TY - JOUR
T1 - Baseline EDSS proportions in MS clinical trials affect the overall outcome and power
T2 - A cautionary note
AU - Wang, Guoqiao
AU - Cutter, Gary R.
AU - Cofield, Stacey S.
AU - Lublin, Fred
AU - Wolinsky, Jerry S.
AU - Gustafson, Tarah
AU - Krieger, Stephen
AU - Salter, Amber
N1 - Funding Information:
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/ or publication of this article: Dr Wang: The NARCOMS Research Fellowship is supported, in part, by the Foundation of the CMSC and an unrestricted educational grant by Biogen. Dr Cutter: consulting and/or DSMB commitments in past 12 months. Participation of Data and Safety Monitoring Committees: all of the below organizations are focused on medical research: Apotek, Biogen Idec, Cleveland Clinic (Vivus), Glaxo Smith Klein Pharmaceuticals, Gilead Pharmaceuticals, Horizon Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Merck/Pfizer, Neuren, Sanofi-Aventis, Teva, NHLBI (Protocol Review Committee), NINDS, and NICHD (OPRU oversight committee). Consulting, Speaking fees and Advisory Boards: Consortium of MS Centers (grant), D3 (Drug Discovery and Development), Genzyme, Genentech, Jannsen Pharmaceuticals, Klein-Buendel Incorporated, Medimmune, Novartis, Opexa Therapeutics, Receptos, Roche, EMD Serono, Spiniflex Pharmaceuticals, Somahlution, Teva pharmaceuticals, and Transparency Life Sciences. Dr Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc., a private consulting company located in Birmingham, AL. Dr Cofield: Consulting fees American Shoulder and Elbow Society, DSMB service Medimmune, and Grant Review Department of Defense. Dr Lublin: Scientific Advisory Board: Acorda Therapeutics Inc.; Actelion Pharmaceuticals Ltd; Bayer; Biogen Idec; EMD Serono, Inc. (Merck & Co., Inc.); F. Hoffman-La Roche Ltd; Facilitate, LTD; Forward Pharma; MedImmune, LLC; Novartis; Osmotica Pharmaceutical Corp.; Questcor Pharmaceuticals, Inc.; Receptos Inc.; Revalesio Corporation; Teva Pharmaceutical Industries Ltd; XenoPort, Inc.; Sanofi-Aventis; to-BBB. Other activities: examples include, but are not limited to, committee participation and data safety monitoring board (DSMB) membership: Gerson Lehrman Group. Dr Wolinsky: consulting fees (AbbVie, Actelion, Alkermes, Athersys, EMD Serono, Forward Pharma, Genentech, Genzyme, Novartis, Roche, Teva, Teva Neuroscience, to-BBB, XenoPort); contracted research (Genzyme, National Institutes of Health, National MS Society through the University of Texas Health Science Center at Houston, Sanofi); and royalties (University of Texas Health Science Center at Houston for monoclonal antibodies out-licensed to Chemicon International). Ms Gustafson has nothing to disclose. Dr Krieger: Consulting/Advisory Board: Acorda Therapeutics; Bayer Healthcare; Biogen Idec; EMD Serono; Genentech, Inc.; Genzyme Corporation; Novartis; Takeda Pharmaceuticals; and Teva Pharmaceuticals. Industry-sponsored non-promotional lectures: Genzyme Corporation and Biogen Idec. Dr Salter has nothing to disclose.
Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: NIH/NINDS 5-U01-NS045719. Biogen Idec and Teva Neuroscience generously contributed study medications and matched placebo without input into the design, conduct, analysis, or interpretation of results of the trial.
