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Steroids in fluid and/or vasoactive infusion dependent pediatric shock: study protocol for a randomized… O’Hearn, Katharine; McNally, Dayre; Choong, Karen; Acharya, Anand; Wong, Hector R; Lawson, Margaret; Ramsay, Tim; McIntyre, Lauralyn; Gilfoyle, Elaine; Tucci, Marisa; Wensley, David; Gottesman, Ronald; Morrison, Gavin; Menon, Kusum May 6, 2016

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STUDY PROTOCOL Open AccessSteroids in fluid and/or vasoactive infusiondependent pediatric shock: study protocolfor a randomized controlled trialKatharine O’Hearn1*, Dayre McNally1,2, Karen Choong3, Anand Acharya4, Hector R. Wong5, Margaret Lawson1,2,Tim Ramsay6,7, Lauralyn McIntyre8, Elaine Gilfoyle9, Marisa Tucci10, David Wensley11, Ronald Gottesman12,Gavin Morrison13, Kusum Menon1,2 and On behalf of the Canadian Critical Care Trials GroupAbstractBackground: Physicians often administer corticosteroids for the treatment of fluid and vasoactive infusiondependent pediatric shock. This use of corticosteroids is controversial, however, and has never been studied in apediatric randomized controlled trial (RCT). This pilot trial will determine the feasibility of a larger RCT on the role ofcorticosteroids in pediatric shock.Methods/design: Steroids in Fluid and/or Vasoactive Infusion Dependent Pediatric Shock (STRIPES) is a pragmatic,seven-center, double-blind, pilot RCT. We aim to randomize 72 pediatric patients with fluid and vasoactive infusiondependent shock to receive either hydrocortisone or a saline placebo for 7 days or until clinical stability, whicheveroccurs first. The primary outcome of this pilot trial is the feasibility of recruitment, defined as the number ofpatients enrolled over a 1-year period. Secondary outcomes include the frequency of, and reasons for, open-labelsteroid use, protocol adherence, incidence of mortality and corticosteroid-associated adverse events, time todiscontinuation of inotropes, and feasibility of blood sampling.Discussion: Corticosteroids are used for the treatment of pediatric shock without sufficient evidence to supportthis practice. While there is a scientific rationale and limited data supporting their use in this setting, there is alsoevidence from other populations suggesting potential harm. The STRIPES pilot study will assess the feasibility of alarger, much needed trial powered for clinically important outcomes.Trial registration: ClinicalTrials.gov: NCT02044159BackgroundFluid and vasoactive infusion dependent shock is acritical form of cardiovascular failure affecting approxi-mately 20,000 North American children annually. Thisform of severe shock results in approximately 5 % ofpediatric intensive care unit admissions [1] and may leadto multi-organ failure with significant morbidity [2, 3]and a 2–10 % mortality rate [4, 5]. The role of cortico-steroids in pediatric patients with severe septic shockwho are not responding to fluids and vasoactive infu-sions has been widely debated for more than 40 years,and current clinical research evidence neither supportsnor refutes this practice [6, 7].The American College of Critical Care Medicine statesthat “fluid and vasoactive infusion dependent shockresults from inadequate cellular corticosteroid activityfor the severity of the patient’s illness” [8]. This condi-tion has been referred to as “relative adrenal insuffi-ciency” or “critical illness related adrenal insufficiency”[9, 10] and is a complex condition resulting from avariety of mechanisms, making it challenging to defineand diagnose [10, 11]. Lack of sufficient cortisol leads tohemodynamic instability through decreased myocardialcontractility, increased vasodilatation, and/or capillaryleak syndrome [12, 13]. Thus, there is some scientificrationale for corticosteroid use in this population;* Correspondence: kohearn@cheo.on.ca1Research Institute, Children’s Hospital of Eastern Ontario, Ottawa, CanadaFull list of author information is available at the end of the article© 2016 O’Hearn et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.O’Hearn et al. Trials  (2016) 17:238 DOI 10.1186/s13063-016-1365-6however, the small numbers of observational studies andrandomized controlled trials on this subject have reportedconflicting conclusions.Eight small randomized controlled trials (RCTs) ofcorticosteroids in pediatric shock have included a totalof 489 patients [2, 3, 14–19]. Each study enrolled fewerthan 100 patients and had methodological limitations,and all were conducted in developing nations with afocus on dengue shock. Two studies demonstrated amortality benefit from corticosteroids in dengue shocksyndrome [14, 18], and the remaining trials were notadequately powered to determine the effect of cortico-steroids on clinically relevant outcomes. None of thetrials were conducted since the publication of the Sur-viving Sepsis Campaign guidelines [20], making themdifficult to interpret in the context of current shock man-agement. Additionally, heterogeneity in steroid agents,dosing regimens, and duration of therapy make interstudycomparisons