Evaluating Liraglutide in Alzheimer's Disease

Study Overview
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Brief Summary
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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.

Detailed Description
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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. .

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

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Liraglutide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Capable of giving and capacity to give informed consent 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 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 Age from 50 years Mini-Mental State Examination (MMSE) score of ≥20 and CDR-Global score of 0.5 or 1 Rosen Modified Hachinski Ischemic score ≤4 On stable medication for 2 months before the screening visit; on or off cholinesterase inhibitors Fluency in English and evidence of adequate premorbid intellectual functioning Likely to be able to participate in all scheduled evaluations and complete all required tests Exclusion Criteria: Patients on treatment for diabetes mellitus 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 Significant neurological disease other than AD that may affect cognition MRI/CT showing unambiguous aetiological evidence of cerebrovascular disease with regard to their dementia or vascular dementia fulfilling NINCDS-AIREN criteria 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) 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 History of epilepsy, where seizures or treatment could have contributed to cognitive impairment 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 Myocardial infarction within the last 1 year History of cancer within the last 5 years, except localised skin cancer Other clinically significant abnormality on physical, neurological or laboratory examination that could compromise the study or be detrimental to the patient History of alcohol or drug dependence or abuse within the last 2 years 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 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 Women of childbearing potential. Women who could become pregnant will be required to use adequate contraception throughout the trial Patients with a personal or family history of medullary thyroid carcinoma (MTC) and patients with multiple endocrine neoplasia type 2 (MEN2) Any contraindications to MRI scanning

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Liraglutide<br>Daily administration of 1.8 mg liraglutide by subcutaneous injection | Drug: Liraglutide<br>* Daily subcutaneous injection<br>* Other names: Victoza;|
| Placebo Comparator: Placebo<br>Daily administration of matched placebo by subcutaneous injection | Drug: Placebo<br>* Daily subcutaneous injection<br>|

What is the study measuring?
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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 |