Intranasal oxytocin for apathy in people with frontotemporal dementia (FOXY): a multicentre, randomised, double-blind, placebo-controlled, adaptive, crossover, phase 2a/2b superiority trial

Kristy K L Coleman¹, Scott Berry², Jeffrey Cummings³, Ging-Yuek R Hsiung⁴, Robert Laforce⁵, Edward Huey⁶, Simon Ducharme⁷, Maria Carmela Tartaglia⁸, Mario F Mendez⁹, Chiadi Onyike¹⁰, Kimiko Domoto-Reilly¹¹, Mario Masellis¹², Nathan Herrmann¹³, Anton Porsteinsson¹⁴, Michelle A Detry², Chloe Stewart¹⁵, Anna L Bosse², Anna McGlothlin², Bryan Dias¹⁶, Sachin Pandey¹⁷, Michael Mayich¹⁷, Stephen H Pasternak¹⁸, Ramiro Ruiz Garcia¹⁹, Miguel Restrepo-Martinez²⁰, Howard Feldman²¹, Adam L Boxer²², Elizabeth C Finger²³

Affiliations

¹ Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada; Department of Cognitive Neurology, St Joseph's Health Care London, London, ON, Canada.
² Company Berry Consultants, Austin, TX, USA.
³ Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA.
⁴ Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
⁵ Département des Sciences Neurologiques, CHU de Québec, Quebec City, QC, Canada; Department of Neurology, Laval University, Quebec City, QC, Canada.
⁶ Department of Psychiatry and Human Behaviour, Brown University Warren Alpert Medical School, Providence, RI, USA; Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
⁷ Department of Psychiatry, McGill University, Montreal, QC, Canada.
⁸ Department of Medicine, University Health Network, Toronto, ON, Canada.
⁹ Department of Neurology and Psychiatry, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA, USA.
¹⁰ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Neurology, University of Washington, Seattle, WA, USA.
¹² Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
¹³ Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
¹⁴ Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
¹⁵ Department of Cognitive Neurology, St Joseph's Health Care London, London, ON, Canada.
¹⁶ Department of Cardiology, London Health Sciences Centre, London, ON, Canada.
¹⁷ Department of Medical Imaging, London Health Sciences Centre, London, ON, Canada.
¹⁸ Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada; Department of Cognitive Neurology, St Joseph's Health Care London, London, ON, Canada.
¹⁹ Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada; Department of Neurology, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico.
²⁰ Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada; Department of Psychiatry, Las Americas Auna Clinic, Medellin, Colombia.
²¹ Department of Neurosciences, University of California, San Diego, CA, USA.
²² Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
²³ Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada; Department of Cognitive Neurology, St Joseph's Health Care London, London, ON, Canada. Electronic address: elizabeth.finger@lhsc.on.ca.

PMID: 39862881
DOI: 10.1016/S1474-4422(24)00456-3

Clinical Trial

Intranasal oxytocin for apathy in people with frontotemporal dementia (FOXY): a multicentre, randomised, double-blind, placebo-controlled, adaptive, crossover, phase 2a/2b superiority trial

Kristy K L Coleman et al. Lancet Neurol. 2025 Feb.

. 2025 Feb;24(2):128-139.

doi: 10.1016/S1474-4422(24)00456-3.

