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* James Cook University Hospital, Middlesbrough, United Kingdom
Hospital Antoine-Beclere, AP/HP, Paris, France
Hospital de Cruces, University of Basque Country, Barakaldo, Bilbao (Bizkaia), Spain
|| State University of New York, Stony Brook, New York
¶ Poznan University of Medical Sciences, Poznan, Poland, and Polish Mother's Memorial Hospital Research Institute, Lódz, Poland
# Semmelweis Egyetem, Budapest, Hungary
** Sharp Mary Birch Hospital for Women, San Diego, California
Hospital General Gregorio Marañon, Madrid, Spain
Discovery Laboratories, Inc, Doylestown, Pennsylvania
|||| Boston University, Boston, Massachusetts
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Objective. We hypothesized that the outcomes for premature infants treated with lucinactant and poractant alfa would be similar. Therefore, we compared lucinactant (Surfaxin; Discovery Laboratories, Doylestown, PA) with porcine-derived, poractant alfa (Curosurf; Chiesi Farmaceutici, Parma, Italy) in a trial to test for noninferiority.
Methods. A total of 252 infants born between 24 and 28 weeks of completed gestation, with birth weights between 600 and 1250 g, were assigned randomly in a multicenter, multinational, noninferiority, randomized, controlled study to receive either lucinactant (n = 124) or poractant alfa (n = 128) within 30 minutes of life. The primary outcome was the incidence of being alive without bronchopulmonary dysplasia (BPD) through 28 days of age. Key secondary outcomes included death at day 28 and 36 weeks postmenstrual age (PMA), air leaks, neuroimaging abnormalities, and other complications related to either prematurity or RDS. An independent, international, data and safety monitoring committee monitored the trial.
Results. The treatment difference between lucinactant and poractant alfa for survival without BPD through 28 days was 4.75% (95% confidence interval [CI]: –7.3% to 16.8%) in favor of lucinactant, with the lower boundary of the 95% CI for the difference, ie, –7.3%, being greater than the prespecified noninferiority margin of –14.5%. At 28 days, 45 of 119 infants given lucinactant were alive without BPD (37.8%; 95% CI: 29.1–46.5%), compared with 41 of 124 given poractant alfa (33.1%; 95% CI: 24.8–41.3%); at 36 weeks PMA, the rates were 64.7% and 66.9%, respectively. The corresponding mortality rate through day 28 for the lucinactant group was lower than that for the poractant alfa group (11.8% [95% CI: 6.0–17.6%] vs 16.1% [95% CI: 9.7–22.6%]), as was the rate at 36 weeks PMA (16% and 18.5%, respectively). There were no differences in major dosing complications. In addition, no significant differences were observed in the incidences of common complications of prematurity, including intraventricular hemorrhage (grades 3 and 4) and cystic periventricular leukomalacia (lucinactant: 14.3%; poractant alfa: 16.9%).
Conclusions. Lucinactant and poractant alfa were similar in terms of efficacy and safety when used for the prevention and treatment of RDS among preterm infants. The ability to enhance the performance of a synthetic surfactant with the addition of a peptide that mimics the action of SP-B, such as sinapultide, brings potential advantages to exogenous surfactant therapy.
Key Words: surfactant protein-B • lucinactant • poractant alfa • bronchopulmonary dysplasia • respiratory distress syndrome • KL4
Abbreviations: RDS, respiratory distress syndrome • BPD, bronchopulmonary dysplasia • PMA, postmenstrual age • SP, surfactant protein • CI, confidence interval
Exogenous surfactant therapy improves pulmonary function and reduces mortality rates among premature infants with respiratory distress syndrome (RDS).1,2 Commercially available surfactants used for the prevention or treatment of RDS are either animal-derived or non–protein-containing synthetic products.3 Synthetic surfactants have highly reproducible compositions, are free of potential risk for immune reactions or infections, are capable of being produced in large quantities, and have been shown to improve outcomes, compared with placebo. However, adverse outcomes, such as pneumothorax, appear to be more frequent with the older, non–protein-containing synthetic surfactants, compared with animal-derived surfactants,4 and excess mortality rates observed in 1 trial led to withdrawal of 1 of these products.5 These differences have been ascribed to the absence of 2 key surfactant proteins (SPs), SP-B and SP-C, from currently available synthetic surfactants.6 The importance of SP-B over the other hydrophobic SP that plays a role in surfactant activity, namely, SP-C, is supported by the observations that knockout mice lacking the SP-B gene7 and human infants born with a genetic deficiency of SP-B exhibit severe fatal respiratory failure.8–10
Because animal-derived surfactants are obtained from either lung minces or lung lavages from cows or pigs and are purified and extracted with organic solvents, the amount of SP-B present in animal-derived surfactants differs among formulations, and the compositions of the same brands of surfactant show variability in protein content. Animal-derived surfactants contain foreign proteins that are potentially immunogenic,11 but data regarding the immunogenicity of modified natural surfactants are conflicting.8,12–14 Moreover, supplies of animal-derived surfactants can be limited because of their nonsynthetic method of production and the requirements for designated herds of animals for manufacture of product.
