Does semaglutide change the build up of Alzheimer's disease proteins in people at risk?
| ISRCTN | ISRCTN71283871 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN71283871 |
| ClinicalTrials.gov (NCT) | Nil known |
| Clinical Trials Information System (CTIS) | 2021-003328-34 |
| Integrated Research Application System (IRAS) | 300550 |
| Protocol serial number | NN6535-4887, IRAS 300550 |
| Sponsor | University of Oxford |
| Funder | Novo Nordisk |
- Submission date
- 21/01/2022
- Registration date
- 02/02/2022
- Last edited
- 25/06/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Nervous System Diseases
Plain English summary of protocol
Background and study aims
The lack of effective treatments for dementia remains one of the key challenges to modern medicine and society. Its leading cause is Alzheimer’s disease (AD), a condition where proteins (called amyloid and tau) build up in the brain causing inflammation and loss of nerve cells. This process begins decades before the first symptoms of dementia appear, offering an opportunity to stop it in its tracks with the right treatment.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of medication used to treat type 2 diabetes and obesity. They have been shown to reduce the risk of heart attack, stroke, and kidney disease in people with diabetes, and in animal experiments, they have also been found to affect the mechanisms thought to be involved in AD.
This study aims to examine the effects of semaglutide (a GLP-1 RA tablet) on the build-up of AD proteins, brain inflammation and thinking ability in people thought to be at high risk of developing AD.
Who can participate?
Men and women aged 55 years and above who do not have dementia and have evidence for a build-up of the amyloid protein in their brains.
What does the study involve?
The study will involve taking a tablet called semaglutide or a placebo (dummy drug). The researchers will conduct several tests over a year to assess the effect of the drug on the risk of Alzheimer's, most notably a head scan to detect the amount of a protein called tau, to see whether those given semaglutide tablets do better compared with those given dummy tablets.
What are the possible benefits and risks of participating?
While there are no immediate benefits for those participating in the study, it is hoped that this research will lead to potential new treatment for AD for which there is currently no effective treatment. While semaglutide is a safe drug, it does carry the risk of side effects like any other medication.
Where is the study run from?
University of Oxford (UK)
When is the study starting and how long is it expected to run for?
March 2021 to March 2026
Who is funding the study?
Novo Nordisk (Denmark)
Who is the main contact?
Hannah Bass
hannah.bass@psych.ox.ac.uk
Contact information
Principal investigator
Department of Psychiatry
Warneford Hospital
Oxford
OX3 7GB
United Kingdom
Public
Department of Psychiatry
University of Oxford
Oxford
OX3 7JX
United Kingdom
| Phone | +44 (0)1865 618291 |
|---|---|
| hannah.bass@psych.ox.ac.uk |
Study information
| Primary study design | Interventional |
|---|---|
| Study design | Double-blind randomized parallel-group placebo-controlled superiority trial |
| Secondary study design | Randomised controlled trial |
| Study type | Participant information sheet |
| Scientific title | Impact of semaglutide in amyloid positivity |
| Study acronym | ISAP |
| Study objectives | To explore possible mechanisms underlying the potential disease modifying effects of semaglutide, a glucagon-like peptide-1 receptor agonist in a group of individuals with preclinical or prodromal Alzheimer’s disease. |
| Ethics approval(s) | Approved, West Midland – Edgbaston Research Ethics Committee (3rd Floor Barlow House, Minshull Street, Manchester, M1 3DZ, UK; +44 (0)207 104 8155, +44 (0)207 104 8357; edgbaston.rec@hra.nhs.uk), ref: NSA 04 |
| Health condition(s) or problem(s) studied | Alzheimer's disease |
| Intervention | Intervention: Semaglutide 3, 7 and 14 mg tablets, titrated to 14 mg once daily, oral Comparator: Matching placebo, once-daily, oral The total duration of treatment is 52 weeks for both arms; follow-up is 5 to 6 weeks following treatment completion. At their randomisation visit, study participants who fulfil all the inclusion criteria and violate none of the exclusion criteria will be assigned a unique randomisation number. Randomisation numbers will be allocated to eligible participants by the ISAP EDC to assign semaglutide or matching placebo in an overall 1:1 ratio. This assignment will be performed using a computerised procedure with minimisation (adaptive stratified sampling) based on T2DM (Yes/No), MCI (Yes/No) and trial site to maintain balance between treatment groups. No participant replacement will be allowed. |
| Intervention type | Drug |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Semaglutide |
| Primary outcome measure(s) |
Current primary outcome measure as of 01/05/2024: |
| Key secondary outcome measure(s) |
Current secondary outcome measures as of 01/05/2024: |
| Completion date | 15/03/2026 |
Eligibility
| Participant type(s) | Other |
|---|---|
| Age group | Adult |
| Lower age limit | 55 Years |
| Sex | All |
| Target sample size at registration | 88 |
| Key inclusion criteria | 1. Participant is willing and able to give informed consent for participation in the trial 2. Male or female, aged 55 years or above 3. Amyloid-positivity as evidenced by PET 4. Fluent English speaker, as assessed by the Investigator 5. In the Investigator’s opinion, is able and willing to comply with all trial requirements 6. Willing to allow his or her General Practitioner (GP), if appropriate, to be notified of participation in the trial 7. Clinical dementia rating (CDR) of 0.5 or below. 8. An informant that is available to the research team for the purposes of CDR scoring |
