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

Mathias Lühr Hansen, Adelina Pellicer, Christian Gluud, Eugene Dempsey, Jonathan Mintzer, Simon Hyttel-Sørensen, Anne Marie Heuchan, Cornelia Hagmann, Ebru Ergenekon, Gabriel Dimitriou, Gerhard Pichler, Gunnar Naulaers, Guoqiang Cheng, Hercilia Guimarães, Jakub Tkaczyk, Karen B Kreutzer, Monica Fumagalli, Olivier Claris, Petra Lemmers, Siv Fredly, Tomasz Szczapa, Topun Austin, Janus Christian Jakobsen, Gorm Greisen, Mathias Lühr Hansen, Adelina Pellicer, Christian Gluud, Eugene Dempsey, Jonathan Mintzer, Simon Hyttel-Sørensen, Anne Marie Heuchan, Cornelia Hagmann, Ebru Ergenekon, Gabriel Dimitriou, Gerhard Pichler, Gunnar Naulaers, Guoqiang Cheng, Hercilia Guimarães, Jakub Tkaczyk, Karen B Kreutzer, Monica Fumagalli, Olivier Claris, Petra Lemmers, Siv Fredly, Tomasz Szczapa, Topun Austin, Janus Christian Jakobsen, Gorm Greisen

Abstract

Background: Cerebral oxygenation monitoring may reduce the risk of death and neurologic complications in extremely preterm infants, but no such effects have yet been demonstrated in preterm infants in sufficiently powered randomised clinical trials. The objective of the SafeBoosC III trial is to investigate the benefits and harms of treatment based on near-infrared spectroscopy (NIRS) monitoring compared with treatment as usual for extremely preterm infants.

Methods/design: SafeBoosC III is an investigator-initiated, multinational, randomised, pragmatic phase III clinical trial. Inclusion criteria will be infants born below 28 weeks postmenstrual age and parental informed consent (unless the site is using 'opt-out' or deferred consent). Exclusion criteria will be no parental informed consent (or if 'opt-out' is used, lack of a record that clinical staff have explained the trial and the 'opt-out' consent process to parents and/or a record of the parents' decision to opt-out in the infant's clinical file); decision not to provide full life support; and no possibility to initiate cerebral NIRS oximetry within 6 h after birth. Participants will be randomised 1:1 into either the experimental or control group. Participants in the experimental group will be monitored during the first 72 h of life with a cerebral NIRS oximeter. Cerebral hypoxia will be treated according to an evidence-based treatment guideline. Participants in the control group will not undergo cerebral oxygenation monitoring and will receive treatment as usual. Each participant will be followed up at 36 weeks postmenstrual age. The primary outcome will be a composite of either death or severe brain injury detected on any of the serial cranial ultrasound scans that are routinely performed in these infants up to 36 weeks postmenstrual age. Severe brain injury will be assessed by a person blinded to group allocation. To detect a 22% relative risk difference between the experimental and control group, we intend to randomise a cohort of 1600 infants.

Discussion: Treatment guided by cerebral NIRS oximetry has the potential to decrease the risk of death or survival with severe brain injury in preterm infants. There is an urgent need to assess the clinical effects of NIRS monitoring among preterm neonates.

Trial registration: ClinicalTrial.gov, NCT03770741. Registered 10 December 2018.

Keywords: Near infrared spectroscopy; Preterm; Protocol; Randomised clinical trial.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schedule for enrolment, intervention and assessment, based on the SPIRIT 2013 guidance for protocols of clinical trials. *If approved by the local ethics committee, deferred informed consent or prior informed assent may be sought. Time to ask parents for deferred consent will be decided individually by clinical staff members

