Noradrenergic Add-on Therapy with Extended-Release Guanfacine in Alzheimer's Disease (NorAD): study protocol for a randomised clinical trial and COVID-19 amendments

Karen Hoang, Hilary Watt, Mara Golemme, Richard J Perry, Craig Ritchie, Danielle Wilson, James Pickett, Chris Fox, Robert Howard, Paresh A Malhotra

Research output: Contribution to journalArticlepeer-review


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: NCT03116126 . Registered on 14 April 2017 EudraCT: 2016-002598-36.

Original languageEnglish
Pages (from-to)623
Issue number1
Early online date1 Aug 2022
Publication statusE-pub ahead of print - 1 Aug 2022


  • Activities of Daily Living
  • Alzheimer Disease/diagnosis
  • Attention Deficit Disorder with Hyperactivity/diagnosis
  • COVID-19
  • Cholinesterase Inhibitors/therapeutic use
  • Clinical Trials, Phase III as Topic
  • Delayed-Action Preparations/therapeutic use
  • Double-Blind Method
  • Guanfacine/adverse effects
  • Humans
  • Randomized Controlled Trials as Topic
  • Treatment Outcome


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