Alzheimer's Disease
Conditions
Brief summary
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
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. .
Interventions
DRUGLiraglutide
Daily subcutaneous injection
DRUGPlacebo
Daily subcutaneous injection
Sponsors
King's College Hospital NHS Trust
University of Oxford
University of Southampton
Avon and Wiltshire Mental Health Partnership NHS Trust
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The change in cerebral glucose metabolic rate | 12 months | The change in cerebral glucose metabolic rate from baseline to follow up (12 months) in the treatment group compared with the placebo group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The change in z-scores for the ADAS Exec, MRI changes, microglial activation, and CSF markers | 12 months | The change in z-scores for the ADAS Exec, MRI changes, microglial activation, and CSF markers |
| The incidence and severity of treatment emergent adverse events | 12 months | The incidence and severity of treatment emergent adverse events or clinically important changes in safety assessments over 12 months. |
| The change in microglial activation | 12 months | 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 |
| The change in tau deposition | 12 months | 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. |
| The change in cortical amyloid | 12 months | Changes in levels of cortical amyloid load in treatment group compared to the placebo group in a subgroup of subjects. |
Countries
United Kingdom
Outcome results
None listed