Authors

Affiliations

¹ Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada; Department of Cognitive Neurology, St Joseph's Health Care London, London, ON, Canada.
² Company Berry Consultants, Austin, TX, USA.
³ Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV, USA.
⁴ Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
⁵ Département des Sciences Neurologiques, CHU de Québec, Quebec City, QC, Canada; Department of Neurology, Laval University, Quebec City, QC, Canada.
⁶ Department of Psychiatry and Human Behaviour, Brown University Warren Alpert Medical School, Providence, RI, USA; Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA.
⁷ Department of Psychiatry, McGill University, Montreal, QC, Canada.
⁸ Department of Medicine, University Health Network, Toronto, ON, Canada.
⁹ Department of Neurology and Psychiatry, University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA, USA.
¹⁰ Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Neurology, University of Washington, Seattle, WA, USA.
¹² Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
¹³ Department of Psychiatry, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
¹⁴ Department of Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
¹⁵ Department of Cognitive Neurology, St Joseph's Health Care London, London, ON, Canada.
¹⁶ Department of Cardiology, London Health Sciences Centre, London, ON, Canada.
¹⁷ Department of Medical Imaging, London Health Sciences Centre, London, ON, Canada.
¹⁸ Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada; Department of Cognitive Neurology, St Joseph's Health Care London, London, ON, Canada.
¹⁹ Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada; Department of Neurology, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Ciudad de México, Mexico.
²⁰ Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada; Department of Psychiatry, Las Americas Auna Clinic, Medellin, Colombia.
²¹ Department of Neurosciences, University of California, San Diego, CA, USA.
²² Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
²³ Department of Clinical Neurological Sciences, University of Western Ontario, London, ON, Canada; Department of Cognitive Neurology, St Joseph's Health Care London, London, ON, Canada. Electronic address: elizabeth.finger@lhsc.on.ca.

PMID: 39862881
DOI: 10.1016/S1474-4422(24)00456-3

Abstract

Background: No treatments exist for apathy in people with frontotemporal dementia. Previously, in a randomised double-blind, placebo-controlled, dose-finding study, intranasal oxytocin administration in people with frontotemporal dementia improved apathy ratings on the Neuropsychiatric Inventory over 1 week and, in a randomised, double-blind, placebo-controlled, crossover study, a single dose of 72 IU oxytocin increased blood-oxygen-level-dependent signal in limbic brain regions. We aimed to determine whether longer treatment with oxytocin improves apathy in people with frontotemporal dementia.

Methods: We conducted a multicentre, randomised, double-blind, placebo-controlled, adaptive, crossover, phase 2a/2b trial, enrolling participants from 11 expert frontotemporal dementia outpatient clinics across Canada and the USA. People aged 30-80 years with a diagnosis of probable frontotemporal dementia, a Neuropsychiatric Inventory apathy score of 2 or higher, a study partner who interacted with them for at least 3 h per day, and stable cognitive and behavioural medications for 30 days were eligible for inclusion. In stage 1, participants were randomly assigned (1:1:1:1:1:1) to one of three dose schedules (every day, every other day, and every third day) of 72 IU intranasal oxytocin or placebo and to the order they would received the intervention in the crossover; intranasal oxytocin or placebo were administered twice daily for 6 weeks, with a 6-week washout and then crossover to the other intervention. In stage 2, new participants were randomised (1:1) to the dose that had been determined as optimal in stage 1 or to placebo, with crossover as in stage 1. Randomisation used variable block sizes and was stratified by participant sex and Clinical Dementia Rating severity score. All kits of investigational product were identical and produced centrally, and all local teams, study staff, and participants were masked to treatment allocation and order. The primary outcome was difference in the change in Neuropsychiatric Inventory apathy scores for oxytocin versus placebo periods in the per-protocol population after 6 weeks of treatment. Safety was assessed at each visit via electrocardiogram, blood work, and collection of data on adverse events. This trial is registered at ClinicalTrials.gov (NCT03260920).

Findings: Between Jan 31, 2018, and Dec 11, 2020, 70 patients were screened for stage 1 and 60 (86%) were enrolled. 45 (75%) completed both treatment periods of stage 1. 72 IU oxytocin every third day was the optimal dose schedule from stage 1 based on its Bayesian posterior probability (Pr(Best)=0·478). Between June 28, 2021, and Jan 31, 2023, 42 patients were screened for stage 2, and 34 (81%) were enrolled. 28 (82%) completed both treatment periods in stage 2. 38 (40%) of 94 participants were female and 56 (60%) were male (mean age 65·9 years, SD 8·2) Treatment with oxytocin every third day resulted in an improved Neuropsychiatric Inventory apathy score, with an estimated -1·32 points (95% CI -2·43 to -0·21) relative to placebo (one sided p=0·010). Two adverse events were reported in at least 5% of participants: upper respiratory tract infection (five [6%] of 78 participants on placebo and three [5%] on every third day at all doses of oxytocin) and headache (two [3%] participants on placebo, one [7%] of 15 participants on oxytocin every day, and two [4%] of 55 participants on oxytocin every third day). No adverse events were attributed to oxytocin treatment.