difficult. Similarly, the two largest RCTsconducted involving critically ill adults also demonstratedcontradictory results [21, 22].The potential adverse effects of corticosteroids inpediatric shock have not been rigorously evaluated. Re-cent observational studies suggest that corticosteroidtherapy in this population may increase hyperglycemiaand secondary infections, suppress adaptive immunity,and increase mortality [23–25]. An adult RCT also sug-gested an increase in secondary infections and mortalitywith the use of corticosteroids in shock [21].Given the poor methodological quality of the existingpediatric RCTs, the variability of administration proto-cols studied, contradictory results from adult trials, andthe lack of information on potential adverse effects, ithas been difficult to develop evidence-based guidelinesfor steroid use in critically ill children with fluid andvasoactive infusion dependent shock. Hydrocortisone isthe most commonly used corticosteroid in large ran-domized controlled shock trials [21, 22] and is currentlythe most commonly used corticosteroid for treatment ofpediatric shock [26]. However, the management of thesepatients remains highly variable with many critical carephysicians having strongly held beliefs both for andagainst steroid use [27, 28].We therefore propose a pragmatic, parallel group,randomized, placebo-controlled pilot trial of hydrocorti-sone for the treatment of pediatric fluid and vasoactiveinfusion dependent shock. The specific objectives of theSTRIPES (Steroids in Fluid and Vasoactive InfusionDependent Pediatric Shock) pilot study are to estimatethe rate of patient recruitment and understand barriersto recruitment, assess the appropriateness of our eligibil-ity criteria for a full trial, assess adherence to the treat-ment protocol, and assess the feasibility of collectingand shipping blood samples.Methods/designThis protocol adheres to the Standard Protocol Items:Recommendations for Interventional Trials (SPIRIT)checklist (see checklist, Additional file 1). A summary ofthe protocol is provided in Table 1.Study settingThe STRIPES pilot study will recruit patients from theemergency department (ED), pediatric ward, and/orpediatric intensive care unit (PICU) of seven academicpediatric centers in Canada (a list of participating studysites is available on ClinicalTrials.gov).Patient enrollmentICU-based clinical research assistants will screen pediatricICU patients for eligibility criteria which include being apatient with fluid and vasoactive infusion dependent shockwho has received inotropic support for at least 1 h, and nomore than 6 h, within their first 24 h of PICU admission.This short period for recruitment is necessary as shock isa progressive process characterized by an early compen-sated phase in which adaptive mechanisms maintainblood pressure and tissue perfusion, an uncompensatedphase where these mechanisms fail but the patient maystill respond to therapeutic interventions, and a final irre-versible stage where shock progresses to permanent organand tissue injury and even death [29]. It is critical that anypotential therapy, including corticosteroids, be providedearly, which is why we have chosen a 6-h cut-off forenrollment. The rationale for this time window thereforeis to enroll patients early in shock when steroids may havethe potential to prevent or reverse end-organ injury, priorto the stage of advanced or irreversible shock. The detailedinclusion and exclusion criteria are summarized in Table 2.Eligible patients will be identified in the ED and PICU bynurses, attending physicians, and trainees at participatingsites at the time the patient is started on a vasoactive agent(see Fig. 1 for the protocol flow diagram).ConsentThe initial resuscitation of a pediatric patient is a highlystressful situation during which parents are often unableto contemplate involvement in a research trial and/ormay not be available within the time frame required by agiven study. Therefore, as per the Canadian Tri-Councilguidelines [30], we will be seeking deferred consentthrough the Research Ethics Board (REB) applications.Informed consent will be obtained from the legal guardianof all patients; however, when the deferred consent modelis employed, informed consent will be obtained followingenrollment. Using this model, children will be enrolledand randomized when they are determined to be eligiblefor the study. A member of the local study team willapproach the legal guardian for written informed consentO’Hearn et al. Trials  (2016) 17:238 Page 2 of 10to continue study participation as soon as possible afterenrollment. If consent is obtained, the patient will remainin the study. If consent is denied, the legal guardian andpatient will be provided the option of having patient dataand the blood sample destroyed. In centers where adeferred consent model is not approved by the REB,informed consent will be sought from the legal guardianin writing or by telephone, after which the patient will beenrolled and randomized. Legal guardians may provideconsent for data collection and