GABA Pathways in Autism Spectrum Disorder (ASD)

Autism Spectrum Disorder Clinical Trial

Official title:

Modulation of the Brain Excitatory/Inhibitory (E/I) Balance Through Neuronal Systems in Autism Spectrum Disorder (ASD)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03678129
• Other study ID #: REC 18/WM/0208
• Status: Recruiting
• Phase: N/A
• Start date: December 7, 2018
• Est. completion date: March 31, 2026

Study information

• Verified date: September 2023
• Source: King's College London
• Contact: Grainne McAlonan, PhD
• Phone: 02078480831
• Email: grainne.mcalonan[@]kcl.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study investigates the brain response to a single acute dose of a GABAa receptor acting drug (Benzodiazepine or positive allosteric modulator) compared to a single dose of placebo in adults with and without autism spectrum disorder.

Description:

Previous research suggests that GABAergic drug compounds could shift brain excitation and inhibition (E-I) in the healthy brain and in neurodevelopmental psychiatric conditions, such as autism spectrum disorder (ASD) - where this balance is disrupted. A study by Ajram et al. (2017) has shown an E-I shifted towards more GABA in individuals with ASD, and not in controls, after a single dose of the anti-glutamatergic and pro-GABAergic drug Riluzole. Moreover, brain connectivity patterns in ASD patients where shifted towards the ones observed in the control group. However, it was unclear whether this changes could be driven by GABA receptors, thus more specific probes may help to clarify the mechanism underlying the E-I coordination in ASD. Therefore, this study will use neuroimaging and electrophysiology to investigate the brain E-I coordination in ASD compared to control participants when the system is responding to a single dose of a GABA-A acting drug.

Please note, when first registered we had access to the specific GABA-A (AZD7325) receptor positive allosteric modulator. Following a pause in the study over the Covid pandemic this compound was not longer available. Therefore, we have updated the protocol and instead are using clobazam, a GABA-A/benzodiazepine receptor agonist. We have also now expanded the information about measures acquired in this study.

Up to 50 adult individuals with ASD and 50 neurotypical adults (25 males and 25 females per group) will be invited to participate. Prior to the pandemic, each participant received a single dose of the drug (10mg or 20mg AZD7325) or matched placebo. Following ethics amendment post pandemic, AZD7325 will no longer be used and participants will receive 5mg of clobazam or placebo.

Brain activity and neurochemistry will be investigated using magnetic resonance imaging, EEG and psychophysics. Further data will be collected through questionnaires, behavioural tasks, blood samples, and retinal physiology.

Our study is defined as a Basic Science study in human participants. It does not address safety or clinical efficacy and the UK Medicines and Health Regulatory Authority (MHRA) has confirmed that our protocol is therefore not a clinical trial of an Investigational Medicinal Product (IMP) as defined by the EU Directive 2001/20/EC

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: March 31, 2026
• Est. primary completion date: March 31, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria

For all participants:

1. Calendar age above 18 years.

2. Able to give informed consent.

3. Not pregnant or breastfeeding.

4. Ideally prescription medication free during the 2-week period preceding a study visit. However, occasional use of over-the-counter medication (e.g. painkillers) on an as needed basis (and not on the day of study visit) may be permitted. In addition, regular prescription medication (use of a stable dose over the two months preceding participation) with a drug that does not affect glutamate or GABA directly may be permitted. Also permitted is topical medication without systemic exposure.

For individuals with ASD:

1. Diagnosis of ASD confirmed on the Autism Diagnostic Interview-Revised (ADI-R) if a relative is available and/or on the Autism Diagnostic Observation Schedule (ADOS-2).

For all relatives:

1. Aged under 18 years.

2. Does not know the participant personally at present or in their childhood.

Exclusion Criteria:

For all participants

1. History of allergy/idiosyncrasy to AZD7325 or chemically related compounds or excipients which may be employed in the study or to any other drug used in the past.

2. Subject has taken systemically (po, iv) any potent or moderate CYP3A4 or CYP2C9 inhibitor or inducer, 1 month prior to screening (topical or inhaled are permitted) such as: aprepitant, barbiturates, carbamazepine, clarithromycin, erythromycin, cyclosporine, diltiazem, efavirenz, fluconazole, HIV protease inhibitors, glucocorticoids, itraconazole (oral/IV), ketoconazole, nefazodone, nevirapine, phenytoin, pioglitazone, primidone, rifabutin, rifampicin, telithromycin, St. John's wort, verapamil.

3. Clinically relevant history or presence of any medical disorder, potentially interfering with this study.

4. Clinically relevant abnormality at screening as judged by the investigator.

5. History of or current abuse of drugs (including prescription medication) or alcohol or solvents.

6. Participation in a research study involving a pharmacological probe or drug trial within last month or more than four in the previous 12 months

7. Subjects with a history of epilepsy, seizures or episodes of unexplained and unprovoked loss of consciousness.

8. Anyone with a history or examination which indicates laboratory testing is needed will be excluded from the study.

9. Intelligence Quotient below 70.

Reproductive safety: Male study participants who are sexually active should avoid procreation for 1 week after study drug administration. Avoidance of procreation can be through use of a highly effective contraception method by the study participant or by the partner. In this case, effective means of contraception are defined as tubal occlusion, copper banded intrauterine device, levonorgestrel medicated intra uterine system (e.g., Mirena), medroxyprogesterone injections (e.g. Depo-Provera), etonogestrel implants (e.g., Implanon, Norplan), normal and low dose combined oral contraceptive pills, norelgestromin / EE transdermal system, intravaginal device (e.g., EE and etonogestrel) and desogestrel (Cerazette).

Pregnancy or breastfeeding (is a routine exclusion for research MRI scanning). Female study participants must be willing to use one form of highly effective non-hormonal contraception for one week after study drug administration. This would include a vasectomised partner (sole partner), tubal occlusion, intrauterine system [IUS]/hormonal coil or copper containing intrauterine device or copper containing IUD, or true abstinence (when this is in line with the preferred and usual lifestyle of the subject). Women should have been stable on their chosen method of birth control for a minimum of 2 months before entering the study. Participants must agree to undergo a pregnancy test prior to each administration of study drug.

For individuals with ASD:

1. ASD caused by a known genetic syndrome, e.g. Fragile X, 22q11 deletion syndrome.

2. Currently treated for epilepsy.

Related Conditions & MeSH terms

• Autism Spectrum Disorder
• Autistic Disorder
• Child Development Disorders, Pervasive

Intervention

Drug:
• AZD7325_10
Single oral dose (10mg)
• AZD7325_20
Single oral dose (20mg)
• Placebo
Single oral dose placebo (capsule)
• Clobazam
Single dose (5mg)

Locations

Country	Name	City	State
United Kingdom	King's College London	London

Sponsors (1)

Lead Sponsor	Collaborator
King's College London

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Brain excitation and inhibition response to GABAergic stimulation as assessed by magnetic resonance spectroscopy.	Quantification and case-control comparison of brain metabolites relevant to regulation of excitation and inhibition (focus on Glx, GABA, GSH) using proton magnetic resonance spectroscopy when 'at rest' (placebo) and when activated by GABA-A compound.	Data collected on up to 3 visit days per participant. Completed within up to 1 year
Other	Tactile perception	Case-control comparison of tactile discrimination during placebo and when GABA-A compound administered.	Data collected on up to 3 visit days per participant. Completed within up to 1 year
Other	Electroretinogram	Case-control comparison of ERG acquired with hand held device during placebo and when GABA-A compound administered. three stimulus protocols: i) the standard white flash; ii) the standard 30-Hz flickering protocol; iii) the photonic negative response (PhNR) protocol.	Data collected on up to 3 visit days per participant. Completed within up to 1 year
Primary	Brain activation and connectivity response to GABAergic stimulation as assessed by functional magnetic resonance imaging.	Comparing whole brain blood-oxygen-level-dependent (BOLD) activation (institutional units) during the resting state in cases and controls when a single oral dose of GABA-A receptor acting compound administered versus the placebo condition.	Data collected on up to 3 visit days per participant. Completed within up to 1 year.
Primary	Brain electrophysiological activity task-free electroencephalography (EEG)	Case-control comparison of task-free Electroencephalogram (EEG) during placebo and when GABA-A compound administered. Analyses approaches will include examining power and phase information across different frequencies and aperiodic signal analysis (1/f like); and evaluation of power spectrum and functional connectivity across source localisations.	Data collected on up to 3 visit days per participant. Completed within up to 1 year
Primary	Brain oscillations under sensory stimulation	Brain oscillations (spectral perturbations) and event-related potentials will be recorded during sensory stimulation - auditory (odd-ball) and visual (contrast saturation, face perception/N170) tasks using electroencephalography during placebo and when GABA-A compound administered.	Data collected on up to 3 visit days per participant. Completed within up to 1 year