Recognition of the limitations of currently available surfactants has led to the development of newer synthetic surfactants containing peptides or recombinant proteins that mimic natural SPs. Lucinactant is a newly developed surfactant preparation containing phospholipids and a high concentration of a novel, synthetic, hydrophobic, 21-amino acid peptide (sinapultide, formerly known as KL4 peptide) that resembles one of the amphipathic domains of SP-B.15,16
The administration of lucinactant was shown to improve lung volume and oxygenation in a primate animal model of RDS.17 Furthermore, in an open-label pilot study,18 the administration of lucinactant to premature newborns with RDS was associated with improvements in oxygenation, ventilator parameters, and other outcomes similar to those observed with animal-derived surfactants.
We were interested to see whether the inclusion of a functional mimic of SP-B in a synthetic surfactant formulation (lucinactant) would provide clinical benefits similar to those of animal-derived surfactants for a population of premature infants at risk for RDS. For this, we chose poractant alfa, an animal-derived surfactant containing SP-B and SP-C, as the comparative agent, because a synthetic surfactant without apoproteins (pumactant, ALEC; Britannia Pharmaceuticals Limited, Redhill, Surrey, United Kingdom) was shown previously to be significantly inferior to this product, with a significantly higher mortality rate.5 We hypothesized that the addition of a synthetic peptide mimic of SP-B to a surfactant preparation of phospholipids would eliminate any clinical disadvantages associated with currently available older synthetic surfactants and that lucinactant would not be inferior to an animal-derived surfactant.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Treatment Strategies and Dosing Schedule
Within the first 30 minutes of life, each subject received 1 dose of either lucinactant at 175 mg/kg (5.8 mL/kg, 30 mg/mL) or poractant alfa at 175 mg/kg (2.2 mL/kg, 80 mg/mL), through the endotracheal tube. In previous clinical trials, similar outcomes were noted with poractant alfa at initial doses of either 100 mg/kg or 200 mg/kg.19 On the basis of the country-specific differences in starting doses recommended by the manufacturer and the recommendations of the scientific advisory board for this project, we chose to have identical amounts of phospholipid (175 mg/kg) delivered in the initial dose of the 2 surfactants. Both surfactants were stored at 4°C and prepared out of sight of study personnel. At this temperature, because of its unique peptide-phospholipid interaction, lucinactant is a gel that requires warming at 44°C in a warming cradle for 15 minutes and subsequent shaking to be converted into liquid form. Once prepared and drawn up into the syringe for administration, lucinactant comes to room temperature. Dosing for both surfactants was divided into 2 equal aliquots, and surfactants were administered 20 to 30 minutes after birth, via a 5-French, end-hole catheter passed through either a Bodai Neo2-Safe valve (B&B Medical Technologies, Orangevale, CA) or a Swivel-Valve (DHD Healthcare, Wampsville, NY), into the endotracheal tube to a location just beyond the tube's tip and above the carina. During dosing, the infant was given positive-pressure inflation either mechanically or manually, to prevent alveolar collapse and to improve distribution of the study drugs. The infants were positioned first in a right lateral decubitus position, with the head and thorax elevated 30 degrees, and then in an identically elevated left lateral decubitus position.
Infants were eligible to receive up to a maximum of 2 additional doses of either lucinactant (175 mg/kg) or poractant alfa (100 mg/kg per label) between 6 and 48 hours after the initial dose, if they met predetermined criteria assessed at 6-hour intervals. These criteria included a continuing requirement for mechanical ventilation, with a fraction of inspired oxygen of 
0.30, and roentgenographic evidence of RDS. Patients who required continued mechanical ventilation were treated with a time-cycled, pressure-limited strategy according to standardized ventilation and weaning guidelines developed specifically for the study. All other aspects of each infant's care were provided according to the local practices.
Definition of Outcome Variables
The primary outcome measure for this study was survival without bronchopulmonary dysplasia (BPD) through day 28. BPD was defined as dependence on supplemental oxygen or mechanical respiratory support through day 28. Secondary outcome parameters included complications typically associated with prematurity, RDS, and mechanical ventilation.