drug administration withor without blood sampling.RandomizationRandomization will employ a password-protected, web-based system. Patients will be randomized in a 1:1 ratiousing random variable block sizes (2–4 patients/block),and randomization will be stratified by site to accountfor site-specific practice variation. The randomizationsystem will assign each randomized patient a uniquestudy ID number. The site pharmacist will match theID number to a treatment arm on a hard-copyrandomization list and dispense the appropriate treat-ment. At sites where a research pharmacist is notTable 1 World Health Organization trial registration data set: structured summaryData category InformationPrimary registry, trial identifying number ClinicalTrials.gov identifier NCT02044159Date of registration in primary registry January 21, 2014Secondary identifying numbers CHEO REB 14/05EProtocol version Version 5, May 7, 2015Sources of monetary support Canadian Institutes of Health Research Operating GrantPrimary sponsor Investigator-initiated studyKusum Menon (KM)Children’s Hospital of Eastern Ontario401 Smyth RoadOttawa, OntarioK1H 8 L1Phone: 613-737-7600 ext. 2538Email: menon@cheo.on.caSecondary sponsor Children’s Hospital of Eastern Ontario Research InstituteContact for public queries KM, Pediatric Critical Care, Children’s Hospital of Eastern Ontario, Ottawa, CanadaContact for scientific queries KM, Pediatric Critical Care, Children’s Hospital of Eastern Ontario, Ottawa, CanadaPublic title Steroids in Fluid and Vasoactive Infusion Dependent Shock (STRIPES) pilot studyScientific title Steroids in Fluid and Vasoactive Infusion Dependent Shock (STRIPES) pilot studyCountry of recruitment Canada, multi- academic center (7) studyHealth problem under investigation Efficacy and safety of hydrocortisone as a treatment of fluid and vasoactive infusion dependent shockKey inclusion and exclusion criteria Eligible for study: started on a vasoactive infusion within 24 h of PICU admissionInclusion criteria: newborn to 17 years of age, receiving vasoactive infusions for 1–6 hExclusion criteria: known or suspected hypothalamic, pituitary or adrenal disease; currently receivingsteroids for shock prior to randomization; are expected to have treatment withdrawn; post cardiacsurgery; primary cardiogenic shock, spinal shock, hemorrhagic, or hypovolemic shock provenor strongly suspected; previously enrolled in the STRIPES study; steroids started for reasons otherthan shock; no longer on inotropes at the time of randomization or first dose of study drug; orphysician refusalStudy type Pragmatic, multi-center, double-blind, pilot randomized controlled trialDate of first enrollment September 4, 2014Target sample size 72Recruitment status Recruiting as of July 2014Primary outcome Patient accrual rate over a 1-year recruitment periodKey secondary outcomes Adherence to the study protocol; frequency of open-label corticosteroid use and the clinicalcharacteristic of patients in whom open-label corticosteroids are used; incidence of mortalityand adverse events; time to discontinuation of inotropes; and the feasibility of mechanisticblood samplingO’Hearn et al. Trials  (2016) 17:238 Page 3 of 10available on evenings and weekends, numbered medica-tion kits will be accessible to research assistants in atemperature-controlled refrigerator.Allocation concealment and blindingAll study personnel (the overall study research coordin-ator, research assistants, site investigators, Principal Inves-tigator, co-investigators, data management personnel, andstatisticians), members of the health care team (treatingphysicians, bedside nurses, and clinical pharmacists if dif-ferent from the research pharmacist), and patients/familieswill be blinded to the study group assignment. To main-tain blinding, the randomization lists will only be access-ible to the Methods Centre at the Ottawa HospitalResearch Institute and to the site pharmacies. The activedrug and the placebo (hydrocortisone and normal saline)will be identical in appearance, volume, and smell ashydrocortisone is made up in normal saline and dissolvescompletely with no visible precipitate.Study procedures are in place to address the possibilityof requests by treating physicians to unblind group allo-cation for a particular patient. The treating physicianwill notify the site investigator, who will ask the phar-macy to reveal to which group the patient has been allo-cated. We expect that the request to unblind patientswill be minimal as treating physicians will be permittedto use open-label corticosteroids if they judge that this isclinically necessary.InterventionsPatients randomized to the hydrocortisone group willreceive a 2-mg/kg hydrocortisone intravenous (IV) bolusat the time of enrollment followed by 1 mg/kg of hydro-cortisone administered intravenously every 6 h (q6h)until the patient has not had an escalation in therapy (asdefined by an increase in their vasoactive infusions or afluid bolus such as normal saline, Ringer’s lactate, albu-min, or any other blood product) for at least 12 h. Oncethese criteria are