Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease

Study protocol for a randomised controlled trial (ELAD study)

Grazia Daniela Femminella, Eleni Frangou, Sharon B. Love, Gail Busza, Clive Holmes, Craig Ritchie, Robert Lawrence, Brady McFarlane, George Tadros, Basil H. Ridha, Carol Bannister, Zuzana Walker, Hilary Archer, Elizabeth Coulthard, Ben R. Underwood, Aparna Prasanna, Paul Koranteng, Salman Karim, Kehinde Junaid, Bernadette McGuinness & 14 others 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

Research output: Contribution to journalArticle

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.

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

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Glucagon-Like Peptide 1
Alzheimer Disease
Randomized Controlled Trials
Placebos
Amyloid
Glucose
Therapeutics
Neuronal Plasticity
Diffusion Tensor Imaging
Neuropsychological Tests
Gyrus Cinguli
Neuroprotective Agents
Temporal Lobe
Activities of Daily Living
Liraglutide
Type 2 Diabetes Mellitus
Dementia
Hippocampus
Stem Cells
Obesity

Bibliographical 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

Cite this

Femminella, G. D., Frangou, E., Love, S. B., Busza, G., Holmes, C., Ritchie, C., ... Edison, P. (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]. https://doi.org/10.1186/s13063-019-3259-x
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 ; Edison, Paul. / Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease : Study protocol for a randomised controlled trial (ELAD study). In: Trials. 2019 ; Vol. 20, No. 1.
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Femminella, GD, Frangou, E, Love, SB, Busza, G, Holmes, C, Ritchie, C, Lawrence, R, McFarlane, B, Tadros, G, Ridha, BH, Bannister, C, Walker, Z, Archer, H, Coulthard, E, Underwood, BR, Prasanna, A, Koranteng, P, Karim, S, Junaid, K, McGuinness, B, Nilforooshan, R, Macharouthu, A, Donaldson, A, Thacker, S, Russell, G, Malik, N, Mate, V, Knight, L, Kshemendran, S, Harrison, J, Brooks, DJ, Passmore, AP, Ballard, C & Edison, P 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, vol. 20, no. 1, 191. https://doi.org/10.1186/s13063-019-3259-x

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

In: Trials, Vol. 20, No. 1, 191, 03.04.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease

T2 - Study protocol for a randomised controlled trial (ELAD study)

AU - Femminella, Grazia Daniela

AU - Frangou, Eleni

AU - Love, Sharon B.

AU - Busza, Gail

AU - Holmes, Clive

AU - Ritchie, Craig

AU - Lawrence, Robert

AU - McFarlane, Brady

AU - Tadros, George

AU - Ridha, Basil H.

AU - Bannister, Carol

AU - Walker, Zuzana

AU - Archer, Hilary

AU - Coulthard, Elizabeth

AU - Underwood, Ben R.

AU - Prasanna, Aparna

AU - Koranteng, Paul

AU - Karim, Salman

AU - Junaid, Kehinde

AU - McGuinness, Bernadette

AU - Nilforooshan, Ramin

AU - Macharouthu, Ajay

AU - Donaldson, Andrew

AU - Thacker, Simon

AU - Russell, Gregor

AU - Malik, Naghma

AU - Mate, Vandana

AU - Knight, Lucy

AU - Kshemendran, Sajeev

AU - Harrison, John

AU - Brooks, David J.

AU - Passmore, Anthony Peter

AU - Ballard, Clive

AU - Edison, Paul

N1 - © 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.

PY - 2019/4/3

Y1 - 2019/4/3

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Cerebral glucose metabolic rate

KW - Dementia

KW - Liraglutide

KW - Randomised controlled trial

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DO - 10.1186/s13063-019-3259-x

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