{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T18:26:15Z","timestamp":1782325575395,"version":"3.54.5"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["DRF-2012-05-364"],"award-info":[{"award-number":["DRF-2012-05-364"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C18027\/A15790"],"award-info":[{"award-number":["C18027\/A15790"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008897","name":"Janssen Pharmaceuticals","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006483","name":"AbbVie","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006483","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>The FLAIR trial in chronic lymphocytic leukaemia has a randomised, controlled, open-label, confirmatory, platform design. FLAIR was successfully amended to include an emerging promising experimental therapy to expedite its assessment, greatly reducing the time to reach the primary outcome compared to running a separate trial and without compromising the validity of the research or the ability to recruit to the trial and report the outcomes. The methodological and practical issues are presented, describing how they were addressed to ensure the amendment was a success.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>FLAIR was designed as a two-arm trial requiring 754 patients. In stage 2, two new arms were added: a new experimental arm and a second control arm to protect the trial in case of a change in practice. In stage 3, the original experimental arm was closed as its planned recruitment target was reached. In total, 1516 participants will be randomised to the trial.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>The changes to the protocol and randomisation to add and stop arms were made seamlessly without pausing recruitment. The statistical considerations to ensure the results for the original and new hypotheses are unbiased were approved following peer review by oversight committees, Cancer Research UK, ethical and regulatory committees and pharmaceutical partners. These included the use of concurrent comparators in case of any stage effect, appropriate control of the type I error rate and consideration of analysis methods across trial stages. The operational aspects of successfully implementing the amendments are described, including gaining approvals and additional funding, data management requirements and implementation at centres.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>FLAIR is an exemplar of how an emerging experimental therapy can be assessed within an existing trial structure without compromising the conduct, reporting or validity of the trial. This strategy offered considerable resource savings and allowed the new experimental therapy to be assessed within a confirmatory trial in the UK years earlier than would have otherwise been possible. Despite the clear efficiencies, treatment arms are rarely added to ongoing trials in practice. This paper demonstrates how this strategy is acceptable, feasible and beneficial to patients and the wider research community.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p>ISRCTN Registry <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.isrctn.com\/ISRCTN01844152\">ISRCTN01844152<\/jats:ext-link>. Registered on August 08, 2014<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13063-020-04971-2","type":"journal-article","created":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T08:04:07Z","timestamp":1610093047000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A platform trial in practice: adding a new experimental research arm to the ongoing confirmatory FLAIR trial in chronic lymphocytic leukaemia"],"prefix":"10.1186","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3333-9783","authenticated-orcid":false,"given":"Dena R.","family":"Howard","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Hockaday","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia M.