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dc.contributor.authorGoemans, Nathalie
dc.contributor.authorWong, Brenda L
dc.contributor.authorVan den Hauwe, Marleen
dc.contributor.authorSignorovitch, James
dc.contributor.authorSajeev, Gautam
dc.contributor.authorCox, David
dc.contributor.authorLandry, John
dc.contributor.authorJenkins, Madeline
dc.contributor.authorDieye, Ibrahima
dc.contributor.authorYao, Zhiwen
dc.contributor.authorHossain, Intekhab
dc.contributor.authorWard, Susan J.
dc.date2022-08-11T08:09:56.000
dc.date.accessioned2022-08-23T16:49:37Z
dc.date.available2022-08-23T16:49:37Z
dc.date.issued2020-06-18
dc.date.submitted2020-07-09
dc.identifier.citation<p>Goemans N, Wong B, Van den Hauwe M, Signorovitch J, Sajeev G, Cox D, Landry J, Jenkins M, Dieye I, Yao Z, Hossain I, Ward SJ; Collaborative Trajectory Analysis Project (cTAP). Prognostic factors for changes in the timed 4-stair climb in patients with Duchenne muscular dystrophy, and implications for measuring drug efficacy: A multi-institutional collaboration. PLoS One. 2020 Jun 18;15(6):e0232870. doi: 10.1371/journal.pone.0232870. PMID: 32555695; PMCID: PMC7302444. <a href="https://doi.org/10.1371/journal.pone.0232870">Link to article on publisher's site</a></p>
dc.identifier.issn1932-6203 (Linking)
dc.identifier.doi10.1371/journal.pone.0232870
dc.identifier.pmid32555695
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41497
dc.description.abstractThe timed 4-stair climb (4SC) assessment has been used to measure function in Duchenne muscular dystrophy (DMD) practice and research. We sought to identify prognostic factors for changes in 4SC, assess their consistency across data sources, and the extent to which prognostic scores could be useful in DMD clinical trial design and analysis. Data from patients with DMD in the placebo arm of a phase 3 trial (Tadalafil DMD trial) and two real-world sources (Universitaire Ziekenhuizen, Leuven, Belgium [Leuven] and Cincinnati Children's Hospital Medical Center [CCHMC]) were analyzed. One-year changes in 4SC completion time and velocity (stairs/second) were analyzed. Prognostic models included age, height, weight, steroid use, and multiple timed function tests and were developed using multivariable regression, separately in each data source. Simulations were used to quantify impacts on trial sample size requirements. Data on 1-year changes in 4SC were available from the Tadalafil DMD trial (n = 92) Leuven (n = 67), and CCHMC (n = 212). Models incorporating multiple timed function tests, height, and weight significantly improved prognostic accuracy for 1-year change in 4SC (R2: 29%-36% for 4SC velocity, and 29%-34% for 4SC time) compared to models including only age, baseline 4SC and steroid duration (R2:8%-17% for 4SC velocity and 2%-13% for 4SC time). Measures of walking and rising ability contributed important prognostic information for changes in 4SC. In a randomized trial with equal allocation to treatment and placebo, adjustment for such a prognostic score would enable detection (at 80% power) of a treatment effect of 0.25 stairs/second with 100-120 patients, compared to 170-190 patients without prognostic score adjustment. Combining measures of ambulatory function doubled prognostic accuracy for 1-year changes in 4SC completion time and velocity. Randomized clinical trials incorporating a validated prognostic score could reduce sample size requirements by approximately 40%. Knowledge of important prognostic factors can also inform adjusted comparisons to external controls.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=32555695&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright: © 2020 Goemans et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectWalking
dc.subjectDuchenne muscular dystrophy
dc.subjectSteroids
dc.subjectPrognosis
dc.subjectClinical trials
dc.subjectPhase III clinical investigation
dc.subjectPediatrics
dc.subjectDrug research and development
dc.subjectClinical Trials
dc.subjectCongenital, Hereditary, and Neonatal Diseases and Abnormalities
dc.subjectMusculoskeletal Diseases
dc.subjectNervous System Diseases
dc.subjectPediatrics
dc.subjectTherapeutics
dc.titlePrognostic factors for changes in the timed 4-stair climb in patients with Duchenne muscular dystrophy, and implications for measuring drug efficacy: A multi-institutional collaboration
dc.typeJournal Article
dc.source.journaltitlePloS one
dc.source.volume15
dc.source.issue6
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5303&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4277
dc.identifier.contextkey18456797
refterms.dateFOA2022-08-23T16:49:37Z
html.description.abstract<p>The timed 4-stair climb (4SC) assessment has been used to measure function in Duchenne muscular dystrophy (DMD) practice and research. We sought to identify prognostic factors for changes in 4SC, assess their consistency across data sources, and the extent to which prognostic scores could be useful in DMD clinical trial design and analysis. Data from patients with DMD in the placebo arm of a phase 3 trial (Tadalafil DMD trial) and two real-world sources (Universitaire Ziekenhuizen, Leuven, Belgium [Leuven] and Cincinnati Children's Hospital Medical Center [CCHMC]) were analyzed. One-year changes in 4SC completion time and velocity (stairs/second) were analyzed. Prognostic models included age, height, weight, steroid use, and multiple timed function tests and were developed using multivariable regression, separately in each data source. Simulations were used to quantify impacts on trial sample size requirements. Data on 1-year changes in 4SC were available from the Tadalafil DMD trial (n = 92) Leuven (n = 67), and CCHMC (n = 212). Models incorporating multiple timed function tests, height, and weight significantly improved prognostic accuracy for 1-year change in 4SC (R2: 29%-36% for 4SC velocity, and 29%-34% for 4SC time) compared to models including only age, baseline 4SC and steroid duration (R2:8%-17% for 4SC velocity and 2%-13% for 4SC time). Measures of walking and rising ability contributed important prognostic information for changes in 4SC. In a randomized trial with equal allocation to treatment and placebo, adjustment for such a prognostic score would enable detection (at 80% power) of a treatment effect of 0.25 stairs/second with 100-120 patients, compared to 170-190 patients without prognostic score adjustment. Combining measures of ambulatory function doubled prognostic accuracy for 1-year changes in 4SC completion time and velocity. Randomized clinical trials incorporating a validated prognostic score could reduce sample size requirements by approximately 40%. Knowledge of important prognostic factors can also inform adjusted comparisons to external controls.</p>
dc.identifier.submissionpathoapubs/4277
dc.contributor.departmentDepartment of Pediatrics
dc.source.pagese0232870


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Copyright: © 2020 Goemans et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Except where otherwise noted, this item's license is described as Copyright: © 2020 Goemans et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.