References

    1. Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller A-B, Narwal R, et al. National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet. 2012;379:2162–2172. doi: 10.1016/S0140-6736(12)60820-4.
    1. 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.
    1. 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.
    1. Volpe JJ. Brain injury in the premature infant: neuropathology, clinical aspects and pathogenesis. Semin Pediatr Neurol. 1998;5:135–151. doi: 10.1016/S1071-9091(98)80030-2.
    1. 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.
    1. Behrman R, Butler AS. Preterm birth: Causes, consequences and prevention. Institute of Medicine. Washington, D.C.: National Academies Press; 2007.
    1. Stephens BE, Vohr BR. Neurodevelopmental outcome of the premature infant. Pediatr Clin N Am. 2009;56:631–646. doi: 10.1016/j.pcl.2009.03.005.
    1. Kluckow M. Low systemic blood flow and pathophysiology of the preterm transitional circulation. Early Hum Dev. 2005;81:429–437. doi: 10.1016/j.earlhumdev.2005.03.006.
    1. 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.
    1. Guzzetta F, Shackelford GD, Volpe S, Perlman JM, Volpe JJ. Periventricular intraparenchymal echodensities in the premature newborn: critical determinant of neurologic outcome. Pediatrics. 1986;78:995–1006.
    1. 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.
    1. Cordeiro CN, Tsimis M, Burd I. Infections and brain development. Obstet Gynecol Surv. 2015;70:644–655. doi: 10.1097/OGX.0000000000000236.
    1. Prado EL, Dewey KG. Nutrition and brain development in early life. Nutr Rev. 2014;72:267–284. doi: 10.1111/nure.12102.
    1. Perlman JM. White matter injury in the preterm infant: An important determination of abnormal neurodevelopment outcome. Early Hum Dev. 1998;53:99–120. doi: 10.1016/S0378-3782(98)00037-1.
    1. Greisen G, Vannucci RC. Is periventricular leucomalacia a result of hypoxic-ischaemic injury? Hypocapnia and the preterm brain. Biol Neonate. 2001;79:194–200. doi: 10.1159/000047090.
    1. Perlman M, Volpe J. Are venous circulatory abnormalities important in the pathogenesis of hemorrhagic and/or ischemic cerebral injury? Pediatrics. 1987;80:705–711.
    1. Alderliesten T, Dix L, Baerts W, Caicedo A, van Huffel S, Naulaers G, et al. Reference values of regional cerebral oxygen saturation during the first 3 days of life in preterm neonates. Pediatr Res. 2016;79:55–64. doi: 10.1038/pr.2015.186.
    1. Hyttel-Sorensen S, Austin T, van Bel F, Benders M, Claris O, Dempsey E, et al. A phase II randomized clinical trial on cerebral near-infrared spectroscopy plus a treatment guideline versus treatment as usual for extremely preterm infants during the first three days of life (SafeBoosC): study protocol for a randomized controlled tria. Trials. 2013;14:120. doi: 10.1186/1745-6215-14-120.
    1. Riera J, Hyttel-Sorensen S, Bravo MC, Cabañas F, López-Ortego P, Sanchez L, et al. The SafeBoosC phase II clinical trial: an analysis of the interventions related with the oximeter readings. Arch Dis Child Fetal Neonatal Ed. 2016;101:F333–F338. doi: 10.1136/archdischild-2015-308829.
    1. European Medicines Agency, Committee for Human Medicinal Products . Guideline on Good Clinical Practice E6(R2) 2017.
    1. Chan A-W, Tetzlaff JM, Gotzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586. doi: 10.1136/bmj.e7586.
    1. Davidson JO, Wassink G, van den Heuij LG, Bennet L, Gunn AJ. Therapeutic hypothermia for neonatal hypoxic–ischemic encephalopathy – where to from here? Front Neurol. 2015;6:198.
    1. Hansen ML, Pellicer A, Gluud C, Dempsey E, Mintzer J, Hyttel-Sorensen S, et al. Detailed statistical analysis plan for the SafeBoosC III trial: a multinational randomised clinical trial assessing treatment guided by cerebral oxygenation monitoring versus treatment as usual in extremely preterm infants. Trials. 2019;20:746.
    1. 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.