met, hydrocortisone will be reduced to1 mg/kg every 8 h and continue at this frequency untilall vasoactive infusions have been discontinued for 12 h.The weaning of hydrocortisone from q6h to q8h isimportant in order to ensure the patient receives theminimum amount of corticosteroid that is necessary forhemodynamic stability so as to prevent adrenal suppres-sion and potential adverse events. If, following the initialhydrocortisone wean, the patient requires fluid bolusesand/or an increase in their vasoactive infusion(s), thedosing frequency will return to every 6 h until the pa-tient meets stability criteria again. Hydrocortisone willbe continued for a maximum of 7 days to minimize theincidence of adrenal suppression. In keeping with thepragmatic nature of this trial, all other patient man-agement, including (but not limited to) use of intub-ation, mechanical ventilation, sedation and analgesia,hemodynamic triggers and endpoints, red cell transfu-sions, antibiotics, and fluid boluses, will be left to thediscretion of the treating physician. The SurvivingSepsis Campaign guidelines flowchart (see [31]) willbe attached to the study protocol for easy referenceby the treating physician, but its use will not bemandated; however, the use of vasoactive infusionsand other therapies will be recorded.Although we will discourage physicians from usingopen-label corticosteroids and carefully record any suchoccurrence, we will not refer to open-label use as aprotocol violation so as not to deter enrollment and toencourage buy-in. In the event that the patient does notreceive the full treatment as per protocol, data collectionwill continue.Patients in the control group will receive a placeboconsisting of normal saline equivalent in volume to theappropriate dose of hydrocortisone. The remainder ofthe protocol will be as per the experimental group.Blood samplingAlthough the primary focus of this pilot study is todetermine the feasibility of conducting a clinical outcome-based RCT of hydrocortisone versus placebo in shock, thispilot also provides an excellent opportunity to performsome exploratory mechanistic studies. Given the expertiseof our team, the specific substudies we chose to conductinclude the utility of free cortisol versus total cortisolTable 2 STRIPES pilot study inclusion and exclusion criteriaInclusion criteria1. Children newborn to 17 years and on any dose of any vasoactiveinfusion for between 1 to 6 hExclusion criteria1. Known or suspected hypothalamic, pituitary, or adrenal disease2. Currently receiving steroids for shock prior to randomization3. Expected to have life support withdrawn4. Premature infants (<38 weeks corrected gestational age)5. Pregnancy6. Post cardiac surgery7. First dose of vasoactive infusion administered >24 h after PICUadmission8. No longer on vasoactive infusion at time of enrollment and/orexpected to no longer be on vasoactive infusion at time first doseof study drug due9. Primary cardiogenic shock suspected or proven10. Spinal shock suspected or proven11. Hemorrhagic or hypovolemic shock suspected or proven12. Previously enrolled in STRIPES13. Started on vasoactive infusion for reasons not related to shock14. Physician refusalO’Hearn et al. Trials  (2016) 17:238 Page 4 of 10Patient in shock within 24 hours of PICU admissionInotropes initiatedPatient on inotropes for ≥1 hour and ≤6hoursPatient screened for eligibility to determine if any exclusion criteria are presentExclusion criteria presentPatient not eligibleNo exclusion criteria presentPatient is eligibleDeferred consent model used Consent to continue in study sought as soon as possible If denied, patient is withdrawnDeferred consent model not used Informed consent sought from legal guardianConsent deniedPatient not eligible for randomizationPatient randomized within 6 hours of initiation of inotropesConsent obtainedHydrocortisone 2mg/kgwithin 8 hours of initiation of inotropesPlacebo equivalent volumewithin 8 hours of initiationof inotropesHydrocortisone 1mg/kgq6h until there has been no escalation in therapy for at least 12 hoursPlacebo equivalent volumePlacebo equivalent volume Hydrocortisone 1mg/kgq8h until patient has been off inotropes for at least 12 hoursIf access for bloodwork or venipuncture done as part of clinical care, then send blood for:• Free cortisol and total cortisol• Stratification biomarkers• 25OHD and 1,25 OHDIf access not available, but becomes available within 24 hours ofenrolment then send the last two samplesD/C study drugFig. 1 Protocol flow diagram for the STRIPES pilot studyO’Hearn et al. Trials  (2016) 17:238 Page 5 of 10measurements, the ability of stratification biomarkers topredict severity of illness, and the interaction betweenthe adrenal and vitamin D axes. More detail on thesesubstudies is provided in Additional file 2. Patientswith existing venous or arterial access and who areundergoing a venipuncture for clinical blood workbefore the first dose of study drug will have a bloodsample sent for analysis of free cortisol and totalcortisol, mortality risk stratification biomarkers, 25-hydroxyvitamin D, and 1,25-hydroxyvitamin D. If accessfor bloodwork is not available before the study drug isinitiated, but it becomes available within the first 24 h ofenrollment, a research sample will be sent for analysisof stratification biomarkers, 25-hydroxyvitamin D, and1,25-dihydroxyvitamin D only.OutcomesThis is a pilot study; hence, the primary outcome isfeasibility, defined by accrual rate over 1 year. Our goalis to recruit 72 patients within this time frame. However,we will consider patient accrual to be adequate if werecruit 60 patients from seven sites within 1 year. Wewill also assess potential barriers to recruitment, includ-ing lack of a deferred consent model, physician- andguardian-related consent issues, availability of researchpersonnel, and the narrow recruitment window (6 hfrom the initiation of vasoactive infusion). The second-ary outcomes are summarized in Table 3; they includethe frequency of open-label steroid use, adverse eventsrelated to corticosteroid use, time to discontinuation ofvasoactive infusions, incidence of mortality, and thefeasibility of blood sampling.An RCT design is necessary to investigate our feasibil-ity outcomes. The main goal of our study is to determinethe feasibility of conducting an RCT of hydrocortisoneversus placebo in pediatric septic shock as determinedby our ability to recruit patients into this trial. Therewere several issues with potential recruitment that weidentified a priori that could only be tested through apilot RCT. Firstly, we identified that some centers couldhave issues with recruiting patients into such a trial be-cause they wished to administer steroids. Thus, determin-ing whether or not they will actually randomize patients isof paramount importance. Secondly, the study has a verynarrow recruitment window; therefore, we need to deter-mine whether or not sites can randomize patients, obtainthe study drug, and administer the first dose within 8 h ofpatient eligibility. This can only be tested by piloting therandomization procedures. Finally, we are proposing anovel deferred consent model for obtaining informedconsent. It will be very important to understand theacceptability of this model for families in the context of arandomized double-blind controlled trial.A randomized controlled trial design is also necessaryto determine if physicians will administer open-labelsteroids to patients if they worsen. It would be importantto determine if the use of open-label steroids would bedifferent between the two groups: Does early administra-tion of steroids lead to physiologic improvements thatremove the necessity for open-label steroids?Sample sizeBased on data from our multi-center retrospective study,we expect to enroll 72 patients. This target takes intoaccount the frequency of septic shock at each center,along with the projected consent rate at each center.This target number will: (1) allow us to assess our feasi-bility objectives over a reasonable time period (1 year),(2) allow each center to recruit between 6 and 24patients, and (3) allow us to test the acceptability of oureligibility criteria as well as open-label steroid use atseven sites and with exposure to 50 different clinicians.Given that this is a pilot study, we will consider recruit-ment to be feasible if we achieve 80 % (60 patients) of ourtarget enrollment, a threshold commonly used in criticalcare pilot studies. With 60 patients, we will have theTable 3 Secondary outcomes for the STRIPES pilot studyOutcome Metric for analysisAdherence to the protocol: We will consider adherence adequate if each of goals a through c is met in 80 %of enrolled patients:a. Time to administration of the first dose of study drugb. Weaning of drug to q8h when hemodynamically stablec. Discontinuation of drug when off all vasoactive infusionsa. Goal is <8 h from starting vasoactive medicationb. Goal is to wean within 12 h of no escalation of therapyc. Goal is to discontinue between 12 and 18 h after vasoactive infusion stoppedOpen-label steroid use We will consider the number of patients started on open-label steroids to beacceptable if it occurs in <10 % of patientsClinical outcomes:a. Adverse eventsb. Clinical endpointsa. Severe bleeding, secondary infections, and use of insulin infusionsb. Time to discontinuation of vasoactive infusion and incidence of mortalitySuccessful blood sampling and processing The percentage of patients from whom blood samples are sentThe percentage of samples sent that are successfully received and analyzed in theirrespective labsO’Hearn et al. Trials  (2016) 17:238 Page 6 of 10ability to detect an adherence rate of 80 ± 10 % (meaning80 ± 10 % of study patients will have fewer than 10 %of monitored values as violations). The median timeto discontinuation of vasoactive agents observed inthis pilot study will be used to better estimate thesample size needed for the full RCT.Recruitment, compliance, and follow-upAll ED and PICU staff will be made aware of the studythrough information sessions, posters in the ED andPICU, weekly rounds with the research assistants, andweekly emails. Monthly recruitment newsletters