The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

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

Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer’s disease: study protocol for a randomised controlled trial (ELAD study)
Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer’s disease: study protocol for a randomised controlled trial (ELAD study)
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.
1745-6215
Femminella, Grazia Daniela
a25a7e4b-d408-492c-80fd-c4fb199ad99d
Frangou, Eleni
e904c739-6861-4371-937a-d0c572949252
Love, Sharon B.
310dcdee-7f96-404b-a50d-fefd5e82ba82
Busza, Gail
12b8e76d-483f-49b0-85cf-54c6f959c861
Holmes, Clive
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Ritchie, Craig
6c9d9049-b42c-468c-ac5f-cd88041761de
Lawrence, Robert
f0cf51e5-7902-4355-ba98-d177c8b53d84
Mcfarlane, Brady
e65d6960-01e9-44fb-947a-a0f963c88376
Tadros, George
c5914ca6-9543-4c62-8b6f-939dbc9e1e14
Ridha, Basil H.
a1e10ca1-6329-4520-b294-c41bd3160f0c
Bannister, Carol
c30d7450-4b27-4cbf-9bac-a1ea6b090c24
Walker, Zuzana
4b450f01-7f2a-44a8-9161-f036637e1d5a
Archer, Hilary
fcb123da-fbff-48ac-9e54-ab0b139987a0
Coulthard, Elizabeth
94b33f2f-d416-42b1-9e48-58bec9919b7d
Underwood, Ben R.
195c5974-15e0-416c-8560-919669e5526b
Prasanna, Aparna
e178fd8a-d617-40f7-9ea4-1ba0b05de0ac
Koranteng, Paul
11413a53-2b45-4570-a628-5a45b0fe6b5f
Karim, Salman
1d1eb30a-8327-40b0-bbe4-553b12e804bd
Junaid, Kehinde
0027cf9c-a48a-4c90-8552-a95bfa8a0d45
Mcguinness, Bernadette
90a0a19e-ed7f-4fe0-8860-74ee73ff037f
Nilforooshan, Ramin
5b7ce319-375a-497c-a981-8786c146cdbf
Macharouthu, Ajay
39a034c7-548a-440a-9161-1d095b51bd8f
Donaldson, Andrew
8dbe15a8-ac0c-4acc-a0bc-9f29985e88a2
Thacker, Simon
bcf565c9-e54d-460c-8114-4221e9605fbb
Russell, Gregor
3880cd93-7c74-4055-b347-c24ce1f49fb7
Malik, Naghma
3770c17c-ebc4-4786-ae6a-83e22a2881ee
Mate, Vandana
cc527229-8022-425b-ab33-a5c25794091c
Knight, Lucy
b54acab9-a1ac-4e43-8a3e-f8e20d7ee3da
Kshemendran, Sajeev
cb3c783c-bdd0-420b-956d-3f5310c58646
Harrison, John
3008e91f-36ed-4d1f-9ebf-0185bb5033df
Brooks, David J.
1b2437af-8323-4461-a9a8-ec74936a3c6c
Passmore, Anthony Peter
774691ef-64a3-495d-b3d1-0e6c6cd84c01
Ballard, Clive
e244c4e5-5dd4-4c66-9efb-6bf2006bdb7e
Edison, Paul
71447356-870d-4e69-a135-a996fcb15272
Femminella, Grazia Daniela
a25a7e4b-d408-492c-80fd-c4fb199ad99d
Frangou, Eleni
e904c739-6861-4371-937a-d0c572949252
Love, Sharon B.
310dcdee-7f96-404b-a50d-fefd5e82ba82
Busza, Gail
12b8e76d-483f-49b0-85cf-54c6f959c861
Holmes, Clive
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Ritchie, Craig
6c9d9049-b42c-468c-ac5f-cd88041761de
Lawrence, Robert
f0cf51e5-7902-4355-ba98-d177c8b53d84
Mcfarlane, Brady
e65d6960-01e9-44fb-947a-a0f963c88376
Tadros, George
c5914ca6-9543-4c62-8b6f-939dbc9e1e14
Ridha, Basil H.
a1e10ca1-6329-4520-b294-c41bd3160f0c
Bannister, Carol
c30d7450-4b27-4cbf-9bac-a1ea6b090c24
Walker, Zuzana
4b450f01-7f2a-44a8-9161-f036637e1d5a
Archer, Hilary
fcb123da-fbff-48ac-9e54-ab0b139987a0
Coulthard, Elizabeth
94b33f2f-d416-42b1-9e48-58bec9919b7d
Underwood, Ben R.
195c5974-15e0-416c-8560-919669e5526b
Prasanna, Aparna
e178fd8a-d617-40f7-9ea4-1ba0b05de0ac
Koranteng, Paul
11413a53-2b45-4570-a628-5a45b0fe6b5f
Karim, Salman
1d1eb30a-8327-40b0-bbe4-553b12e804bd
Junaid, Kehinde
0027cf9c-a48a-4c90-8552-a95bfa8a0d45
Mcguinness, Bernadette
90a0a19e-ed7f-4fe0-8860-74ee73ff037f
Nilforooshan, Ramin
5b7ce319-375a-497c-a981-8786c146cdbf
Macharouthu, Ajay
39a034c7-548a-440a-9161-1d095b51bd8f
Donaldson, Andrew
8dbe15a8-ac0c-4acc-a0bc-9f29985e88a2
Thacker, Simon
bcf565c9-e54d-460c-8114-4221e9605fbb
Russell, Gregor
3880cd93-7c74-4055-b347-c24ce1f49fb7
Malik, Naghma
3770c17c-ebc4-4786-ae6a-83e22a2881ee
Mate, Vandana
cc527229-8022-425b-ab33-a5c25794091c
Knight, Lucy
b54acab9-a1ac-4e43-8a3e-f8e20d7ee3da
Kshemendran, Sajeev
cb3c783c-bdd0-420b-956d-3f5310c58646
Harrison, John
3008e91f-36ed-4d1f-9ebf-0185bb5033df
Brooks, David J.
1b2437af-8323-4461-a9a8-ec74936a3c6c
Passmore, Anthony Peter
774691ef-64a3-495d-b3d1-0e6c6cd84c01
Ballard, Clive
e244c4e5-5dd4-4c66-9efb-6bf2006bdb7e
Edison, Paul
71447356-870d-4e69-a135-a996fcb15272

