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

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ClinicalTrials.gov Identifier: NCT03594552
Recruitment Status : Recruiting
First Posted : July 20, 2018
Last Update Posted : July 20, 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 Arbaclofen, the R-enantiomer of the GABA-B agonist Baclofen, compared to a single dose of placebo in healthy men with and without autism spectrum disorder.

Condition or disease Intervention/treatment Phase
Autism Spectrum Disorder Drug: Arbaclofen_15 Drug: Arbaclofen_30 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-B (STX209) 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 (15mg or 30mg Arbaclofen) 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, arbaclofen low dose and arbaclofen 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 and Glial Systems in Autism Spectrum Disorder (ASD
Actual Study Start Date : February 1, 2018
Estimated Primary Completion Date : September 30, 2019
Estimated Study Completion Date : February 2, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Placebo, Arbaclofen_15, Arbaclofen_30
Dose order: Placebo, Arbaclofen 15mg, Arbaclofen 30mg
Drug: Arbaclofen_15
Single oral dose (15mg)
Other Name: r-baclofen, STX209

Drug: Arbaclofen_30
Single oral dose (30mg)
Other Name: r-baclofen, STX209

Drug: Placebo
Single oral dose placebo (oral tablet)
Other Name: Placebo oral tablet

Experimental: Placebo, Arbaclofen_30, Arbaclofen_15
Dose order: Placebo, Arbaclofen 30mg, Arbaclofen 15 mg
Drug: Arbaclofen_15
Single oral dose (15mg)
Other Name: r-baclofen, STX209

Drug: Arbaclofen_30
Single oral dose (30mg)
Other Name: r-baclofen, STX209

Drug: Placebo
Single oral dose placebo (oral tablet)
Other Name: Placebo oral tablet

Experimental: Arbaclofen_30, Placebo, Arbaclofen_15
Dose order: Arbaclofen 30mg, Placebo, Arbaclofen 15mg
Drug: Arbaclofen_15
Single oral dose (15mg)
Other Name: r-baclofen, STX209

Drug: Arbaclofen_30
Single oral dose (30mg)
Other Name: r-baclofen, STX209

Drug: Placebo
Single oral dose placebo (oral tablet)
Other Name: Placebo oral tablet

Experimental: Arbaclofen_15, Placebo, Arbaclofen_30
Dose order: Arbaclofen 15mg, Placebo, Arbaclofen 30mg
Drug: Arbaclofen_15
Single oral dose (15mg)
Other Name: r-baclofen, STX209

Drug: Arbaclofen_30
Single oral dose (30mg)
Other Name: r-baclofen, STX209

Drug: Placebo
Single oral dose placebo (oral tablet)
Other Name: Placebo oral tablet

Experimental: Arbaclofen_15, Arbaclofen_30, Placebo
Dose order: Arbaclofen 15mg, Arbaclofen 30mg, Placebo
Drug: Arbaclofen_15
Single oral dose (15mg)
Other Name: r-baclofen, STX209

Drug: Arbaclofen_30
Single oral dose (30mg)
Other Name: r-baclofen, STX209

Drug: Placebo
Single oral dose placebo (oral tablet)
Other Name: Placebo oral tablet

Experimental: Arbaclofen_30, Arbaclofen_15, Placebo
Dose order: Arbaclofen 30mg, Arbaclofen 15mg, Placebo
Drug: Arbaclofen_15
Single oral dose (15mg)
Other Name: r-baclofen, STX209

Drug: Arbaclofen_30
Single oral dose (30mg)
Other Name: r-baclofen, STX209

Drug: Placebo
Single oral dose placebo (oral tablet)
Other Name: Placebo oral tablet




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-B drug Arbaclofen 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:

  • ASD participants must pass diagnostic threshold for ASD on the Autism Diagnostic Interview-Revised (if and informant is available)
  • ASD participants must be currently symptomatic on Autism Diagnostic Observation Schedule (ADOS)
  • Age 18-60 years
  • Can give informed consent
  • medication free in the month preceding participation; but regular medication (used in a stable dose over the two months previous to participation) with drug which does not affect glutamate or GABA directly may be permitted
  • IQ>70

Exclusion Criteria:

  • IQ<70
  • history of psychosis, co-morbid major mental illness, significant physical illness (heart disease, high blood pressure, seizures) habitual substance misuse (including alcohol)
  • ASD caused by a known genetic syndrome e.g. Fragile X or 22q11 deletion syndrome,
  • past/present treatment for epilepsy
  • Women will be excluded from this pilot study to reduce heterogeneity in a small sample; avoid the issues around exposing women of reproductive age to a drug; and because pregnancy is a routine exclusion criteria for research MRI. Lastly, ASD is more common in men.
  • Change of medication dose/start of a new pharmacological therapy in the month prior to participation

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): NCT03594552


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
Investigators
Principal Investigator: Grainne McAlonan, PhD King's College London

Responsible Party: Dr Grainne McAlonan, Deputy head of department, King's College London
ClinicalTrials.gov Identifier: NCT03594552     History of Changes
Other Study ID Numbers: HR16-17 4081
First Posted: July 20, 2018    Key Record Dates
Last Update Posted: July 20, 2018
Last Verified: July 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
Product Manufactured in and Exported from the U.S.: Yes

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

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