will besent to all sites to encourage enrollment and discusscommonly encountered questions.Compliance is likely to be high as the protocol issimple and closely follows usual clinical practice in thesepatients. This assumption is based on experience fromthe Vasopressin in Pediatric Shock (VIP) study, whichrandomized children in vasodilatory shock to vasopres-sin or placebo and used many of the same sites andinvestigators as our current proposal. Despite utilizing amore complex protocol and recruiting sicker patients,the VIP trial had only two protocol violations and wassuccessfully completed [32]. It is possible that open-labelcorticosteroid use will be higher than the anticipated10 % rate. However, we will collect specific data on thecircumstances in which this occurs in order to providemore targeted education around this practice in the fulltrial. Follow-up for the STRIPES pilot study ends athospital discharge or death. Therefore, we anticipate afollow-up rate of 100 %.Data collection and managementData for each patient will be entered by trained researchassistants at each site and managed using an electronicdata capture tool, REDCap (Research Electronic DataCapture), which will be hosted at the Children’s Hospitalof Eastern Ontario (CHEO) Clinical Research Unit [33].REDCap is a secure, web-based application designed tosupport data collection for research studies. Predefinedranges for all data values will be set up in this applica-tion to allow data entry personnel to validate data assoon as it is entered and send data queries immediately.Missing data will be similarly managed. For each en-rolled patient, we will collect information from theirmedical chart. Data will be entered into the case reportform (CRF, available on the STRIPES study website athttp://stripes.ccctg.ca/Home.aspx), and each record willbe identified only by study ID number to maintainpatient confidentiality. The following information will becollected: demographic information, inotrope use, dur-ation of mechanical ventilation, PRISM III and PELOD-2 scores, insulin infusion use, gastrointestinal bleeding,laboratory results, and basic resource utilization data.Research assistants at each site will maintain a dailypaper screening log which will track every patient who isstarted on a vasoactive infusion within their first 24 h ofPICU admission. When eligible patients are not enrolled,we will classify the reason for non-enrollment as: (1)refusal from patient and/or legal guardian (specifyingreason for refusal, if provided); (2) inability to contactlegal guardian in centers without deferred consent (spe-cifying reason contact could not be made, if available);(3) refusal from attending physician (specifying reasonfor refusal); (4) lack of availability of the research assist-ant; and (5) patient died before enrollment. We will alsorecord age, gender, and PRISM III scores for thesepatients to determine if there are demographic differencesbetween eligible patients who are and are not enrolled. Adata management plan has been developed for the studyand is available on the STRIPES study website.Statistical analysisTo meet the feasibility objectives of this pilot RCT, wehave planned descriptive analyses. We will present recruit-ment rate, feasibility events, and open-label corticosteroiduse as proportions with 95 % confidence intervals. Re-cruitment feasibility will be defined as achieving 80 % ofour target goal of 72 patients. We will present continuousdata as means and standard deviations, or medians andinterquartile ranges, as appropriate. Patients who arerandomized but withdraw or do not provide consent willbe analyzed using intention to treat if they providedconsent to keep their data.MonitoringThe Data Monitoring and Safety Committee (DMSC) willinclude a senior biostatistician, a pediatric endocrinologist,and a pediatric intensive care specialist. The DMSC willreview all serious adverse events (SAEs) — any seriousevents that the attending site intensivist believes may bedirectly related to enrollment in this trial. Study sites willreport all SAEs to the Coordinating Center within 24 h ofbecoming aware of the event. The site will fill out a SAEreport and provide any related clinical documentation(de-identified) to the Coordinating Center for distributionto the Principal Investigator and the DMSC chair. TheDMSC chair will determine whether immediate inputfrom other DMSC members is required before sendingthe final DMSC determination to the Principal Investi-gator. There will be no stopping rules; however, theDMSC can make recommendations to the PrincipalInvestigator, who will communicate back to the Steer-ing Committee at the end of the trial regarding anysafety concerns for the full trial. We will provide theDMSC with analyses by group (blinded as group A and B)at the completion of this pilot RCT. These analyses willinclude relative rates of gastrointestinal bleeding,O’Hearn et al. Trials  (2016) 17:238 Page 7 of 10infections, and hospital mortality. Due to the small samplesize and short duration of this pilot trial, we have notplanned for any interim