Evaluating Liraglutide in Alzheimer's Disease (ELAD)

Evaluating the Effects of the Novel GLP-1 Analogue, Liraglutide, in Patients With Mild Alzheimer's Disease (ELAD Study)

This is a 12-month, multicentre randomised double-blind placebo-controlled Phase IIb study in patients with mild Alzheimer's dementia (AD). Patients will be randomised on a 1:1 ratio to receive liraglutide or matching placebo.

Study Overview

• Status: Unknown
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: Liraglutide; Drug: Placebo

Detailed Description

The investigators aim to recruit patients with mild Alzheimer's dementia as defined by the National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer's Disease and Related Disorder Association (NINCDS-ADRDA) Criteria for Probable Alzheimer's Dementia or meeting Dubois criteria for early AD, with Mini Mental State Evaluation score of at least 20 out of a maximum of 30 and a CDR Global score of 0.5 or 1.

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• Study Type: Interventional
• Enrollment (Actual): 204
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, W12 0NN
    • Imperial College, Hammersmith Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 48 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Capable of giving and capacity to give informed consent
2. An individual who can act as a reliable study partner with regular contact (combination of face to face visits / telephone contact acceptable) who has sufficient subject interaction to provide meaningful input into rating scales and, if necessary, supervise or perform the injections, as judged by the investigator
3. Diagnosis of Probable Alzheimer's disease according to Dubois criteria (Dubois, Feldman et al. 2007) or National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria
4. Age from 50 years
5. Mini-Mental State Examination (MMSE) score of ≥20 and CDR-Global score of 0.5 or 1
6. Rosen Modified Hachinski Ischemic score ≤4
7. On stable medication for 2 months before the screening visit; on or off cholinesterase inhibitors
8. Fluency in English and evidence of adequate premorbid intellectual functioning
9. Likely to be able to participate in all scheduled evaluations and complete all required tests

Exclusion Criteria:

1. Patients on treatment for diabetes mellitus
2. Any contraindications to the use of liraglutide as per the Summary of Product Characteristics (hepatic impairment, renal impairment with CKD stage 4 and above (eGFR <30 ml/min/1.73m2), inflammatory bowel disease). Patients with eGFR less than 45 ml/min/1.73m2 will have the renal function monitored very closely
3. Significant neurological disease other than AD that may affect cognition
4. MRI/CT showing unambiguous aetiological evidence of cerebrovascular disease with regard to their dementia or vascular dementia fulfilling NINCDS-AIREN criteria
5. Current presence of a clinically significant major psychiatric disorder (e.g., Major Depressive Disorder) according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)
6. Current clinically significant systemic illness that is likely to result in deterioration of the patient's condition or affect the patient's safety during the study
7. History of epilepsy, where seizures or treatment could have contributed to cognitive impairment
8. Treatment with immunosuppressive medications (e.g. systemic corticosteroids) within the last 90 days (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted) or chemotherapeutic agents for malignancy within the last 3 years
9. Myocardial infarction within the last 1 year
10. History of cancer within the last 5 years, except localised skin cancer
11. Other clinically significant abnormality on physical, neurological or laboratory examination that could compromise the study or be detrimental to the patient
12. History of alcohol or drug dependence or abuse within the last 2 years
13. Current use of anticonvulsant, anti-Parkinson's, anticoagulant (excluding the use of aspirin 325 mg/day or less) or narcotic medications. Subjects on anticoagulants will be allowed, but will not have an arterial line inserted
14. Use of experimental medications for AD or any other investigational medication or device within 60 days. Patients who have been involved in a monoclonal antibody study are excluded unless it is known that they were receiving placebo in that trial
15. Women of childbearing potential. Women who could become pregnant will be required to use adequate contraception throughout the trial
16. Patients with a personal or family history of medullary thyroid carcinoma (MTC) and patients with multiple endocrine neoplasia type 2 (MEN2)
17. Any contraindications to MRI scanning

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Liraglutide; Daily administration of 1.8 mg liraglutide by subcutaneous injection	Drug: Liraglutide; Daily subcutaneous injection; Other Names: Victoza
Placebo Comparator: Placebo; Daily administration of matched placebo by subcutaneous injection	Drug: Placebo; Daily subcutaneous injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in cerebral glucose metabolic rate	The change in cerebral glucose metabolic rate from baseline to follow up (12 months) in the treatment group compared with the placebo group.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in z-scores for the ADAS Exec, MRI changes, microglial activation, and CSF markers	The change in z-scores for the ADAS Exec, MRI changes, microglial activation, and CSF markers	12 months
The incidence and severity of treatment emergent adverse events	The incidence and severity of treatment emergent adverse events or clinically important changes in safety assessments over 12 months.	12 months
The change in microglial activation	To establish whether there is a reduction in microglial activation in subjects with mild AD following daily subcutaneous injection of liraglutide for 1 year using TSPO PET scanning compared with subjects receiving placebo injections in a subgroup of patients	12 months
The change in tau deposition	The change in the hippocampal, entorhinal and other cortical changes in tau deposition in treatment group compared to the placebo group in a subgroup of subjects.	12 months
The change in cortical amyloid	Changes in levels of cortical amyloid load in treatment group compared to the placebo group in a subgroup of subjects.	12 months

Collaborators and Investigators

• Sponsor: Imperial College London
• Collaborators: King's College Hospital NHS Trust; University of Oxford; University of Southampton; Avon and Wiltshire Mental Health Partnership NHS Trust
• Investigators: Principal Investigator: Paul Edison, PhD FRCPI, Imperial College London

Publications and helpful links

General Publications

• Muscogiuri G, DeFronzo RA, Gastaldelli A, Holst JJ. Glucagon-like Peptide-1 and the Central/Peripheral Nervous System: Crosstalk in Diabetes. Trends Endocrinol Metab. 2017 Feb;28(2):88-103. doi: 10.1016/j.tem.2016.10.001. Epub 2016 Oct 27.
• 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, Holscher C, Brooks DJ, Passmore AP, Ballard C, Edison P. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomised controlled trial (ELAD study). Trials. 2019 Apr 3;20(1):191. doi: 10.1186/s13063-019-3259-x. Erratum In: Trials. 2020 Jul 19;21(1):660.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2014
• Primary Completion (Anticipated): December 1, 2019
• Study Completion (Anticipated): December 1, 2019

Study Registration Dates

• First Submitted: April 24, 2013
• First Submitted That Met QC Criteria: April 26, 2013
• First Posted (Estimate): April 30, 2013

Study Record Updates

• Last Update Posted (Actual): June 10, 2019
• Last Update Submitted That Met QC Criteria: June 6, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide
• Other Study ID Numbers: U1111-1131-9252

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No