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A Pilot Randomized, Controlled Trial of Later Treatment With a Peptide-Containing, Synthetic Surfactant for the Prevention of Bronchopulmonary Dysplasia

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A Pilot Randomized, Controlled Trial of Later Treatment With a Peptide-Containing, Synthetic Surfactant for the Prevention of Bronchopulmonary Dysplasia
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  DOI: 10.1542/peds.2007-2680 2009;123;89 Pediatrics Genzhou LiuChristopher Morabito, James John Cummings, Robert Segal, Carlos Guardia and Matthew Laughon, Carl Bose, Fernando Moya, Judy Aschner, Steven Mark Donn, Bronchopulmonary DysplasiaPeptide-Containing, Synthetic Surfactant for the Prevention of A Pilot Randomized, Controlled Trial of Later Treatment With a   http://pediatrics.aappublications.org/content/123/1/89.full.html located on the World Wide Web at: The online version of this article, along with updated information and services, is   of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2009 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1948. PEDIATRICS is owned, PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly  by guest on May 31, 2013pediatrics.aappublications.orgDownloaded from   ARTICLE A Pilot Randomized, Controlled Trial of LaterTreatment With a Peptide-Containing, SyntheticSurfactant for the Prevention of Bronchopulmonary Dysplasia MatthewLaughon,MD,MPH a ,CarlBose,MD a ,FernandoMoya,MD b ,JudyAschner,MD c ,StevenMarkDonn,MD d ,ChristopherMorabito,MD e ,JamesJohnCummings,MD f  ,RobertSegal,MD g ,CarlosGuardia,MD g ,GenzhouLiu,PhD g ,fortheSurfaxinStudyGroup a School of Medicine, University of North Carolina, Chapel Hill, North Carolina;  b Department of Neonatology, New Hanover Regional Medical Center, Wilmington, NorthCarolina;  c Division of Neonatology, Department of Pediatrics, and Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, Tennessee;  d Division of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Michigan Health System, C.S. Mott Children’s Hospital, Ann Arbor, Michigan;  e Division of Neonatology, Lehigh Valley Hospital, Allentown, Pennsylvania;  f  Brody School of Medicine, East Carolina University, Greenville, North Carolina;  g Discovery Laboratories,Inc, Warrington, Pennsylvania Financial Disclosure: Drs Laughon, Bose, Moya, Aschner, and Donn were compensated by Discovery Laboratories, Inc, for their time and effort as members of the scientific advisory board for this study; DrsLaughon, Cummings, and Morabito were site investigators; and Drs Segal, Guardia, and Liu are employees of Discovery Laboratories, Inc. What’sKnownonThisSubject Surfactant therapy in the first 48 to 72 postnatal hours reduces the incidence of pneu-mothorax and mortality. It is unclear if later surfactant therapy, after 72 postnatal hours,might reduce the incidence of BPD. WhatThisStudyAdds  This randomized, controlled trial adds information regarding the risks and benefits of later surfactant therapy. Infants assigned to later surfactant therapy with 175 mg/kglucinactant had non–statistically significant trends towards a lower incidence of mor-tality or BPD. ABSTRACT OBJECTIVE. Oxidant injury and lung inflammation in extremely premature infants areassociated with the development of bronchopulmonary dysplasia. Surfactant dys-function resulting from these events may contribute to the pathogenesis of bron-chopulmonary dysplasia. Treatment with exogenous surfactant may decrease theincidence or severity of bronchopulmonary dysplasia. We conducted a masked,multicenter,multinational,randomized,controlled,pilotstudytoestimatetheeffectsof treating infants at high risk for developing bronchopulmonary dysplasia withlucinactant, a synthetic, peptide-containing surfactant, on safety during dosing andthe incidence of death or bronchopulmonary dysplasia. METHODS. Preterminfantsbetween600and900grequiringmechanicalventilationanda fraction of inspired oxygen of  0.30 between 3 and 10 days of age were randomlyassigned to receive either sham air (placebo) or 1 of 2 doses of lucinactant (90 or 175mg/kg total phospholipid) every 48 hours to a maximum of 5 doses, if they remainedon mechanical ventilation. RESULTS. Of 136 infants enrolled at 34 sites, 44 received placebo, 47 received 90 mg/kgtotal phospholipid, and 45 received 175 mg/kg total phospholipid. The 90 mg/kggroup had a significantly higher percentage of boys (64%) compared with theplacebo group (39%); no other significant differences in baseline characteristicsamong groups were present. Compared with placebo, both the 90 mg/kg and 175mg/kg groups experienced a significantly higher incidence of desaturation and bradycardia during dosing. Twenty-four hours after dosing, the mean fraction ofinspired oxygen was lower in both lucinactant groups (33%) compared with theplacebo group (39%). The incidence of mortality or bronchopulmonary dysplasiawas 66% in the placebo group, 79% in the 90 mg/kg group, and 58% in the 175mg/kg group. These differences were not statistically significant. There were nostatistical differences among groups for pneumothorax, pulmonary interstitial emphysema, intraventricular hemor-rhage, periventricular leukomalacia, retinopathy of prematurity, or mortality. CONCLUSIONS. There were trends toward lower oxygen requirements and toward a lower incidence of mortality or bronchopulmonary dysplasia at 36 weeks’ postmenstrual age in infants who received the higher dose of lucinactant,and this warrants further investigation.  Pediatrics  2009;123:89–96 www.pediatrics.org/cgi/doi/10.1542/peds.2007-2680doi:10.1542/peds.2007-2680  This trial has been registered atwww.clinicaltrials.gov (identifierNCT00215540). KeyWords premature infant, surfactant,bronchopulmonary dysplasia Abbreviations BPD—bronchopulmonary dysplasiaF IO 2 —fraction of inspired oxygenDOL—day of lifeS-90—90 mg/kg lucinactantS-175—175 mg/kg lucinactantPMA—postmenstrual ageCI—confidence intervalOR—odds ratio Accepted for publication Apr 2, 2008Address correspondence to MatthewLaughon, MD, MPH, UNC Hospital, Division of Neonatal-Perinatal Medicine, CB 7596, 4thFloor, Chapel Hill, NC 27599-7596. E-mail:matt    laughon@med.unc.eduPEDIATRICS(ISSNNumbers:Print,0031-4005;Online,1098-4275).Copyright©2009bytheAmericanAcademyofPediatrics PEDIATRICS Volume 123, Number 1, January 2009  89  by guest on May 31, 2013pediatrics.aappublications.orgDownloaded from   B RONCHOPULMONARY DYSPLASIA (BPD)  is the mostfrequent serious complication of extremely prema-ture birth. 1,2 The pathogenesis of BPD is multifactorialand includes features related to immaturity of the lung,such as underdeveloped parenchyma, altered alveolar-ization, and deficient surfactant production, as well aslung inflammation. 3 The early administration of surfac-tant improves pulmonary function and survival, but ithas not been shown to consistently reduce the incidenceof BPD. 4–6 Evaluation of ventilated preterm infants withevolving BPD has demonstrated several abnormalities ofthe surfactant system, such as a quantitative deficiencyof surfactant components (particularly surfactant pro-teins), a decreased ability of endogenous surfactant tolower surface tension, and increased surfactant turn-over. 7–9 Temporary improvement in pulmonary functionafter surfactant administration has been reported in pre-term infants requiring prolonged mechanical ventila-tion. 10–12 Therefore, it is plausible that administration ofsurfactant therapy beyond the first few days of life may be beneficial in preventing BPD.Many infants who develop BPD have early, severelung disease characterized by a need for substantial sup-plemental oxygen and mechanical ventilation. In con-trast, approximately one third of infants who developBPD experience a period of minimal lung disease duringthe first week of life, during which little or no supple-mental oxygen or mechanical ventilation is required.This period of minimal support is followed by pulmonarydeterioration during the second week of life. 13 Therapiesfor the prevention of BPD should target both of theseat-risk populations.We hypothesized that later additional administrationof surfactant to infants at risk for developing BPD, de-fined by either persistent early moderate lung disease orpulmonary deterioration after a period of relative stabil-ity, would reduce the incidence of BPD. Therefore, weconducted a masked, multicenter, multinational, ran-domized, controlled, pilot study to estimate the effects oftreating infants at high risk for developing BPD with apeptide-containing synthetic surfactant, lucinactant. Lu-cinactant was selected as the surfactant of choice be-cause of evidence showing resistance to inactivation byplasma proteins and oxidant species 14–16 and inherentanti-inflammatory properties. 17 In our study, we exam-ined the tolerability of lucinactant by infants at risk fordeveloping BPD and the effect on the incidence of deathor BPD. METHODS StudyPopulation Infants were enrolled at 34 sites, 19 in the United States,5 in Chile, 7 in Poland, and 3 in Hungary. All of the USand international sites were selected based on their ca-pabilities to conduct rigorous clinical trials. In addition,all of the non-US centers and some US centers hadparticipated in previous randomized, controlled trialswith lucinactant. 18,19 All provided care comparable totertiary care centers in the United States (eg, use andmanagement of mechanical ventilation, access to intra-venous nutrition and management of nutrition, surfac-tant therapy, and general management of the extremelylow birth weight infant). Infants were eligible for thestudy if they were mechanically ventilated, requiredfraction of inspired oxygen (F IO 2 )   0.30, and weretreated with surfactant during the first 2 days of lifewhen clinically indicated. The srcinal protocol enrolledinfants on day of life (DOL) 3 only. Subsequently, weamended the protocol to include infants who met entrycriteria any time between DOL 3 and 10. 13 Exclusioncriteria included delivery after prolonged (  2 weeks)rupture of membranes, culture-proven sepsis, severe in-traventricular hemorrhage (determined by profoundlyabnormal neurologic examination or a cranial sonogramdemonstrating a grade IV intraventricular hemor-rhage 20 ), congenital heart disease other than a patentductus arteriosus, congenital anomalies inconsistentwith life or likely to confound efficacy or safety endpoints, or previous treatment with inhaled nitric oxideor steroids (with the exception of hydrocortisone for blood pressure support). In addition, infants with severelung disease, defined as treatment with F IO 2   0.80 andmean airway pressure   12 cm H 2 O were excluded. In-fants were also excluded if the F IO 2  fell below 0.25 at anytime between eligibility and random assignment. Thestudy was approved by each center’s institutional review board, and written, informed parental consent was ob-tained before enrollment. A data, safety, and monitoring board reviewed masked safety data at the time pointwhen one third of patients completed the study. Thedata, safety, and monitoring board recommended thestudy to continue as planned after this interim analysis. StudySurfactantandPreparation Lucinactant (Surfaxin [Discovery Laboratories, Inc,Warrington, PA]) is a sterile, white suspension suppliedin 10-mL (30 mg of phospholipids per mL) single-usevials consisting of a phospholipid combination of di-palmitoyl-phosphatidylcholine (22.5 mg/mL), palmi-toyl-oleyl phosphatidylglycerol (7.5 mg/mL), andpalmitic acid (4 mg/mL), as well as a 21-residue syn-thetic peptide, sinapultide, which mimics the functionsof surfactant-associated protein B. 18,19,21 Lucinactant waswarmed for 15 minutes at 44°C using a specially de-signed heating block, followed by vigorous shaking untila uniform, free-flowing suspension was obtained. Theappropriate volume of lucinactant (or sham air for mask-ing purposes) was drawn into syringes marked with thepatient’s name and identification number that were par-tially covered with opaque labels designed to make thecontents not readily visible. StudyDesign Infants were stratified only by center, using only sealedenvelopes, and were randomly assigned to 1 of 3 treat-ment groups: sham air (placebo), 90 mg/kg lucinactant(S-90), or 175 mg/kg lucinactant (S-175), a dose used inprevious clinical trials and demonstrated to be effica-cious. 18,19 Because there was no established surfactantdosing data for the treatment of infants at risk for BPD, 90  LAUGHON et al  by guest on May 31, 2013pediatrics.aappublications.orgDownloaded from   we designed a dose-ranging study, which included 2lucinactant doses, and sought to determine whetherthere was a dose response in this population. Treatmentallocations were assigned in randomized blocks of 3 persite. Randomization occurred as soon as possible afterdetermination of eligibility but no later than 8 hoursafter meeting entry criteria. In the case where bothmembers of a twin set were eligible for and enrolled inthe study, each twin was treated as a randomly assignedevent. Treatment was administered every 48 hours for amaximum of 5 doses, as long as the infant was stillreceiving mechanical ventilation. For infants extubated before receiving all 5 doses of the study treatment butwho were subsequently reintubated, dosing was re-sumed and continued at 48-hour intervals, up to themaximum of 5 total doses, or until DOL 18, whicheveroccurred first.Clinical providers were masked to study treatment.Management of mechanical ventilation, includingweaningandextubation,waslefttotheclinicalprovider.The preparation of lucinactant/sham air was restricted toa location not visible to patient caregivers. The individ-uals responsible for preparing lucinactant/sham air wereeither a pharmacist or another professional not involvedin the clinical management of any study infant. Infantswere screened from view during treatments, and indi-viduals administering study treatments did not partici-pate in subsequent clinical decision-making.During dosing, the drug administrator placed the in-fant in a head-up, left lateral decubitus position andslowly (over 1–2 minutes) administered one quarter ofthe syringe volume. After allowing a brief recovery pe-riod, the infant was placed in the right lateral decubitusposition for administration of another quarter of studydrug. Administration of the remaining dose was re-peated while the infant was in the left and right lateraldecubitus position, respectively. Infants assigned to re-ceive sham air for masking purposes were given 3.0mL/kg. For the lucinactant groups, the drug administra-tor gave either 3.0 mL/kg (S-90) or 5.8 mL/kg (S-175).All of the doses were administered through cathetersintroduced into the distal end of the endotracheal tubevia a side port or Bodai Neo2-Safe valve (B&B MedicalTechnologies, Orangevale, CA) without disconnectingthe infant from mechanical ventilation. After dosing, thehead of the infant was raised slightly to reduce thelikelihood of reflux of surfactant. Endotracheal suction-ing was avoided for   1 hour after dosing, unless therewere obvious signs of endotracheal tube obstruction. Wedefined desaturation during dosing as pulse oxygen sat-uration  75% for  30 seconds and bradycardia duringdosing as a heart rate   100 beats per minute for   30seconds. OutcomesandStatisticalMethods This was a pilot randomized, controlled trial to estimatethe treatment effects of administering lucinactant begin-ning on DOL 3 in infants at high risk for BPD. Thetreatment effect of primary interest was the incidence ofmortality or BPD at 36 weeks’ postmenstrual age (PMA).Gestational age was determined by best obstetrical mea-surement. We also examined the effect of treatment onother complications of prematurity and evaluated safetyand tolerability during dosing.A sample size estimate could not be calculated in theabsence of preliminary data describing the effect of sur-factant treatment for this indication. Therefore, the sam-ple size was selected based on practical issues but was ofsufficient size to detect a large treatment effect, ifpresent. Analysis of data from 2 clinical studies of luci-nactant indicated that the estimated incidence of deathor BPD at 36 weeks’ PMA in the patient populationselected for this study was   70% to 75%. 18,19 With aplanned sample size of 70 infants per group, if the ob-served incidence of mortality and/or BPD at 36 weeks’PMA was comparable to the data derived from the pre-vious lucinactant trials (70% in the placebo group), the90% confidence intervals (CIs) of a 14% absolute riskreduction of the treatment difference (from 70% to56%) would be  27.3% to  0.72%.Statistical analyses included all of the randomly as-signed patients using an intention-to-treat approach.Categorical demographic variables were compared usingthe Cochrane-Mantel-Haenszel test for general associa-tion. Continuous variables were assessed by treatmentgroup using either analysis of variance or the Wilcoxonrank-sum test if the data were not normally distributed.Comparisons for the death or BPD efficacy end pointswere performed using the logistic regression model. Pro-portional hazard models were used to compare the pro-portions of infants requiring mechanical ventilation orsupplemental oxygen over time. The Cochrane-Mantel-Haenszel or    2 tests were used to assess categorical vari-ables of safety and tolerability. All of the tests were 2sided. We did not adjust for the distribution of twin pairsamong treatment groups. RESULTS From December 2004 to May 2006, 809 infants with a birth weight of 600 to 900 g were screened, and 136were enrolled (17%; Fig 1). Of these, 56 (41%) wereenrolled in US centers. There were 6 twin pairs enrolledin the study; all of these pairs were randomly assigned todifferent treatment groups. The study was electively ter-minated after two thirds of the planned subject enroll-ment was achieved because of both slow accrual ofpatients and issues regarding availability of lucinactantproduct. The lucinactant used in the study patients metall of the product specifications throughout the studyperiod. However, other lucinactant batches manufac-tured during the same period failed to meet certainstability criteria. Considering this circumstance, thesponsor, in consultation with the steering committee,decided that it was in the best interest of patients todiscontinue further enrollment while an investigationinto the stability failure was conducted and resolved.Table 1 displays the baseline demographic and clinicalcharacteristics of each group. Compared with the pla-cebo group, a statistically significant larger percentage ofinfants in the S-90 group were boys (64% vs 39%), andthere was a trend toward more infants with a 5-minuteApgar score   3 (11% vs 0%). Otherwise, the 3 groups PEDIATRICS Volume 123, Number 1, January 2009  91  by guest on May 31, 2013pediatrics.aappublications.orgDownloaded from   had similar characteristics. Four infants (2.9%) enrolledwere outside of the eligible weight range but were in-cluded in the analyses.Figure 2 demonstrates the mean F IO 2  of infants 15minutes before the first dose of study medication and 2,6, 24, and 48 hours after the first dose. The baseline F IO 2 was highest in the placebo group. The mean F IO 2  tran-siently increased after dosing in the S-175 and S-90lucinactant groups (peaking at 49% and 44%, respec-tively) and then decreased thereafter. Twenty-fourhours after dosing, the mean F IO 2  was lower in bothlucinactant groups (33%) compared with the placebogroup (39%). At 48 hours after dosing, the mean F IO 2 was lower in the S-175 group (31%) compared with theS-90 group (33%) and the placebo group (38%). Be-cause this analysis was not planned a priori, we did not TABLE 1  DemographicsandBaselineCharacteristics Characteristic S-90( N   47)S-175( N   45)Placebo/ShamAir ( N   44)S-90 vsPlacebo, P  S-175 vsPlacebo, P  Gestational age, wkMean (SD) 25.5(1.4) 26.0(1.7) 25.7(1.4) .56 .12Median (range) 25(23–29) 26(23–29) 26(23–29)Birth weight, gMean (SD) 733(88) 773(97) 753(95) .31 .35Median (range) 740(500–887) 780(605–950) 740(605–950)Gender,  n  (%)Male 30(64) 24(53) 17(39) .02 .16Female 17(36) 21(47) 27(61)Race,  n  (%)White 30(64) 36(80) 31(70) .90 .50Black 7(15) 3(7) 6(14)Hispanic 9(19) 6(13) 6(14)Other 1(2) 0(0) 1(2)Multiplicity of birth,  n (%)Single 41(87) 29(64) 33(75) .14 .28Multiple 6(13) 16(36) 11(25)Mode of delivery,  n  (%)Vaginal 13(28) 14(31) 12(28) .97 .69Cesarean section 34(72) 31(69) 32(72)Apgar score at 5 min,  n  (%)  3 5(11) 1(2) 0(0) .08 .604–6 17(36) 18(40) 17(39)  7 25(53) 26(58) 27(61)Surfactant,  n  (%) 46(98) 44(98) 40(91) .15 .16IVH,  n  (%) 19(40) 17(38) 11(25) .13 .26 IVH indicates intraventricular hemorrhage. 809 infants 600–900 g136 enrolled47 lucinactant 90 mg/kg44 placebo/sham air  673 not enrolled:574 not eligible:185 not receiving mechanical ventilation97 other 93 F IO 2  < 0.3046 F IO 2  > 0.30 but less than 0.25 before randomization42 grade III/IV IVH22 did not receive surfactant on DOL 121 F IO 2  > 0.8 and MAP > 1215 rupture of membranes > 2 wk14 sepsis 11 congenital malformation10 another clinical trial/device8congenital heart disease6previous use of nitric oxide2previous use of corticosteroids2use of surfactant after 48 h99 eligible, not enrolled:71 no informed consent 28 not randomly assigned within 8 h of meeting eligibility 45 lucinactant 175 mg/kg FIGURE 1 Flow diagram of participants in the study. 92  LAUGHON et al  by guest on May 31, 2013pediatrics.aappublications.orgDownloaded from 
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