title: Outcome measures for early phase clinical trials.
abstract: As the number of potential neuroprotective agents for ALS increases, the need for early phase trials that screen drugs before proceeding to efficacy trials also grows. However, it is not known which outcome measures perform best and also provide the most meaningful information in brief small trials. We assessed the performance of different outcome measures for use in early phase clinical trials in ALS, and determined what degree of change in the ALSFRS-R that patients could perceive. Thirty patients underwent six monthly ALS Functional Rating Scale (ALSFRS-R), forced vital capacity, manual muscle testing (MMT) and quality of life assessments. Patients rated their perceived level of change with algorithm scales. Linear mixed effects models assessed the associations among variables and Cox proportional-hazards models examined the ability to predict survival. The quantity of missing data was assessed using descriptive statistics. Correlations were found between all variables. The ALSFRS-R provided the most complete data (99.5%), showed a large within-subject correlation (0.91), and best predicted survival (p = 0.002). One-unit change in patient-perceived clinical function paralleled a 9-point decrease in the ALSFRS-R (p = 0.025; 95% CI 8, 10). This trial assessed just 30 patients over six months, but the standard outcome measures each performed dependably; all could be used in short-duration, early phase trials. The ALSFRS-R most strongly predicted survival and provided the most complete data, but large changes may be necessary before patients perceive treatment effects.
authors.affiliation: Department of Neurology, The Eleanor and Lou Gehrig MDA/ALS Research Center, College of Physicians and Surgeons, Mailman School of Public Health, Columbia University, New York, NY 10032, USA. phg8@columbia.edu
authors.forename: Paul H
authors.initials: PH
authors.lastname: Gordon
authors.forename: Bin
authors.initials: B
authors.lastname: Cheng
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Montes
authors.forename: Carolyn
authors.initials: C
authors.lastname: Doorish
authors.forename: Steven M
authors.initials: SM
authors.lastname: Albert
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsumoto
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000503:physiopathology; D002986:Clinical Trials as Topic / Q000379:methods*; D004311:Double-Blind Method; D000068717:Glatiramer Acetate; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D017063:Outcome Assessment, Health Care; D010147:Pain Measurement; D010455:Peptides / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D011446:Prospective Studies; D015203:Reproducibility of Results; D012107:Research Design; D012720:Severity of Illness Index
chemical_list: D007166:Immunosuppressive Agents; D010455:Peptides; D000068717:Glatiramer Acetate