{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T02:49:08Z","timestamp":1771296548371,"version":"3.50.1"},"reference-count":22,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,10,7]],"date-time":"2020-10-07T00:00:00Z","timestamp":1602028800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,10,7]],"date-time":"2020-10-07T00:00:00Z","timestamp":1602028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>To date, targeted temperature management (TTM) is the only neuroprotective intervention after resuscitation from cardiac arrest that is recommended by guidelines. The evidence on the effects of TTM is unclear.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods\/design<\/jats:title>\n<jats:p>The Targeted Hypothermia Versus Targeted Normothermia After Out-of-hospital Cardiac Arrest (TTM2) trial is an international, multicentre, parallel group, investigator-initiated, randomised, superiority trial in which TTM with a target temperature of 33\u2009\u00b0C after cardiac arrest will be compared with a strategy to maintain normothermia and active treatment of fever (\u2265\u200937.8\u2009\u00b0C). Prognosticators, outcome assessors, the steering group, the trial coordinating team, and trial statisticians will be blinded to treatment allocation. The primary outcome will be all-cause mortality at 180\u2009days after randomisation. We estimate a 55% mortality in the targeted normothermia group. To detect an absolute risk reduction of 7.5% with an alpha of 0.05 and 90% power, 1900 participants will be enrolled. The secondary neurological outcome will be poor functional outcome (modified Rankin scale 4\u20136) at 180\u2009days after cardiac arrest. In this paper, a detailed statistical analysis plan is presented, including a comprehensive description of the statistical analyses, handling of missing data, and assessments of underlying statistical assumptions. Final analyses will be conducted independently by two qualified statisticians following the present plan.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Discussion<\/jats:title>\n<jats:p>This SAP, which was prepared before completion of enrolment, should increase the validity of the TTM trial by mitigation of analysis-bias.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s13063-020-04654-y","type":"journal-article","created":{"date-parts":[[2020,10,7]],"date-time":"2020-10-07T12:03:02Z","timestamp":1602072182000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest: a statistical analysis plan"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3642-2120","authenticated-orcid":false,"given":"Janus Christian","family":"Jakobsen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josef","family":"Dankiewicz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theis","family":"Lange","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tobias","family":"Cronberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gisela","family":"Lilja","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena","family":"Levin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"B\u011blohl\u00e1vek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clifton","family":"Callaway","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alain","family":"Cariou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Erlinge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan","family":"Hovdenes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Joannidis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Per","family":"Nordberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mauro","family":"Oddo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paolo","family":"Pelosi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans","family":"Kirkegaard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Glenn","family":"Eastwood","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Rylander","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manoj","family":"Saxena","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Storm","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio Silvio","family":"Taccone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew P.","family":"Wise","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matt P. G.","family":"Morgan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Young","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alistair","family":"Nichol","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans","family":"Friberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susann","family":"Ull\u00e9n","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Niklas","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,10,7]]},"reference":[{"issue":"23","key":"4654_CR1","doi-asserted-by":"publisher","first-page":"2197","DOI":"10.1056\/NEJMoa1310519","volume":"369","author":"N Nielsen","year":"2013","unstructured":"Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, Horn J, Hovdenes J, Kjaergaard J, Kuiper M, et al. Targeted temperature management at 33\u00b0C versus 36\u00b0C after