Interpretation: Intranasal oxytocin given every third day was well tolerated and was associated with a small reduction in apathy in patients with frontotemporal dementia. Future trials might investigate intermittent dosing of more potent formulations than in this study, to establish whether larger effects are possible.

Funding: Canadian Institutes of Health Research and Weston Foundation.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests ECF received grant support for the FOXY trial from the Canadian Institutes for Health Research, the Weston Foundation, and the Physician Services Incorporated Foundation, and serves as a scientific advisor for and has received consulting fees from Psilera. AdLB has received consulting fees from AGTC, Alchemab, Alector, Alzprotect, Amylyx, Arkuda, Arrowhead, Arvinas, Aviado, Eli Lilly, GSK, Humana, Merck, Modalis, Muna, Oligomerix, Oscotec, Pfizer, Roche, Switch, Transposon, and UnlearnAI and stock or stock options from Alector, and Arvinas. SHP has received consulting fees from Zywie Bio and honorarium from Eli Lilly and has a leadership role in the Consortium of Canadian Centers for Clinical Cognitive Research. CO has received clinical trial funding, trial drug, and materials from Alector, Transposon Therapeutics, and Denali Therapeutics; consulting fees from Acadia Pharmaceuticals, Reata Pharmaceuticals, Otsuka Pharmaceutical, Eisai Pharmaceutical, Lykos Therapeutics, and Zevra Therapeutics; honoraria from the Philadelphia Psychiatric Society, the American Academy of Neurology Institute, and the Lewy body Dementia Association; and support for travel from Cure VCP and the Lewy Body Dementia Association. He has had leadership roles in the Association for Frontotemporal Degeneration Medical Advisory Council, the FTD Disorders Scientific Advisory Board, the Tau Consortium Scientific Advisory Board, the International Society for Frontotemporal Dementias Executive Committee, International Society to Advance Alzheimer's Research and Treatment Frontotemporal Dementia Professional Interest Area Executive Committee, and the International Society for Neurodegenerative Diseases. MCT has received consulting fees from Eisai, Eli Lilly, and Novo Nordisk and served as a scientific advisor to the Women's Brain Foundation, Brain Injury Canada, and Progressive Supranuclear Palsy Society of Canada; her institution has received support to serve as a clinical trial site for Janssen, Biogen, Avanex, Green Valley, UCB, Novo Nordisk, GSK, Bristol Myers Squibb, and Passage Bio and materials and funding for research from Roche. Berry Consultants (SB, MAD, AnLB, and AM) received consulting fees paid from the Canadian Institutes of Health Research and Weston grants through the Lawson Health Research Institute for the FOXY trial design and analysis. KD-R has received grant funding to her institution from US National Institutes of Health (NIH) grants U19 AG063911 and P30 AG066509. EH has received grant funding from the NIH/National Institute on Aging (NIA) R01 AG062268, U01 AG079850, and NIH/National Institute of Mental Health (NIMH) R01 MH120794. He participated on a DSMB for R21AG07895. AP has received grant funding from Alector, Athira, Biogen, Cassava, Eisai, Eli Lilly, Genentech/Roche, Vaccinex, NIA, NIMH, and Department of Defense; received consulting fees from Athira, Biogen, Eisai, IQVIA, Lundbeck, Otsuka, ONO Pharmaceuticals, WIRB-Copernicus Group received honoraria from WebMD; and participated on DSMB or advisory boards for Acadia, Bristol Myers Squibb, Cognitive Research Corporation, Functional Neuromodulation, Novartis, and Xenon. He has held leadership for fiduciary roles for boards for Alzheon, Athira, and Cognition Therapeutics. SD has received grant and research funding from the Alzheimer Drug Discovery Foundation, Canadian Institutes for Health Research (CIHR), Fond de recherche du Québec, Novo Nordisk, Biogen, Janssen, Alnylam, and Innodem Neurosciences; received consulting fees from Eisai, QurAlis, and