Clinical Trial

. 2025 Jan 1;82(1):11-18.

doi: 10.1001/jamaneurol.2024.3733.

Deferiprone in Alzheimer Disease: A Randomized Clinical Trial

Scott Ayton^{1

2}, David Barton³, Bruce Brew^{4

5}, Amy Brodtmann^{1

6}, Roger Clarnette⁷, Patricia Desmond⁸, David Devos⁹, Kathryn A Ellis¹⁰, Amir Fazlollahi^{8

11}, Caroline Fradette¹², Anita M Y Goh¹³, Pawel Kalinowski¹, Christopher Kyndt¹⁴, Rosalyn Lai¹⁵, Yen Ying Lim^{16

17}, Paul Maruff^{1

18}, Terence J O'Brien⁶, Christopher Rowe^{1

19}, Olivier Salvado²⁰, Peter W Schofield^{21

22}, Michael Spino²³, Fernando Tricta¹², Aaron Wagen^{24

25

26}, Robert Williams^{1

27}, Michael Woodward¹⁹, Ashley I Bush^{1

2}

Affiliations

¹ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
² Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
³ NeuroCentrix, Carlton, Australia.
⁴ Department of Neurology and Peter Duncan Neurosciences Research Unit, St Vincent's Hospital, Darlinghurst, Australia.
⁵ University of New South Wales, Sydney, Australia.
⁶ Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Australia.
⁷ Curtin Health Innovation Research Institute, Curtin University, Bentley, Australia.
⁸ Department of Radiology, Royal Melbourne Hospital, The University of Melbourne, Parkville, Australia.
⁹ Department of Medical Pharmacology, Expert Center of Parkinson's Disease, ALS, and Neurogenetics, University of Lille, Lille Neuroscience & Cognition Research Center, Lille, France.
¹⁰ Department of Psychiatry, Melbourne School of Psychological Sciences, The University of Melbourne, Parkville, Australia.
¹¹ Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
¹² Chiesi Global Rare Diseases, Chiesi Canada Corporation, Woodbridge, Canada.
¹³ National Ageing Research Institute, The University of Melbourne, Parkville, Australia.
¹⁴ Melbourne Health Cognitive Neurology Clinic, The Royal Melbourne Hospital, Parkville, Australia.
¹⁵ KaRa Institute of Neurological Diseases, Macquarie Park, Australia.
¹⁶ School of Psychological Sciences, Monash University, Melbourne, Australia.
¹⁷ Turner Institute for Brain and Mental Health, Monash University, Melbourne, Australia.
¹⁸ Cogstate Ltd, Melbourne, Australia.
¹⁹ Austin Health, The University of Melbourne, Parkville, Australia.
²⁰ Data61, Commonwealth Scientific and Industrial Research Organization, Eveleigh, Australia.
²¹ Neuropsychiatry Service, Hunter New England Local Health District, Newcastle, Australia.
²² University of Newcastle, Callaghan, Australia.
²³ Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.
²⁴ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom.
²⁵ The Francis Crick Institute, London, United Kingdom.
²⁶ Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
²⁷ National Imaging Facility, St Lucia, Australia.

PMID: 39495531
PMCID: PMC11536302 (available on 2025-11-04)
DOI: 10.1001/jamaneurol.2024.3733

Clinical Trial

Deferiprone in Alzheimer Disease: A Randomized Clinical Trial

Scott Ayton et al. JAMA Neurol. 2025.

. 2025 Jan 1;82(1):11-18.

doi: 10.1001/jamaneurol.2024.3733.

Authors

Affiliations

¹ The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
² Florey Department of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.
³ NeuroCentrix, Carlton, Australia.
⁴ Department of Neurology and Peter Duncan Neurosciences Research Unit, St Vincent's Hospital, Darlinghurst, Australia.
⁵ University of New South Wales, Sydney, Australia.
⁶ Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Australia.
⁷ Curtin Health Innovation Research Institute, Curtin University, Bentley, Australia.
⁸ Department of Radiology, Royal Melbourne Hospital, The University of Melbourne, Parkville, Australia.
⁹ Department of Medical Pharmacology, Expert Center of Parkinson's Disease, ALS, and Neurogenetics, University of Lille, Lille Neuroscience & Cognition Research Center, Lille, France.
¹⁰ Department of Psychiatry, Melbourne School of Psychological Sciences, The University of Melbourne, Parkville, Australia.
¹¹ Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
¹² Chiesi Global Rare Diseases, Chiesi Canada Corporation, Woodbridge, Canada.
¹³ National Ageing Research Institute, The University of Melbourne, Parkville, Australia.
¹⁴ Melbourne Health Cognitive Neurology Clinic, The Royal Melbourne Hospital, Parkville, Australia.
¹⁵ KaRa Institute of Neurological Diseases, Macquarie Park, Australia.
¹⁶ School of Psychological Sciences, Monash University, Melbourne, Australia.
¹⁷ Turner Institute for Brain and Mental Health, Monash University, Melbourne, Australia.
¹⁸ Cogstate Ltd, Melbourne, Australia.
¹⁹ Austin Health, The University of Melbourne, Parkville, Australia.
²⁰ Data61, Commonwealth Scientific and Industrial Research Organization, Eveleigh, Australia.
²¹ Neuropsychiatry Service, Hunter New England Local Health District, Newcastle, Australia.
²² University of Newcastle, Callaghan, Australia.
²³ Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.
²⁴ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom.
²⁵ The Francis Crick Institute, London, United Kingdom.
²⁶ Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom.
²⁷ National Imaging Facility, St Lucia, Australia.

