Experimental fMRI Study of Guanfacine and Lisdexamfetamine in ADHD Adolescents (AGUALIS)

Experimental fMRI Study on the Comparison of the Brain Function Effects of a Single Dose of Guanfacine and Lisdexamfetamine Relative to Placebo in Children and Adolescents With ADHD.

This is not a clinical trial. The aim of this study is to understand the mechanism of action of two recently licensed drugs for ADHD on brain function. We will compare the brain activation changes elicited by Guanfacine extended release (GXR; a non-stimulant drug) with the brain activation changes elicited by Lisdexamfetamine (LISDEX; a stimulant drug) and by placebo in 20 drug-free patients with ADHD using functional Magnetic Resonance Imaging (fMRI). For this purpose we intend to scan participants during their performance of tasks of attention, working memory, and inhibition, which we know from previous studies to elicit abnormal brain activation patterns in ADHD patients (Rubia et al., 2005; Smith et al., 2006).

Study Overview

• Status: Active, not recruiting
• Conditions: ADHD
• Intervention / Treatment: Drug: Lisdexamfetamine dimesylate; Drug: Placebo; Drug: Guanfacine Extended Release Oral Tablet

Detailed Description

Twenty ADHD patients between 8 and 20 years of age will participate in the double-blind, randomised, active drug condition, within-group, placebo-controlled experimental fMRI study. Each participant will be assessed in baseline measures during a pre-assessment visit. Then the patient will be scanned 3 times under each of these 3 drug conditions: GXR, LISDEX, and placebo. Every patient will receive a single typical clinical weight-adjusted dose of GXR (0.05mg/kg rounded down to the closest dose of 1mg, 2mg, or a maximum of 3mg), LISDEX (for participants aged 8-9 years 20mg regardless of weight; for participants aged 10-20 years the dose will be calculated at 0.5mg/kg rounded to the closest 30, 40, or 50mg, middle doses, e.g. 35mg, will be rounded down) and placebo (10mg Vit C) in one of the scans, in a randomised order. Patients will perform a battery of cognitive tests 3.5 hours after drug administration, after which the will undergo an fMRI scan. The scan will start 4.5 hours after drug administration where drugs have shown to have maximum plasma concentration. Participants will be scanned 3 times, one week apart, under each drug condition.

• Study Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SE5 8AF
    • Institute of Psychiatry, Psychology & Neuroscience; King's College London

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age range: 8-20 years
• Medication-naïve or non-medicated for two weeks or on stimulant medication, and willing to take the medication off for 48 hours before scans.
• Meeting DSM-5 diagnosis of ADHD
• Score above clinical cut-off on the ADHD module of the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) (Kaufman et al., 1997)
• Score above clinical cut-off for ADHD on the short forms of the Conners Parent Rating Scales, CPRS (Conners et al., 2008)
• Score above cut-off on the ADHD Rating Scale, ADHD-RS (DuPaul, et al., 1998)
• IQ > 70 as tested on the WASI-II (Wechsler et al., 1999)
• Mood and depression symptoms will be allowed as long as they are not the primary diagnosis.

Exclusion Criteria:

• IQ < 70 (Wechsler et al., 1999).
• Comorbidity with schizophrenia, bipolar disorder, learning disability, OCD, severe depression with current suicidal behaviour (as assessed by a clinical interview)
• Neurological problems, i.e. a history of severe neurological illness, e.g. brain tumour, epilepsy or a history of symptomatic seizures, polyneuropathy etc.
• Substance abuse history
• Other illness (cardiovascular, renal, hepatic, metabolic) that would impact the data integrity or safety of the subject (i.e. contraindicated to any of the treatments) as determined by the investigators
• Contraindication to MRI. i.e., previous implantation of metallic material, pacemaker, implanted medication pumps, neural stimulators, claustrophobia
• Unable to give informed assent or consent in the case of the parent
• Contraindications for LISDEX and GXR use (i.e. advanced arteriosclerosis, agitated states, hyperexcitability, hyperthyroidism, moderate or severe hypertension, symptomatic cardiovascular disease)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Lisdexamfetamine - Placebo	Drug: Lisdexamfetamine dimesylate; Lisdexamfetamine dimesylate (30mg for smaller, 50mg for larger boys) tablet; Other Names: Vyvanse (Shire Pharmaceuticals Ltd.); Drug: Placebo; Vitamin C (10mg) tablet
Active Comparator: Guanfacine - Placebo	Drug: Placebo; Vitamin C (10mg) tablet; Drug: Guanfacine Extended Release Oral Tablet; Guanfacine Extended Release (0.05mg/kg) tablet; Other Names: Intuniv (Shire Pharmaceuticals Ltd.)
Experimental: Lisdexamfetamine - Guanfacine	Drug: Lisdexamfetamine dimesylate; Lisdexamfetamine dimesylate (30mg for smaller, 50mg for larger boys) tablet; Other Names: Vyvanse (Shire Pharmaceuticals Ltd.); Drug: Guanfacine Extended Release Oral Tablet; Guanfacine Extended Release (0.05mg/kg) tablet; Other Names: Intuniv (Shire Pharmaceuticals Ltd.)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in brain activation under the three drug conditions (LISDEX, GXR, placebo)	Brain activation as measured by blood-oxygen-level-dependent (BOLD) response obtained by fMRI for each of the 3 below listed tasks and functional connectivity measures for the resting state scan.; A working memory task (N-back); A tracking stop task; A parametric sustained attention task	2 weeks (3 hourly scans one week apart)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in dependent variables extracted from performance on the fMRI tasks used under the three drug conditions (LISDEX, GXR, placebo)	A working memory task (N-back); A tracking stop task; A parametric sustained attention task	2 weeks (3 hourly scans one week apart)
Changes in dependent variables extracted from performance on a task battery outside the MRI scanner	Gonogo task, Simon task, Continuous performance task, Vigilance task, Time Discrimination task	2 weeks (3 sessions one week apart)

Collaborators and Investigators

• Sponsor: King's College London
• Collaborators: Shire
• Investigators: Principal Investigator: Katya Rubia, PhD, King's College London

Publications and helpful links

General Publications

• Rubia K, Smith AB, Brammer MJ, Toone B, Taylor E. Abnormal brain activation during inhibition and error detection in medication-naive adolescents with ADHD. Am J Psychiatry. 2005 Jun;162(6):1067-75. doi: 10.1176/appi.ajp.162.6.1067.
• Smith AB, Taylor E, Brammer M, Toone B, Rubia K. Task-specific hypoactivation in prefrontal and temporoparietal brain regions during motor inhibition and task switching in medication-naive children and adolescents with attention deficit hyperactivity disorder. Am J Psychiatry. 2006 Jun;163(6):1044-51. doi: 10.1176/ajp.2006.163.6.1044.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2018
• Primary Completion (Anticipated): December 31, 2022
• Study Completion (Anticipated): March 31, 2025

Study Registration Dates

• First Submitted: October 31, 2017
• First Submitted That Met QC Criteria: November 3, 2017
• First Posted (Actual): November 7, 2017

Study Record Updates

• Last Update Posted (Actual): August 17, 2022
• Last Update Submitted That Met QC Criteria: August 16, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Attention Deficit Hyperactivity Disorder; functional Magnetic Resonance Imaging; Guanfacine; Lisdexamfetamine
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Lisdexamfetamine Dimesylate; Guanfacine
• Other Study ID Numbers: PCCWUAR

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• 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.: No