Eli Lilly; received honoraria from Eisai; participated on advisory boards for IntelGenX and Aviado Bio; and held stock or stock options as co-founder of AFX Medical. RRG has received honoraria for lectures from Carnot Pharma and Torrent Pharma and has served on an advisory board for Silanes Pharma. JC has received grant funding from National Institute of General Medical Services (grant P20GM109025), NIA (R35AG71476 and R25AG083721–01), and National Institute of Neurological Disorders and Stroke (RO1NS139383); received royalties from the Neuropsychiatric Inventory; consulting fees from Acadia, Acumen, ALZpath, Annovis, Aprinoia, Artery, Biogen, Biohaven, BioXcel, Bristol Myers Squib, Eisai, Fosun, GAP Foundation, Green Valley, Janssen, Kinoxis, Lighthouse, Lilly, Lundbeck, LSP/eqt, Merck, MoCA Cognition, New Amsterdam, Novo Nordisk, Optoceutics, Otsuka, Oxford Brain Diagnostics, Prothena, ReMYND, Roche, Scottish Brain Sciences, Signant Health, Simcere, Sinaptica, and Vaxxinity; received honoraria from Eisai; participated on a DSMB for Johns Hopkins University; and held stock options for Annovis, Artery, Vaxxinity, Behrens, Alzheon, MedAvante-Prophase, and Acumen. MaM has received grants from the University of Washington, CIHR, The Weston Brain Foundation, Brain Canada, and the Women's Brain Health Initiative; has research contracts with Roche and Alector; has received royalties from the Henry Stewart Talks; has received consulting fees from Eli Lilly Canada, Alector, Biogen Canada, Wave Life Sciences, Eisai Canada, and Novo-Nordisk Canada; has received honoraria from the MINT Memory Clinics and the ECHO Dementia Series; and has held unpaid leadership roles in the Alzheimer Society of Canada and Parkinson Canada. G-YRH has had research contracts with Biogen, Cassava, Eli Lilly, and Eisai; received research grants from the NIH (Asian Cohort on Alzheimer's Disease) and CIHR; received consulting fees from Biogen, Eli Lilly, Eisai, Novo-Nordisk, and Roche; and held the unpaid position of President of the Consortium of Canadian Centers for Clinical Cognitive Research. HF has received grant support from Allyx Therapeutics, Vivoryon (Probiodrug), Biohaven Pharmaceuticals, and LuMind Foundation; has had service agreements with US San Diego for consulting activities with LuMind Foundation, Novo Nordisk, Axon Neuroscience, and Arrowhead Pharmaceuticals; has received support for travel-related expenses to conferences from Novo Nordisk, the Royal Society of Canada, Translating Research in Elder Care, the Association for Frontotemporal Dementia, and the Rainwater Charitable Foundation. He holds US patent number PCT/US2007/07008; has participated on a DSMB and Data Safety Monitoring Committee for Roche/Genetch Pharmaceuticals and Janssen Research and Development; and served on the Scientific Advisory Board for the Tau Consortium. He has received philanthropic support for Alzheimer's therapeutic research from the Epstein Family Alzheimer's Research Collaboration. All other authors declare no competing interests.

Publication types

Actions
Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions

Associated data

Actions
- Search in PubMed
- Search in ClinicalTrials.gov

LinkOut - more resources

Full Text Sources
- ClinicalKey
- Elsevier Science
Medical
- ClinicalTrials.gov
Research Materials
- NCI CPTC Antibody Characterization Program

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Intranasal oxytocin for apathy in people with frontotemporal dementia (FOXY): a multicentre, randomised, double-blind, placebo-controlled, adaptive, crossover, phase 2a/2b superiority trial

Affiliations

Intranasal oxytocin for apathy in people with frontotemporal dementia (FOXY): a multicentre, randomised, double-blind, placebo-controlled, adaptive, crossover, phase 2a/2b superiority trial

Authors

Affiliations

Abstract

Conflict of interest statement

Publication types

MeSH terms

Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical

Research Materials