Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: Study protocol for a randomised controlled trial (ELAD study)

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Authors

  • Grazia Daniela Femminella
  • Eleni Frangou
  • Sharon B. Love
  • Gail Busza
  • Clive Holmes
  • Craig Ritchie
  • Robert Lawrence
  • Brady McFarlane
  • Basil H. Ridha
  • Carol Bannister
  • Zuzana Walker
  • Hilary Archer
  • Elizabeth Coulthard
  • Ben R. Underwood
  • Aparna Prasanna
  • Paul Koranteng
  • Salman Karim
  • Kehinde Junaid
  • Bernadette McGuinness
  • Ramin Nilforooshan
  • Ajay Macharouthu
  • Andrew Donaldson
  • Simon Thacker
  • Gregor Russell
  • Naghma Malik
  • Vandana Mate
  • Lucy Knight
  • Sajeev Kshemendran
  • John Harrison
  • David J. Brooks
  • Anthony Peter Passmore
  • Clive Ballard
  • Paul Edison

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Abstract

Background: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer's disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer's disease compared to those who are receiving placebo. Methods/design: ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer's dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer's Disease Assessment Scale - Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer's Disease Cooperative Study - Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group. Discussion: Alzheimer's disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer's treatment. Trial registration: ClinicalTrials.gov, NCT01843075. Registration 30 April 2013.

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  • Evaluating the effects of the novel GLP-1 analogue liraglutide

    Rights statement: © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.

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Details

Original languageEnglish
Article number191
JournalTrials
Volume20
Issue number1
DOIs
Publication statusPublished - 3 Apr 2019

Bibliographic note

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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.

    Keywords

  • Alzheimer's disease, Cerebral glucose metabolic rate, Dementia, Liraglutide, Randomised controlled trial

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