Study Design and Sample Size Calculation
Given the previously observed significant inferiority of pumactant (a surfactant made solely of phospholipids), compared with poractant alfa, this investigation was designed as a noninferiority trial in which we hypothesized that newborn infants treated with lucinactant would do no worse than those receiving poractant alfa. Therefore, the treatment effect had to be referenced to historical data involving poractant alfa in comparison with placebo, according to the guidelines of the International Conference on Harmonization.20 For lucinactant to be considered statistically noninferior to poractant alfa, the lower margin of the 95% confidence interval (CI) of the treatment difference (lucinactant minus poractant alfa) needed to be at least one half of the treatment difference observed in the only available controlled trial of poractant alfa versus placebo.21 In the latter historical investigation, 55% of infants who received poractant alfa were alive without BPD through day 28, compared with 26% of placebo-treated infants. Therefore, to achieve statistical noninferiority, the lower margin of the 95% CI for the treatment difference between lucinactant and poractant alfa had to be greater than –14.5% (26% – 55% = –29%; one half = –14.5%). With 2-sided testing with 
= .05 and ß = .1, the sample size calculation indicated that the number of patients needed per group to achieve this goal was 248.
Statistical Analyses
The noninferiority objective and other comparisons were assessed for all randomized patients who received at least 1 dose of surfactant. The primary outcome variable was tested with a 2-sided 95% CI of the treatment differences, with proportions based on a binomial distribution. Logistic regression analyses, adjusting for study center and weight, were used to analyze overall mortality rates and the incidence of BPD at 28 days of age and at 36 weeks postmenstrual age (PMA). For categorical analyses of secondary end points, the Cochran-Mantel-Haenszel test was used to compare treatment differences for nonparametric data and Fisher's exact test was used for comparisons of outcomes with small cell sizes. Statistical analyses were performed with SAS software, version 8.1 (SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Dosing
The mean numbers of doses (± SD) administered were similar for lucinactant and poractant alfa (1.5 ± 0.7 vs 1.3 ± 0.5). Eighty (67%) of the lucinactant-treated neonates received a single dose, compared with 92 (74%) of the poractant alfa-treated infants. During administration of the surfactants, there were no significant differences in the incidences of the following dosing complications: apnea, oxygen desaturation, bradycardia, or the need to cease administration.
Primary Outcome
The incidence of being alive without BPD through 28 days of age was 37.8% (95% CI: 29.1–46.5%) for the lucinactant-treated neonates, compared with 33.1% (95% CI: 24.8–41.3%) for the poractant alfa-treated infants. The treatment difference (lucinactant minus poractant alfa) was 4.7% (95% CI: –7.3% to 16.8%); the lower boundary of the 95% CI (–7.3%) was greater than the –14.5% limit needed to achieve statistical noninferiority (Fig 2). Calculations for the population studied indicated that the treatment difference of 4.7% would have a 99% CI lower boundary of –11.0%, which was still greater than the –14.5% limit needed to achieve statistical noninferiority. A supportive intention-to-treat analysis was also consistent in demonstrating noninferiority of lucinactant and poractant alfa.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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These observations contrast with what was observed in the pumactant versus poractant alfa study, in which 212 infants who were 25 to 29 weeks of gestational age and intubated for presumed surfactant deficiency, were randomized to receive 100 mg/kg of either the animal-derived surfactant poractant alfa or the non–protein-containing synthetic surfactant pumactant, containing phospholipids only.5 That trial was stopped after an interim analysis, which revealed that the all-cause mortality rate was 
65% lower among the infants assigned to poractant alfa (11% vs 25% overall; P < .01). The mortality rate for poractant alfa in our trial (18%), with adjustment for gestational age of up to 28 weeks, was similar to that observed in the pumactant versus poractant alfa trial (17%).5 Of particular importance is the observation that proportionally more patients were alive with lucinactant, compared with poractant alfa, throughout the course of the study (Fig 4 presents Kaplan-Meier survival plots). Although this difference in survival rates with lucinactant, compared with poractant alfa, was not statistically significant, the finding is in stark contrast to that observed with the non–protein-containing synthetic surfactant pumactant, compared with poractant alfa, supporting our hypothesis that peptide-containing lucinactant would not be inferior to protein-containing poractant alfa.
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The 2 surfactants in this study were equally effective in preventing RDS in a very low birth weight population. They had comparable incidences of common complications, and almost two thirds of infants, irrespective of treatment group, required only 1 dose of surfactant, which suggests comparable efficacy and safety.