| Key exclusion criteria | 1. Diagnosis of dementia 2. Treatment with a GLP-1 RA: current or in the past 6 months 3. Women who are pregnant, breastfeeding or of childbearing potential (see Appendix D for definition) 4. People with type 1 diabetes mellitus, secondary diabetes, or maturity-onset diabetes of the young (MODY) 5. People with T2DM who have pre-proliferative or proliferative diabetic retinopathy, or diabetic maculopathy 6. People with T2DM if the cap of 30% of participants with T2DM randomised has been met 7. Poorly controlled T2DM, defined as HbA1c ≥10% (86 mmol/mol) 8. Evidence of severe renal impairment or an estimated glomerular filtration rate (eGFR) derived from serum creatinine (using the simple CKD-EPI formula) of <30 ml/min/1.73 m² 9. Evidence of hepatic cirrhosis as assessed by medical history 10. A psychiatric condition which in the opinion of the investigator may affect the safety of the participant or the outcomes of the study. 11. Any contraindication for MRI or PET scans, including but not limited to: MR-incompatible pacemakers, pregnancy, aneurysm clip, implanted neural stimulator, implanted cardiac pacemaker or auto-defibrillator, cochlear implant, ocular foreign body, recent carotid stent, CSF shunt, other implanted medical device, e.g., Swan Ganz catheter, insulin pump, as assessed by a standard pre-MRI questionnaire 12. Participant with a life expectancy of fewer than 6 months 13. Currently enrolled in another investigational device or drug study, or less than 30 days between randomisation and ending another investigational device or drug study or receiving other investigational treatment(s). Patients participating in a purely observational trial will not be excluded 14. Presence or history of malignant neoplasm (other than basal or squamous cell skin cancer, in-situ carcinomas of the cervix, or in situ prostate cancer) within 5 years prior to the day of screening 15. Lack of access to a suitable digital technology to allow remote cognitive testing (PC or tablet connected to the internet) 16. Significant eye or hearing impairment that in the opinion of the investigator may affect study procedures 17. People with the low-affinity binding variant of the rs6971 allele of the TSPO gene 18. Known or suspected hypersensitivity to the trial product or related products 19. Poor venous access or other contraindications that would make blood sampling difficult 20. Participant that in the view of the investigator will experience significant distress in the event of a positive amyloid status disclosure. Such individuals will not undergo amyloid screening 21. Diabetic individuals treated with sulphonylureas or insulin where dose adjustment as described in protocol is not possible for whatever reason 22. Individuals with significant radiation exposure in the past year for whom in the opinion of the investigator the additional exposure will result in an unacceptable risk |
| Date of first enrolment | 15/08/2022 |
| Date of final enrolment | 15/11/2024 |
Locations
Countries of recruitment
- United Kingdom
- England
Study participating centres
Warneford Lane
Oxford
OX3 7JX
United Kingdom
Barrack Road
Exeter
EX2 5DW
United Kingdom
St Marys Hospital
South Wharf Road
London
W2 1NY
United Kingdom
First Floor
8-11 Queen Square
London
WC1N 3BG
United Kingdom
Southmead Hospital
Southmead Road
Westbury-on-Trym
Bristol
BS10 5NB
United Kingdom
Fulbourn Hospital
Fulbourn
Cambridge
CB21 5EF
United Kingdom
Results and Publications
| Individual participant data (IPD) Intention to share | Yes |
|---|---|
| IPD sharing plan summary | Available on request |
| IPD sharing plan | Current IPD sharing plan as of 25/07/2023: Requests for access to ISAP data should be submitted to the Trial Steering Committee. Contact details and information will be available at: https://www.rdm.ox.ac.uk/about/our-clinical-facilities-and-mrc-units/DTU/diabetes-trial-unit Previous IPD sharing plan: Requests for access to ISAP data should be submitted to the Trial Steering Committee. Contact details and information will be available at: https://www.dtu.ox.ac.uk/ISAP/. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | 25/06/2024 | 25/06/2024 | Yes | No | |
| Participant information sheet | Participant information sheet | 11/11/2025 | 11/11/2025 | No | Yes |
| Study website | Study website | 11/11/2025 | 11/11/2025 | No | Yes |
Editorial Notes
25/06/2024: Publication reference added.
01/05/2024: The following changes were made to the study record:
1. The primary and secondary outcome measures were updated.
2. Cambridgeshire & Peterborough NHS Foundation Trust was added to the study participating centres.
07/12/2023: The study contacts were updated.
21/11/2023: The following changes were made to the study record:
1. The recruitment end date was changed from 15/11/2023 to 15/11/2024.
2. The overall study end date was changed from 15/11/2024 to 15/03/2026.
3. Ethics approval details added.
26/07/2023: Secondary outcome measures were added to the study record.
25/07/2023: The following changes were made to the study record:
1. The recruitment start date was changed from 19/07/2022 to 15/08/2022.
2. The sponsor's contact information was updated.
3. The website link was added.
4. The Individual participant data (IPD) sharing plan was changed.
5. The Royal Devon University Healthcare NHS Foundation Trust, Imperial College Healthcare NHS Trust, St Mary’s Hospital, University College London Hospitals and North Bristol NHS Trust were added to the study participating centres.
24/02/2023: The following changes were made to the study record:
1. The recruitment start date was changed from 23/02/2022 to 19/07/2022.
2. The recruitment end date was changed from 14/03/2023 to 15/11/2023.
3. The overall end date was changed from 31/08/2024 to 15/11/2024.
4. The plain English summary was updated to reflect these changes.
25/01/2022: Trial's existence confirmed by the University of Oxford.