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter M.","family":"Gregory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Todd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahla","family":"Munir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie B.","family":"Oughton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Dimbleby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Hillmen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,8]]},"reference":[{"issue":"1","key":"4971_CR1","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1186\/s13063-017-2138-6","volume":"18","author":"L Collett","year":"2017","unstructured":"Collett L, Howard DR, Munir T, McParland L, Oughton JB, Rawstron AC, et al. Assessment of ibrutinib plus rituximab in front-line CLL (FLAIR trial): study protocol for a phase III randomised controlled trial. Trials. 2017;18(1):387.","journal-title":"Trials."},{"issue":"4","key":"4971_CR2","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/s41416-019-0653-9","volume":"122","author":"SP Blagden","year":"2020","unstructured":"Blagden SP, Billingham L, Brown LC, Buckland SW, Cooper AM, Ellis S, et al. Effective delivery of Complex Innovative Design (CID) cancer trials\u2014a consensus statement. Br J Cancer. 2020;122(4):473\u201382.","journal-title":"Br J Cancer"},{"issue":"1","key":"4971_CR3","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1056\/NEJMra1510062","volume":"377","author":"J Woodcock","year":"2017","unstructured":"Woodcock J, LaVange LM. Master protocols to study multiple therapies, multiple diseases, or both. N Engl J Med. 2017;377(1):62\u201370.","journal-title":"N Engl J Med"},{"issue":"16","key":"4971_CR4","doi-asserted-by":"publisher","first-page":"1619","DOI":"10.1001\/jama.2015.2316","volume":"313","author":"SM Berry","year":"2015","unstructured":"Berry SM, Connor JT, Lewis RJ. The platform trial: an efficient strategy for evaluating multiple treatments. JAMA. 2015;313(16):1619\u201320.","journal-title":"JAMA."},{"issue":"10","key":"4971_CR5","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1038\/s41573-019-0034-3","volume":"18","author":"DC Angus","year":"2019","unstructured":"Angus DC, Alexander BM, Berry S, Buxton M, Lewis R, Paoloni M, et al. Adaptive platform trials: definition, design, conduct and reporting considerations. Nat Rev Drug Discov. 2019;18(10):797\u2013807.","journal-title":"Nat Rev Drug Discov"},{"issue":"3","key":"4971_CR6","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1080\/10543400600614742","volume":"16","author":"P Gallo","year":"2006","unstructured":"Gallo P, Chuang-Stein C, Dragalin V, Gaydos B, Krams M, Pinheiro J. Adaptive designs in clinical drug development - an executive summary of the PhRMA Working Group. J Biopharm Stat. 2006;16(3):275\u201383.","journal-title":"J Biopharm Stat"},{"issue":"9747","key":"4971_CR7","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1016\/S0140-6736(10)61381-5","volume":"376","author":"M Hallek","year":"2010","unstructured":"Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376(9747):1164\u201374.","journal-title":"Lancet"},{"key":"4971_CR8","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1038\/leu.2015.313","volume":"30","author":"AC Rawstron","year":"2015","unstructured":"Rawstron AC, Fazi C, Agathangelidis A, Villamor N, Letestu R, Nomdedeu J, et al. A complementary role of multiparameter flow cytometry and high-throughput sequencing for minimal residual disease detection in chronic lymphocytic leukemia: an European Research Initiative on CLL study. Leukemia. 2015;30:929.","journal-title":"Leukemia."},{"key":"4971_CR9","unstructured":"Bloodwise. Trials Acceleration Programme (TAP) https:\/\/bloodwise.org.uk\/research\/clinical-trials\/tap: Bloodwise; 2018 [cited 2019 May]."},{"key":"4971_CR10","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1186\/s13063-015-0697-y","volume":"16","author":"DR Cohen","year":"2015","unstructured":"Cohen DR, Todd S, Gregory WM, Brown JM. Adding a treatment arm to an ongoing clinical trial: a review of methodology and practice. Trials. 2015;16:179.","journal-title":"Trials."},{"issue":"1","key":"4971_CR11","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1186\/1745-6215-13-168","volume":"13","author":"MR Sydes","year":"2012","unstructured":"Sydes MR, Parmar MKB, Mason MD, Clarke NW, Amos C, Anderson J, et al. Flexible trial design in practice - stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial. Trials. 2012;13(1):168.","journal-title":"Trials."},{"issue":"1","key":"4971_CR12","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1186\/s13063-019-3216-8","volume":"20","author":"F Schiavone","year":"2019","unstructured":"Schiavone F, Bathia R, Letchemanan K, Masters L, Amos C, Bara A, et al. This is a platform alteration: a trial management perspective on the operational aspects of adaptive and platform and umbrella protocols. Trials. 