    1. Kleiser S, Ostojic D, Andresen B, Nasseri N, Isler H, Scholkmann F, et al. Comparison of tissue oximeters on a liquid phantom with adjustable optical properties: an extension. Biomed Opt Express. 2018;9:86. doi: 10.1364/BOE.9.000086.
    1. Vermont Oxford Network . Manual of operations: Part 2 data definitions & infant data forms. 2018.
    1. 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.
    1. 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.
    1. 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.
    1. Greisen G, van Bel F. Equipoise is necessary for randomising patients to clinical trials. Acta Paediatr Int J Paediatr. 2016;105:1259–1260. doi: 10.1111/apa.13549.
    1. 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.
    1. Hunter CL, Oei JL, Suzuki K, Lui K, Schindler T. Patterns of use of near-infrared spectroscopy in neonatal intensive care units: international usage survey. Acta Paediatr. 2018;107:1198–1204. doi: 10.1111/apa.14271.
    1. Bevan PJW. Should cerebral near-infrared spectroscopy be standard of care in adult cardiac surgery? Hear Lung Circ. 2015;24:544–550. doi: 10.1016/j.hlc.2015.01.011.
    1. 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.
    1. 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.
    1. 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.
    1. 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.
    1. Anthon CT, Granholm A, Perner A, Laake JH, Møller MH. No firm evidence that lack of blinding affects estimates of mortality in randomized clinical trials of intensive care interventions: a systematic review and meta-analysis. J Clin Epidemiol. 2018;100:71–81. doi: 10.1016/j.jclinepi.2018.04.016.
    1. Hintz SR, Slovis T, Bulas D, Van Meurs KP. Interobserver reliability and accuracy of cranial ultrasound interpretation in premature infants. J Pediatr. 2007;150:592–596. doi: 10.1016/j.jpeds.2007.02.012.
    1. Campbell M. Framework for design and evaluation of complex interventions to improve health. BMJ. 2000;321:694–696. doi: 10.1136/bmj.321.7262.694.
    1. Zwarenstein M, Treweek S, Gagnier JJ, Altman DG, Tunis S, Haynes B, et al. Improving the reporting of pragmatic trials: an extension of the CONSORT statement. BMJ. 2008;337:a2390. doi: 10.1136/bmj.a2390.
    1. Boutron I, Altman DG, Moher D, Schulz KF, Ravaud P. CONSORT statement for randomized trials of nonpharmacologic treatments: A 2017 update and a CONSORT extension for nonpharmacologic trial abstracts. Ann Intern Med. 2017;167:40. doi: 10.7326/M17-0046.
    1. Brierley J, Larcher V. Emergency research in children: options for ethical recruitment. J Med Ethics. 2011;37:429–432. doi: 10.1136/jme.2010.040667.
    1. Beauchamp TL, Childress JF, Press. OU . Principles of biomedical ethics. 7. Oxford: Oxford University Press; 2012.
    1. Mason SA, Allmark PJ. Obtaining informed consent to neonatal randomised controlled trials: interviews with parents and clinicians in the Euricon study. Lancet. 2000;356:2045–2051. doi: 10.1016/S0140-6736(00)03401-2.
    1. Gale C, Juszczak E. A paediatrician’s guide to clinical trials units. Arch Dis Child Educ Pract Ed. 2016;101:265–267. doi: 10.1136/archdischild-2015-310036.
    1. Gale C, Hyde MJ, Modi N. Research ethics committee decision-making in relation to an efficient neonatal trial. Arch Dis Child Fetal Neonatal Ed. 2017;102:F291–F298. doi: 10.1136/archdischild-2016-310935.
    1. Hafström M, Källén K, Serenius F, Maršál K, Rehn E, Drake H, et al. Cerebral palsy in extremely preterm infants. Pediatrics. 2018;141:e20171433. doi: 10.1542/peds.2017-1433.
    1. Roberts G, Anderson PJ, De Luca C, Doyle LW. Changes in neurodevelopmental outcome at age eight in geographic cohorts of children born at 22-27 weeks’ gestational age during the 1990s. Arch Dis Child Fetal Neonatal Ed. 2010;95:F90–F94. doi: 10.1136/adc.2009.165480.
    1. Stanley F, Blair E, Alberman E. Cerebral palsies: epidemiology and casual pathways. Cambridge: Cambridge University Press; 2000.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться