Investigating GABA pathways in autism spectrum disorder

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

This study is testing how a single dose of a brain drug affects brain activity in adults with autism and those without to see if it helps balance brain signals.

Quick facts

• Phase: Not applicable
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 18 Years to 60 Years
• Sex: All
• Sponsor: King's College London (Academic / other)
• Locations: 1 site (London)
• Trial ID: NCT03678129 on ClinicalTrials.gov

What this trial studies

This study examines how a single dose of a GABA-A receptor acting drug affects brain responses in adults with and without autism spectrum disorder (ASD). It aims to understand the balance of excitation and inhibition in the brain, which is often disrupted in individuals with ASD. Using neuroimaging and electrophysiology, the study will compare the brain's response to the drug clobazam against a placebo. The research builds on previous findings that suggest GABAergic compounds can influence brain connectivity patterns in ASD. Up to 100 participants, including 50 with ASD and 50 neurotypical adults, will be recruited for this investigation.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with a confirmed diagnosis of autism spectrum disorder.

Not a fit: Patients who are pregnant, breastfeeding, or currently taking medications that affect glutamate or GABA directly may not benefit from this study.

Why it matters

Potential benefit: If successful, this study could lead to improved understanding and treatment options for individuals with autism spectrum disorder.

How similar studies have performed: Previous studies have shown promising results with GABAergic compounds in shifting brain excitation and inhibition in ASD, indicating potential for success in this approach.

Eligibility criteria

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.

Where this trial is running

London

• King's College London — London, United Kingdom (Recruiting)

Study contacts

• Principal investigator: Grainne McAlonan, PhD — King's College London, UK
• Study coordinator: Grainne McAlonan, PhD

Conditions Autism Spectrum Disorder; E-I balance; AZD7325; pharmacological imaging; GABA