cardiac arrest. N Engl J Med. 2013;369(23):2197\u2013206.","journal-title":"N Engl J Med"},{"issue":"24","key":"4654_CR2","doi-asserted-by":"publisher","first-page":"2327","DOI":"10.1056\/NEJMoa1906661","volume":"381","author":"JB Lascarrou","year":"2019","unstructured":"Lascarrou JB, Merdji H, Le Gouge A, Colin G, Grillet G, Girardie P, Coupez E, Dequin PF, Cariou A, Boulain T, et al. Targeted temperature management for cardiac arrest with nonshockable rhythm. N Engl J Med. 2019;381(24):2327\u201337.","journal-title":"N Engl J Med"},{"key":"4654_CR3","doi-asserted-by":"crossref","unstructured":"Dankiewicz J, Cronberg T, Gisela Lilja G, Jakobsen J, B\u011blohl\u00e1vek J, Callaway C, Cariou A, Eastwood G, Erlinge D, Hovdenes J, et al. Targeted hypothermia versus targeted normothermia after out-of-hospital cardiac arrest (TTM2). A randomised clinical trial \u2013 rationale and design. Am Heart J. 2019;217:23\u201331.","DOI":"10.1016\/j.ahj.2019.06.012"},{"issue":"1","key":"4654_CR4","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1186\/s13054-018-2119-5","volume":"22","author":"F Ebner","year":"2018","unstructured":"Ebner F, Harmon MBA, Aneman A, Cronberg T, Friberg H, Hassager C, Juffermans N, Kjaergaard J, Kuiper M, Mattsson N, et al. Carbon dioxide dynamics in relation to neurological outcome in resuscitated out-of-hospital cardiac arrest patients: an exploratory Target Temperature Management Trial substudy. Crit Care. 2018;22(1):196.","journal-title":"Crit Care"},{"key":"4654_CR5","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.resuscitation.2020.03.004","volume":"150","author":"G Lilja","year":"2020","unstructured":"Lilja G, Nielsen N, Ullen S, Blennow Nordstrom E, Dankiewicz J, Friberg H, Heimburg K, Jakobsen JC, Levin H, Callaway C, et al. Protocol for outcome reporting and follow-up in the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest trial (TTM2). Resuscitation. 2020;150:104\u201312.","journal-title":"Resuscitation"},{"key":"4654_CR6","doi-asserted-by":"publisher","first-page":"e027092","DOI":"10.1136\/bmjopen-2018-027092","volume":"9","author":"JC Jakobsen","year":"2019","unstructured":"Jakobsen JC, Ovesen C, Winkel P, Hilden J, Gluud C, Wetterslev J. Power estimations for non-primary outcomes in randomised clinical trials. BMJ Open. 2019;9:e027092. https:\/\/doi.org\/10.1136\/bmjopen-2018-027092.","journal-title":"BMJ Open"},{"issue":"3","key":"4654_CR7","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1161\/01.STR.0000258355.23810.c6","volume":"38","author":"JL Banks","year":"2007","unstructured":"Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke. 2007;38(3):1091\u20136.","journal-title":"Stroke"},{"issue":"7","key":"4654_CR8","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1007\/s11136-012-0322-4","volume":"22","author":"MF Janssen","year":"2013","unstructured":"Janssen MF, Pickard AS, Golicki D, Gudex C, Niewada M, Scalone L, Swinburn P, Busschbach J. Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient groups: a multi-country study. Qual Life Res. 2013;22(7):1717\u201327.","journal-title":"Qual Life Res"},{"issue":"7","key":"4654_CR9","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1111\/j.1399-6576.2009.02021.x","volume":"53","author":"N Nielsen","year":"2009","unstructured":"Nielsen N, Hovdenes J, Nilsson F, Rubertsson S, Stammet P, Sunde K, Valsson F, Wanscher M, Friberg H, Hypothermia N. Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest. Acta Anaesthesiol Scand. 2009;53(7):926\u201334.","journal-title":"Acta Anaesthesiol Scand"},{"issue":"8","key":"4654_CR10","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1056\/NEJMoa003289","volume":"346","author":"SA Bernard","year":"2002","unstructured":"Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557\u201363.","journal-title":"N Engl J Med"},{"issue":"8","key":"4654_CR11","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1056\/NEJMoa012689","volume":"346","author":"Hypothermia after Cardiac Arrest Study G","year":"2002","unstructured":"Hypothermia after Cardiac Arrest Study G. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346(8):549\u201356.","journal-title":"N Engl J Med"},{"key":"4654_CR12","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/1471-2288-14-34","volume":"14","author":"JC Jakobsen","year":"2014","unstructured":"Jakobsen JC, Gluud C, Winkel P, Lange T, Wetterslev J. The thresholds for statistical and clinical significance - a five-step procedure for evaluation of intervention effects in randomised clinical trials. BMC Med Res Methodol. 2014;14:34.","journal-title":"BMC Med Res Methodol"},{"key":"4654_CR13","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1002\/sim.4431","volume":"31","author":"BC Kahan","year":"2011","unstructured":"Kahan BC, Morris TP. Improper analysis of trials randomised using stratified blocks or minimisation. Stat Med. 2011;31:328\u201340.","journal-title":"Stat Med"},{"key":"4654_CR14","doi-asserted-by":"publisher","first-page":"e5840","DOI":"10.1136\/bmj.e5840","volume":"345","author":"BC Kahan","year":"2012","unstructured":"Kahan BC, Morris TP. Reporting and analysis of trials using stratified randomisation in leading medical journals: review and reanalysis. BMJ. 2012;345:e5840.","journal-title":"BMJ"},{"key":"4654_CR15","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/1471-2288-3-26","volume":"3","author":"AA Montgomery","year":"2003","unstructured":"Montgomery AA, Peters TJ, Little P. Design, analysis and presentation of factorial randomised controlled trials. BMC Med Res Methodol. 2003;3:26.","journal-title":"BMC Med Res Methodol"},{"issue":"1","key":"4654_CR16","first-page":"227","volume":"6","author":"JC Jakobsen","year":"2015","unstructured":"Jakobsen JC, Tamborrino M, Winkel P, Haase N, Perner A, Wetterslev J, Gluud C. Count data analysis in randomised clinical trials. J Biomet Biostat. 2015;6(1):227.","journal-title":"J Biomet Biostat"},{"issue":"1","key":"4654_CR17","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1186\/s12874-017-0442-1","volume":"17","author":"JC Jakobsen","year":"2017","unstructured":"Jakobsen JC, Gluud C, Wetterslev J, Winkel P. When and how should multiple imputation be used for handling missing data in randomised clinical trials - a practical guide with flowcharts. BMC Med Res Methodol. 2017;17(1):162.","journal-title":"BMC Med Res Methodol"},{"issue":"5","key":"4654_CR18","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1136\/bmjebm-2019-111174","volume":"24","author":"EE Nielsen","year":"2019","unstructured":"Nielsen EE, Norskov AK, Lange T, Thabane L, Wetterslev J, Beyersmann J, de Una-Alvarez J, Torri V, Billot L, Putter H, et al. Assessing assumptions for statistical analyses in randomised clinical trials. BMJ Evid Based Med. 2019;24(5):185\u20139.","journal-title":"BMJ Evid Based Med"},{"key":"4654_CR19","doi-asserted-by":"publisher","unstructured":"N\u00f8rskov AK, Lange T, Nielsen EE, Gluud C, Winkel P, Beyersmann J, de U\u00f1a-\u00c1lvarez J, Torri V, Billot L, Putter H, et al. Assessment of assumptions of statistical analysis methods in randomised clinical trials: the what and how. BMJ Evid Based Med. 2020;bmjebm-2019-111268. https:\/\/doi.org\/10.1136\/bmjebm-2019-111268.","DOI":"10.1136\/bmjebm-2019-111268"},{"key":"4654_CR20","unstructured":"Frydenberg SJM. An introduction to Stata for health researchers. 4th ed. College Station: Stata Press; 2014."},{"key":"4654_CR21","doi-asserted-by":"crossref","unstructured":"Oliveira AG. Biostatistics decoded: Wiley; 2013.","DOI":"10.1002\/9781118670767"},{"issue":"2","key":"4654_CR22","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1111\/j.0006-341X.2000.00455.x","volume":"56","author":"S Duval","year":"2000","unstructured":"Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56(2):455\u201363.","journal-title":"Biometrics"}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-020-04654-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13063-020-04654-y\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-020-04654-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,7]],"date-time":"2021-10-07T03:14:57Z","timestamp":1633576497000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-020-04654-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,7]]},"references-count":22,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["4654"],"URL":"https:\/\/doi.org\/10.1186\/s13063-020-04654-y","relation":{},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,7]]},"assertion":[{"value":"3 February 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 August 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 October 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Ethical approval has been confirmed from the Regional Ethics Committee at Lund University (2015\/228), and the study has been approved by all relevant ethics boards in all participating countries. Written informed consent is waived, delayed, or obtained from a legal surrogate, depending on the circumstances, and is obtained from participants who regain mental capacity. The trial is conducted in accordance with The Declaration of Helsinki. Registered within ClinicalTrials.gov ().","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":"Dr. Cariou reports personal fees from Bard, outside the submitted work; Dr. Saxena has received an unrestricted grant from Bard BD and have spoken at educational events for BD Bard and provided advice on educational events and product development; Dr. Storm reports personal fees from BD Bard, personal fees from ZOLL GmbH, personal fees from Braincool Inc., personal fees from Xenios, and personal fees from Philips, outside the submitted work; Pr. Taccone reports lecture fees from BD Bard and ZOLL; Dr. Morgan reports personal fees from BD Bard for teaching use of surface cooling devices, outside the submitted work; Dr. Friberg reports receiving lecture fees from BD Bard and consulting fees from QuickCool, outside the submitted work; and Dr. Young reports personal fees from Bard Medical, outside the submitted work.All remaining authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"831"}}