PMID: 39495531
PMCID: PMC11536302 (available on 2025-11-04)
DOI: 10.1001/jamaneurol.2024.3733

Abstract

Importance: Interventions that substantially slow neurodegeneration are needed to address the growing burden of Alzheimer disease (AD) to societies worldwide. Elevated brain iron observed in AD has been associated with accelerated cognitive decline and may be a tractable drug target.

Objective: To investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD.

Design, setting, and participants: This phase 2, double-masked, placebo-controlled randomized clinical trial of 12-month duration was conducted at 9 sites in Australia between August 2, 2018, and April 1, 2023. Patients older than 54 years with amyloid-confirmed mild cognitive impairment or early AD (a Mini-Mental State Examination score of 20 or higher) were screened. Randomization was 2:1 and masked to participants and all study staff.

Interventions: Deferiprone 15 mg/kg twice a day or placebo administered orally for 12 months.

Main outcomes and measures: The primary outcome was a composite cognitive measure assessed at baseline, 6 months, and 12 months using a neuropsychological test battery (NTB) of memory, executive function, and attention tasks. Secondary outcomes included change in brain iron burden measured by quantitative susceptibility mapping (QSM) magnetic resonance imaging (target engagement), brain volume changes (secondary efficacy measure), and adverse events (safety analysis).

Results: Of 167 patients screened for eligibility, 81 were included, with 53 randomly assigned to the deferiprone group (mean [SD] age, 73.0 [8.0] years; 29 male [54.7%]) and 28 to the placebo group (mean [SD] age, 71.6 [7.2] years; 17 male [60.7%]); 54 participants completed the study (7 [25.0%] withdrew from the placebo group and 20 [37.7%] from the deferiprone group). In an intention-to-treat analysis, participants in the deferiprone group showed accelerated cognitive decline on the NTB primary outcome (β for interaction = -0.50; 95% CI, -0.80 to -0.20) compared with placebo (change in NTB composite z score for deferiprone, -0.80 [95% CI, -0.98 to -0.62]; for placebo, -0.30 [95% CI, -0.54 to -0.06]). Secondary analysis revealed that this result was driven by worsening performance on executive function tests. The QSM confirmed that deferiprone decreased iron in the hippocampus compared with placebo (change in hippocampal QSM for deferiprone, -0.36 ppb [95% CI, -0.76 to 0.04 ppb]; for placebo, 0.32 ppb [95% CI, -0.12 to 0.75 ppb]; β for interaction = -0.68 [95% CI, -1.27 to -0.09]). Longitudinal hippocampal volume loss was not affected by deferiprone, but exploratory analysis of other brain regions revealed increased volume loss with deferiprone in frontal areas. The frequency of the adverse effect of neutropenia (4 participants [7.5%] in the deferiprone group) was higher than in similar studies (1.6%-4.4%).

Conclusions: These trial findings show that deferiprone 15 mg/kg twice a day decreased hippocampal QSM and accelerated cognitive decline in patients with amyloid-confirmed early AD, suggesting that lowering iron with deferiprone is detrimental to patients with AD.

Trial registration: ClinicalTrials.gov Identifier: NCT03234686.

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Conflict of interest statement

Conflict of Interest Disclosures: Prof Ayton reported receiving personal fees from Eisai Australia and MSD outside the submitted work and being issued patent WO/2016/154682. Dr Barton reported receiving personal fees from The University of Melbourne during the conduct of the study and personal fees from Eli Lilly, Biogen, Pfizer, Actinogen, Eisai, Janssen, and Bristol Myers Squibb and advisory board fees from Eisai, Biogen, and Janssen outside the submitted work. Prof Brodtmann reported serving on scientific advisory boards for Biogen Australia, Roche Australia, Eisai, and Eli Lilly and receiving grants from the National Health and Medical Research Council (NHMRC) outside the submitted work. Prof Devos reported receiving travel fees from ApoPharma during the conduct of the study. Dr Lai reported receiving research funding paid to her institution from GlaxoSmithKline, Biogen, INmune Bio, Eli Lilly, Alector, Cassava Sciences, Actinogen, and Roche outside the submitted work. Prof O’Brien reported receiving grants from the NHMRC, National Institute of Neurological Disorders and Stroke, Department of Defense, and Medical Research Future Fund; clinical trial fees from Eisai, UCB, and Supernus; and consulting fees from Livanova outside the submitted work. Dr Spino reported receiving a salary from Apotex Inc outside the submitted work; a patent for delayed-release deferiprone tablets and methods of using the same issued to Chiesi Farmaceutici; and being former president of ApoPharma Inc. Dr Tricta reported former employment with ApoPharma during the conduct of the study. Dr Wagen reported receiving clinical research fellowship grants from Wolfson outside the submitted work. Mr Williams reported receiving personal fees from Lilly Australia outside the submitted work. Prof Woodward reported receiving research funding from Roche, Novo Nordisk, Actinogen, and INmune Bio during the conduct of the study. Prof Bush reported receiving a fellowship grant from the NHMRC during the conduct of the study. No other disclosures were reported.

References

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Deferiprone in Alzheimer Disease: A Randomized Clinical Trial

Affiliations

Deferiprone in Alzheimer Disease: A Randomized Clinical Trial

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous