Noradrenergic add-on therapy with extended-release guanfacine in alzheimer’s disease: study protocol for a randomised clinical trial (NorAD) and COVID-19 amendments
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Published version
Author(s)
Type
Journal Article
Abstract
Background:
Guanfacine is a α2A adrenergic receptor agonist approved for treating Attention Deficit Hyperactivity Disorder (ADHD). It is thought to act via postsynaptic receptors in the prefrontal cortex, modulating executive functions including the regulation of attention. Attention is affected early in Alzheimer’s Disease (AD), and this may relate to pathological changes within the locus coeruleus, the main source of noradrenergic pathways within the brain. Given that cholinergic pathways, also involved in attention, are disrupted in AD, the combination of noradrenergic and cholinergic treatments may have a synergistic effect in symptomatic AD. The primary objective of the NorAD trial is to evaluate change in cognition with 12 weeks treatment of extended-release guanfacine (GXR) against a placebo as a combination therapy with cholinesterase inhibitors in participants with mild to moderate Alzheimer’s Disease.
Methods/Design:
NorAD is a 3-month, single-centre, randomised, double-blind, placebo-controlled, phase III trial of extended-release guanfacine (GXR) in participants with mild to moderate Alzheimer’s Disease. A total of 160 participants will be randomised to receive either daily guanfacine or placebo in combination with approved cholinesterase treatment for 12 weeks. The primary outcome is change in cognition, as measured by the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog), from baseline to follow-up in the treatment group compared to the placebo group. Secondary outcomes include change in additional cognitive measures of attention (Tests of Attention: Trails A and B, Digit-symbol substitution, Test of Everyday attention and CANTAB-RVP), neuropsychiatric symptoms (Neuropsychiatric Inventory), caregiver burden (Zarit Burden Interview) and activities of daily living (Alzheimer’s Disease Co-operative Study – Activities of Daily Living Inventory). From July 2020 observation of change following cessation of treatment is also being assessed.
Discussion:
There is strong evidence for early noradrenergic dysfunction in Alzheimer’s Disease. The NorAD trial aims determine whether guanfacine, a noradrenergic alpha-2 agonist, improves attention and cognition when used in addition to standard cholinergic treatment.
Trials registration
ClinicalTrials.gov, NCT03116126. Registration 14 April 2017
EudraCT: 2016-002598-36
Guanfacine is a α2A adrenergic receptor agonist approved for treating Attention Deficit Hyperactivity Disorder (ADHD). It is thought to act via postsynaptic receptors in the prefrontal cortex, modulating executive functions including the regulation of attention. Attention is affected early in Alzheimer’s Disease (AD), and this may relate to pathological changes within the locus coeruleus, the main source of noradrenergic pathways within the brain. Given that cholinergic pathways, also involved in attention, are disrupted in AD, the combination of noradrenergic and cholinergic treatments may have a synergistic effect in symptomatic AD. The primary objective of the NorAD trial is to evaluate change in cognition with 12 weeks treatment of extended-release guanfacine (GXR) against a placebo as a combination therapy with cholinesterase inhibitors in participants with mild to moderate Alzheimer’s Disease.
Methods/Design:
NorAD is a 3-month, single-centre, randomised, double-blind, placebo-controlled, phase III trial of extended-release guanfacine (GXR) in participants with mild to moderate Alzheimer’s Disease. A total of 160 participants will be randomised to receive either daily guanfacine or placebo in combination with approved cholinesterase treatment for 12 weeks. The primary outcome is change in cognition, as measured by the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog), from baseline to follow-up in the treatment group compared to the placebo group. Secondary outcomes include change in additional cognitive measures of attention (Tests of Attention: Trails A and B, Digit-symbol substitution, Test of Everyday attention and CANTAB-RVP), neuropsychiatric symptoms (Neuropsychiatric Inventory), caregiver burden (Zarit Burden Interview) and activities of daily living (Alzheimer’s Disease Co-operative Study – Activities of Daily Living Inventory). From July 2020 observation of change following cessation of treatment is also being assessed.
Discussion:
There is strong evidence for early noradrenergic dysfunction in Alzheimer’s Disease. The NorAD trial aims determine whether guanfacine, a noradrenergic alpha-2 agonist, improves attention and cognition when used in addition to standard cholinergic treatment.
Trials registration
ClinicalTrials.gov, NCT03116126. Registration 14 April 2017
EudraCT: 2016-002598-36
Date Issued
2022-08-01
Date Acceptance
2022-03-21
Citation
Trials, 2022, 23
ISSN
1745-6215
Publisher
BioMed Central
Journal / Book Title
Trials
Volume
23
Copyright Statement
© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
License URL
Sponsor
National Institute for Health Research
Identifier
https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-022-06190-3
Grant Number
PB-PG-0214-33098/RDA24
Subjects
Science & Technology
Life Sciences & Biomedicine
Medicine, Research & Experimental
Research & Experimental Medicine
Alzheimer's disease
Guanfacine
Add-on therapy
COVID-19
DOUBLE-BLIND
ATTENTION
DYSFUNCTION
INVENTORY
Add-on therapy
Alzheimer’s disease
COVID-19
Guanfacine
Activities of Daily Living
Alzheimer Disease
Attention Deficit Disorder with Hyperactivity
COVID-19
Cholinesterase Inhibitors
Clinical Trials, Phase III as Topic
Delayed-Action Preparations
Double-Blind Method
Guanfacine
Humans
Randomized Controlled Trials as Topic
Treatment Outcome
Humans
Alzheimer Disease
Guanfacine
Cholinesterase Inhibitors
Delayed-Action Preparations
Treatment Outcome
Activities of Daily Living
Double-Blind Method
Attention Deficit Disorder with Hyperactivity
Randomized Controlled Trials as Topic
Clinical Trials, Phase III as Topic
COVID-19
Cardiovascular System & Hematology
General & Internal Medicine
1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
Publication Status
Published
Article Number
ARTN 623