Does semaglutide change the build up of Alzheimer's disease proteins in people at risk?
| ISRCTN | ISRCTN71283871 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN71283871 |
| EudraCT/CTIS number | 2021-003328-34 |
| IRAS number | 300550 |
| Secondary identifying numbers | NN6535-4887, IRAS 300550 |
- 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
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
| Study design | Double-blind randomized parallel-group placebo-controlled superiority trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Prevention |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | Impact of semaglutide in amyloid positivity |
| Study acronym | ISAP |
| Study hypothesis | 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 |
| Condition | 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Semaglutide |
| Primary outcome measure | Current primary outcome measure as of 01/05/2024: The primary endpoint is the annualised change in cortical tau. It is measured at baseline and 52-week visits using PET tau and expressed in standardised uptake value ratio (SUVR). Previous primary outcome measure: Tau cortical standardized uptake value ratio (SUVR) measured using positron emission tomography (PET) at baseline and following treatment at week 52 (visit 7) |
| Secondary outcome measures | Current secondary outcome measures as of 01/05/2024: 1. Cortical neuroinflammatory signal measured using translocator protein (TSPO) PET SUVR at baseline and 52 weeks 2. Plasma biomarkers of neuroinflammation measured by estimating plasma glial fibrillary acidic protein (GFAP) protein levels at screening, baseline, weeks 4, 8, 26, 39 and 52 3. Plasma AD biomarkers: p-tau181 levels and Aβ42/40 ratio at screening, baseline, weeks 4, 8, 26, 39 and 52 4. Cognition measured in-clinic with pen and paper cognitive test (Addenbrooke’s Cognitive Assessment [ACE-III]) scores at baseline, weeks 26 and 52 as well as computerised in-clinic cognitive battery (CANTAB) at baseline, weeks 26 and 52. Cognition is also measured remotely through a browser-based cognitive battery (Cognitron) 1 at baseline, weeks 26 and 52 5. Presence of Adverse Events (AEs), Serious Adverse Events (SAEs), Adverse Reactions (ARs), Serious Adverse Reactions (SARs) and Suspected Unexpected Serious Adverse Reactions (SUSARs). Information on those is collected through interviews at baseline, weeks 4, 8, 26, 39, 52 and follow-up call 6. Neurodegeneration measured by determination of hippocampal volume using structural MRI at baseline and 52 weeks as well as plasma levels of neurofilament light (NFL) measured at screening, baseline, weeks 4, 8, 26, 39 and 52 7. Depression and anxiety scores measured by the Center for Epidemiologic Studies Depression Scale (CES-D) and Health Anxiety Inventory (HAI) scales at baseline and 52 weeks 8. Levels of distress at AD risk disclosure measured through the Impact of Genetic Testing for Alzheimer's disease scale at weeks 26 and 52 9. Quality of life measured by EQ-5D-5L scales at baseline and 52 weeks 10. Level and pattern of physical activity and circadian rhythms measured using wrist-worn actigraphy at baseline and 52 weeks Previous secondary outcome measures: 1. Neuroinflammation measured using Translocator protein (TSPO) PET SUVR, plasma glial fibrillary acidic protein (GFAP) protein level at Baseline & week 52 for TSPO PET; Screening, baseline, weeks 4, 8, 26, 39 & 52 for GFAP 2. AD blood biomarkers measured using AD plasma biomarkers (p-tau181, Aβ42/40) at Screening, baseline, weeks 4, 8, 26, 39 & 52 3. Cognition measured using the Pen and paper cognitive test (ACE-III), Computerised in-clinic cognitive battery (CANTAB): Performance and speech-derived metrics and the Remote cognitive battery (Cognitron) at Baseline, weeks 26 & 52 4. Safety measured using Adverse Event reports at Baseline, week 4, 8, 26, 39, 52 and follow-up call 5. Neurodegeneration measured using Hippocampal volume (MRI), plasma neurofilament light (NFL) at Baseline & week 52 MRI; Screening, baseline, weeks 4, 8, 26, 39 & 52 NFL 6. Quality of life measured using the EuroQol EQ-5D-5L scale at Baseline & week 52 7. Physical activity and circadian rhythms measured using a Wrist-worn actigraphy at Baseline & week 52 |
| Overall study start date | 01/03/2021 |
| Overall study end date | 15/03/2026 |
Eligibility
| Participant type(s) | Other |
|---|---|
| Age group | Adult |
| Lower age limit | 55 Years |
| Sex | Both |
| Target number of participants | 88 |
| Participant 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 |
| Participant 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 |
| Recruitment start date | 15/08/2022 |
| Recruitment end date | 15/11/2024 |
Locations
Countries of recruitment
- England
- United Kingdom
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
Sponsor information
University/education
Boundary Brook House
Churchill Drive
Headington
Oxford
OX3 7GB
England
United Kingdom
| Phone | +44 (0)1865 289886 |
|---|---|
| RGEA.sponsor@admin.ox.ac.uk | |
| Website | https://www.ox.ac.uk/ |
"ROR" |
https://ror.org/052gg0110 |
Funders
Funder type
Industry
Private sector organisation / For-profit companies (industry)
- Alternative name(s)
- Novo Nordisk Global
- Location
- Denmark
Results and Publications
| Intention to publish date | 01/03/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The Steering Committee will recommend a writing group for each manuscript with a lead author and approve the production of all ISAP trial manuscripts. Writing groups will comprise typically of three to seven individuals identified usually from trial members. The lead author will be responsible for ensuring that the paper is written in a timely manner, liaising with the trial statistician as necessary, and keeping the ISAP Trial Manager informed of progress. For papers involving analysis of data generated by the ISAP Trial, at least one member of the writing group will be from the MRC Biostatistics Unit. Major publications will be authored “on behalf of the ISAP Trial group” and produced in accordance with CONSORT guidelines. The first substantive publication will list all trial staff and committee members. Individual authorship will be governed by the international standards for the publication of academic research. The Trial Steering Committee (TSC) will review and comment on drafts of papers to ensure accurate, uniform, timely and high-quality reporting of the ISAP trial and will be responsible for the final approval and submission of all ISAP publications. |
| 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 |
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.
