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Contact Information:

None Shabinah Ali
mrcctu.adsmart@ucl.ac.uk


Dr Paresh Malhotra
p.malhotra@imperial.ac.uk


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Be Part of Research - Trial Details - A flexible initiative to test therapies for Alzheimer’s disease
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A flexible initiative to test therapies for Alzheimer’s disease

Recruiting

Open to: All Genders

Age: Mixed

Cambridge Chertsey

Medical Conditions

Medical condition: Symptomatic Alzheimer’s Disease (Mild Cognitive Impairment, Mild Dementia, Moderate Dementia) Medical condition in lay language: Alzheimer’s disease (AD) Therapeutic areas: Diseases [C] - Nervous System Diseases [C10]

This information is provided directly by researchers, and we recognise that it isn't always easy to understand. We are working with researchers to improve the accessibility of this information. In some summaries, you may come across links to external websites. These websites will have more information to help you better understand the study.


Research into Alzheimer’s disease is making progress, but big challenges remain. The proposed project, AD-SMART, is a quicker, more efficient way of identifying effective treatments for Alzheimer’s. The trial will be for a period of about four years. It will test whether either of two existing medicines (atomoxetine and immediate-release (IR) metformin) can relieve and improve symptoms in patients with Alzheimer’s. Currently, they are used for other illnesses and are known to be safe and effective for those diseases. It will also assess each treatment’s side effects (if any), whether they improve quality of life, and offer the health service sufficient value for money.

Start dates may differ between countries and research sites. The research team are responsible for keeping the information up-to-date.  

The recruitment start and end dates are as follows:

01 May 2026 30 Sep 2029

The trial will compare current standard care and each of two treatments with that care. There will also be a dummy treatment, known as a placebo. The drugs were chosen by an international panel review process, together with patient and public input.
A drug treatment will be considered successful in AD-SMART if, over 18 months, it is both safe and shows a meaningful difference to patients’ quality of life in one or more of the following measures:
• cognitive symptoms (e.g. memory, problem solving).
• ability to perform daily activities (e.g. showering, cooking).
These will be tested in person at the start of the trial, and at intervals of six, twelve and eighteen months.
The research team will collect blood samples at the same time as these clinical tests to learn how changes in levels of certain blood markers are linked to the progression and severity of Alzheimer’s. They will also conduct MRI scans at the start and end of the trial to look for changes in brain structure.
This information will allow us to improve our understanding of how the treatments work to reduce symptoms and affect the progression of the disease.
Following the screening and baseline appointments and once randomisation in the trial database is complete, participants will be contacted for follow-up visits with an additional weekly telephone call during the 4-week titration phase. Trial treatment should ideally be started within 2 weeks of randomisation. The screening, randomisation, week 26, week 52 and week 78 visits must be conducted in person at the AD-SMART trial site. All other study visits can be conducted remotely (via video or telephone). If bloods are required for a remote labelled visit, these can be collected via primary care or other phlebotomy clinics and results provided to the site team.
Participants will only move up in titration if the dose is tolerated, there are no adverse events, or the clinician deems it appropriate to move up in titration if there is an adverse event reported, and only after the telephone assessment.
Prior to entering the study, the participant will be asked to have a blood test and an ECG for safety tests. Additional research blood samples for translational work will also be requested at baseline, week 26, week 52 and week 78 (final visit).
At the same time, the participant and their study partner will be asked to complete several assessments and questionnaires each visit to assess how they are living with AD, e.g. the EQ-5D-5L, ZBI, A-IADL-Q-SV (at baseline, week 26, week 52 and week 78).


Patients with symptoms of Alzheimer’s disease.

You can take part if:



You may not be able to take part if:


