New directions in clinical trials for frontotemporal lobar degeneration: Methods and outcome measures

Adam L Boxer; Michael Gold; Howard Feldman; Bradley F Boeve; Susan L-J Dickinson; Howard Fillit; Carole Ho; Robert Paul; Rodney Pearlman; Margaret Sutherland; Ajay Verma; Stephen P Arneric; Brian M Alexander; Bradford C Dickerson; Earl Ray Dorsey; Murray Grossman; Edward D Huey; Michael C Irizarry; William J Marks; Mario Masellis; Frances McFarland; Debra Niehoff; Chiadi U Onyike; Sabrina Paganoni; Michael A Panzara; Kenneth Rockwood; Jonathan D Rohrer; Howard Rosen; Robert N Schuck; Holly D Soares; Nadine Tatton

doi:10.1016/j.jalz.2019.06.4956

New directions in clinical trials for frontotemporal lobar degeneration: Methods and outcome measures

Alzheimers Dement. 2020 Jan;16(1):131-143. doi: 10.1016/j.jalz.2019.06.4956. Epub 2020 Jan 6.

Authors

Adam L Boxer¹, Michael Gold², Howard Feldman³, Bradley F Boeve⁴, Susan L-J Dickinson⁵, Howard Fillit⁶, Carole Ho⁷, Robert Paul⁸, Rodney Pearlman⁹, Margaret Sutherland¹⁰, Ajay Verma¹¹, Stephen P Arneric¹², Brian M Alexander¹³, Bradford C Dickerson¹⁴, Earl Ray Dorsey¹⁵, Murray Grossman¹⁶, Edward D Huey¹⁷, Michael C Irizarry¹⁸, William J Marks¹⁹, Mario Masellis^{20

21}, Frances McFarland²², Debra Niehoff⁵, Chiadi U Onyike²³, Sabrina Paganoni²⁴, Michael A Panzara²⁵, Kenneth Rockwood²⁶, Jonathan D Rohrer²⁷, Howard Rosen¹, Robert N Schuck²⁸, Holly D Soares²⁹, Nadine Tatton⁵

Affiliations

¹ Memory and Aging Center, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
² Development Neurosciences, AbbVie, Chicago, IL, USA.
³ Department of Neurosciences, University of California San Diego, San Diego, CA, USA.
⁴ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
⁵ Association for Frontotemporal Degeneration, Radnor, PA, USA.
⁶ Alzheimer's Drug Discovery Foundation, New York, NY, USA.
⁷ Denali Therapeutics, San Francisco, CA, USA.
⁸ Alector, Inc., South San Francisco, CA, USA.
⁹ The Bluefield Project, San Francisco, CA, USA.
¹⁰ Chan Zuckerberg Initiative, Redwood City, CA, USA.
¹¹ United Neuroscience, Dublin, Ireland.
¹² Critical Path Institute, Tucson, AZ, USA.
¹³ Dana-Farber Cancer Institute, Harvard University, Boston, MA, USA.
¹⁴ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Center for Health and Technology, University of Rochester, Rochester, NY, USA.
¹⁶ Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
¹⁷ Departments of Psychiatry and Neurology, Columbia University, NY, USA.
¹⁸ Formerly of Early Phase Neurosciences, Eli Lilly, Indianapolis, IN, USA.
¹⁹ Clinical Neurology, Verily Life Sciences, South San Francisco, CA, USA.
²⁰ Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, University of Toronto, ON, Canada.
²¹ Department of Medicine (Neurology), Sunnybrook Health Sciences Centre, University of Toronto, ON, Canada.
²² McFarland Writing, Annapolis, MD, USA.
²³ Department Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University, Baltimore, MD, USA.
²⁴ Healey Center for ALS, Massachusetts General Hospital, Boston, MA, USA.
²⁵ Development, Wave Life Sciences, Boston, MA, USA.
²⁶ Division of Geriatric Medicine, Dalhousie University, Halifax, NS, Canada.
²⁷ Dementia Research Centre, UCL Institute of Neurology, Queen Square, London, UK.
²⁸ Office of Clinical Pharmacology, Center for Drug Evaluation and Research, FDA, Silver Spring, MD, USA.
²⁹ Department of Neurology, AbbVie, Chicago, IL, USA.

Abstract

Introduction: Frontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed.

Methods: In March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD.

Results: Challenges exist for conducting clinical trials in FTLD. Two of the greatest challenges are (1) the heterogeneity of FTLD syndromes leading to difficulties in efficiently measuring treatment effects and (2) the rarity of FTLD disorders leading to recruitment challenges.

Discussion: New personalized endpoints that are clinically meaningful to individuals and their families should be developed. Personalized approaches to analyzing MRI data, development of new fluid biomarkers and wearable technologies will help to improve the power to detect treatment effects in FTLD clinical trials and enable new, clinical trial designs, possibly leveraged from the experience of oncology trials. A computational visualization and analysis platform that can support novel analyses of combined clinical, genetic, imaging, biomarker data with other novel modalities will be critical to the success of these endeavors.

Keywords: ARTFL; Biomarker; C9orf72; Clinical trial; FTD; FTLD; Frontotemporal dementia; Frontotemporal lobar degeneration; GRN; LEFFTDS; MAPT; Primary progressive aphasia; Progressive supranuclear palsy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Atrophy
Biomarkers*
Clinical Trials as Topic*
Congresses as Topic
Frontotemporal Lobar Degeneration / genetics*
Humans
Magnetic Resonance Imaging*

Substances

Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding