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Review
. 2020 Oct 29;12(1):137.
doi: 10.1186/s13195-020-00703-5.

Challenges and opportunities for improving the landscape for Lewy body dementia clinical trials

Jennifer G Goldman  1 , Leah K Forsberg  2 , Bradley F Boeve  2 , Melissa J Armstrong  3 , David J Irwin  4 , Tanis J Ferman  5 , Doug Galasko  6 , James E Galvin  7 , Daniel Kaufer  8 , James Leverenz  9 , Carol F Lippa  10 , Karen Marder  11 , Victor Abler  12 , Kevin Biglan  13 , Michael Irizarry  14 , Bill Keller  12 , Leanne Munsie  13 , Masaki Nakagawa  15 , Angela Taylor  16 , Todd Graham  16
Affiliations
Review

Challenges and opportunities for improving the landscape for Lewy body dementia clinical trials

Jennifer G Goldman et al. Alzheimers Res Ther. .

Abstract

Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson's disease dementia, affects over a million people in the USA and has a substantial impact on patients, caregivers, and society. Symptomatic treatments for LBD, which can include cognitive, neuropsychiatric, autonomic, sleep, and motor features, are limited with only two drugs (cholinesterase inhibitors) currently approved by regulatory agencies for dementia in LBD. Clinical trials represent a top research priority, but there are many challenges in the development and implementation of trials in LBD. To address these issues and advance the field of clinical trials in the LBDs, the Lewy Body Dementia Association formed an Industry Advisory Council (LBDA IAC), in addition to its Research Center of Excellence program. The LBDA IAC comprises a diverse and collaborative group of experts from academic medical centers, pharmaceutical industries, and the patient advocacy foundation. The inaugural LBDA IAC meeting, held in June 2019, aimed to bring together this group, along with representatives from regulatory agencies, to address the topic of optimizing the landscape of LBD clinical trials. This review highlights the formation of the LBDA IAC, current state of LBD clinical trials, and challenges and opportunities in the field regarding trial design, study populations, diagnostic criteria, and biomarker utilization. Current gaps include a lack of standardized clinical assessment tools and evidence-based management strategies for LBD as well as difficulty and controversy in diagnosing LBD. Challenges in LBD clinical trials include the heterogeneity of LBD pathology and symptomatology, limited understanding of the trajectory of LBD cognitive and core features, absence of LBD-specific outcome measures, and lack of established standardized biologic, imaging, or genetic biomarkers that may inform study design. Demands of study participation (e.g., travel, duration, and frequency of study visits) may also pose challenges and impact trial enrollment, retention, and outcomes. There are opportunities to improve the landscape of LBD clinical trials by harmonizing clinical assessments and biomarkers across cohorts and research studies, developing and validating outcome measures in LBD, engaging the patient community to assess research needs and priorities, and incorporating biomarker and genotype profiling in study design.

Keywords: Biomarker; Clinical trial readiness; Dementia; Lewy bodies; Neuropsychology; Outcome measure; Parkinsonism; Parkinson’s disease; Primary endpoint; Randomized controlled trial.

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Conflict of interest statement

Goldman—Dr. Goldman has received grant/research funding from Michael J. Fox Foundation and Parkinson’s Foundation, served as consultant for Worldwide Med, and has received honoraria from Davis Phinney Foundation, International Parkinson and Movement Disorder Society, and Parkinson’s Foundation.

Forsberg—Dr. Forsberg has nothing to disclose.

Boeve—Dr. Boeve has received grant/research funding from the NIH (AG016574, AG062677, NS100620, AG056639, AG054256, AG050326), the Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, and the Little Family Foundation and serves as an investigator for clinical trials sponsored by Biogen, Alector, and EIP Pharma; Scientific Advisory Board of the Tau Consortium.

Armstrong—Dr. Armstrong has received grant/research funding from AHRQ (K08HS24159), NIA P30AG047266, and the Florida Department of Health (grant 20A08) and compensation from the AAN for work as an evidence-based medicine methodology consultant and is on the level of evidence editorial board for Neurology® and related publications (uncompensated).

Irwin—Dr. Irwin has received grant/research funding from NIH NS109260, U01-NS100610, R01-AG056014, P30-AG010124, U19-AG062418, and Penn Institute on Aging.

Ferman—Dr. Ferman has nothing to disclose.

Galasko—Dr. Galasko has received grant/research funding from NIH/NIA, State of California, and Michael J Fox Foundation and serves as a consultant to Esai, Biogen, Fujirebio, Amprion, vTv Pharmaceuticals, and DSMB for Cognition Therapeutics.

Galvin—Dr. Galvin is the creator of the Lewy Body Composite Risk Score.

Kaufer—Dr. Kaufer has nothing to report.

Leverenz—Dr. Leverenz has received grant/research funding from NIH/NINDS and GE Healthcare and has received consultant fees from Acadia, Eisai, and Sunovion.

Lippa—Dr. Lippa has received clinical trial research support from Acadia and Axovant.

Marder—Dr. Marder has received grant/research funding from NIH (U01NS100600, U24NA107168, UL1TR001873, R01NS0736 71, R01LM00986, R01NS-9435, RM1HG007257), Michael J. Fox Foundation, Parkinson’s Foundation, CHDI, and Huntington's Disease Society of America.

Abler—Dr. Abler is a full-time employee of Acadia Pharmaceuticals.

Biglan—Dr. Biglan is a full-time employee and has a minor shareholder stake in Eli Lilly and Company.

Irizarry—Dr. Irizarray is a full-time employee of Eisai, Inc.

Keller—Mr. Keller is a full-time employee of Acadia Pharmaceuticals.

Munsie—Ms. Munsie is a full-time employee and has a minor shareholder stake in Eli Lilly and Company.

Nakagawa—Mr. Nakagawa is a full-time employee of Eisai Co., Ltd.

Taylor—Ms. Taylor is a full-time employee and Senior Director of Research and Advocacy for the Lewy Body Dementia Association.

Graham—Mr. Graham is the Executive Director of the Lewy Body Dementia Association.

Drs. Goldman, Boeve, Armstrong, Irwin, Galasko, Galvin, Kaufer, Leverenz, Lippa, and Marder have received grant funding from the Lewy Body Dementia Association Research Center of Excellence program.

Figures

Fig. 1
Fig. 1
Considerations and an example for optimizing LBD clinical trial design. CSF, cerebrospinal fluid; DLB, dementia with Lewy bodies; LBD, Lewy body dementia; MCI, mild cognitive impairment; PDD, Parkinson’s disease dementia
See this image and copyright information in PMC

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