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, Ramin Nilforooshan, Ajay Macharouthu, Andrew Donaldson, Simon Thacker, Gregor Russell, Naghma Malik, Vandana Mate, Lucy Knight, Sajeev Kshemendran, John Harrison, Christian Hölscher, David J Brooks, Anthony Peter Passmore, Clive Ballard, Paul Edison, 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, Ramin Nilforooshan, Ajay Macharouthu, Andrew Donaldson, Simon Thacker, Gregor Russell, Naghma Malik, Vandana Mate, Lucy Knight, Sajeev Kshemendran, John Harrison, Christian Hölscher, David J Brooks, Anthony Peter Passmore, Clive Ballard, Paul Edison

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.

Keywords: Alzheimer’s disease; Cerebral glucose metabolic rate; Dementia; Liraglutide; Randomised controlled trial.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the local and regional regulatory ethics committees (London Riverside Research Ethics Committee – study reference number 13/LO/0699, and Health Research Authority, UK), and the Medicines and Healthcare products Regulatory Agency (MHRA – EudraCT number 2013–000962-13). Approval for administration of radioactivity was given by the Administration of Radioactive Substances Advisory Committee (ARSAC).

All participants and study partners signed an Informed Consent Form prior to entry into the study.

Consent for publication

NA.

Competing interests

Dr Edison was funded by the Medical Research Council and now by the Higher Education Funding Council for England (HEFCE). He has also received grants from Alzheimer’s Research, UK, Alzheimer’s Drug Discovery Foundation, Alzheimer’s Society, UK, Novo Nordisk, GE Healthcare, Astra Zeneca, Pfizer, Eli Lilly and Piramal Life Sciences. The other authors have nothing to declare.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
ELAD trial schedule of visits. ADAS-Exec Alzheimer’s Disease Assessment Scale—Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, ApoE Apolipoprotein, CDR Clinical Dementia Rating, CT computed tomography, DSM-IV Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, ECG elecrocardiogram, Incl/Excl inclusion/exclusion, MMSE Mini Mental State Examination, MRI magnetic resonance imaging, NINCDS-ADRDA National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association, PET positron emission tomography, SoB Sum of Boxes, W week
Fig. 2
Fig. 2
Schedule of enrolment

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