GABA Pathways in Autism Spectrum Disorder (ASD)

Last updated: September 22, 2023
Sponsor: King's College London
Overall Status: Active - Recruiting

Phase

N/A

Condition

Asperger's Disorder

Autism

Williams Syndrome

Treatment

AZD7325_20

Clobazam

AZD7325_10

Clinical Study ID

NCT03678129
REC 18/WM/0208
  • Ages 18-60
  • All Genders
  • Accepts Healthy Volunteers

Study 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.

Eligibility Criteria

Inclusion

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 asneeded 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 precedingparticipation) with a drug that does not affect glutamate or GABA directly may bepermitted. Also permitted is topical medication without systemic exposure. For individuals with ASD:
  5. Diagnosis of ASD confirmed on the Autism Diagnostic Interview-Revised (ADI-R) if arelative is available and/or on the Autism Diagnostic Observation Schedule (ADOS-2). For all relatives:
  6. Aged under 18 years.
  7. Does not know the participant personally at present or in their childhood.

Exclusion

Exclusion Criteria: For all participants

  1. History of allergy/idiosyncrasy to AZD7325 or chemically related compounds orexcipients 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 CYP2C9inhibitor 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'swort, verapamil.
  3. Clinically relevant history or presence of any medical disorder, potentiallyinterfering 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 orsolvents.
  6. Participation in a research study involving a pharmacological probe or drug trialwithin last month or more than four in the previous 12 months
  7. Subjects with a history of epilepsy, seizures or episodes of unexplained andunprovoked loss of consciousness.
  8. Anyone with a history or examination which indicates laboratory testing is needed willbe excluded from the study.
  9. Intelligence Quotient below 70. Reproductive safety: Male study participants who are sexually active should avoidprocreation for 1 week after study drug administration. Avoidance of procreation can bethrough use of a highly effective contraception method by the study participant or by thepartner. 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 studyparticipants must be willing to use one form of highly effective non-hormonal contraceptionfor one week after study drug administration. This would include a vasectomised partner (sole partner), tubal occlusion, intrauterine system [IUS]/hormonal coil or coppercontaining intrauterine device or copper containing IUD, or true abstinence (when this isin line with the preferred and usual lifestyle of the subject). Women should have beenstable on their chosen method of birth control for a minimum of 2 months before enteringthe study. Participants must agree to undergo a pregnancy test prior to each administrationof study drug. For individuals with ASD:
  10. ASD caused by a known genetic syndrome, e.g. Fragile X, 22q11 deletion syndrome.
  11. Currently treated for epilepsy.

Study Design

Total Participants: 50
Treatment Group(s): 4
Primary Treatment: AZD7325_20
Phase:
Study Start date:
December 07, 2018
Estimated Completion Date:
March 31, 2026

Study 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

Connect with a study center

  • King's College London

    London, SE5 8AF
    United Kingdom

    Active - Recruiting

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