Alzheimer's Disease (AD), Mild Cognitive Impairment Due to Alzheimer's Disease, Alzheimer Disease Dementia
Conditions
Brief summary
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.
Detailed description
AD-SMART is a platform trial using a multi-arm multi-stage (MAMS) adaptive design. Participants are randomised (1:1:1) to standard of care plus placebo, atomoxetine, or metformin. Interim analyses are conducted in stages (Stage 1, Stage 2, and Stage 3) to determine whether treatment arms should continue or stop early for lack of activity. The primary objective is to assess therapeutic benefit by measuring change in cognitive function and activities of daily living over 18 months. Secondary outcomes include neuropsychiatric symptoms, quality of life, caregiver burden, safety, and health economic outcomes. Exploratory analyses include blood biomarkers and MRI imaging to investigate disease progression and treatment response.
Interventions
DRUGPlacebo
Oral capsule matching active treatments
DRUGAtomoxetine
Atomoxetine (Oral, up to 100 mg/day)
Metformin IR Oral, up to 2000 mg/day
Sponsors
University College, London
National Institute for Health Research, United Kingdom
Imperial College London
UK Dementia Research Institute Ltd
Alzheimers Research UK
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Double (Participant, Investigator)
Eligibility
Sex/Gender
ALL
Age
55 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient meets all inclusion criteria: 1\. Adults aged ≥55 years on the day of screening, no upper age limit 2. Either: 1. Confirmed clinical diagnosis of Alzheimer's Disease (AD) 2. Confirmed clinical diagnosis of Mixed Dementia consisting of Alzheimer's Disease and Vascular Dementia 3. Mini Mental State Examination score of ≥17 4. Confirmatory blood biomarker testing (pTau-217) (positive or intermediate via validated assays) ≤ 365 days prior to screening or between screening and randomisation or a positive amyloid PET scan (if available) or a positive amyloid CSF test (if available) 5. Randomisation should ideally take place within 4 weeks of the screening visit but no later than 8 weeks after the screening visit 6. Must be able and willing to comply with the treatment and assessment schedule and requirements including being able to start trial treatment ≤ 2 weeks after randomisation 7. Willing and able to have MRI scans in accordance with the assessment schedule unless participant is clinically contraindicated due to: <!-- --> 1. Pacemakers or defibrillators (unless MRI-conditional models) 2. Aneurysm clips, stents or metal implants (unless MRI safe) 3. Cochlear implants (unless MRI-conditional models) 4. Metal fragments in the body 5. Severe claustrophobia 8. Negative pregnancy test ≤4 weeks prior to randomisation for women of child-bearing potential 9. Normal liver function at screening consisting of all the following: <!-- --> 1. Total serum bilirubin \<1.5 x ULN (except for participants with Gilbert's disease, for whom the upper limit of total serum bilirubin is 51.3 μmol/l or 3mg/dl) 2. Alanine aminotransferase (ALT) \<3 x ULN; 3. Alkaline phosphatase \<3 x ULN 10. Documented participant and study partner informed consent 11. If a participant is being re-randomised into the trial, additional timing of entry requirements must also be met: <!-- --> 1. For participants being re-randomised after completing 18 months' follow-up and the arm was not closed due to lack of activity, a 12-week washout period from last dose of IMP must be completed before their screening visit. If the efficacy analysis indicates that the IMP was ineffective then this washout period can be reduced to 6 weeks. 2. For participants being re-randomised following treatment arm termination due to lack of activity, a 6-week washout period from their last dose of IMP must be completed prior to screening assessment Study Partner inclusion criteria: 1. Participant that meets the AD-SMART eligibility criteria has consented to participation in the trial 2. Has at least twice-weekly contact with participant 3. Be 18 years or older at the time of providing consent 4. Willing to complete study partner questionnaires as outlined in visit schedule 5. Willing to attend remote and in-person study visits with participant 6. Documented informed consent
Exclusion criteria
* Patient meets none of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) score | Baseline to 18 months | 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 | Baseline to 18 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Neuropsychiatric Inventory (NPI) total score | Baseline to 18 months | 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) | Baseline to 18 months | 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) | Baseline to 18 months | 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 | Baseline to 18 months | 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. |
| Incidence of treatment-emergent adverse events and serious adverse events | Baseline to 18 months | Safety profile of investigational medicinal products (IMPs), including all adverse events (AEs), serious adverse events (SAEs), adverse reactions (ARs), and suspected unexpected serious adverse reactions (SUSARs). Events will be systematically collected, assessed, and analysed throughout the study from first dose until end of follow-up (Unit of Measure: Number of participants experiencing at least one AE or SAE) |
| Change in health and social care resource use and associated costs | Baseline to 18 months | Health and social care resource utilisation will be measured using a structured Resource Use Questionnaire (RUQ). The RUQ captures participant use of primary care, secondary care, community services, urgent and emergency care, social care, and informal care. It also collects information needed to estimate costs for economic evaluation. Unit of Measure: Resource use counts and costs (GBP). Resource use will be assessed at baseline (covering the preceding 6 months), month 6, month 12, and month 18 (end of study), and changes over time will be evaluated. |
Countries
United Kingdom
Contacts
CONTACTTrial Management Team UCL InCTU
Outcome results
None listed