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Intrapleural Dornase and Tissue Plasminogen Activator in pediatric empyema (DTPA): a study protocol for… Livingston, Michael H; Mahant, Sanjay; Ratjen, Felix; Connolly, Bairbre L; Thorpe, Kevin; Mamdani, Muhammad; Maclusky, Ian; Laberge, Sophie; Giglia, Lucy; Walton, J. M; Yang, Connie L; Roberts, Ashley; Shawyer, Anna C; Brindle, Mary; Parsons, Simon J; Stoian, Cristina A; Cohen, Eyal Jun 24, 2017

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STUDY PROTOCOL Open AccessIntrapleural Dornase and TissuePlasminogen Activator in pediatricempyema (DTPA): a study protocol for arandomized controlled trialMichael H. Livingston4, Sanjay Mahant1, Felix Ratjen1, Bairbre L. Connolly1, Kevin Thorpe2,3, Muhammad Mamdani3,Ian Maclusky5, Sophie Laberge6, Lucy Giglia4, J. Mark Walton4, Connie L. Yang7, Ashley Roberts7, Anna C. Shawyer8,Mary Brindle8, Simon J. Parsons8, Cristina A. Stoian8 and Eyal Cohen1*AbstractBackground: A randomized controlled trial of adults with empyema recently demonstrated decreased length ofstay in hospital in patients treated with intrapleurally administered dornase alfa and fibrinolytics compared tofibrinolytics alone. Whether this treatment strategy is safe and effective in children remains unknown.Methods/design: This study protocol is for a superiority, placebo-controlled, parallel-design, multicenterrandomized controlled trial. The participants are previously well children admitted to a children’s hospital with adiagnosis of empyema requiring chest tube insertion and fibrinolytics administered intrapleurally. Children will berandomized after the treating physician has decided that pleural drainage is required but prior to chest tubeinsertion. After chest tube insertion, participants in the treatment group will receive intrapleurally administeredtissue plasminogen activator (tPA) 4 mg followed by dornase alfa 5 mg. Participants in the placebo group willreceive tPA 4 mg followed by normal saline. Study treatments will be administered once daily for 3 days. Allparticipants, parents or caregivers, clinicians, and research personnel will remain blinded. The primary outcome islength of stay from chest tube insertion to discharge from hospital. Secondary outcomes include time to meetingdischarge criteria, chest tube duration, fever duration, need for additional procedures, adverse events, hospitalreadmission, cost of hospitalization, and mortality.Discussion: This multicenter randomized controlled trial will assess the safety, effectiveness, and cost-effectivenessof combined treatment with dornase alfa and fibrinolytics compared to fibrinolytics alone for the treatmentof empyema in children.Trial registration: ClinicalTrials.gov: NCT01717742. Registered on 8 October 2012.Keywords: Empyema, Children, Chest tubes, Fibrinolytic agents, Randomized controlled trial* Correspondence: eyal.cohen@sickkids.ca1The Hospital for Sick Children, Department of Pediatrics, University ofToronto, 555 University Avenue, Toronto, ON M5G 1X8, CanadaFull list of author information is available at the end of the article© The Author(s). 2017 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.Livingston et al. Trials  (2017) 18:293 DOI 10.1186/s13063-017-2026-0BackgroundPneumonia is one of the most common reasons forchildren to be admitted to hospital and accounts formore inpatient costs than any other diagnosis outsideof the newborn period [1, 2]. Up to 50% of these pa-tients have an associated parapneumonic effusion [2].Most are small and uncomplicated and will resolvewith antimicrobial treatment of the underlying infec-tion. In some cases, however, a complicated effusioncan develop, leading to respiratory compromise and/or extensive loculations. Such effusions, commonly re-ferred to as pleural empyema, lead to substantialmorbidity, including respiratory distress, pain, andprolonged hospitalization, as well as child school loss,parental work loss, and stress on families. Over thepast few decades, there has been a dramatic increasereported in the incidence of pediatric pleural empy-ema in multiple countries [3–11]. More recent datafrom Scotland suggests that since 2010, the incidence ofempyema may have begun to fall, possibly due to theintroduction of a 13-valent pneumococcal vaccine [12].Published clinical practice guidelines support the useof pleural drainage procedures in addition to antibioticsfor the management of moderate to large empyemas inchildren [13–16]. These guidelines are based on reportssuggesting longer hospital stays, duration of antibiotictherapy, and higher rate of progression to surgical inter-vention in children treated with antibiotics alone [17]. Avariety of drainage procedures have been described,including chest tube placement with or without fib-rinolytics, repeated ultrasound-guided thoracentesis inaddition to surgical procedures such as video-assistedthoracoscopic surgery (VATS), and open thoracotomywith decortication [13–16]. Systematic reviews andguidelines suggest that chest tube insertion with intra-pleurally administered fibrinolytics and primary VATSare equally effective but fibrinolytics are more cost-effective [18, 19].Even with the use of fibrinolytics, pleural drainage canbe challenging and lead to prolonged hospitalization.Associated morbidities include prolonged chest tubeduration, which can be painful, and “treatment failure,”where undrained pleural disease necessitates salvageprocedures such as additional chest tubes, VATS, orthoracotomy. The frequency and type of salvage proce-dures varies by center but is typically 15% [20–22]. Onepotential explanation for inadequate drainage leading totreatment failure is the presence of extracellular uncoileddeoxyribonucleic acid (DNA) liberated from dead leuko-cytes and other bacterial components. Such residualmaterial may increase viscosity, permit biofilm forma-tion, and interfere with drainage [23–26]. Recombinanthuman dornase (dornase alfa) has been shown in vitroto decrease viscosity by cleaving free DNA andliquefying parapneumonic pus [26]. Subsequent animalstudies have also demonstrated that the combined ad-ministration of the fibrinolytic tissue plasminogen acti-vator (tPA) and dornase alfa is more effective than eitheragent alone [27]. Small case series in adult patients havealso described benefit from the addition of dornase alfato the treatment of empyema [28, 29]. Safety data ondornase alfa is primarily derived from its currently li-censed indication, nebulization at a dose of 2.5 to 5 mgonce or twice daily for the reduction of sputum viscosityin patients with cystic fibrosis. This formulation isgenerally well tolerated. Common side effects of in-haled dornase alfa include rash, voice alteration, chestpain, and laryngitis [30].A randomized controlled trial of adults with empyemarecently demonstrated improved outcomes with dornasealfa and fibrinolytics compared to fibrinolytics alone[31]. This study used a blinded, 2-by-2 factorial designin which 210 adults with empyema were randomlyassigned to one of four study treatments for 3 days:double placebo, intrapleurally administered tPA anddornase alfa, tPA and placebo, or dornase and placebo.The primary outcome was the change in pleural opacity,measured as the percentage of the hemithorax occupiedby effusion on chest radiography on day 7 comparedwith day 1. Secondary outcomes included referral forsurgery, duration of hospital stay and adverse events.For the primary outcome, the authors found a sig-nificantly greater reduction in pleural opacity in thetPA-dornase alfa group compared with the placebogroup (−29.5 ± 23.3% versus −17.2 ± 19.6%; mean differ-ence −7.9%; 95% confidence interval (CI), −13.4 to −2.4;p = 0.005). The change in pleural opacity observed withtPA alone or dornase alfa alone was not statistically dif-ferent from that observed with placebo. All secondaryoutcomes also pointed to superiority of tPA-dornase alfacompared with other study arms. Hospital stay for thetPA-dornase alfa group (11.8 ± 9.4 days) was about 50%shorter compared with placebo (24.8 ± 56.1 days),whereas in the dornase alfa-only group and the tPA-onlygroup, length of stay was similar to placebo. The fre-quency of surgical referral at 3 months was lower in thetPA-dornase alfa group compared with placebo (4% versus16%; odds ratio (OR), 0.17; 95% CI, 0.03 to 0.87, p = 0.03).Surgical referrals were increased in the dornase alfa-onlygroup (OR, 3.56; 95% CI, 1.30–9.75, p = 0.01), and werenonsignificantly reduced in the tPA-only group (OR, 0.29;95% CI, 0.07 to 1.29, p = 0.10). Mortality rates were 8% at3 months and 12% at 12 months, but were similar acrossall study groups. Inflammatory measures (C-reactive pro-tein, systemic white blood cell count, and odds of fever)were also assessed. Significant differences were found inmean white blood cell count on day 7 and fever on day 6or day 7 between tPA-dornase alfa and placebo. The newLivingston et al. Trials  (2017) 18:293 Page 2 of 11treatment was not associated with any excess of adverseevents. Serious adverse events described included intra-pleural hemorrhage (n = 2, both in the tPA-dornase alfagroup), gastrointestinal bleeding (n = 2, both in thedornase alfa group), hemoptysis (n = 1, in the tPA-dornase alfa group, and clinical deterioration (n = 1,in the placebo group).Applying the results of adult studies of pleural empy-ema to children is problematic as pediatric pleural em-pyema is a different disease for several reasons. First, themortality rates in adult patients can be as high as 10-20%, since many patients have pre-existing comorbidities[32, 33]. Most children who develop pleural empyema,however, are otherwise healthy and mortality is ex-tremely rare. To date, no mortalities have been re-ported in any of the randomized controlled trials ofchildren with empyema [20, 21, 33, 34]. Second, epide-miologic trends showing a rising incidence in empyemahave been primarily demonstrated in children. Althoughmicrobiologic confirmation is often elusive, this doessuggest that the microbial etiology of pediatric empyema(e.g., pneumococcal serotypes not covered by conventionalvaccines) may differ from adult patients. Third, therapiesthat have been found to be ineffective in adult patientshave been effective in children. Therefore, although thereis a biological rationale and clinical efficacy data fromadults, the evidence remains unclear whether the additionof dornase alfa to tPA will provide improvement inoutcomes among children with empyema.Methods/designResearch questionIn previously well children who present with pleural empy-ema, does the administration of intrapleurally administeredtPA and dornase alfa once daily for 3 days decrease thelength of stay in hospital compared to tPA alone? We willalso explore whether there are differences between treat-ment groups in terms of effectiveness, cost, and safety.DesignThe Intrapleural dornase alfa and Tissue Plasminogen Acti-vator in pediatric empyema (DTPA) trial is a superiority,placebo-controlled, parallel-design, pragmatic, multicenterrandomized controlled trial. This study will assess the safety,effectiveness, and cost-effectiveness of Dornase alfa com-bined with tPA compared to tPA alone. Overviews of enroll-ment, interventions, and assessments are depicted in Figs. 1and 2 (which depicts the Standard Protocol Items Recom-mendations for Interventional Trials (SPIRIT) figure). TheSPIRIT checklist is included in Additional file 1.SettingThe DTPA trial will be conducted at six tertiary chil-dren’s hospitals across Canada: The Hospital for SickChildren, Children’s Hospital of Eastern Ontario, CentreHospitalier Universitaire Sainte-Justine, McMaster Chil-dren’s Hospital, British Columbia Children’s Hospital,and Alberta Children’s Hospital. These sites are the lar-gest children’s hospitals in Canada and preferentially relyon chest tube insertion and fibrinolytics (as opposed toVATS) as first-line treatment. Furthermore, in all sixcenters, chest tube insertion is almost always performedusing an image-guided, percutaneous technique by aninterventional radiologist. Finally, all six centers haveimplemented clinical pathways to standardize the man-agement of this condition.ParticipantsThe DTPA trial will include children diagnosed withpleural empyema who require pleural drainage based onhistory, physical examination, laboratory investigations,and results of chest ultrasound. Current guidelines donot recommend that children with empyema undergothoracentesis for the purpose of diagnosis prior to de-finitive pleural drainage via chest tube insertion orVATS [13–16].Inclusion criteria1. Age 6 months to 18 years2. Hospitalized with a diagnosis of pleural empyemarequiring chest tube insertion and fibrinolytics (asjudged by the attending physician) with thefollowing criteria:a. Pneumonia with pleural effusion based on chestultrasound; andb. Need for further intervention based on clinicalcriteria (persistent fever despite antibiotics for atleast 48 h, significant respiratory distress,tachypnea, or hypoxia as a result of the pleuraleffusion)Exclusion criteria1. Empyema as a result of tuberculosis, fungus, ornoninfectious causes (e.g., malignancy)2. Known coagulation impairment3. Suspected or proven allergy to tPA or dornase alfa4. Chronic lung disease or other chronic illnesses (e.g.,immunodeficiency or neurologic impairment)5. Child has already undergone a drainage procedure(e.g., chest tube or VATS)6. Recent administration of an investigational drug(within previous 30 days)7. Pregnancy8. Breastfeeding9. Presence of pneumothorax prior to chest tubeinsertion (i.e., possible bronchopleural fistula)Livingston et al. Trials  (2017) 18:293 Page 3 of 11InterventionsParticipants will be randomized to receive either: (1) tPA(alteplase (Cathflo®), Roche) 4 mg followed by dornasealfa (Pulmozyme®, Roche) 5 mg or (2) tPA 4 mg followedby a placebo (saline). These medications will be adminis-tered through the chest tube once daily for a total ofthree doses. Weight-based dosing will not be used fortPA or dornase alfa as pleural concentrations are unpre-dictable and variable. Dornase alfa will be constituted bythe research pharmacies in clear liquids in a polyethyl-ene syringe. Since the stability of a tPA-dornase alfaadmixture is unknown, the drugs will be administeredsequentially with a 1-h indwelling time for each drug, asdescribed in the trial of adults with empyema treatedwith dornase alfa and tPA [31].For tPA, the contents of the vial will be diluted toa total volume of 10 ml normal saline for childrenweighing less than or equal to 10 kg and 20 ml forFig. 1 Overview of the intrapleural Dornase and Tissue Plasminogen Activator in pediatric empyema (DTPA) trialLivingston et al. Trials  (2017) 18:293 Page 4 of 11children weighing more than 10 kg. A flush of 5 mlof normal saline will be instilled after drug adminis-tration. Following the instillation of tPA, the chesttube will be clamped for 1 h and then opened to anegative pressure of −15 to −20 cm H2O for 1 h.Then, either dornase alfa or placebo will be instilledas a volume of 10 ml for children weighing less thanor equal to 10 kg and 20 ml for children weighingmore than 10 kg. These treatments will once again befollowed by a 5-ml normal saline flush, 1 h of chesttube clamping, and then negative pressure to −20 cmH2O. In total, each administration of study drugs anddrainage will take 4 h to complete.The pharmacies will prepare the two arms (dornasealfa or placebo) in a manner such that both are identical(packaging, color, volume, texture, and odor) to ensureblinding. The contents of the vials (tPA followed bydornase alfa or placebo) will be instilled into the chestdrain by clinicians caring for the child. The first dose oftPA will be given immediately (within 1 h) after insertionof the chest drain by the interventional radiologist orsurgeon in the procedure suite or by clinicians on theward. Dornase alfa or placebo will be instilled on theward. On the following day (day 1) and subsequent day(day 2), a dose of tPA followed by the study drug will beadministered in the morning, between 9:00 a.m. and10:00 a.m., in a similar fashion. Thus, each patient willreceive a total of three doses of either tPA or tPA-dornase alfa over 48 h or less. Participants will notreceive any intrapleurally administered drug other thandirected from this study.Criteria for discontinuing study interventionsParticipants who develop anaphylaxis or serious he-mothorax (requiring a transfusion or resulting in ahemoglobin drop of greater than or equal to 20 g/L)while receiving study interventions will not receivefurther study drugs. Participants whose chest tube isdislodged will only be replaced if clinically indicated forpleural fluid drainage and not for the sole purpose ofstudy drug administration.Standard careParticipants will otherwise receive standard care, includingsupportive care, laboratory investigations, imaging, antibi-otics, chest tube care and removal, and discharge. Althoughsome variability is expected, rigorous randomization andblinding should ensure that confounders are equally distrib-uted between groups. A detailed care map will be adaptedfrom the existing clinical practice guideline co-authored byteam investigators and other members of the CanadianPediatric Society [35]. Specific elements in the care planinclude:(a)Antimicrobial managementParticipants in both treatment arms will receivestandard antibiotic therapy for pleural empyemain children as directed by the most responsiblephysician. All participating hospitals currentlyrecommend a second- or third-generationcephalosporin (cefuroxime, ceftriaxone, orcefotaxime) as empiric antimicrobial therapywith possible addition of cloxacillin, clindamycin,Fig. 2 Overview of enrollment, interventions, and assessments as per the Standard Protocol Items Recommendations for Interventional Trials(SPIRIT) Statement [45]Livingston et al. Trials  (2017) 18:293 Page 5 of 11or vancomycin if Staphylococcus aureus issuspected. It is expected that antibiotic regimensmay be tailored based on local microbiologypatterns and sensitivities.(b)Chest tube insertionChest tubes will be placed by an interventionalradiologist using an image-guided percutaneoustechnique or by another physician. The recom-mended size is an 8 or 10 French pigtail catheter.(c)Chest tube managementManagement of chest tubes be dictated by thetreating physicians. Suggested managementincludes maintaining −20 cm H2O of continuoussuction and once daily flushes with 10 ml normalsaline (on days when no study drug isadministered) to maintain patency.(d)Diagnostic imaging post chest tube insertionThere is no consensus on the type (ultrasoundversus plain radiograph) or frequency of diagnosticimaging required after chest tube insertion inhospitalized children. As such, decisions aboutfollow-up imaging will be at the discretion of theresponsible physician. Furthermore, results fromfollow-up radiographs will only be assessed as anexploratory outcome.(e)Criteria for chest tube removalOur study protocol recommends that chest tubes beremoved once drainage decreases to less than 1 mL/kg/day. Ultimately, however, the decision will be atthe discretion of the responsible physician and likelybased on a gestalt assessment of clinical parameters(e.g., amount of drainage, appearance of the child,fever, etc.).Primary outcomeThe primary outcome will be length of stay from thetime of chest tube insertion to discharge from hospital.This variable is the most common outcome reported intrials of empyema in children [20, 21, 33, 34]. In thecurrent study, length of stay will be reported for eachparticipant as days rounded to a single decimal point.All calculations will be based on the number of hours inhospital.Secondary outcomesSecondary outcomes include measures of effectiveness,harm, and cost-effectiveness. This includes time to meet-ing discharge criteria, defined as the number of daysfrom insertion of the chest drain to meeting dischargecriteria. This will be assessed by a research assistant on atwice-daily basis (9:00 a.m. and 4:00 p.m.) and definedas: no fever (temperature <38 °C) for 24 h, normalrespiratory rate for age (using the World HealthOrganization age-specific criteria: <50 breaths/min for2–12 months, <40 breaths/min for 1 to 5 years, and <20breaths/min for ≥5 years), no hypoxia (oxygen saturationgreater than 92% on room air), and drinking fluids well.All values will be measured in hours and reported indays rounded to a single decimal point. We will use asimilar approach to calculate days from chest tube inser-tion to removal.We will also report the duration of fever after chesttube insertion. This will be defined as the length of timemeasured in hours and reported in days rounded to asingle decimal point from chest tube insertion to the lastrecorded incidence of temperature >38 °C (recorded byany method). Dichotomous outcomes include in-hospitalmortality due to any cause; need for ventilatory supportor noninvasive ventilation following chest tube insertion;clinically significant bleeding (defined as intrapleuralbleeding resulting in a drop in hemoglobin of greaterthan 20 g/L or requiring a transfusion of packed redblood cells); and the need for further pleural drainageprocedures, including additional chest tube insertion,VATS, or thoracotomy. We will also document hospitalreadmissions within 3 months related to pleural empy-ema or its treatment.Previous studies have demonstrated that early pleuraldrainage (i.e., within 48 h of admission) is associatedwith decreased length of stay in hospital [36, 37]. Thisfinding has important implications regarding the timingof pleural drainage but does not help clinicians to deter-mine which medications would be most beneficial (i.e.,dornase and fibrinolytics versus fibrinolytics alone). As aresult, we plan to report the timing of pleural drainageas a baseline variable to explore whether this is balancedbetween the two groups.An economic evaluation will compare the relativecosts of dornase alfa and tPA with tPA alone usingparticipant-level data from the trial. We will conduct theanalysis from a hospital’s perspective because hospitaladministrators will be making reimbursement decisionsfor this intervention. Since empyema is an acute condi-tion, and the long-term consequences are negligible, thetime horizon of the analysis will be the length of hospitalstay. The cost for each patient includes the cost of inter-vention (dornase alfa and tPA or tPA alone) and costsincurred during the hospital stay (i.e., “hospitalizationcost”). We will obtain hospitalization costs for eachpatient from case costing data from hospital financedepartments. We will calculate mean cost per patient ineach treatment group, based on initial interventionassignment, and incremental cost using simple linearregression:Ci ¼ αi þ βti þ εi;where Ci is the cost for each patient i, α is the interceptLivingston et al. Trials  (2017) 18:293 Page 6 of 11term, t is an intervention dummy term (t = 1 if the pa-tient received dornase alfa-tPA and t = 0 for tPA alone),and ε is the stochastic error term. The regression coeffi-cient β estimates the incremental cost of dornase alfa-tPA compared with tPA alone. The regression statisticswill show mean cost per patient by intervention groupand the uncertainty around the mean estimates. We willalso conduct sensitivity analysis to assess the robustnessof the results.We will not subject participants to standardized diag-nostic assessments in follow-up. The long-term out-comes of pediatric empyema are almost universallypositive. In our previous prospective cohort study ofchildren with empyema, we found that by 6 monthsvirtually all patients were asymptomatic, radiographshad normalized in 95% of patients, and pulmonary func-tion tests were normal in 96% [38].Exploratory outcomeIn the trial of dornase alfa among adults with empyema,changes in pleural opacity, measured as the percentage ofthe hemithorax occupied by effusion on day 7 comparedwith day 1, was the primary outcome. In pediatric empy-ema, this outcome is problematic because: (1) some chil-dren will be discharged prior to day 7, (2) hemithorax sizediffers substantially across different-sized children, and (3)requiring an additional chest radiograph may be a sub-stantial disincentive for a parental caregiver to provideconsent given the rising concerns of ionizing radiation indeveloping children. Further, radiographic changes areconsidered surrogate measures of clinical changes as theyoften lag behind clinical improvement.Chest ultrasound is not used routinely or consistentlyto assess response to therapy following pleural drainageprocedures. Thus, using this modality in a pragmatictrial has little relevance for clinicians who routinely carefor children with empyema. Further, ultrasound is ex-tremely user-dependent, resource-intensive, and pre-cludes truly blinded assessment by external reviewers.The most objective and reproducible way to assessresponse to pleural drainage radiologically would bechest computed tomography (CT). Unfortunately, chestCT is associated with less interobserver agreement forpleural disease, substantial cost, and radiation exposure,and so its use is not recommended in the managementof children with pleural empyema [39].There is currently no standard as to the timing ofchest radiographs in hospital, but in our experience,virtually all children will have a radiograph performedbefore and/or shortly after chest tube removal. Theradiograph closest to the time of removal will bereviewed by a blinded study radiologist to determine thepercentage of hemithorax occupied using a five-pointordinal scale utilized in previous studies ranging fromno fluid present to fluid occupying more than 75% ofthe most affected hemithorax. Given that radiographicimprovement is time-dependent, we do not have any apriori hypotheses about the results of this outcomeacross groups. Using a chest radiograph allows for ablinded assessment by an external reviewer and is themodality used in routine clinical practice, particularly toensure that the patient does not develop a pneumo-thorax and/or that the chest tube does not becomedislodged or kinked while in situ. Thus, the degree ofresolution on chest radiograph post chest tube insertionis both meaningful to clinicians and more in keepingwith the goals of a pragmatic trial.We are also collecting data on concomitant medicationuse, including analgesia. We did not include pain as a pre-specified outcome measure as we did not hypothesize dif-ferences between treatment groups. We will explore thesedata in post hoc analyses.Sample sizeThe primary outcome in this trial is time to hospital dis-charge after chest tube insertion. In previous studies, themean time to hospital discharge post insertion rangesfrom 6 to 15 days [20, 21, 33, 34]. Hospital length of staytends to be shorter in published randomized controlledtrials compared to observational studies of empyema,and a recent randomized controlled trial using an identi-cal tPA dosing regimen to that which we are proposingdescribed a mean of 6.8 (standard deviation (SD) 2.9)days [21]. The desired power for the current proposal is90% to detect a difference of 2 days in the mean time tohospital discharge between the treatment arms. Basedon discussions with clinical experts, hospital administra-tors, and parents of children with pleural empyema, it isbelieved that a 2-day difference between treatment groupsis a minimal clinically meaningful difference, and this hasbeen used in previous trials on this topic [38]. The adultdornase alfa trial found a 50% difference in length of staybetween treatment and placebo groups [40].Assuming a type 1 error rate of 0.05 (two-sided), power(1 − β) of 90%, and a SD of 2.9 days for each group, ourtrial needs 46 participants in each group to detect a differ-ence of 2 days in length of stay. Sample size would have tobe 34 participants in each group to provide 80% power.Calculations were performed based on a t test of inde-pendent groups. There will be no other adjustment to thesample size requirements due to loss to follow-up for theprimary outcome as the primary outcome is assessed inhospital where the research coordinator will be able toensure complete data collection.RecruitmentAll study participants will be initially identified by re-search assistants who will review new admissions to theLivingston et al. Trials  (2017) 18:293 Page 7 of 11relevant inpatient units twice daily. They will also reviewnew referrals for chest tube insertion at each center.Most chest tubes will be inserted by interventional radi-ologists, although a minority may be inserted by generalsurgeons or intensivists. Physicians, radiologists, andsurgeons at each site will be asked to notify the researchassistant and/or site investigator of children admittedwith pleural empyema who may be eligible for the study.Potential participants will be approached, eligibility cri-teria confirmed, consent obtained, and enrolled after thedecision to proceed with pleural drainage but beforechest tube insertion occurs.RandomizationAfter informed consent is obtained, participants will berandomized into treatment groups using a random alloca-tion sequence created by the coordination and manage-ment center for this trial. Randomization will be stratifiedby center. Blocking will be used to ensure that the twocomparison groups are approximately the same sizethroughout the trial for each center and for the trial as awhole. An allocation ratio of 1:1 with random block sizewill be used within each stratum (i.e., center). This will en-sure that clinicians, investigators, and outcome assessorswill not be able to decipher the block size. A computer-based pseudo-random number generator will be used tocreate treatment allocation tables for each study center.After patient eligibility has been confirmed, consentobtained, and just as the patient leaves the inpatient unitto the radiology suite or operating room for chest tubeinsertion, the site investigator (or delegate) will assignthe patient a unique study identification number insequential order. The study identification number willcorrespond with the randomization table held in theresearch pharmacy for dispensing blinded dornase alfaor placebo. The biostatistician will maintain a securemaster list of the randomization codes and the assignedtreatments will be checked against the master list at theend of the study.BlindingParticipants, parents or other caregivers, site investiga-tors, research assistants and coordinators, treating physi-cians (pediatricians, radiologists, and interventionalradiologists or surgeons), treating nurses, and data man-agers will be blinded to the treatment allocation. Groupallocation will be concealed until the final data analysisis performed. Study drugs will be blinded by the researchpharmacy. Both arms will be constituted by the researchpharmacies in clear liquids in a polyethylene containerin a manner such that both are identical (packaging,color, volume, texture, and odor) to ensure blinding.After obtaining the treatment number from the centralrandomization center, the study pharmacist will retrievethe corresponding vial and one of its treatment numberlabels will be attached to the participant’s Case ReportForm. We do not anticipate any circumstances thatwould require unblinding as knowledge of the study armis not anticipated to affect treatment for patients.Data collectionData collection for outcome measures will be collectedin hospital by the research assistant at each center. Atbaseline, the following data will be obtained for descrip-tive purposes: age, sex, duration of antibiotic treatmentprior to chest tube insertion (in days), duration of feverprior to chest tube insertion, hypoxia while breathingroom air (oxygen saturations less than 92% prior tointervention), microbiologic identification of causativeagent (culture or polymerase chain reaction results fromblood, throat swab, or pleural fluid), size of empyema onultrasound, stage of empyema on ultrasound (stage 1:anechoic, nonseptated fluid; stage 2: echoic fluid withoutseptation; stage 3: septated fluid; and stage 4: septationswith solid appearing components comprising more thanone third of the effusion). All ultrasounds will bereviewed by a blinded study radiologist. In addition, allparticipants will receive a follow-up phone call from theresearch assistant at 3 months enquiring about any pos-sible readmissions and ongoing symptoms of fever,shortness of breath, and/or exercise intolerance.Data managementThe Applied Health Research Center of the Li Ka ShingKnowledge Institute of St. Michael’s Hospital will serveas the data management center. The Applied HealthResearch Center employs state-of-the-art web-baseddata management software, Medidata RAVE™ (5.6.3), asecure, encrypted web-based clinical trial data manage-ment system which is fully configurable and incorporatessophisticated data validation rules to ensure high-qualitydata capture. RAVE™ allows for remote web-based dataentry directly from the hospital sites, facilitating real-time data access.Statistical analysisBaseline characteristicsPatient characteristics and descriptive variables will bepresented for each treatment arm: age, sex, duration ofantibiotic treatment prior to chest tube insertion (days),duration of fever prior to chest tube insertion (days),hypoxia (defined as the presence of saturation less than92% without supplemental oxygen), bacterial identifica-tion and subtype, pleural effusion size on ultrasound(>10 mm or <10 mm), stage of empyema on ultrasound(frequency). For continuous variables, means and SDs ormedians (interquartile ranges) will be presented. Forcategorical variables, proportions will be presented.Livingston et al. Trials  (2017) 18:293 Page 8 of 11Primary outcomeData will be analyzed according to intention-to-treat princi-ples for the primary outcome (i.e., patients who do notreceive all three doses of study drug will be analyzed in thegroup they were assigned to). Exceptions to this principlewill only include any patient who dies in hospital and willbe excluded from the analysis of time to hospital discharge.Given that the primary outcome and other acute secondaryoutcomes are obtained during hospitalization, it is antici-pated that there will be no missing data for these outcomeswith the possible, but unlikely, exception of in-hospitaldeath which is rare in childhood empyema.For the follow-up outcomes at 3 months, the propor-tion of patients with follow-up will be presented for eachtreatment arm, and patients who are lost to follow-upwill be stated but omitted from the analysis. The primaryoutcome, time (in days) to hospital discharge, will bedescribed as the difference between the two means withthe 95% CIs. The Student’s t test (independent two-sample test assuming equal group size and variance), willbe used to detect a difference between the two treatmentgroups. If the resulting data is inappropriate for a t test(increasing variance with the mean is the biggest concernsince the test is quite robust to non-normality in thepopulation), a suitable transformation or nonparametrictest may be used. If feasible, a secondary analysis of theprimary outcome will analyze time to discharge, treatingdeath as a competing risk, using methods for survival data.Subgroup analyses will also be conducted to explore anypotential differences in outcomes by age or sex.Secondary and exploratory outcomesFor the secondary and exploratory outcomes that arecontinuous variables (i.e., duration of tube insertion,hospital stay after intervention to meeting discharge cri-teria, duration of fever after the intervention, amount ofhemithorax occupied by pleural effusion in radiographs)the difference between the two means with the 95% con-fidence intervals will be presented. The Student’s t testwill be used to detect a difference between the treatmentgroups. Dichotomous outcomes (serious bleeding, needfor further interventions, need for ventilator support,mortality) will be described as the absolute number andproportion. A Fisher’s exact test will be used to detect asignificant (p < 0.05) difference between the two treat-ment arms. The treatment effect will also be presentedas the relative risk with 95% CIs. These analyses will beviewed as hypothesis-generating, and therefore, nocorrection for multiple testing is planned.Data monitoring and safetyData monitoring will be conducted by a Data MonitoringCommittee (DMC) composed of a pediatric hospitalist, arespiratory physician, and an interventional radiologist.The DMC will be completely independent of the investi-gators, and will be provided with clinical information fromthe Case Report Forms for death, surgical interventions,and adverse events, including those that were described inthe adult dornase alfa trial (hemoptysis, gastrointestinalbleeding, chest pain, nausea, transient confusion, andrash). The DMC will be able to request additional infor-mation from clinicians as needed. All adverse events willbe reported to the principal investigator within 24 h andto the local Research Ethics Board. Serious adverse drugreactions to the study medication will be reported toHealth Canada within fifteen calendar days and withinseven calendar days for life-threatening events or death.Adverse reactions will be managed by the treating phys-ician and clinical team.This project will be monitored by Applied HealthResearch Center during the data collection phase of theproject. The aim is to ensure that all researchers aremaintaining the highest ethical, scientific, and safetystandards for all study participants, and are in compli-ance with all relevant policies, provincial and federallegislation, and international guidelines (such as GoodClinical Practice).Ethical considerationsInformed consent will be obtained from parents or legalguardians. Given the young age of children with empyema(average age less than 5 years), it is anticipated that mostwill not be able to consent or even assent to participate.Informed consent and assent will be obtained from allchildren who are able to provide it. Potential knownadverse events from study interventions are mainly localas the drugs are not systemically absorbed. Aside from re-ceiving the study interventions, participation will requireparents to agree to be contacted by research personnel fora short phone call (duration less than 5 min) 3 monthspost discharge from hospital. Ethics review and approvalwill be obtained from the Research Ethics Board at each ofthe participating institutions.DisseminationKnowledge Translation activities will occur locally, nation-ally, and internationally. Locally, findings will be presentedto clinical groups and incorporated into the empyemaClinical Practice Guidelines at all sites. Nationally, findingswill be presented at the Canadian Pediatric Society’sAnnual Meeting focused on the Hospital PediatricsSection. Internationally, we will present findings at thePediatric Academic Society’s Annual Meeting, the largestinternational pediatric research meeting, facilitated by thePediatric Research in Inpatient Settings group, an inter-national hospitalist research and Knowledge Translationorganization that is co-led by Dr. Mahant. Given thebroad interest in empyema in children, we also plan toLivingston et al. Trials  (2017) 18:293 Page 9 of 11submit the results of our trial for publication in a high-impact general medical or pediatric journal.DiscussionThere are important gaps in the scientific literatureregarding the optimal therapy for pleural empyema inchildren [13, 14, 16]. This problem is pervasive in childhealth research. High-quality evidence is based on the re-sults of randomized controlled trials but there is a paucityof these studies in children. Over the past 20 years, thenumber of adult randomized controlled trials published inleading general and subspecialty medical journals has in-creased substantially, while the number of pediatric trialshas increased only modestly [41, 42]. This problem is par-ticularly relevant in pharmaceutical trials, and has un-doubtedly led to the widespread use of pharmaceuticalproducts in children without sufficient data on effective-ness or safety [43]. Despite some legislative initiatives inthe United States and Europe to promote drug trials inchildren, extensive logistical and financial disincentivespersist. Consequently, 79% of hospitalized children aretreated with drugs for unapproved indications, otherwiseknown as “off-label” use [44].Randomized controlled trials have demonstrated thatusing fibrinolytics is a safe and effective therapy for chil-dren with empyema [20, 21, 34, 35]. Despite this, manypatients continue to experience significant short-termmorbidity due to prolonged hospitalization, pain fromindwelling chest tubes, and the need for additional drain-age procedures. Data from a randomized controlled trialin adults with empyema suggests that adding dornase alfamay be superior to using fibrinolytics alone. This treat-ment strategy requires further study in a pediatric settingsince differences in the underlying disease may affectresponse to treatment. As such, we are now conducting amulticenter randomized controlled trial to assess thesafety, effectiveness, and cost-effectiveness of dornase alfaand tPA in the management of empyema in children.Trial statusThe DTPA trial started recruiting participants in December2012 and is on track to complete enrollment of 92 par-ticipants by April 2018. An update with results will beprovided in late 2018. A copy of the full-length protocolis available upon request.Additional fileAdditional file 1: Recommended items to address in a clinical trialprotocol and related documents. (DOCX 47 kb)AbbreviationsCI: Confidence interval; DMC: Data Monitoring Committee;DTPA: Intrapleural Dornase and Tissue Plasminogen Activator in pediatricempyema; OR: Odds ratio; tPA: Tissue plasminogen activator; VATS:Video-assisted thoracoscopic surgeryAcknowledgementsWe would like to thank our study coordinator, Jodi Tiffany Shim, for herongoing efforts and dedication, as well as our stellar team of researchassistants, Carol Chan, Lynda Hoey, Hélène Gagnon, Lauré-Anne Parent,Adam Pow, Ali MacRobie, and Shamini Selvakumar.FundingThis study was funded by Physicians’ Services Incorporated and theCanadian Institutes of Health Research. Dr. Michael Livingston issupported by the Clinician Investigator Program at McMaster University(funded by the Ontario Ministry of Health and Long-term Care). Dr. MaryBrindle is supported by the Brian and Brenda MacNeill Chair in PediatricSurgery at the University of Calgary. None of these agencies had a rolein developing the protocol for this study.Availability of data and materialsNot applicable.Authors’ contributionsEC designed the study, wrote the study protocol, obtained funding, andsupervised the conduct of the trial. MHL revised the study protocol andprepared the first draft of this manuscript. EC, MHL, SM, FR, BC, KT, MM, IM,SL, LG, JMW, CLY, AR, ACS, MB, SP, and CS contributed to the conduct of thetrial, participated in study meetings, provided feedback, and read andapproved the final manuscript as written.Competing interestsThe authors declare that they have no competing interests.Consent for publicationNot applicable.Ethics approval and consent to participateThe study is being conducted in accordance with Good Clinical Practiceguidelines and has been approved by the Research Ethics Board for TheHospital for Sick Children (reference number 1000033767). Informed consentis being obtained from all participants and/or their parents or legalguardians where applicable.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1The Hospital for Sick Children, Department of Pediatrics, University ofToronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada. 2Dalla LanaSchool of Public Health, University of Toronto, 155 College Street, Toronto,ON M5T 3M7, Canada. 3Applied Health Research Centre of the Li Ka ShingKnowledge Institute, St. Michael’s Hospital, University of Toronto, 30 BondStreet, Toronto, ON M5B 1W8, Canada. 4McMaster Children’s Hospital,McMaster University, 1280 Main Street West, Hamilton, ON L8S 4K1, Canada.5Children’s Hospital of Eastern Ontario, University of Ottawa, 401 SmythRoad, Ottawa, ON K1H 5B2, Canada. 6Centre Hospitalier UniversitaireSainte-Justine, Université de Montréal, 3175 Chemin de laCôte-Sainte-Catherine, Montréal, QC H3T 1C5, Canada. 7Department ofPediatrics, Division of Respiratory Medicine, British Columbia’s Children’sHospital, University of British Columbia, 4480 Oak Street, Vancouver, BC V6H3V4, Canada. 8Alberta Children’s Hospital, University of Calgary, 2888Shaganappi Trail NW, Calgary, AB T3B 6A9, Canada.Received: 27 June 2016 Accepted: 30 May 2017References1. 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