Funding Information:
The CombiRx trial was a Phase III double-blind, randomized, three-armed, multi-center treatment trial with 1008 RRMS participants comparing 50% of participants on combination therapy (interferon beta 1a and glatiramer acetate) versus 25% on each of the single agents with matching placebo. The duration of the primary study was 36 months. The study cohort included participants 18–60 years of age with a baseline EDSS score ⩽5.5. Details of the specific participant inclusion and exclusion criteria, description of the study design, baseline characteristics of the participants, and primary results have been reported previously.3,4The CombiRx trial was approved by the applicable central or institutional review boards and the data and safety monitoring committee (DSMC) appointed by National Institutes of Health (NIH)/ National Institute of Neurological Disorders and Stroke (NINDS) before site initiation and recruitment of participants. Informed consent was obtained prior to any screening procedures or enrollment.
Publisher Copyright:
© SAGE Publications.
PY - 2017/6/1
Y1 - 2017/6/1
N2 - Background: In randomized clinical trials, when treatments do not work equally effectively across stratifications of participants, observed event rates may differ from those hypothesized leading to deviations in estimated power. Objectives: To investigate the effect of distributions of baseline Expanded Disability Status Scale (EDSS) proportions in relapsing-remitting multiple sclerosis (RRMS) on the trial outcome, confirmed disability progression rate (CDPR), and power. Methods: We reported CDPRs in the CombiRx trial by baseline EDSS and by groups (1st (0, 1), 2nd (1.5, 2), 3rd (2.5, 3), and 4th (≥3/43.5)) and investigated the effect of different combinations of baseline EDSS proportions on the trial outcome and power. Results: There were 244 (25.4%) participants in the 1st group, 368 (38.4%) in the 2nd group, 223 (23.3%) in the 3rd group, and 124 (12.9%) in the 4th group with CDPRs of 40.1%, 13.9%, 11.2%, and 16.9%, respectively. Both CDPR and power increased when the proportion of the 1st group increased in hypothetical trials with equal sample sizes in each arm, and a 10% increase in the 1st group led to a 5% increase in power. Conclusion: Various baseline EDSS proportions yielded different CDPRs and power, suggesting caution in interpretation of treatment effects across trials that enrolled participants with different proportions of baseline EDSS.
AB - Background: In randomized clinical trials, when treatments do not work equally effectively across stratifications of participants, observed event rates may differ from those hypothesized leading to deviations in estimated power. Objectives: To investigate the effect of distributions of baseline Expanded Disability Status Scale (EDSS) proportions in relapsing-remitting multiple sclerosis (RRMS) on the trial outcome, confirmed disability progression rate (CDPR), and power. Methods: We reported CDPRs in the CombiRx trial by baseline EDSS and by groups (1st (0, 1), 2nd (1.5, 2), 3rd (2.5, 3), and 4th (≥3/43.5)) and investigated the effect of different combinations of baseline EDSS proportions on the trial outcome and power. Results: There were 244 (25.4%) participants in the 1st group, 368 (38.4%) in the 2nd group, 223 (23.3%) in the 3rd group, and 124 (12.9%) in the 4th group with CDPRs of 40.1%, 13.9%, 11.2%, and 16.9%, respectively. Both CDPR and power increased when the proportion of the 1st group increased in hypothetical trials with equal sample sizes in each arm, and a 10% increase in the 1st group led to a 5% increase in power. Conclusion: Various baseline EDSS proportions yielded different CDPRs and power, suggesting caution in interpretation of treatment effects across trials that enrolled participants with different proportions of baseline EDSS.
KW - Expanded Disability Status Scale
KW - Multiple sclerosis
KW - confirmed disability progression rate
KW - relapsing-remitting multiple sclerosis
UR - http://www.scopus.com/inward/record.url?scp=85020233542&partnerID=8YFLogxK
U2 - 10.1177/1352458516670733
DO - 10.1177/1352458516670733
M3 - Article
C2 - 27682227
AN - SCOPUS:85020233542
SN - 1352-4585
VL - 23
SP - 982
EP - 987
JO - Multiple Sclerosis
JF - Multiple Sclerosis
IS - 7
ER -