An Evaluation of Treatments for Sustained Clinical Response (18 Months) in Symptomatic Alzheimer's Disease (AD-SMART)

Alzheimer's Disease- Systematic Multi-Arm Adaptive Randomised Trial

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.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer's Disease (AD); Mild Cognitive Impairment Due to Alzheimer's Disease; Alzheimer Disease Dementia
• Intervention / Treatment: Drug: Placebo; Drug: Atomoxetine; Drug: Metformin 1000 mg Oral Tablet

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.

• Study Type: Interventional
• Enrollment (Estimated): 1200
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Trial Management Team UCL InCTU; Phone Number: +44 (0)20 7670 4700; Email: mrcctu.adsmart@ucl.ac.uk

Study Locations

• United Kingdom
  • Cambridge, United Kingdom, CB21 5EF
    • Recruiting
    • Windsor Research Unit
  • Chertsey, United Kingdom, KT16 9AU
    • Recruiting
    • Two Bridges Research & Development Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 exclusion criteria:

  1. 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
  2. Clinical diagnosis of Dementia with Lewy bodies
  3. Clinical diagnosis of Parkinson's disease
  4. Clinical diagnosis of Frontotemporal Dementia
  5. Cardiac failure (American Heart Association Stage C or D)
  6. Significant respiratory comorbidity (hospitalisation within the previous ≤6 months due to respiratory comorbidity)
  7. Renal failure (CKD IV or eGFR ≤45 mL/min/1.73m²) at any time point prior to randomisation
  8. Malignancy (except if in complete remission) e.g. solid organ or haematological or melanoma
  9. Score of ≥1 on C-SSRS at screening visit
  10. Individuals without an identified study partner (refer to Section 4 for further details on study partners)
  11. Individuals who have an Alzheimer's Disease or Central Nervous System medication (e.g. antidepressant) change or dose change ≤28 days prior to screening
  12. Use of an Investigational Medicinal Product (IMP) or Investigational Medical Device (IMD) ≤26 weeks prior to randomisation (except for AD-SMART participants that are being re-randomised. See Section 5.4 for further information).
  13. Receiving antibody-based amyloid clearing treatment for Alzheimer's Disease within 26 weeks prior to randomisation
  14. Unable or unwilling to comply with study procedures
  15. Unable to swallow whole capsules
  16. Individuals who are living in the same household as an AD-SMART participant who is actively taking trial medication
  17. Female participants that are pregnant or breastfeeding
  18. Women of child-bearing potential (WOCBP) who are unwilling or unable to use an acceptable method of contraception (see acceptable methods of contraception) whilst on trial treatment and up to 12 weeks after the last dose of study drug
  19. Male participants with a partner of child-bearing potential unwilling or unable to use an acceptable method of contraception whilst on trial treatment and up to 12 weeks after the last dose of the study drug.
  20. Male participants unwilling to desist from sperm donation during the trial and for 12 weeks after the last dose of trial treatment
  21. Current or previous exposure to any of the currently recruiting AD-SMART IMPs ≤26 weeks before randomisation.
  22. History of alcohol and/or drug abuse and/or dependence within the 5 years prior to screening visit.
  23. Any concurrent medical condition, abnormal laboratory tests or uncontrolled, clinically significant systemic disease that, in the opinion of the Investigator, could cause study participation to be detrimental to the participant.
  24. Participants who are not eligible for any of the trial IMPs, according to the eligibility criteria listed in the individual drug appendices. Please note that participants can enter the trial if they are eligible for at least one of the trial treatment arms, but do not need to be eligible for all.

Arm-specific eligibility criteria:

Atomoxetine-specific exclusion eligibility criteria:

In addition to the core inclusion and exclusion criteria, refer to section 2.2 of AD-SMART Appendix 1 Atomoxetine' for the arm-specific exclusion eligibility criteria for the Atomoxetine arm which must also be met.

Metformin-specific exclusion eligibility criteria:

In addition to the core inclusion and exclusion criteria, refer to section 2.2 of AD-SMART Appendix 2 Metformin' for the arm-specific exclusion eligibility criteria for the metformin arm which must also be met.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Standard of Care + Placebo; Placebo arm (Oral capsule matching active treatments)	Drug: Placebo; Oral capsule matching active treatments
Active Comparator: Standard of Care + Atomoxetine; Atomoxetine (Oral, up to 100 mg/day)	Drug: Atomoxetine; Atomoxetine (Oral, up to 100 mg/day)
Active Comparator: Standard of Care + Metformin; Metformin (immediate release) Oral, up to 2000 mg/day	Drug: Metformin 1000 mg Oral Tablet; Metformin IR Oral, up to 2000 mg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline to 18 months
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.	Baseline to 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline to 18 months
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.	Baseline to 18 months
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.	Baseline to 18 months
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.	Baseline to 18 months
Incidence of treatment-emergent adverse events and serious adverse events	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)	Baseline to 18 months
Change in health and social care resource use and associated costs	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.	Baseline to 18 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in plasma pTau-217 concentration	Exploratory biomarker outcome assessing change in plasma pTau-217 levels (Unit of Measure: pg/mL)	Baseline to 18 months
MRI structural brain changes	Exploratory Outcome Measures	Baseline to 18 months
Change in plasma amyloid-β concentrations	Exploratory biomarker outcome assessing change in plasma amyloid-β isoforms (Unit of Measure: pg/mL)	Baseline to 18 months
Change in plasma neurofilament light chain (NfL) concentration	Exploratory biomarker outcome assessing change in plasma NfL levels (Unit of Measure: pg/mL)	Baseline to 18 months

Collaborators and Investigators

• Sponsor: University College, London
• Collaborators: Imperial College London; National Institute for Health Research, United Kingdom; UK Dementia Research Institute Ltd; Alzheimers Research UK

Study record dates

Study Major Dates

• Study Start (Estimated): July 24, 2026
• Primary Completion (Estimated): March 1, 2031
• Study Completion (Estimated): March 1, 2031

Study Registration Dates

• First Submitted: September 11, 2025
• First Submitted That Met QC Criteria: July 21, 2026
• First Posted (Actual): July 23, 2026

Study Record Updates

• Last Update Posted (Actual): July 23, 2026
• Last Update Submitted That Met QC Criteria: July 21, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organic Chemicals; Pharmaceutical Preparations; Dosage Forms; Amines; Biguanides; Guanidines; Amidines; Propylamines; Atomoxetine Hydrochloride; Metformin; Tablets
• Other Study ID Numbers: ND003; 70766 (Other Identifier: Central Portfolio Management System (CPMS)); ISRCTN17108793 (Registry Identifier: ISRCTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Research teams may approach the UCL InCTU (mrcctu.adsmart@ucl.ac.uk) with a formal data-sharing request detailing the specific requirement, proposed research, qualification of researchers and publication plan if they are interested in using AD-SMART data. The request will be reviewed by the trial committees.

Data and/or samples will be available for sharing following the end of a trial arm and the unblinding of participants. Researchers wishing to access the AD-SMART Trial data should contact the Trial Management Group in the first instance. Following trial completion, requests for data and/ or sample sharing will be reviewed by an AD-SMART access committee, which will include the trial's Chief Investigators.

Data and/ or samples will be shared during the trial according to the CTU's controlled access approach.

• IPD Sharing Time Frame: After publication of primary results

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No