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

NCT07724132 | Recruiting Phase 3 DMC

• 3 other identifiers: ND003ISRCTN1710879370766
• Study Type: interventional
• Target: 1,200
• Locations: 1 country
• Sites: 2

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.

Conditions

Alzheimer's Disease (AD); Mild Cognitive Impairment Due to Alzheimer's Disease; Alzheimer Disease Dementia

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (6)

• Change in Neuropsychiatric Inventory (NPI) total score

  Baseline to 18 months

• Change in EQ-5D-5L health-related quality-of-life score (participant-reported)

  Baseline to 18 months

• Change in EQ-5D-5L health-related quality-of-life score (study partner-reported)

  Baseline to 18 months

• Change in Zarit Burden Interview (ZBI) total score

  Baseline to 18 months

• Incidence of treatment-emergent adverse events and serious adverse events

  Baseline to 18 months

Other Outcomes (4)

• Change in plasma pTau-217 concentration

  Baseline to 18 months

• MRI structural brain changes

  Baseline to 18 months

• Change in plasma amyloid-β concentrations

  Baseline to 18 months

Study Arms (3)

Standard of Care + Placebo

PLACEBO COMPARATOR

Placebo arm (Oral capsule matching active treatments)

Drug: Placebo

Standard of Care + Atomoxetine

ACTIVE COMPARATOR

Atomoxetine (Oral, up to 100 mg/day)

Drug: Atomoxetine

Standard of Care + Metformin

ACTIVE COMPARATOR

Metformin (immediate release) Oral, up to 2000 mg/day

Drug: Metformin 1000 mg Oral Tablet

Interventions

Placebo DRUG

Oral capsule matching active treatments

Standard of Care + Placebo

Atomoxetine DRUG

Atomoxetine (Oral, up to 100 mg/day)

Standard of Care + Atomoxetine

Metformin 1000 mg Oral Tablet DRUG

Metformin IR Oral, up to 2000 mg/day

Standard of Care + Metformin

Eligibility Criteria

• Age: 55 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Adults aged ≥55 years on the day of screening, no upper age limit 2. Either:
• Confirmed clinical diagnosis of Alzheimer's Disease (AD)
• 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:
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• Pacemakers or defibrillators (unless MRI-conditional models)
• Aneurysm clips, stents or metal implants (unless MRI safe)
• Cochlear implants (unless MRI-conditional models)
• Metal fragments in the body
• 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:
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• 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)
• Alanine aminotransferase (ALT) \<3 x ULN;
• 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:
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• 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.

You may not qualify if:

• Clinical diagnosis of Dementia with Lewy bodies
• Clinical diagnosis of Parkinson's disease
• Clinical diagnosis of Frontotemporal Dementia
• Cardiac failure (American Heart Association Stage C or D)
• Significant respiratory comorbidity (hospitalisation within the previous ≤6 months due to respiratory comorbidity)
• Renal failure (CKD IV or eGFR ≤45 mL/min/1.73m²) at any time point prior to randomisation
• Malignancy (except if in complete remission) e.g. solid organ or haematological or melanoma
• Score of ≥1 on C-SSRS at screening visit
• Individuals without an identified study partner (refer to Section 4 for further details on study partners)
• Individuals who have an Alzheimer's Disease or Central Nervous System medication (e.g. antidepressant) change or dose change ≤28 days prior to screening
• 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).
• Receiving antibody-based amyloid clearing treatment for Alzheimer's Disease within 26 weeks prior to randomisation
• Unable or unwilling to comply with study procedures
• Unable to swallow whole capsules
• Individuals who are living in the same household as an AD-SMART participant who is actively taking trial medication

Sponsors & Collaborators

• University College, London: lead
• National Institute for Health Research, United Kingdom: collaborator
• Imperial College London: collaborator
• UK Dementia Research Institute Ltd: collaborator
• Alzheimers Research UK: collaborator

Study Sites (2)

Windsor Research Unit

Cambridge, CB21 5EF, United Kingdom

RECRUITING

Two Bridges Research & Development Clinic

Chertsey, KT16 9AU, United Kingdom

RECRUITING

MeSH Terms

Interventions

Atomoxetine Hydrochloride; Metformin; Tablets

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Biguanides; Guanidines; Amidines; Dosage Forms; Pharmaceutical Preparations

Central Study Contacts

Trial Management Team UCL InCTU

CONTACT

+44 (0)20 7670 4700; mrcctu.adsmart@ucl.ac.uk

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Double (Participant, Investigator)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 11, 2025
• First Posted: July 23, 2026
• Study Start: July 24, 2026
• Primary Completion (Estimated): March 1, 2031
• Study Completion (Estimated): March 1, 2031
• Last Updated: July 23, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share
• Time Frame: After publication of primary results

Locations

GB (2)