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Published in: Trials 1/2022

Open Access 01-12-2022 | Attention Deficit Hyperactivity Disorder | Study protocol

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

Published in: Trials | Issue 1/2022

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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.​govNCT03116126. Registered on 14 April 2017
EudraCT: 2016-002598-36
Appendix
Available only for authorised users
Literature
1.
Wenk GL. Neuropathologic changes in Alzheimer's disease. J Clin Psychiatry. 2003;64 7-10.
2.
Hampel H, Mesulam MM, Cuello AC, Farlow MR, Giacobini E, Grossberg GT, et al. The cholinergic system in the pathophysiology and treatment of Alzheimer's disease. Brain. 2018;141(7):1917-33.
3.
4.
Cummings JL. Alzheimer's disease. N Engl J Med. 2004;351(1):56-67.
5.
Perry RJ, Hodges JR. Attention and executive deficits in Alzheimer's disease. A critical review. Brain. 1999;122(Pt 3):383-404.
6.
Bondareff W, Mountjoy CQ, Roth M, Rossor MN, Iversen LL, Reynolds GP, et al. Neuronal degeneration in locus ceruleus and cortical correlates of Alzheimer disease. Alzheimer Dis Assoc Disord. 1987;1(4):256-62.
7.
Jacobs HIL, Riphagen JM, Ramakers I, Verhey FRJ. Alzheimer's disease pathology: pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms. Mol Psychiatry. 2021.
8.
Weinshenker D. Long Road to Ruin: Noradrenergic Dysfunction in Neurodegenerative Disease. Trends Neurosci. 2018;41(4):211-23.
9.
Ehrenberg AJ, Suemoto CK, Franca Resende EP, Petersen C, Leite REP, Rodriguez RD, et al. Neuropathologic Correlates of Psychiatric Symptoms in Alzheimer's Disease. J Alzheimers Dis. 2018;66(1):115-26.
10.
Malhotra PA. Impairments of attention in Alzheimer's disease. Curr Opin Psychol. 2019;29:41-8.
11.
Chalermpalanupap T, Kinkead B, Hu WT, Kummer MP, Hammerschmidt T, Heneka MT, et al. Targeting norepinephrine in mild cognitive impairment and Alzheimer's disease. Alzheimers Res Ther. 2013;5(2):21.
12.
Robertson IH. A noradrenergic theory of cognitive reserve: implications for Alzheimer's disease. Neurobiol Aging. 2013;34(1):298-308.
13.
Yu AJ, Dayan P. Uncertainty, neuromodulation, and attention. Neuron. 2005;46(4):681-92.
14.
Bierer LM, Aisen PS, Davidson M, Ryan TM, Schmeidler J, Davis KL. A pilot study of clonidine plus physostigmine in Alzheimer's disease. Dementia. 1994;5(5):243-6.
15.
Mohs RC, Shiovitz TM, Tariot PN, Porsteinsson AP, Baker KD, Feldman PD. Atomoxetine augmentation of cholinesterase inhibitor therapy in patients with Alzheimer disease: 6-month, randomized, double-blind, placebo-controlled, parallel-trial study. Am J Geriatr Psychiatry. 2009;17(9):752-9.
16.
Arnsten AF, Jin LE. Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. Yale J Biol Med. 2012;85(1):45-58.
17.
Arnsten AF. The use of α-2A adrenergic agonists for the treatment of attention-deficit/hyperactivity disorder. Expert Rev Neurother. 2010;10(10):1595-605.
18.
Strange BC. Once-daily treatment of ADHD with guanfacine: patient implications. Neuropsychiatr Dis Treat. 2008;4(3):499-506.
19.
Kauser H, Sahu S, Kumar S, Panjwani U. Guanfacine is an effective countermeasure for hypobaric hypoxia-induced cognitive decline. Neuroscience. 2013;254:110-9.
20.
Barcelos NM, Van Ness PH, Wagner AF, MacAvoy MG, Mecca AP, Anderson GM, et al. Guanfacine treatment for prefrontal cognitive dysfunction in older participants: a randomized clinical trial. Neurobiol Aging. 2018;70:117-24
21.
Dalmaijer ES, Li KMS, Gorgoraptis N, Leff AP, Cohen DL, Parton AD, et al. Randomised, double-blind, placebo-controlled crossover study of single-dose guanfacine in unilateral neglect following stroke. J Neurol Neurosurg Psychiatry. 2018;89(6):593-8.
22.
Malhotra PA, Parton AD, Greenwood R, Husain M. Noradrenergic modulation of space exploration in visual neglect. Ann Neurol. 2006;59(1):186-90.
23.
Singh-Curry V, Malhotra P, Farmer SF, Husain M. Attention deficits following ADEM ameliorated by guanfacine. J Neurol Neurosurg Psychiatry. 2011;82(6):688-90.
24.
McEntee WJ, Crook TH, Jenkyn LR, Petrie W, Larrabee GJ, Coffey DJ. Treatment of age-associated memory impairment with guanfacine. Psychopharmacol Bull. 1991;27(1):41-6.
25.
Sagar HJ, Cohen NJ, Sullivan EV, Corkin S, Growdon JH. Remote memory function in Alzheimer's disease and Parkinson's disease. Brain. 1988;111 (Pt 1):185-206.
26.
Crook T, Wilner E, Rothwell A, Winterling D, McEntee W. Noradrenergic intervention in Alzheimer's disease. Psychopharmacol Bull. 1992;28(1):67-70.
27.
Schlegel J, Mohr E, Williams J, Mann U, Gearing M, Chase TN. Guanfacine treatment of Alzheimer's disease. Clin Neuropharmacol. 1989;12(2):124-8.
28.
Mohs RC, Rosen WG, Davis KL. The Alzheimer's disease assessment scale: an instrument for assessing treatment efficacy. Psychopharmacol Bull. 1983;19(3):448-50.
29.
Reitan RM, Wolfson D. The Halstead-Reitan neuropsychological test battery: theory and clinical interpretation. Tucson, Arizona: Neuropsychology Press; 1985.
30.
Wechsler D. Measurement of adult intelligence. Baltimore: Williams amp; Wilkins Co; 1939.
31.
Robertson IH, Ward T, Ridgeway V, Nimmo-Smith I. The structure of normal human attention: The Test of Everyday Attention. J Int Neuropsychol Soc. 1996;2(6):525-34.
32.
Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994;44(12):2308-14.
33.
Zarit S, Orr NK, Zarit JM. The hidden victims of Alzheimer's disease: Families under stress. NYU press; 1985.
34.
Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, et al. An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S33-9.
35.
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540-5.
36.
Schneider LS, Olin JT, Doody RS, Clark CM, Morris JC, Reisberg B, et al. Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord. 1997;11 Suppl 2:S22-32.
37.
Kahan BC, Jairath V, Dore CJ, Morris TP. The risks and rewards of covariate adjustment in randomized trials: an assessment of 12 outcomes from 8 studies. Trials. 2014;15:139.
38.
Raina P, Santaguida P, Ismaila A, Patterson C, Cowan D, Levine M, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med. 2008;148(5):379-97.
39.
Feldstein CA, Cohen AA, Sabaris RP, Burucua JE. Hemodynamic effects of guanfacine in essential hypertension. Clin Ther. 1984;6(3):325-34.
40.
Jerie P. Long-term evaluations of therapeutic efficacy and safety of guanfacine. Am J Cardiol. 1986;57(9):55E-9E.
41.
Posey DJ, McDougle CJ. Guanfacine and guanfacine extended release: treatment for ADHD and related disorders. CNS Drug Rev. 2007;13(4):465-74.
42.
43.
44.
45.
Twisk J, Bosman L, Hoekstra T, Rijnhart J, Welten M, Heymans M. Different ways to estimate treatment effects in randomised controlled trials. Contemporary Clinical Trials Communications. 2018;10:80-5.
Metadata
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
Publication date
01-12-2022
Published in
Trials / Issue 1/2022
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-022-06190-3

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