E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with mild Alzheimer’s dementia as defined by NINCDS-ADRDA Criteria for Probable Alzheimer’s dementia or meeting NIA-AA criteria for early AD, with MMSE ≥22 and a CDR Global score of 0.5 or 1 using the University of Washington on-line algorithm |
|
E.1.1.1 | Medical condition in easily understood language |
Treatment of patients with early / mild Alzheimer’s dementia |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012271 |
E.1.2 | Term | Dementia Alzheimer's type |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
A 12-month, multicentre randomised double-blind placebo-controlled study in patients with mild Alzheimer’s dementia. Patients will be randomised on a 1:1 ratio to receive liraglutide or identical matching placebo. Participants will be maintained at the highest well-tolerated dose level (either 1.2 or 1.8 mg).
Is there a change in cerebral glucose metabolic rate (rCMRglc) in composite cortical region (hippocampal, medial temporal lobe and posterior cingulate) from baseline to follow up (12 months) in the treatment group compared with the placebo group?
|
|
E.2.2 | Secondary objectives of the trial |
1. The change from baseline to 12 months in z-scores for the cognitive tests (logical memory, battery of other neuropsychometric tests) in the treatment group compared with the placebo group 2. The incidence and severity of treatment emergent adverse events or clinically important changes in safety assessments over 12 months 3. Is there a reduction in microglial activation in subjects with mild AD following daily subcutaneous injection of liraglutide for 1 year using TSPO ([18F]GE180) PET scanning compared to subjects receiving placebo injections in a subgroup of patients? 4. The change in the MRI volume measures in the brain (entorhinal cortex and hippocampal volume, and ventricular volume) from baseline to 12 month in the treatment group compared with the placebo group. 5. The change from baseline to 12 months in the composite scores using Support Vector Machine algorithm derived from neuropsychometric tests, changes in the MRI derived numerical summaries (hippocampal, temporal |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male/female aged 50-85. 2. Capable of giving and capacity to give informed consent. 3. A carer who can act as a reliable study partner. 4. Diagnosis of probable Alzheimer's disease according to NIA-AA criteria. 5. Mini-Mental State Examination (MMSE) score of ≥22. 6. Rosen Modified Hachinski Ischemic score ≤4. 7. On stable medication for 3months; 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.
|
|
E.4 | Principal exclusion criteria |
1.Any contraindications to the use of Liraglutide as per the Summary of Product Characteristics. (hepatic impairment, renal impairment with CKD stage 3 and above, inflammatory bowel disease). 2.Significant neurological disease other than AD that may affect cognition. 3.MRI/CT showing unambiguous aetiological evidence of cerebrovascular disease with regards to their dementia. 4.Diabetes Mellitus. 5.Currently taking or having taken memantine on the 30 days prior to screening. 6.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). 7.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. 8. History of seizures, excluding febrile seizures in childhood. 9. 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. 10. Myocardial infarction within the last 1 year. 11. History of cancer within the last 5 years. 12. Other clinically significant abnormality on physical, neurological, laboratory, examination that could compromise the study or be detrimental to the patient. 13. History of alcohol or drug dependence or abuse within the last 2 years. 14. Current use of anticonvulsant, anti-Parkinson’s, anticoagulant (excluding the use of aspirin 325 mg/day or less) or narcotic medications. 15. 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. 16. Women of childbearing potential. Women who could become pregnant will be required to use adequate contraception throughout the trial. 17. Patients with a personal or family history of medullary thyroid carcinoma (MTC) and patients with multiple endocrine neoplasia type 2 (MEN2).
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary outcome: The change in cerebral glucose metabolic rate in the composite cortical region of the brain from baseline to follow up (12 months) in the treatment group compared with the placebo group.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Twelve months after baseline assessments. |
|
E.5.2 | Secondary end point(s) |
Key secondary outcomes: 1 - The change from baseline to 12 months in z-scores for the ADAS Exec (ADAS-cog and the Executive domain scores from the Neuropsychological Test Battery in the treatment group compared to the placebo group. 2 - The incidence and severity of treatment emergent adverse events or clinically important changes in safety assessments over 12 months.
Other secondary outcomes: 1 - The change in the entorhinal cortex and hippocampal volume from baseline to 12 months in the treatment group compared with the placebo group. 2 - 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. 3 - The change from baseline to 12 months in the composite scores using Support Vector Machine algorithm derived from neuropsychometric tests, changes in the MRI derived numerical summaries (hippocampal, temporal and ventricular volume), changes in [18F]FDG-PET, ApoE4 status and age.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Twelve months after baseline assessments. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
Last visit of last subject (LVLS) |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 1 |