2019;20(1):264.","journal-title":"Trials."},{"issue":"1","key":"4971_CR13","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1186\/s13063-019-3322-7","volume":"20","author":"D Hague","year":"2019","unstructured":"Hague D, Townsend S, Masters L, Rauchenberger M, Van Looy N, Diaz-Montana C, et al. Changing platforms without stopping the train: experiences of data management and data management systems when adapting platform protocols by adding and closing comparisons. Trials. 2019;20(1):294.","journal-title":"Trials."},{"issue":"1","key":"4971_CR14","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1186\/s13063-019-3377-5","volume":"20","author":"L Morrell","year":"2019","unstructured":"Morrell L, Hordern J, Brown L, Sydes MR, Amos CL, Kaplan RS, et al. Mind the gap? The platform trial as a working environment. Trials. 2019;20(1):297.","journal-title":"Trials."},{"issue":"23","key":"4971_CR15","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1182\/blood.V126.23.830.830","volume":"126","author":"S Ma","year":"2015","unstructured":"Ma S, Brander DM, Seymour JF, Kipps TJ, Barrientos JC, Davids MS, et al. Deep and durable responses following venetoclax (ABT-199 \/ GDC-0199) combined with rituximab in patients with relapsed\/refractory chronic lymphocytic leukemia: results from a phase 1b study. Blood. 2015;126(23):830.","journal-title":"Blood."},{"issue":"21","key":"4971_CR16","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1182\/blood.V124.21.509.509","volume":"124","author":"CA Portell","year":"2014","unstructured":"Portell CA, Axelrod M, Brett LK, Gordon VL, Capaldo B, Xing JC, et al. Synergistic cytotoxicity of Ibrutinib and the BCL2 antagonist, ABT-199(GDC-0199) in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL): molecular analysis reveals mechanisms of target interactions. Blood. 2014;124(21):509.","journal-title":"Blood."},{"issue":"23","key":"4971_CR17","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1182\/blood.V126.23.490.490","volume":"126","author":"J Deng","year":"2015","unstructured":"Deng J, Isik E, Fernandes SM, Brown JR, Letai A, Davids MS. Ibrutinib therapy increases BCL-2 dependence and enhances sensitivity to venetoclax in CLL. Blood. 2015;126(23):490.","journal-title":"Blood."},{"issue":"30","key":"4971_CR18","doi-asserted-by":"publisher","first-page":"2722","DOI":"10.1200\/JCO.19.00894","volume":"37","author":"P Hillmen","year":"2019","unstructured":"Hillmen P, Rawstron AC, Brock K, Mu\u00f1oz-Vicente S, Yates FJ, Bishop R, et al. Ibrutinib plus venetoclax in relapsed\/refractory chronic lymphocytic leukemia: the CLARITY Study. J Clin Oncol. 2019;37(30):2722\u20139.","journal-title":"J Clin Oncol"},{"issue":"25","key":"4971_CR19","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.1056\/NEJMoa1509388","volume":"373","author":"JA Burger","year":"2015","unstructured":"Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425\u201337.","journal-title":"N Engl J Med"},{"issue":"3","key":"4971_CR20","doi-asserted-by":"publisher","first-page":"549","DOI":"10.2307\/2530245","volume":"35","author":"PC O\u2019Brien","year":"1979","unstructured":"O\u2019Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35(3):549\u201356.","journal-title":"Biometrics."},{"issue":"10","key":"4971_CR21","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1182\/blood-2018-10-879429","volume":"133","author":"JA Burger","year":"2019","unstructured":"Burger JA, Sivina M, Jain N, Kim E, Kadia T, Estrov Z, et al. Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood. 2019;133(10):1011\u20139.","journal-title":"Blood."},{"issue":"4","key":"4971_CR22","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1177\/0141076818764320","volume":"111","author":"DG Altman","year":"2018","unstructured":"Altman DG. Avoiding bias in trials in which allocation ratio is varied. J R Soc Med. 2018;111(4):143\u20134.","journal-title":"J R Soc Med"},{"issue":"1","key":"4971_CR23","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1186\/s12874-020-01043-6","volume":"20","author":"KM Lee","year":"2020","unstructured":"Lee KM, Wason J. Including non-concurrent control patients in the analysis of platform trials: is it worth it? BMC Med Res Methodol. 