BACKGROUND: Infants born extremely preterm are at high risk of dying or suffering from severe brain injuries. Treatment guided by monitoring of cerebral oxygenation may reduce the risk of death and neurologic complications. The SafeBoosC III trial evaluates the effects of treatment guided by cerebral oxygenation monitoring versus treatment as usual. This article describes the detailed statistical analysis plan for the main publication, with the aim to prevent outcome reporting bias and data-driven analyses. METHODS/DESIGN: The SafeBoosC III trial is an investigator-initiated, randomised, multinational, pragmatic phase III trial with a parallel group structure, designed to investigate the benefits and harms of treatment based on cerebral near-infrared spectroscopy monitoring compared with treatment as usual. Randomisation will be 1:1 stratified for neonatal intensive care unit and gestational age (lower gestational age (< 26 weeks) compared to higher gestational age (≥ 26 weeks)). The primary outcome is a composite of death or severe brain injury at 36 weeks postmenstrual age. Primary analysis will be made on the intention-to-treat population for all outcomes, using mixed-model logistic regression adjusting for stratification variables. In the primary analysis, the twin intra-class correlation coefficient will not be considered. However, we will perform sensitivity analyses to address this. Our simulation study suggests that the inclusion of multiple births is unlikely to significantly affect our assessment of intervention effects, and therefore we have chosen the analysis where the twin intra-class correlation coefficient will not be considered as the primary analysis. DISCUSSION: In line with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines, we have developed and published this statistical analysis plan for the SafeBoosC III trial, prior to any data analysis. TRIAL REGISTRATION: ClinicalTrials.org, NCT03770741. Registered on 10 December 2018.

Center for Statistical Science Peking University Beijing China

Copenhagen Trial Unit Centre for Clinical Intervention Research Rigshospitalet Copenhagen University Hospital Blegdamsvej 9 2100 Copenhagen Denmark

Department of Cardiology Holbæk Hospital Smedelundsgade 60 4300 Holbæk Denmark

Department of Clinical Sciences and Community Health University of Milan Milan Italy

Department of Neonatology Centrohospitalar Universitário de São João Alameda Prof Hernâni Monteiro 4200 319 Porto Portugal

Department of Neonatology Children's Hospital of Fudan University 399 Wanyuan Rd Minhang Qu Shanghai Shi China

Department of Neonatology Children's University Hospital of Zürich Steinweisstrasse 75 8037 Zurich Switzerland

Department of Neonatology Hospices Civil De Lyon 3 Quai des Célestins 69002 Lyon France

Department of Neonatology La Paz University Hospital Paseo De La Castellana 261 28046 Madrid Spain

Department of Neonatology Oslo University Hospital Kirkeveien 166 0450 Oslo Norway

Department of Neonatology Poznan University of Medical Sciences Polna 33 60 535 Poznań Poland

Department of Neonatology Rigshospitalet Copenhagen University Hospital Blegdamsvej 9 2100 Copenhagen Denmark

Department of Neonatology Royal Hospital for Children 1345 Govan Rd Glasgow G51 4TF UK

Department of Neonatology University Children's Hospital Tuebingen Hoppe Seyler Straße 1 72076 Tuebingen Germany

Department of Neonatology University Hospital Leuven Herestraat 49 Leuven Belgium

Department of Neonatology University Hospital Motol 5 Uvalu 84 150 06 Prague 5 Czech Republic

Department of Pediatrics Medical University of Graz Auenbruggerplatz 30 Graz Austria

Department of Regional Health Research The Faculty of Health Sciences University of Southern Denmark Odense Denmark

Division of Neonatal Perinatal Medicine Mountainside Medical Center Montclair NJ USA

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Milan Via della Commenda 12 20122 Milan Italy

Infant Centre and Department of Paediatrics and Child Health University College Cork College Road Cork Ireland

NICU Department of Pediatrics University General Hospital of Patras 265 04 Patras Greece

Section of Biostatistics Department of Publich Health Copenhagen University Øster Farimagsgade 5 Copenhagen K Denmark

Zobrazit více v PubMed

Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC, et al. Neonatal outcomes of extremely preterm infants from the NICHD neonatal research network. Pediatrics. 2010;126:443–456. doi: 10.1542/peds.2009-2959. PubMed DOI PMC

Volpe JJ. Brain injury in the premature infant: overview of clinical aspects, neuropathology, and pathogenesis. Semin Pediatr Neurol. 1998;5:135–151. doi: 10.1016/S1071-9091(98)80030-2. PubMed DOI

Adams-Chapman I, Heyne RJ, DeMauro SB, Duncan AF, Hintz SR, Pappas A, et al. Neurodevelopmental impairment among extremely preterm infants in the neonatal research network. Pediatrics. 2018;141:e20173091. doi: 10.1542/peds.2017-3091. PubMed DOI PMC

Behrman R, Butler AS. Preterm birth: causes, consequences and prevention. Institute of Medicine. Washington, DC: National Academies Press; 2007. PubMed

Volpe JJ. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances. Lancet Neurol. 2009;8:110–124. doi: 10.1016/S1474-4422(08)70294-1. PubMed DOI PMC

Hyttel-Sørensen S, Pellicer A, Alderliesten T, Austin T, Van Bel F, Benders M, et al. Cerebral near infrared spectroscopy oximetry in extremely preterm infants: phase II randomised clinical trial. BMJ. 2015;350:1–11. doi: 10.1136/bmj.g7635. PubMed DOI PMC

Hyttel-Sørensen S, Greisen G, Als-Nielsen B, Gluud C. Cerebral near-infrared spectroscopy monitoring for prevention of brain injury in very preterm infants. Cochrane Database Syst Rev. 2017;9:CD011506. PubMed PMC

Guideline on Good Clinical Practice E6(R2). London: European Medicines Agency, Committee for Human Medicinal Products. 2017.

World Health Organization. Preterm birth. https://www.who.int/news-room/fact-sheets/detail/preterm-birth. 2018. Accessed 24 Nov 2019.

Hansen ML, Pellicer A, Gluud C, Dempsey E, Mintzer J, Hyttel-Sørensen S, et al. Cerebral near-infrared spectroscopy monitoring versus treatment as usual for extremely preterm infants. A protocol for the SafeBoosC phase III randomized clinical trial. Manuscript accepted for publication in Trials. 2019 PubMed PMC

Pellicer A, Greisen G, Benders M, Claris O, Dempsey E, Fumagally M, et al. The SafeBoosC phase II randomised clinical trial: a treatment guideline for targeted near-infrared-derived cerebral tissue oxygenation versus standard treatment in extremely preterm infants. Neonatology. 2013;104:171–178. doi: 10.1159/000351346. PubMed DOI

Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr. 1978;92:529–534. doi: 10.1016/S0022-3476(78)80282-0. PubMed DOI

Holsti A, Serenius F, Farooqi A. Impact of major neonatal morbidities on adolescents born at 23–25 weeks of gestation. Acta Paediatr. 2018;107:1893–1901. doi: 10.1111/apa.14445. PubMed DOI

Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg. 1978;187:1–7. doi: 10.1097/00000658-197801000-00001. PubMed DOI PMC

Valls-I-Soler A, Carnielli V, Claris O, de la Cruz BJ, Halliday HL, Hallman M, Hummler H. Weindling M; Scientific Steering Committee von EuroNeoStat (siehe Anhang). [EuroNeoStat: a European information system on the outcomes of care for very-low-birth-weight infants (< 1500 g)] Z Geburtshilfe Neonatol. 2008;212(3):116–8. doi: 10.1055/s-2008-1076802.German. PubMed DOI

Hintz SR, Barnes PD, Bulas D, Slovis TL, Finer NN, Wrage LA, et al. Neuroimaging and neurodevelopmental outcome in extremely preterm infants. Pediatrics. 2015;135:e32–e42. doi: 10.1542/peds.2014-0898. PubMed DOI PMC

Schmidt B, Roberts RS, Davis PG, Doyle LW, Asztalos EV, Opie G, et al. Prediction of late death or disability at age 5 years using a count of 3 neonatal morbidities in very low birth weight infants. J Pediatr. 2015;167:982–986.e2. doi: 10.1016/j.jpeds.2015.07.067. PubMed DOI

Davidson L, Berkelhamer S. Bronchopulmonary dysplasia: chronic lung disease of infancy and long-term pulmonary outcomes. J Clin Med. 2017;6:4. doi: 10.3390/jcm6010004. PubMed DOI PMC

Vermont Oxford Network. Vermont Oxford Network. 2019. https://public.vtoxford.org/. Accessed 24 Nov 2019.

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. doi: 10.1186/1471-2288-14-34. PubMed DOI PMC

Amrhein V, Greenland S, McShane B. Scientists rise up against statistical significance. Nature. 2019;567:305–307. doi: 10.1038/d41586-019-00857-9. PubMed DOI

Zhang J, Quan H, Ng J, Stepanavage ME. Some statistical methods for multiple endpoints in clinical trials. Control Clin Trials. 1997;18:204–221. doi: 10.1016/S0197-2456(96)00129-8. PubMed DOI

Goodman SN. Introduction to Bayesian methods I: measuring the strength of evidence. Clin Trials J Soc Clin Trials. 2005;2:282–290. doi: 10.1191/1740774505cn098oa. PubMed DOI

Wasserstein RL, Schirm AL, Lazar NA. Moving to a world beyond “p < 0.05”. Am Stat. 2019;73:1–19. doi: 10.1080/00031305.2019.1583913. DOI

DeMets DL, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med. 1994;13:1341–1352. doi: 10.1002/sim.4780131308. PubMed DOI

Guyatt GH, Briel M, Glasziou P, Bassler D, Montori VM. Problems of stopping trials early. BMJ. 2012;344:e3863. doi: 10.1136/bmj.e3863. PubMed DOI

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;17:162. doi: 10.1186/s12874-017-0442-1. PubMed DOI PMC

Little RJ, D’Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, et al. The prevention and treatment of missing data in clinical trials. N Engl J Med. 2012;367:1355–1360. doi: 10.1056/NEJMsr1203730. PubMed DOI PMC

Groenwold RHH, Moons KGM, Vandenbroucke JP. Randomized trials with missing outcome data: how to analyze and what to report. Can Med Assoc J. 2014;186:1153–1157. doi: 10.1503/cmaj.131353. PubMed DOI PMC

Gates S, Brocklehurst P. How should randomised trials including multiple pregnancies be analysed? BJOG An Int J Obstet Gynaecol. 2004;111:213–219. doi: 10.1111/j.1471-0528.2004.00059.x. PubMed DOI

Yelland LN, Sullivan TR, Collins CT, Price DJ, McPhee AJ, Lee KJ. Accounting for twin births in sample size calculations for randomised trials. Paediatr Perinat Epidemiol. 2018;32:380–387. doi: 10.1111/ppe.12471. PubMed DOI

Shaffer ML, Hiriote S. Analysis of time-to-event and duration outcomes in neonatal clinical trials with twin births. Contemp Clin Trials. 2009;30:150–154. doi: 10.1016/j.cct.2008.11.001. PubMed DOI PMC

Kahan BC, Morris TP. Reporting and analysis of trials using stratified randomisation in leading medical journals: review and reanalysis. BMJ. 2012;345:e5840. doi: 10.1136/bmj.e5840. PubMed DOI PMC

Kahan BC, Morris TP. Improper analysis of trials randomised using stratified blocks or minimisation. Stat Med. 2012;31:328–340. doi: 10.1002/sim.4431. PubMed DOI

Brennan KC. Accounting for centre-effects in multicentre trials with a binary outcome – when, why, and how? BMC Med Res Methodol. 2014;14:1–11. doi: 10.1186/1471-2288-14-1. PubMed DOI PMC

Deeks JJ, Higgins JPT, Altman DG. Chapter 10: analysing data and undertaking meta-analyses. Draft version (29 January 2019) for inclusion. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, editors. Cochrane handbook for systematic reviews of interventions. London: Cochrane. In Press.

Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c869. doi: 10.1136/bmj.c869. PubMed DOI PMC

Li G, Taljaard M, Van den Heuvel ER, Levine MA, Cook DJ, Wells GA, et al. An introduction to multiplicity issues in clinical trials: the what, why, when and how. Int J Epidemiol. 2017;46:746–755. doi: 10.1093/ije/dyx211. PubMed DOI

Abdi H. The Bonferonni and Šidák corrections for multiple comparisons. In: Salkind N, editor. Encyclopedia of measurement and statistics. Thousand Oaks: Sage; 2007. pp. 1–9.

Akobeng AK. Understanding type I and type II errors, statistical power and sample size. Acta Paediatr. 2016;105:605–660. doi: 10.1111/apa.13384. PubMed DOI

Yu Y, Zhang K, Zhang L, Zong H, Meng L, Han R. Cerebral near-infrared spectroscopy (NIRS) for perioperative monitoring of brain oxygenation in children and adults. Cochrane Database Syst Rev. 2018;1:CD010947. PubMed PMC

Taillefer MC, Denault AY. Cerebral near-infrared spectroscopy in adult heart surgery: systematic review of its clinical efficacy. Can J Anaesth. 2005;52:79–87. doi: 10.1007/BF03018586. PubMed DOI

Rothwell PM. External validity of randomised controlled trials: “To whom do the results of this trial apply?”. Lancet. 2005;365:82–93. doi: 10.1016/S0140-6736(04)17670-8. PubMed DOI

Ward RM, Beachy JC. Neonatal complications following preterm birth. BJOG An Int J Obstet Gynaecol. 2003;110:8–16. doi: 10.1046/j.1471-0528.2003.00012.x. PubMed DOI

Savović J, Turner RM, Mawdsley D, Jones HE, Beynon R, Higgins JPT, et al. Association between risk-of-bias assessments and results of randomized trials in Cochrane Reviews: the ROBES Meta-Epidemiologic Study. Am J Epidemiol. 2018;187:1113–1122. doi: 10.1093/aje/kwx344. PubMed DOI PMC

Hrobjartsson A, Thomsen ASS, Emanuelsson F, Tendal B, Hilden J, Boutron I, et al. Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors. Can Med Assoc J. 2013;185:E201–E211. doi: 10.1503/cmaj.120744. PubMed DOI PMC

Hróbjartsson A, Thomsen ASS, Emanuelsson F, Tendal B, Rasmussen JV, Hilden J, et al. Observer bias in randomized clinical trials with time-to-event outcomes: systematic review of trials with both blinded and non-blinded outcome assessors. Int J Epidemiol. 2014;43:937–948. doi: 10.1093/ije/dyt270. PubMed DOI

Hróbjartsson A, Emanuelsson F, Skou Thomsen AS, Hilden J, Brorson S. Bias due to lack of patient blinding in clinical trials. A systematic review of trials randomizing patients to blind and nonblind sub-studies. Int J Epidemiol. 2014;43:1272–1283. doi: 10.1093/ije/dyu115. PubMed DOI PMC

EMA (European Medicines Agency). Guideline on multiplicity issues in clinical trials. 2017.

Cerebral oximetry monitoring versus usual care for extremely preterm infants: a study protocol for the 2-year follow-up of the SafeBoosC-III randomised clinical trial

Cerebral near-infrared spectroscopy monitoring versus treatment as usual for extremely preterm infants: a protocol for the SafeBoosC randomised clinical phase III trial

Zobrazit více v PubMed

ClinicalTrials.gov
NCT03770741