analyses.The study coordinator will monitor the sites at studyinitiation, midway through the recruitment period, andat study close-out to ensure compliance with the proto-col and to troubleshoot any barriers to recruitment. Dataentered into the electronic CRF will be verified on anongoing basis, and the Data Quality function in REDCapwill be used to send and resolve data queries whererequired. Given the pilot nature of this study, a formalaudit of the trial will not be conducted.EthicsResearch ethics board approval has been obtained from allparticipating centers. Protocol amendments will be com-municated as necessary to those involved with the study.An application for deferred consent was approved at fivesites (Ottawa, Vancouver, Calgary, Hamilton, and Halifax).Deferred consent was not possible in Quebec as perprovincial legislation. The study protocol was approved bythe following ethics review boards: the Children’s Hospitalof Eastern Ontario Research Ethics Board, Ottawa, On-tario (reference number: 14/05E); the Hamilton IntegratedResearch Ethics Board, Hamilton, Ontario (referencenumber: 14–636); Comité d’éthique de la recherche àCHU Sainte-Justine, Montreal, Quebec (reference num-ber: 3990); the Montreal Children’s Hospital Research Eth-ics Board, Montreal, Quebec (reference number: 14-121-PED); the Conjoint Health Research Ethics Board of theUniversity of Calgary, Calgary, Alberta (reference number:REB14-0606); the University of British Columbia Chil-dren’s and Women’s Research Ethics Board, Vancouver,British Columbia (reference number: H14-01109); andthe IWK Research Ethics Board in Halifax, Nova Scotia(reference number: 1017182).Close-outAll data and source documentation will be stored ina locked, secure storage facility for 25 years fromthe time of study close-out. The study drug will bedestroyed and reconciled at each site according tothe procedures of the site pharmacy. Only the Prin-cipal Investigator, the research coordinator, or theirdelegate will have access to the data once the studyis closed.DiscussionWe recently published a systematic review [6] on theuse of corticosteroids in pediatric shock. The reviewconcluded that “The literature on the use of steroids inpediatric shock is limited in amount, methodologicalquality and demonstrates conflicting results. The limitedevidence on which current guidelines are based stronglysupports the need for a well-designed, pragmatic ran-domized controlled trial on the use of steroids inpediatric shock to inform future guidelines.” There aretwo small RCTs currently listed on www.clinicaltrials.gov(NCT01047670, NCT00732277); however, neither studyhas been updated since 2010. Given their size andunclear recruitment status, it is unlikely that either ofthe latter two trials will be able to answer the ques-tion of whether corticosteroids improve outcomes inpediatric shock.This study is the first step towards a large RCT toprovide clarity on the use of corticosteroids in criticallyill children with shock. Results of the STRIPES pilotstudy will provide essential feasibility data for planningand conducting a larger, multi-center trial that will helpto establish the role of corticosteroids in children withfluid and vasoactive infusion dependent shock. Our goalis to enroll a minimum of 60 patients at seven sites overa 1-year period. Failure to do so will prompt us tomodify our plans for a future trial. If our recruitmentrate is as anticipated or better, we will not modifyeligibility criteria. If our recruitment rate is marginal(that is, barely achieves our goals), we will examine thenumber of patients excluded on the basis of each exclu-sion criterion, and will reconsider the necessity for anycriterion that has resulted in a large number of excludedpatients. We will record the number of eligible non-randomized patients and reasons for non-enrollment,and on the basis of these results, we will consider deter-rents to randomization and methods to enhance enroll-ment of eligible patients. If the pilot study demonstratesfeasibility, no major protocol changes are needed, andno safety concerns are raised by the STRIPES DMSC,then the results of the pilot study will be rolled intothe full trial. However, if any of the above criteria arenot met, then the protocol will be re-evaluated andthe feasibility results of the pilot study publishedindependently.Trial statusRecruitment for the STRIPES pilot study started atthe Coordinating Centre (Children's Hospital of East-ern Ontario, Ottawa) in July 2014. Four of the sixother Canadian PICUs initiated recruitment betweenDecember 2014 and February 2015. The remainingtwo sites will commence recruitment in July of 2015and in the fall of 2015, respectively. The first patientwas enrolled on September 4, 2014, and recruitment isexpected to continue until March of 2016.Additional filesAdditional file 1: SPIRIT Checklist. (DOC 143 kb)O’Hearn et al. Trials  (2016) 17:238 Page 8 of 10Additional file 2: Summary of mechanistic studies. This tablesummarizes the mechanistic studies that will be performed as part of theSTRIPES pilot study, including the