. 2024 Jun 21;14(6):e081401.

doi: 10.1136/bmjopen-2023-081401.

Protocol for a double-blind placebo-controlled randomised controlled trial assessing the impact of oral semaglutide in amyloid positivity (ISAP) in community dwelling UK adults

Ivan Koychev¹, Amanda I Adler², Paul Edison³, Brian Tom⁴, Joanne E Milton², Joe Butchart^{5

6}, Adam Hampshire³, Charles Marshall⁷, Elizabeth Coulthard⁸, Henrik Zetterberg^{9

10

11

12

13

14}, Peter Hellyer³, Francesca Cormack¹⁵, Benjamin R Underwood^{16

17}, Catherine J Mummery¹⁸, Rury R Holman²

Affiliations

¹ Department of Psychiatry, University of Oxford, Oxford, UK ivan.koychev@psych.ox.ac.uk.
² Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
³ Faculty of Medicine, Department of Brain Sciences, Imperial College London, London, UK.
⁴ Medical Research Council Biostatistics Unit, University of Cambridge, UK.
⁵ Royal Devon University Healthcare Foundation Trust, Exeter, UK.
⁶ University of Exeter Medical School, Exeter, UK.
⁷ Preventive Neurology Unit, Wolfson Institute of Population Health, Queen Mary University of London, London, UK.
⁸ Bristol Medical School, University of Bristol, Bristol, UK.
⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
¹⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹¹ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
¹² UK Dementia Research Institute at UCL, London, UK.
¹³ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, People's Republic of China.
¹⁴ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA18 Dementia Research Centre, Institute of Neurology, University College London, Queen Square, London, UK.
¹⁵ Cambridge Cognition Ltd, Cambridge, UK.
¹⁶ Department of Psychiatry, University of Cambridge, Cambridge, UK.
¹⁷ Cambridgeshire and Peterborough NHS Foundation trust, Cambridge, UK.
¹⁸ Dementia Research Centre, Institute of Neurology, University College London, Queen Square, London, UK.

PMID: 38908839
PMCID: PMC11328662
DOI: 10.1136/bmjopen-2023-081401

Protocol for a double-blind placebo-controlled randomised controlled trial assessing the impact of oral semaglutide in amyloid positivity (ISAP) in community dwelling UK adults

Ivan Koychev et al. BMJ Open. 2024.

. 2024 Jun 21;14(6):e081401.

doi: 10.1136/bmjopen-2023-081401.

Authors

Affiliations

¹ Department of Psychiatry, University of Oxford, Oxford, UK ivan.koychev@psych.ox.ac.uk.
² Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
³ Faculty of Medicine, Department of Brain Sciences, Imperial College London, London, UK.
⁴ Medical Research Council Biostatistics Unit, University of Cambridge, UK.
⁵ Royal Devon University Healthcare Foundation Trust, Exeter, UK.
⁶ University of Exeter Medical School, Exeter, UK.
⁷ Preventive Neurology Unit, Wolfson Institute of Population Health, Queen Mary University of London, London, UK.
⁸ Bristol Medical School, University of Bristol, Bristol, UK.
⁹ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
¹⁰ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
¹¹ Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, UK.
¹² UK Dementia Research Institute at UCL, London, UK.
¹³ Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, People's Republic of China.
¹⁴ Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA18 Dementia Research Centre, Institute of Neurology, University College London, Queen Square, London, UK.
¹⁵ Cambridge Cognition Ltd, Cambridge, UK.
¹⁶ Department of Psychiatry, University of Cambridge, Cambridge, UK.
¹⁷ Cambridgeshire and Peterborough NHS Foundation trust, Cambridge, UK.
¹⁸ Dementia Research Centre, Institute of Neurology, University College London, Queen Square, London, UK.

PMID: 38908839
PMCID: PMC11328662
DOI: 10.1136/bmjopen-2023-081401

Abstract

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), currently marketed for type 2 diabetes and obesity, may offer novel mechanisms to delay or prevent neurotoxicity associated with Alzheimer's disease (AD). The impact of semaglutide in amyloid positivity (ISAP) trial is investigating whether the GLP-1 RA semaglutide reduces accumulation in the brain of cortical tau protein and neuroinflammation in individuals with preclinical/prodromal AD.

Methods and analysis: ISAP is an investigator-led, randomised, double-blind, superiority trial of oral semaglutide compared with placebo. Up to 88 individuals aged ≥55 years with brain amyloid positivity as assessed by positron emission tomography (PET) or cerebrospinal fluid, and no or mild cognitive impairment, will be randomised. People with the low-affinity binding variant of the rs6971 allele of the Translocator Protein 18 kDa (TSPO) gene, which can interfere with interpreting TSPO PET scans (a measure of neuroinflammation), will be excluded.At baseline, participants undergo tau, TSPO PET and MRI scanning, and provide data on physical activity and cognition. Eligible individuals are randomised in a 1:1 ratio to once-daily oral semaglutide or placebo, starting at 3 mg and up-titrating to 14 mg over 8 weeks. They will attend safety visits and provide blood samples to measure AD biomarkers at weeks 4, 8, 26 and 39. All cognitive assessments are repeated at week 26. The last study visit will be at week 52, when all baseline measurements will be repeated. The primary end point is the 1-year change in tau PET signal.

Ethics and dissemination: The study was approved by the West Midlands-Edgbaston Research Ethics Committee (22/WM/0013). The results of the study will be disseminated through scientific presentations and peer-reviewed publications.

Trial registration number: ISRCTN71283871.

Keywords: dementia; nuclear medicine; protocols & guidelines.

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Conflict of interest statement

Competing interests: IK has received speaker fees and grant funding (ISAP trial) from Novo Nordisk and is a remunerated medical advisor to digital healthcare companies (Five Lives SAS, Cognetivity, Mantrah) in the dementia field. RRH reports personal fees from Anji Pharmaceuticals, AstraZeneca, Novartis and Novo Nordisk. AIA has received grant funding (ISAP trial) from Novo Nordisk. HZ has served at scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, Wave, has given lectures with honoraria in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Programme (outside submitted work). PE was a consultant to Pfizer, Novo Nordisk, Roche, AstraZeneca, Piramal Life Science, GE Healthcare. He has received speaker fees from Novo Nordisk, Pfizer, Nordea, Piramal Life Science. He has received educational and research grants from GE Healthcare, Novo Nordisk, Piramal Life Science/Life Molecular Imaging, Avid Radiopharmaceuticals and Eli Lilly. He was a member of the Scientific Advisory Board for Novo Nordisk and Cytodyn. CM consults for Biogen, Roche, Eli Lilly, Eisai, IONIS, Alnylam, Prevail, WAVE. She has been awarded an investigator grant from Biogen for ultrafast MRI programme.

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Protocol for a double-blind placebo-controlled randomised controlled trial assessing the impact of oral semaglutide in amyloid positivity (ISAP) in community dwelling UK adults

Affiliations

Protocol for a double-blind placebo-controlled randomised controlled trial assessing the impact of oral semaglutide in amyloid positivity (ISAP) in community dwelling UK adults

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

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Associated data

LinkOut - more resources

Full Text Sources

Medical