Femminella, Grazia Daniela, Frangou, Eleni, Love, Sharon B., Busza, Gail, Holmes, Clive, Ritchie, Craig, Lawrence, Robert, Mcfarlane, Brady, Tadros, George, Ridha, Basil H., Bannister, Carol, Walker, Zuzana, Archer, Hilary, Coulthard, Elizabeth, Underwood, Ben R., Prasanna, Aparna, Koranteng, Paul, Karim, Salman, Junaid, Kehinde, Mcguinness, Bernadette, Nilforooshan, Ramin, Macharouthu, Ajay, Donaldson, Andrew, Thacker, Simon, Russell, Gregor, Malik, Naghma, Mate, Vandana, Knight, Lucy, Kshemendran, Sajeev, Harrison, John, Brooks, David J., Passmore, Anthony Peter, Ballard, Clive and Edison, Paul (2019) Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer’s disease: study protocol for a randomised controlled trial (ELAD study). Trials, 20 (1), [191]. (doi:10.1186/s13063-019-3259-x).

Record type: Article

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.

Text
s13063-019-3259-x - Version of Record
Available under License Creative Commons Attribution.
Download (1MB)

More information

Accepted/In Press date: 27 February 2019
Published date: 3 April 2019

Identifiers

Local EPrints ID: 430645
URI: http://eprints.soton.ac.uk/id/eprint/430645
ISSN: 1745-6215
PURE UUID: 0236c29a-ad50-4a79-80b4-4478d22c83c9
ORCID for Clive Holmes: ORCID iD orcid.org/0000-0003-1999-6912

Catalogue record

Date deposited: 07 May 2019 16:30
Last modified: 26 Nov 2021 02:42

Export record

Altmetrics

Contributors

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

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×