2020;20(1):165.","journal-title":"BMC Med Res Methodol"},{"key":"4971_CR24","unstructured":"CPMP (Committee for Proprietary Medicinal Products). Point to consider on multiplicity issues in clinical trials [PDF]. EMEA (European Medicines Agency); 2002 [Available from: http:\/\/www.ema.europa.eu\/docs\/en_GB\/document_library\/Scientific_guideline\/2009\/09\/WC500003640.pdf]. Accessed 18 Dec 2020."},{"issue":"5","key":"4971_CR25","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1177\/0962280216664759","volume":"27","author":"DR Howard","year":"2018","unstructured":"Howard DR, Brown JM, Todd S, Gregory WM. Recommendations on multiple testing adjustment in multi-arm trials with a shared control group. Stat Methods Med Res. 2018;27(5):1513\u201330.","journal-title":"Stat Methods Med Res"},{"issue":"14","key":"4971_CR26","doi-asserted-by":"publisher","first-page":"4368","DOI":"10.1158\/1078-0432.CCR-08-0325","volume":"14","author":"B Freidlin","year":"2008","unstructured":"Freidlin B, Korn EL, Gray R, Martin A. Multi-arm clinical trials of new agents: some design considerations. Clin Cancer Res. 2008;14(14):4368\u201371.","journal-title":"Clin Cancer Res"},{"key":"4971_CR27","unstructured":"Howard DR. Analysis methods when adding an arm to an ongoing trial. Statistical issues when incorporating emerging therapies into ongoing randomised clinical trials. University of Leeds: White Rose eTheses Online, http:\/\/etheses.whiterose.ac.uk\/22288\/; 2018. Accessed 18 Dec 2020."},{"key":"4971_CR28","doi-asserted-by":"publisher","unstructured":"Brown S, Thorpe H, Hawkins K, Brown J. Minimization\u2014reducing predictability for multi-centre trials whilst retaining balance within centre. Stat Med. 2005;24(24):3715-27. https:\/\/doi.org\/10.1002\/sim.2391.","DOI":"10.1002\/sim.2391"},{"issue":"1","key":"4971_CR29","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1186\/s13063-020-4073-1","volume":"21","author":"M Bennett","year":"2020","unstructured":"Bennett M, Mander AP. Designs for adding a treatment arm to an ongoing clinical trial. Trials. 2020;21(1):251.","journal-title":"Trials."},{"key":"4971_CR30","doi-asserted-by":"publisher","unstructured":"Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, Ding W, et al. Ibrutinib alone or in combination with rituximab produces superior progression free survival (PFS) compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia (CLL): results of Alliance North American Intergroup Study A041202. Blood. 2018;132(Supplement 1):6. https:\/\/doi.org\/10.1182\/blood-2018-99-116653.","DOI":"10.1182\/blood-2018-99-116653"},{"key":"4971_CR31","unstructured":"BBC News. Have they found a cure for our cancer? http:\/\/www.bbc.co.uk\/news\/stories-42920045: BBC; 2018 [updated 06 Feb 2018; cited 2019 May]."}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-020-04971-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13063-020-04971-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-020-04971-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,11]],"date-time":"2021-01-11T16:17:10Z","timestamp":1610381830000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-020-04971-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,8]]},"references-count":31,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["4971"],"URL":"https:\/\/doi.org\/10.1186\/s13063-020-04971-2","relation":{},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,8]]},"assertion":[{"value":"28 July 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 December 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 January 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Ethical approval has been obtained from the National Research Ethics Service Committee Yorkshire & Humber \u2013 Leeds East (reference 14\/YH\/0085), including approval to perform the study at all centres. All participants will give written informed consent before taking part.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"PH has received research support and honoraria for lecturing from Roche, Janssen, Gilead, Abbvie and Novartis. Since completing this work at the University of Leeds, DRH became an employee of Roche Products Ltd. The other authors declare they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"38"}}