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GABA Pathways in Autism Spectrum Disorder (ASD)

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ClinicalTrials.gov Identifier: NCT03678129
Recruitment Status : Recruiting
First Posted : September 19, 2018
Last Update Posted : September 19, 2018
Sponsor:
Information provided by (Responsible Party):
Dr Grainne McAlonan, King's College London

Brief Summary:
This study investigates the brain response to a single acute dose of AZD7325, a GABA-A positive allosteric modulator, compared to a single dose of placebo in adults with and without autism spectrum disorder.

Condition or disease Intervention/treatment Phase
Autism Spectrum Disorder Drug: AZD7325_10 Drug: AZD7325_20 Drug: Placebo Not Applicable

Detailed 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 the specific GABA-A (AZD7325) receptor agonist. 50 adult individuals with ASD and 50 neurotypical adults (25 males and 25 females per group) will be invited to participate. Each participant will receive a single dose of the drug (10mg or 20mg AZD7325) or matched placebo. Brain activity and neurochemistry will be investigated using magnetic resonance imaging. Further data will be collected through questionnaires, behavioural tasks, blood samples, and sensory tasks using electroencephalography and retinal imaging.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Repeated-measures cross-over study, where each subject received each one of the three pharmacological probes in separate visits (i.e., placebo, AZD7325 low dose and AZD7325 high dose), with the order of tablet administration being pseudorandomized.
Masking: Double (Participant, Investigator)
Masking Description: Participants and investigators were blinded to the drug condition
Primary Purpose: Basic Science
Official Title: Modulation of the Brain Excitatory/Inhibitory (E/I) Balance Through Neuronal Systems in Autism Spectrum Disorder (ASD)
Estimated Study Start Date : September 28, 2018
Estimated Primary Completion Date : February 15, 2020
Estimated Study Completion Date : September 14, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Placebo, AZD7325_10, AZD7325_20
Dose order: Placebo, AZD7325 10mg, AZD7325 20mg
Drug: AZD7325_10
Single oral dose (10mg)

Drug: AZD7325_20
Single oral dose (20mg)

Drug: Placebo
Single oral dose placebo (capsule)

Experimental: Placebo, AZD7325_20, AZD7325_10
Dose order: Placebo, AZD7325 20mg, AZD7325 10 mg
Drug: AZD7325_10
Single oral dose (10mg)

Drug: AZD7325_20
Single oral dose (20mg)

Drug: Placebo
Single oral dose placebo (capsule)

Experimental: AZD7325_20, Placebo, AZD7325_10
Dose order: AZD7325 20mg, Placebo, AZD7325 10mg
Drug: AZD7325_10
Single oral dose (10mg)

Drug: AZD7325_20
Single oral dose (20mg)

Drug: Placebo
Single oral dose placebo (capsule)

Experimental: AZD7325_10, Placebo, AZD7325_20
Dose order: AZD7325 10mg, Placebo, AZD7325 20mg
Drug: AZD7325_10
Single oral dose (10mg)

Drug: AZD7325_20
Single oral dose (20mg)

Drug: Placebo
Single oral dose placebo (capsule)

Experimental: AZD7325_10, AZD7325_20, Placebo
Dose order: AZD7325 10mg, AZD7325 20mg, Placebo
Drug: AZD7325_10
Single oral dose (10mg)

Drug: AZD7325_20
Single oral dose (20mg)

Drug: Placebo
Single oral dose placebo (capsule)

Experimental: AZD7325_20, AZD7325_10, Placebo
Dose order: AZD7325 20mg, AZD7325 10mg, Placebo
Drug: AZD7325_10
Single oral dose (10mg)

Drug: AZD7325_20
Single oral dose (20mg)

Drug: Placebo
Single oral dose placebo (capsule)




Primary Outcome Measures :
  1. Neurochemical response to GABAergic stimulation. [ Time Frame: Through study completion, an average of 2 years. ]
    Comparing brain excitation-inhibition measures (i.e., glutamate and GABA) when the GABAergic system is activated by a single oral dose of the GABA-A drug AZD7325 versus the placebo condition.


Secondary Outcome Measures :
  1. Functional connectivity measures using resting state functional magnetic resonance imaging. [ Time Frame: Through study completion, an average of 2 years. ]
    Maps of functional connectivity will be obtained for each condition and compared between adults with and without ASD.

  2. Brain oscillations under sensory stimulation [ Time Frame: Through study completion, an average of 2 years. ]
    Brain oscillations and event-related potentials will be recorded during sensory stimulation using high density electroencephalography.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03678129


Contacts
Contact: Grainne McAlonan, PhD 02078480831 grainne.mcalonan@kcl.ac.uk
Contact: Eileen Daly, PhD 02078480700 eileen.daly@kcl.ac.uk

Locations
United Kingdom
King's College London Recruiting
London, United Kingdom, SE5 8AF
Contact: Gráinne McAlonan, PhD    02078480831    grainne.mcalonan@kcl.ac.uk   
Sponsors and Collaborators
King's College London

Responsible Party: Dr Grainne McAlonan, Professor, King's College London
ClinicalTrials.gov Identifier: NCT03678129     History of Changes
Other Study ID Numbers: REC 18/WM/0208
First Posted: September 19, 2018    Key Record Dates
Last Update Posted: September 19, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Dr Grainne McAlonan, King's College London:
Autism Spectrum Disorder
E-I balance
AZD7325
pharmacological imaging
GABA

Additional relevant MeSH terms:
Disease
Autistic Disorder
Autism Spectrum Disorder
Child Development Disorders, Pervasive
Pathologic Processes
Neurodevelopmental Disorders
Mental Disorders