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dc.contributor.authorWilkins, Martin R
dc.contributor.authorMckie, Mikel A
dc.contributor.authorLaw, Martin
dc.contributor.authorRoussakis, Andreas A
dc.contributor.authorHarbaum, Lars
dc.contributor.authorChurch, Colin
dc.contributor.authorCoghlan, J Gerry
dc.contributor.authorCondliffe, Robin
dc.contributor.authorHoward, Luke S
dc.contributor.authorKiely, David G
dc.contributor.authorLordan, Jim
dc.contributor.authorRothman, Alexander
dc.contributor.authorSuntharalingam, Jay
dc.contributor.authorToshner, Mark
dc.contributor.authorWort, Stephen J
dc.contributor.authorVillar, Sofía S
dc.date.accessioned2021-10-18T14:27:13Z
dc.date.available2021-10-18T14:27:13Z
dc.date.issued2021-10
dc.date.submitted2021-06-15
dc.identifier.issn2045-8932
dc.identifier.other10.1177_20458940211052823
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/329570
dc.description.abstractPulmonary arterial hypertension is an unmet clinical need. Imatinib, a tyrosine kinase inhibitor, 200 to 400 mg daily reduces pulmonary artery pressure and increases functional capacity in this patient group, but is generally poorly tolerated at the higher dose. We have designed an open-label, single-arm clinical study to investigate whether there is a tolerated dose of imatinib that can be better targeted to patients who will benefit. The study consists of two parts. Part 1 seeks to identify the best tolerated dose of Imatinib in the range from 100 and up to 400 mg using a Bayesian Continuous Reassessment Method. Part 2 will measure efficacy after 24 weeks treatment with the best tolerated dose using a Simon's two-stage design. The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) >1000 dynes · s · cm-5, success is defined by an absolute reduction in PVR of ≥300 dynes · s · cm-5 at 24 weeks. For patients with a baseline PVR ≤1000 dynes · s · cm-5, success is a 30% reduction in PVR at 24 weeks. PVR will also be evaluated as a continuous variable by genotype as an exploratory analysis. Evaluating the response to that dose by genotype may inform a prospective biomarker-driven study.
dc.languageen
dc.publisherWiley
dc.rightsEmbargo: ends 2021-10-17
dc.subjectOriginal Research Article
dc.subjectAdaptive design
dc.subjectsafety
dc.subjecttolerability
dc.subjectefficacy
dc.titlePositioning imatinib for pulmonary arterial hypertension: A phase I/II design comprising dose finding and single-arm efficacy.
dc.typeArticle
dc.date.updated2021-10-18T14:27:12Z
prism.issueIdentifier4
prism.publicationNamePulm Circ
prism.volume11
dc.identifier.doi10.17863/CAM.77018
dcterms.dateAccepted2021-09-19
rioxxterms.versionofrecord10.1177/20458940211052823
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2021-10-17
dc.contributor.orcidWilkins, Martin R [0000-0003-3926-1171]
dc.contributor.orcidLaw, Martin [0000-0001-9594-348X]
dc.contributor.orcidRoussakis, Andreas A [0000-0001-5748-6978]
dc.contributor.orcidRothman, Alexander [0000-0002-7847-4500]
dc.contributor.orcidToshner, Mark [0000-0002-3969-6143]
dc.identifier.eissn2045-8940
pubs.funder-project-idMedical Research Council (MC_UU_00002/15)
pubs.funder-project-idBritish Heart Foundation (RE/18/4/34215)
pubs.funder-project-idEfficacy and Mechanism Evaluation Programme (NIHR128465)
cam.issuedOnline2021-10-17
rioxxterms.freetoread.startdate2021-10-17


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