Patient 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)2. 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)3. 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 (refer to Section 7.4)4. Clinical diagnosis of Dementia with Lewy bodies5. Clinical diagnosis of Parkinson’s disease6. Clinical diagnosis of Frontotemporal Dementia 7. Cardiac failure (American Heart Association Stage C or D) 8. Significant respiratory comorbidity (hospitalisation within the previous ≤6 months due to respiratory comorbidity)9. Renal failure (CKD IV or eGFR ≤45 mL/min/1.73m²) at any time point prior to randomisation10. Malignancy (except if in complete remission) e.g. solid organ or haematological or melanoma11. Individuals without an identified study partner (refer to Section 4 for further details on study partners)12. Individuals who have an Alzheimer’s Disease or Central Nervous System medication (e.g. antidepressant) change or dose change ≤28 days prior to screening13. 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). 14. Receiving antibody-based amyloid clearing treatment for Alzheimer's Disease within 6 months prior to randomisation15. Unable or unwilling to comply with study procedures16. Unable to swallow whole capsules 17. Individuals who are living in the same household as an AD-SMART participant who is actively taking trial medication18. Female participants that are pregnant or breastfeeding 19. Women of child-bearing potential (WOCBP) who are unwilling or unable to use an acceptable method of contraception (see Appendix 1) whilst on trial treatment and up to 12 weeks after the last dose of study drug20. 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. 21. Male participants unwilling to desist from sperm donation during the trial and for 12 weeks after the last dose of trial treatment22. Current or previous exposure to any of the currently recruiting AD-SMART IMPs ≤26 weeks before randomisation.23. History of alcohol and/or drug abuse and/or dependence within the 5 years prior to screening visit.24. 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.25. 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.

Information on repeating screening tests due to abnormal results and re-completing the screening visit can be found in Section 3.5.5 of the main Protocol. If a treatment arm is stopped early following interim analysis, or a new treatment arm is introduced to the trial, the overall and treatment-specific inclusion/exclusion criteria will be reassessed and updated as needed.

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.


Below are the locations for where you can take part in the trial. Please note that not all sites may be open.

  • Windsor Research Unit
    Cambridgeshire & Peterborough NHS Foundation Trust Fulbourn Hospital
    Cambridge
    CB21 5EF
  • Two Bridges Research & Development Clinic
    Surrey and Borders Partnership NHS Foundation Trust Guildford Street
    Chertsey
    KT16 9AU

It is hoped that participants will be helped by having any of the medications in this study, but this cannot be guaranteed. That is the reason the study is being conducted.
It is possible that the results may not help the participants, but the information obtained from this study will help us to improve treatment for future patients with AD.
The tests completed as part of the trial may find other health care concerns or illnesses that may be affecting the trial participants. If they do, the study team will follow their usual process to address these. This may include informing their GP so that they can follow up with them.
If benefit is shown, an application will be submitted to the Medicines and Healthcare products Regulatory Agency (MHRA) with supporting documentation showing its effect. The MHRA will review this and ensure it meets the strict standards for quality, safety and effectiveness before licensing it for use within mild to moderate Alzheimer’s Disease. This information will then be passed on to the National Institute for Health and Care Excellence (NICE), which will assess the cost-effectiveness for the NHS to fund the medication. If approved, the medication will then be available on the NHS as treatment for mild to moderate Alzheimer’s Disease. Licensing may also be applied for in other countries around the world.
Questionnaires: Some of the questions asked may be upsetting, or the participant and their study partner may feel uncomfortable answering them.
Blood samples: Taking blood from a participant's arm may cause faintness and/or swelling, pain, redness, bruising, bleeding
at the collection site, or infection (infection rarely happens) at the site where the needle is inserted.
Electrocardiogram (ECG): Skin irritation is rare but could occur during an ECG from the electrode patches or gel that
is used.
Whilst MRI scans are part of standard care for AD, some people find it uncomfortable to have the scans due to the need to lie still or claustrophobia. Some people are unable to have an MRI due to other clinical reasons. If this is the case, the participant will not have to have an MRI test to take part in the study.
The AD-SMART trial treatments, atomoxetine and IR metformin, are repurposed drugs and therefore have a well-known safety profile. The participant might experience different or extra side effects from the treatments that they take in this study. If a participant is experiencing adverse events, it is clinical discretion whether they should be assessed in person.
There is a potential risk that an analysis at stage 1 and 2 may result in a treatment arm being discontinued before it has a chance to have any cognitive effect. Against this has to be balanced the risk of continuing randomisation to a clinically ineffective treatment longer than necessary.

Dr Paresh Malhotra
p.malhotra@imperial.ac.uk


None Shabinah Ali
mrcctu.adsmart@ucl.ac.uk



The study is sponsored by University College London and funded by UK Dementia Research Institute.



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Read full details for Trial ID: ISRCTN17108793

Or CPMS: 70766

Last updated 20 July 2026

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