Predicting disease progression in progressive supranuclear palsy in multicenter clinical trials

Jee Bang, Iryna V. Lobach, Anthony E. Lang, Murray Grossman, David S. Knopman, Bruce L. Miller, Lon S. Schneider, Rachelle S. Doody, Andrew Lees, Michael Gold, Bruce H. Morimoto, Adam L. Boxer, David Williams, Anne Louise Lafontaine, Connie Marras, Mandar Jog, Michael Panisset, Anthony Lang, Lesley Parker, Alistair J. StewartJean Christophe Corvol, Jean Philippe Azulay, Philippe Couratier, Brit Mollenhauer, Stefan Lorenzl, Albert Ludolph, Reiner Benecke, Gunter Hoglinger, Axel Lipp, Heinz Reichmann, Dirk Woitalla, Dennis Chan, Adam Zermansky, David Burn, Illana Gozes, Erik Roberson, Lawrence Honig, Edward Zamrini, Rajesh Pahwa, Yvette Bordelon, Erika Driver-Dunkley, Stephanie Lessig, Mark Lew, Kyle Womack, Brad Boeve, Joseph Ferrara, Argyle Hillis, Daniel Kaufer, Rajeev Kumar, Tao Xie, Steven Gunzler, Theresa Zesiewicz, Praveen Dayalu, Lawrence Golbe, Joseph Jankovic, Scott McGinnis, Anthony Santiago, Paul Tuite, Stuart Isaacson, Julie Leegwater-Kim, Irene Litvan, Lawrence I. Golbe, Erik D. Roberson, Mary Koestler, Clifford R. Jack, Viviana Van Deerlin, Christopher Randolph, Steve Whitaker, Joe Hirman

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Introduction: Clinical and MRI measurements can track disease progression in PSP, but many have not been extensively evaluated in multicenter clinical trials. We identified optimal measures to capture clinical decline and predict disease progression in multicenter PSP trials. Methods: Longitudinal clinical rating scales, neuropsychological test scores, and volumetric MRI data from an international, phase 2/3 clinical trial of davunetide for PSP (intent to treat population, n = 303) were used to identify measurements with largest effect size, strongest correlation with clinical change, and best ability to predict dropout or clinical decline over one year as measured by PSP Rating Scale (PSPRS). Results: Baseline cognition as measured by Repeatable Battery for Assessing Neuropsychological Status (RBANS) was associated with attrition, but had only a small effect. PSPRS and Clinical Global Impression (CGI) had the largest effect size for measuring change. Annual change in CGI, RBANS, color trails, and MRI midbrain and ventricular volumes were most strongly correlated with annual PSPRS and had the largest effect sizes for detecting annual change. At baseline, shorter disease duration, more severe depression, and lower performance on RBANS and executive function tests were associated with faster worsening of the PSPRS in completers. With dropouts included, SEADL, RBANS, and executive function tests had significant effect on PSPRS trajectory of change. Conclusion: Baseline cognitive status and mood influence the rate of disease progression in PSP. Multiple clinical, neuropsychological, and volumetric MRI measurements are sensitive to change over one year in PSP and appropriate for use in multicenter clinical trials.

Original languageEnglish (US)
Pages (from-to)41-48
Number of pages8
JournalParkinsonism and Related Disorders
Volume28
DOIs
StatePublished - Jul 1 2016

Bibliographical note

Funding Information:
David Knopman: Dr. Knopman serves on a Data Safety Monitoring Board for Lundbeck Pharmaceuticals and for the DIAN study; is an investigator in clinical trials sponsored by Biogen, TauRX Pharmaceuticals, Lilly Pharmaceuticals and the Alzheimer’s Disease Cooperative Study; and receives research support from the NIH.

Funding Information:
Supported by R01AG038791, U54NS092089, T32 AG23481, and the Tau Consortium . These sources had no involvement in the study design. The funding for AL-108-231 was provided by Allon Therapeutics Inc.

Funding Information:
Lon Schneider: Dr. Schneider (within the past 3 years) has received grant or research support for industry-sponsored studies from Pfizer, Baxter, Eli Lilly, Forum, Lundbeck,, Merck, Novartis (with the Alzheimer Prevention Initiative and NIH), Roche/Genentech, Tau Rx; for NIH sponsored research, USC ADRC, ADCS (UCSD), ADNI (NCIRE), phytoSERMs, allopreganolone, clinical trials simulations, Banner Alzheimer Prevention Initiative, P50 AG05142, R01 AG033288, R01 AG037561, UF1 AG046148; from the State of California, the California Alzheimer Disease Center (CADC) and California Institute for Regenerative Medicine (CIRM). Dr. Schneider, within the past 3 years, has consulted or served on committees for AC Immune, Accera, Allon, Avraham, Axovant, Baxter, Boehringer Ingelheim, Cerespir, Cognition, Forum, Insys, Merck, Neurim, Novartis, Roche, Stemedica, Takeda, TauRx, Transition, vTv Therapeutics, Toyama/FujiFilm, and Zinfandel.

Publisher Copyright:
© 2016 Elsevier Ltd.

Keywords

  • Clinical trial methodology
  • Progressive supranuclear palsy

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