, Mittra ES, Zaharchuk G, Gambhir SS, McCurdy CR, Chin FT, Biswal S. Biodistribution and Radiation Dosimetry of 18F-FTC-146 in Humans. J Nucl Med. 2017 Dec;58(12):2004-2009. doi: 10.2967/jnumed.117.192641. Epub 2017 Jun 1.