Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer’s Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments
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 affe...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | Trials |
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| Online Access: | https://doi.org/10.1186/s13063-022-06190-3 |
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| author | Karen Hoang Hilary Watt Mara Golemme Richard J. Perry Craig Ritchie Danielle Wilson James Pickett Chris Fox Robert Howard Paresh A. Malhotra |
| author_facet | Karen Hoang Hilary Watt Mara Golemme Richard J. Perry Craig Ritchie Danielle Wilson James Pickett Chris Fox Robert Howard Paresh A. Malhotra |
| author_sort | Karen Hoang |
| collection | DOAJ |
| description | 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 on symptomatic AD. The primary objective of the NorAD trial is to evaluate the change in cognition with 12 weeks of 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 the 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 the 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 to determine whether guanfacine, a noradrenergic alpha-2 agonist, improves attention and cognition when used in addition to standard cholinergic treatment. Trial registration ClinicalTrials.gov NCT03116126 . Registered on 14 April 2017 EudraCT: 2016-002598-36 |
| first_indexed | 2024-04-13T20:03:55Z |
| format | Article |
| id | doaj.art-5392fbb433a4452d9f1ef8fe7d617c09 |
| institution | Directory Open Access Journal |
| issn | 1745-6215 |
| language | English |
| last_indexed | 2024-04-13T20:03:55Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Trials |
| spelling | doaj.art-5392fbb433a4452d9f1ef8fe7d617c092022-12-22T02:32:07ZengBMCTrials1745-62152022-08-0123111310.1186/s13063-022-06190-3Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer’s Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendmentsKaren Hoang0Hilary Watt1Mara Golemme2Richard J. Perry3Craig Ritchie4Danielle Wilson5James Pickett6Chris Fox7Robert Howard8Paresh A. Malhotra9Department of Brain Sciences, Imperial College LondonDepartment of Public Health and Primary Care, Imperial College LondonUK Dementia Research Institute Care Research and Technology Centre, Imperial College London and the University of SurreyDepartment of Brain Sciences, Imperial College LondonEdinburgh Dementia Prevention and Centre for Clinical Brain Sciences, Edinburgh Medical School, University of EdinburghUK Dementia Research Institute Care Research and Technology Centre, Imperial College London and the University of SurreyDepartment of Brain Sciences, Imperial College LondonNorwich Medical School, University of East AngliaDivision of Psychiatry, University College LondonDepartment of Brain Sciences, Imperial College LondonAbstract 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 on symptomatic AD. The primary objective of the NorAD trial is to evaluate the change in cognition with 12 weeks of 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 the 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 the 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 to determine whether guanfacine, a noradrenergic alpha-2 agonist, improves attention and cognition when used in addition to standard cholinergic treatment. Trial registration ClinicalTrials.gov NCT03116126 . Registered on 14 April 2017 EudraCT: 2016-002598-36https://doi.org/10.1186/s13063-022-06190-3Alzheimer’s diseaseGuanfacineAdd-on therapyCOVID-19 |
| spellingShingle | Karen Hoang Hilary Watt Mara Golemme Richard J. Perry Craig Ritchie Danielle Wilson James Pickett Chris Fox Robert Howard Paresh A. Malhotra Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer’s Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments Trials Alzheimer’s disease Guanfacine Add-on therapy COVID-19 |
| title | Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer’s Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments |
| title_full | Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer’s Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments |
| title_fullStr | Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer’s Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments |
| title_full_unstemmed | Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer’s Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments |
| title_short | Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer’s Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments |
| title_sort | noradrenergic add on therapy with extended release guanfacine in alzheimer s disease norad study protocol for a randomised clinical trial and covid 19 amendments |
| topic | Alzheimer’s disease Guanfacine Add-on therapy COVID-19 |
| url | https://doi.org/10.1186/s13063-022-06190-3 |
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