rationale, timing, and amount of bloodsample required for each test. (PDF 202 kb)AbbreviationsDMSC: Data Monitoring and Safety Committee; ED: emergency department;IV: intravenous; PELOD: pediatric logistic organ dysfunction; PICU: pediatricintensive care unit; PRISM: pediatric risk of mortality; RCT: randomizedcontrolled trial; REB: Research Ethics Board; STRIPES: Steroid Use in Fluid andVasoactive Infusion Dependent Shock; VIP: Vasopressin in Pediatric Shock.Competing interestsThe authors declare that they have no competing interests. The studysponsors and funders were not involved in the study design, collection,or management. There are no contractual agreements that limit accessfor the investigators.Authors’ contributionsKO contributed significantly to the study design, data management andcollection, ethics considerations, and implementation strategies, and draftedthe manuscript (Study Coordinator, Coordinating Center). DM (SteeringCommittee member) was involved in development of the concept, studydesign, sample size calculation, and ancillary studies. KC (Steering Committeemember) contributed to development of the concept, study design,outcomes, refining of the intervention, and deferred consent process. AAhad significant input into the study design, the economic evaluation, anddata required to be collected. HW (Steering Committee member) helped todevelop the concept, study design, ancillary studies, and outcomes. ML(Steering Committee member) contributed significantly to the study design,development of the intervention, definition of adverse events, and datamonitoring. TR (Steering Committee member) contributed significantly tosample size calculation, statistical analysis proposal, randomization processes,and blinding. LM (Steering Committee member) contributed to the studydesign, patient recruitment strategies, and development of the feasibilityoutcomes. EG contributed to the development of the intervention and theoutcomes and to refinement of the deferred consent process. MT wasinvolved in the study design, implementation strategies, and the consentprocess. DW was involved in the study design, data collection andmanagement, and the consent process. RG was involved in development ofthe feasibility objectives, data collection and management, andimplementation strategies. GM was involved in implementation strategiesand the consent process. KM (Steering Committee member) significantlycontributed to the study design, development of the intervention, outcomes,sample size calculation, data collection and management, and developmentand implementation of the deferred consent process. All authors wereinvolved in the review of this manuscript and have seen and are inagreement with the final manuscript.AcknowledgementsThis work is supported by an Operating Grant from the Canadian Institutesof Health Research. The authors wish to thank the Canadian Critical CareTrials Group members and the Grant and Manuscript Review Committeemembers (Jennifer Foster and Maureen Meade) for their valuable appraisal.In addition, the authors are grateful to the research assistants andcoordinators at all participating sites.Financial supportFinancial support was provided by a Canadian Institutes of Health Research(CIHR) Operating Grant from CIHR, Ottawa, Ontario, Canada.Author details1Research Institute, Children’s Hospital of Eastern Ontario, Ottawa, Canada.2Department of Pediatrics, Faculty of Medicine, University of Ottawa,Children’s Hospital of Eastern Ontario, Ottawa, Canada. 3McMaster Children’sHospital, McMaster University, Hamilton, Canada. 4Department of Economics,Faculty of Public Affairs, Carleton University, Ottawa, Canada. 5CincinnatiChildren’s Hospital Medical Center, University of Cincinnati College ofMedicine, Cincinnati, USA. 6Department of Epidemiology, University ofOttawa and Ottawa Hospital Research Institute (OHRI), University of Ottawa,Ottawa, Canada. 7Clinical Epidemiology Program, The Ottawa HospitalResearch Institute (OHRI), Ottawa, Canada. 8Department of Medicine (Divisionof Critical Care), Ottawa Hospital Research Institute (OHRI), University ofOttawa, Ottawa, Canada. 9Section of Critical Care Medicine, Department ofPediatrics, Alberta Children’s Hospital, Calgary, Canada. 10Department ofPediatrics, CHU Sainte-Justine Hospital, Montreal, Canada. 11Department ofPediatrics, Faculty of Medicine, The University of British Columbia, BritishColumbia Children’s Hospital, Vancouver, Canada. 12Department of Pediatrics,Faculty of Medicine, McGill University, Montreal Children’s Hospital, Montreal,Canada. 13Department of Critical Care Medicine, IWK Health Centre, Halifax,Canada.Received: 29 September 2015 Accepted: 27 April 2016References1. 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Researchelectronic data capture (REDCap)—a metadata-driven methodology andworkflow process for providing translational research informatics support.J Biomed Inform. 2009;42(2):377–81.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:O’Hearn et al. Trials  (2016) 17:238 Page 10 of 10


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