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J Neurol Neurosurg Psychiatry. 2018 Oct 25. pii: jnnp-2018-318603. doi: 10.1136/jnnp-2018-318603. [Epub ahead of print]

Therapeutic trial design for frontotemporal dementia and related disorders.

Author information

Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
LC Campbell Cognitive Neurology Research Unit, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.
Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Division of Geriatric Medicine, Department of Medicine, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Rotman Research Institute, Baycrest Centre for Geriatric Care, Toronto, Ontario, Canada.
Department of Psychology, University of Toronto, Toronto, Ontario, Canada.
Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
Memory and Aging Center, Department of Neurology, University of California, San Francisco, California, USA.
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Department of Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands.
Centre for Neurodegenerative Disorders, Neurology Clinic, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Department of Neurosciences, University of California, San Diego, California, USA.
Division of Neurology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Cognitive & Movement Disorders Clinic, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada


The frontotemporal dementia (FTD) spectrum is a heterogeneous group of neurodegenerative syndromes with overlapping clinical, molecular and pathological features, all of which challenge the design of clinical trials in these conditions. To date, no pharmacological interventions have been proven effective in significantly modifying the course of these disorders. This study critically reviews the construct and methodology of previously published randomised controlled trials (RCTs) in FTD spectrum disorders in order to identify limitations and potential reasons for negative results. Moreover, recommendations based on the identified gaps are elaborated in order to guide future clinical trial design. A systematic literature review was carried out and presented in conformity with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. A total of 23 RCTs in cohorts with diagnoses of behavioural and language variants of FTD, corticobasal syndrome and progressive supranuclear palsy syndrome were identified out of the 943 citations retrieved and were included in the qualitative review. Most studies identified were early-phase clinical trials that were small in size, short in duration and frequently underpowered. Diagnoses of populations enrolled in clinical trials were based on clinical presentation and rarely included precision-medicine tools, such as genetic and molecular testing. Uniformity and standardisation of research outcomes in the FTD spectrum are essential. Several elements should be carefully considered and planned in future clinical trials. We anticipate that precision-medicine approaches will be crucial to adequately address heterogeneity in the FTD spectrum research.


frontotemporal dementia; neurogenetics; pharmacology; randomised trials; systematic reviews


Conflict of interest statement

Competing interests: PD and QDN have nothing to disclose. SEB and MM are supported by the Department of Medicine (Sunnybrook Health Sciences Centre and the University of Toronto), the Sunnybrook Foundation, the Hurvitz Brain Sciences Research Program and the Sunnybrook Research Institute. MM also receives support as co-lead of the Ontario Neurodegenerative Disease Research Initiative funded by the Ontario Brain Institute. SEB also receives support as the executive director of the Toronto Dementia Research Alliance. SEB does contract research for Eli Lilly, Biogen, GE Healthcare, Genentech, Novartis, Optina and Roche; received peer-reviewed funding from CIHR, CPSR, Brain Canada, ADDF, NIA, NIH, Leducq Foundation, OBI and Weston Brain Institute; and received speaker fees from Novartis and Eli Lilly. MM receives peer-reviewed research support from the Canadian Institutes of Health Research, Weston Brain Institute, Washington University, Parkinson Society Canada, Alzheimer’s Drug Discovery Foundation, Brain Canada, Canadian Consortium on Neurodegeneration in Aging and Ontario Brain Institute. MM has also served as an advisor to Bioscape Medical Imaging CRO, Novartis, Ionis Pharmaceuticals, Arkuda Therapeutics and UCB; received honoraria from Novartis; received royalties from Henry Stewart Talks; received an investigator-initiated research grant from Teva; and received contract research support from Roche, Novartis and Axovant. NH is supported by the Canadian Consortium on Neurodegeneration in Aging and peer-reviewed grants from the Alzheimer Society of Canada (grant 15-17), Alzheimer’s Drug Discovery Foundation (grant 20140503), Canadian Institutes of Health Research, National Institute on Aging of the National Institutes of Health (grant R01AG046543), and the Heart and Stroke Foundation (grant NA 7220), in addition to research contracts funded by Roche, Axovant and Lundbeck Canada. NH received consultation fees from Astellas, Lilly, Merck, Pfizer and Mediti. AEL has served as an advisor for AbbVie, Acorda, Biogen, Bristol-Myers Squibb, Janssen, Sun Pharma, Kallyope, Merck, Paladin and Corticobasal Degeneration Solutions; received honoraria from Sun Pharma, Medichem, Medtronic, AbbVie and Sunovion; received grants from Brain Canada, Canadian Institutes of Health Research, Corticobasal Degeneration Solutions, Edmond J Safra Philanthropic Foundation, Michael J Fox Foundation, the Ontario Brain Institute, National Parkinson Foundation, Parkinson Society Canada and W Garfield Weston Foundation; received publishing royalties from Elsevier, Saunders, Wiley-Blackwell, Johns Hopkins Press and Cambridge University Press. HHF receives peer-reviewed grant funding support from the Canadian Consortium on Neurodegeneration in Aging (CIHR 137794), National Institute on Aging (U19AG010483) (2UF1Ago32438-07), CIHR and Weston Brain Institute (Grant # 363926), and Brain Canada (IMPACT AD study), and other grant funding from Toyama Pharmaceutical, Biohaven Pharmaceuticals and Probiodrug. He has either current or past service agreements through UC San Diego with Banner Health, Roche Genentech, Arkuda Therapeutics, Samus, Samumed, Eisai, Merck and TauRx, and has received travel expenses from Axon Neurosciences, Alion Pharmaceuticals and Probiodrug. All other authors declare no competing interests.

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