Inclusive Trial Designs in Acute Spinal Cord Injuries: Prediction-Based Stratification of Clinical Walking Outcome and Projected Enrolment Frequencies.
Spinal cord injury
clinical trials methodology/study design
gait disorders
rehabilitation
stratification
unbiased recursive partitioning
Journal
Neurorehabilitation and neural repair
ISSN: 1552-6844
Titre abrégé: Neurorehabil Neural Repair
Pays: United States
ID NLM: 100892086
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
pubmed:
16
2
2022
medline:
13
4
2022
entrez:
15
2
2022
Statut:
ppublish
Résumé
New therapeutic approaches in neurological disorders are progressing into clinical development. Past failures in translational research have underlined the critical importance of selecting appropriate inclusion criteria and primary outcomes. Narrow inclusion criteria provide sensitivity, but increase trial duration and cost to the point of infeasibility, while broader requirements amplify confounding, increasing the risk of trial failure. This dilemma is perhaps most pronounced in spinal cord injury (SCI), but applies to all neurological disorders with low frequency and/or heterogeneous clinical manifestations. Stratification of homogeneous patient cohorts to enable the design of clinical trials with broad inclusion criteria. Prospectively-gathered data from patients with acute cervical SCI were analysed using an unbiased recursive partitioning conditional inference tree (URP-CTREE) approach. Performance in the 6-minute walk test at 6 months after injury was classified based on standardized neurological assessments within the first 15 days of injury. Functional and neurological outcomes were tracked throughout rehabilitation up to 6 months after injury. URP-CTREE identified homogeneous outcome cohorts in a study group of 309 SCI patients. These cohorts were validated by an internal, yet independent, validation group of 172 patients. The study group cohorts identified demonstrated distinct recovery profiles throughout rehabilitation. The baseline characteristics of the analysed groups were compared to a reference group of 477 patients. URP-CTREE enables inclusive trial design by revealing the distribution of outcome cohorts, discerning distinct recovery profiles and projecting potential patient enrolment by providing estimates of the relative frequencies of cohorts to improve the design of clinical trials in SCI and beyond.
Sections du résumé
BACKGROUND
New therapeutic approaches in neurological disorders are progressing into clinical development. Past failures in translational research have underlined the critical importance of selecting appropriate inclusion criteria and primary outcomes. Narrow inclusion criteria provide sensitivity, but increase trial duration and cost to the point of infeasibility, while broader requirements amplify confounding, increasing the risk of trial failure. This dilemma is perhaps most pronounced in spinal cord injury (SCI), but applies to all neurological disorders with low frequency and/or heterogeneous clinical manifestations.
OBJECTIVE
Stratification of homogeneous patient cohorts to enable the design of clinical trials with broad inclusion criteria.
METHODS
Prospectively-gathered data from patients with acute cervical SCI were analysed using an unbiased recursive partitioning conditional inference tree (URP-CTREE) approach. Performance in the 6-minute walk test at 6 months after injury was classified based on standardized neurological assessments within the first 15 days of injury. Functional and neurological outcomes were tracked throughout rehabilitation up to 6 months after injury.
RESULTS
URP-CTREE identified homogeneous outcome cohorts in a study group of 309 SCI patients. These cohorts were validated by an internal, yet independent, validation group of 172 patients. The study group cohorts identified demonstrated distinct recovery profiles throughout rehabilitation. The baseline characteristics of the analysed groups were compared to a reference group of 477 patients.
CONCLUSION
URP-CTREE enables inclusive trial design by revealing the distribution of outcome cohorts, discerning distinct recovery profiles and projecting potential patient enrolment by providing estimates of the relative frequencies of cohorts to improve the design of clinical trials in SCI and beyond.
Identifiants
pubmed: 35164574
doi: 10.1177/15459683221078302
pmc: PMC9003761
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
274-285Références
Spine J. 2020 Feb;20(2):213-224
pubmed: 31525468
Clin Physiol Funct Imaging. 2018 May 31;:
pubmed: 29851229
Spinal Cord. 2013 Apr;51(4):282-8
pubmed: 23184026
J Neurotrauma. 2015 Feb 1;32(3):194-9
pubmed: 24963966
Neurosci Lett. 2017 Jun 23;652:25-34
pubmed: 28007647
Lancet Neurol. 2021 Feb;20(2):117-126
pubmed: 33357514
Spinal Cord. 2010 Sep;48(9):657-63
pubmed: 20585327
J Neurotrauma. 2012 Sep;29(13):2263-71
pubmed: 22709268
Spine (Phila Pa 1976). 2001 Dec 15;26(24 Suppl):S87-98
pubmed: 11805614
Spinal Cord. 2018 Jul;56(7):628-642
pubmed: 29700477
Spinal Cord. 2008 Apr;46(4):246-54
pubmed: 17923844
IEEE Trans Neural Syst Rehabil Eng. 2012 May;20(3):341-50
pubmed: 22203726
Spinal Cord. 2007 Mar;45(3):206-21
pubmed: 17179972
J Spinal Cord Med. 2011 Nov;34(6):535-46
pubmed: 22330108
Neurorehabil Neural Repair. 2014 Jul;28(6):507-15
pubmed: 24477680
Brain. 2012 Apr;135(Pt 4):1224-36
pubmed: 22505632
Physiol Rev. 1956 Jul;36(3):307-35
pubmed: 13359126
Respir Care. 2003 Aug;48(8):783-5
pubmed: 12890299
J Neurosurg Spine. 2012 Sep;17(1 Suppl):11-26
pubmed: 22985366
Ageing Res Rev. 2018 Nov;47:123-132
pubmed: 30048806
Nature. 2018 Nov;563(7729):65-71
pubmed: 30382197
Eur J Phys Rehabil Med. 2013 Jun;49(3):373-84
pubmed: 23486305
Spinal Cord. 2007 Mar;45(3):190-205
pubmed: 17179973
Neurorehabil Neural Repair. 2015 Oct;29(9):867-77
pubmed: 25644238
J Bone Joint Surg Br. 1997 Nov;79(6):952-4
pubmed: 9393910
J Neurotrauma. 2022 Feb;39(3-4):266-276
pubmed: 33619988
Spine J. 2004 Jul-Aug;4(4):373-8
pubmed: 15246294
Lancet. 2011 Mar 19;377(9770):1004-10
pubmed: 21377202
Neurorehabil Neural Repair. 2020 Aug;34(8):723-732
pubmed: 32659165
Spinal Cord. 2007 Mar;45(3):222-31
pubmed: 17179971
J Neurotrauma. 2009 Oct;26(10):1707-17
pubmed: 19413491
BMC Neurol. 2013 Nov 09;13:168
pubmed: 24206943
Disabil Rehabil. 2013 Oct;35(21):1808-13
pubmed: 23343359
AMIA Annu Symp Proc. 2013 Nov 16;2013:1472-7
pubmed: 24551421
Spinal Cord. 2006 Sep;44(9):523-9
pubmed: 16389270
Spine J. 2017 Oct;17(10):1383-1392
pubmed: 28716636