A multicentre, interventional, multi-arm, multi-stage Phase 3 trial including randomisation, double blinding, placebo control evaluation of treatments for sustained clinical response (18 months) in symptomatic Alzheimer's Disease in a population representative of people with Alzheimer's disease in the UK.
Confirmed clinical diagnosis of Alzheimer's Disease (AD)
Pacemakers or defibrillators (unless MRI-conditional models)
Aneurysm clips, stents or metal implants (unless MRI safe)
Cochlear implants (unless MRI-conditional models)
Fazekas Score =3 reported from an MRI taken at any time prior to randomisation, if an MRI is not clinically contraindicated (reasons specified in Inclusion Criteria 7) A. MRI does not need to be repeated if Fazekas score = 0, 1 or 2 reported from an MRI performed ≤365 days to screening visit (if Fazekas score has not been reported, refer to Section 7.4) b. MRI should be conducted if participant is not clinically contraindicated to MRIs and previous MRI where Fazekas score = 0, 1 or 2 was >365 days or previous MRI scan is not available for Fazekas score reporting or participant has never had an MRI
Clinical diagnosis of Dementia with Lewy bodies
Clinical diagnosis of Parkinson's disease
Clinical diagnosis of Frontotemporal Dementia
Parallel
Placebo
DrugOral capsule matching active treatments
Atomoxetine
DrugAtomoxetine (Oral, up to 100 mg/day)
Metformin 1000 mg Oral Tablet
DrugMetformin IR Oral, up to 2000 mg/day
Change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score
The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) measures the severity of cognitive impairment in dementia. Scores range from 0 to 70, with higher scores indicating worse cognitive performance (Unit of Measure: ADAS-Cog score (0-70). ADAS-Cog will be administered at baseline, month 6, month 12, and month 18 (end of study), and change over time will be assessed.
Change in Amsterdam Instrumental Activities of Daily Living Questionnaire - Short Version (A-IADL-Q-SV) score
The Amsterdam Instrumental Activities of Daily Living Questionnaire - Short Version (A-IADL-Q-SV) assesses functional impairment in instrumental activities of daily living. Scores range from 0 to 100, with higher scores indicating better functional performance (Unit of Measure: A-IADL-Q-SV score (0-100). The A-IADL-Q-SV will be administered at baseline, month 6, month 12, and month 18 (end of study), and change over time will be evaluated.
Change in Neuropsychiatric Inventory (NPI) total score
The Neuropsychiatric Inventory (NPI) is a structured, informant-based interview assessing neuropsychiatric and behavioural symptoms across 12 domains. Total scores range from 0 to 144 (Unit of Measure: NPI total score (0-144)), with higher scores indicating more severe neuropsychiatric symptoms. The NPI will be administered at baseline, month 6, month 12, and month 18 (end of study), and change over time will be evaluated.
Change in EQ-5D-5L health-related quality-of-life score (participant-reported)
The EQ-5D-5L (EuroQol 5-Dimension 5-Level) questionnaire measures participant-reported health-related quality of life across five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses are converted into a health utility index score ranging from less than 0 (health states worse than death) to 1 (full health), with higher scores indicating better health-related quality of life (Unit of Measure: EQ-5D-5L utility score (\<0 to 1)). The EQ-5D-5L will be administered at baseline, month 3, month 6, month 12, month 15, and month 18 (end of study), and change over time will be assessed.
Change in EQ-5D-5L health-related quality-of-life score (study partner-reported)
The EQ-5D-5L (EuroQol 5-Dimension 5-Level) questionnaire measures study partner-reported health-related quality of life across five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses are converted into a health utility index score ranging from less than 0 (health states worse than death) to 1 (full health), with higher scores indicating better health-related quality of life (Unit of Measure: EQ-5D-5L utility score (\<0 to 1)). The EQ-5D-5L will be administered at baseline, month 6, month 12, and month 18 (end of study), and change over time will be assessed.
Change in Zarit Burden Interview (ZBI) total score
The Zarit Burden Interview (ZBI) assesses subjective caregiver burden, including emotional, social, and physical strain associated with providing care. Total scores range from 0 to 88, with higher scores indicating greater caregiver burden (Unit of Measure: ZBI total score (0-88)). The ZBI will be administered at baseline, month 6, month 12, and month 18 (end of study), and change over time will be evaluated.
Change in plasma pTau-217 concentration
Exploratory biomarker outcome assessing change in plasma pTau-217 levels (Unit of Measure: pg/mL)
MRI structural brain changes
Exploratory Outcome Measures
Change in plasma amyloid-β concentrations
Exploratory biomarker outcome assessing change in plasma amyloid-β isoforms (Unit of Measure: pg/mL)
Change in plasma neurofilament light chain (NfL) concentration
Exploratory biomarker outcome assessing change in plasma NfL levels (Unit of Measure: pg/mL)
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University College, London
Lead sponsor
National Institute for Health Research, United Kingdom
Collaborator
Imperial College London
Collaborator
UK Dementia Research Institute Ltd
Collaborator
Alzheimers Research UK
Collaborator