In the current trial, we did not find significant differences in the occurrence of major dosing complications in the lucinactant group, compared with the poractant alfa group, despite the larger volumes of administration. Theoretically, administering a lower dosing volume of surfactant should result in fewer complications being noted during dosing. However, there are no data that support the contention that a smaller volume of surfactant has any clinical advantage in the treatment of RDS. In fact, in a comparison trial of 2.5 mL/kg (200 mg/mL) poractant alfa versus 1.25 mL/kg (100 mg/mL), decreased duration of oxygen requirements was observed for the higher-volume group.25 Some animal studies of induced surfactant deficiency suggested that a more homogeneous distribution of surfactant is achieved when larger volumes of surfactant are administered.26,27
This study was designed as a noninferiority trial, based on preservation of the benefits seen with poractant alfa in an earlier placebo-controlled trial.21 The latter trial was a rescue (treatment) trial, not one involving prophylactic administration of surfactant. Nonetheless, because it is the only published placebo-controlled trial of poractant alfa, it was necessary to use that trial to calculate the sample size for this investigation. The concepts underlying noninferiority trials are likely new to many readers. A randomized, double-blind, placebo-controlled trial is the optimal method for evaluating new treatments. However, once a new therapy has become a general standard of care, such as surfactant treatment of premature neonates, it is impossible to perform additional placebo-controlled trials with new surfactants. Therefore, we used an active-control, noninferiority, trial design. This trial design was discussed in several recent overviews.28–31 A possible limitation of our trial was the smaller sample size than originally estimated. Nonetheless, on the basis of the number of patients who were actually enrolled, it can be concluded that lucinactant is noninferior to poractant alfa. Even when we extended the analysis to calculate the 99% CI of the differences between the 2 groups (–11.0% to 20.5%), the lower limit of –11.0% remained above –14.5%, which strongly supports statistical noninferiority.
The findings of this trial are also consistent with the results of earlier in vitro studies in which sinapultide-containing lucinactant was superior to older non–protein-containing surfactants, as well as the protein-containing, animal-derived surfactants.32,33 With pulsating bubble surfactometry and capillary surfactometry, lucinactant was shown to be as efficient or more efficient in lowering surface tension than the animal-derived, protein-containing beractant, calfactant, and poractant alfa.34 Inactivation of endogenous surfactant by plasma proteins that leak into the alveolar space is a critical part of the lung injury sequence occurring in RDS. In comparison with the animal-derived surfactants, lucinactant is more resistant to inhibition by both plasma proteins and oxidants released during the inflammatory process.35 The therapeutic potential of lucinactant has also been noted in several other disorders, including meconium aspiration syndrome36 and acute RDS.37
This is the first clinical trial of lucinactant versus poractant alfa, which is the most widely used surfactant in Europe. The findings of our study indicated that lucinactant and poractant alfa were similar in efficacy and safety when used for the prevention and treatment of RDS among preterm infants. The ability to improve the performance of synthetic surfactants with the addition of a peptide that mimics the action of SP-B has potential advantages in terms of the absence of immunogenicity, the absence of risk for disease transmission, and the ability to manufacture large quantities with a high degree of consistency.
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ACKNOWLEDGMENTS |
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The contributors to the Surfaxin Therapy Against Respiratory Distress Syndrome (STAR) study included the following centers, investigators, and contributors.
Steering Committee: Sunil K. Sinha (chair), James Cook University Hospital (Middlesbrough, United Kingdom); T. Lacaze-Masmonteil, Hospital Antoine-Beclere, Assistance Publique/Hopitaux de Paris (Paris, France); A. Valls i Soler, Hospital de Cruces, University of Basque Country, Barakaldo, Bilbao (Bizkaia, Spain); J. Gadzinowski, Poznan University of Medical Sciences (Poznan, Poland) and Polish Mother's Memorial Hospital Research Institute (Lódz, Poland); and M. Sanchez-Luna, Hospital General Gregorio Marañon (Madrid, Spain).
Scientific Advisory Committee: C.G. Cochrane, the Scripps Institute (La Jolla, CA); S. M. Donn, Mott Children's Hospital, University of Michigan (Ann Arbor, MI); N. Finer, University of California, San Diego (San Diego, CA); J. Gadzinowski, Poznan University of Medical Sciences, Poznan, Poland and Polish Mother's Memorial Hospital Research Institute (Lódz, Poland); T. Allen Merritt, St Charles Medical Center (Bend, OR); and Fernando Moya (chair), University of Texas-Houston School of Medicine (Houston, TX).
Data and Safety Monitoring Committee: D.L. DeMets (chair), University of Wisconsin Medical School; E. Hey (retired neonatologist) (Newcastle on Tyne, United Kingdom); and I. Gross, Yale University School of Medicine (New Haven, CT).
Participating Investigators and Study Centers: United Kingdom: S. Sinha, James Cook University Hospital (Middlesbrough, United Kingdom); and D.A. Ducker, Medway Maritime Hospital (Kent, United Kingdom); Poland: J. Gadzinowski, Poznan University of Medical Sciences (Poznan, Poland) and Polish Mother's Memorial Hospital Research Institute (Lódz, Poland); E. Gulczynska, Polish Mother's Memorial Hospital Research Institute (Lódz, Poland); and M. Kornacka, Klinika Neonatologii Warsaw Medical University (Warsaw, Poland); Hungary: J. Hajdu, Semmelweis Egyetem (Budapest, Hungary); A. Nobilis, Semmelweis University (Budapest, Hungary); and G. Balla, University of Debrecen (Debrecen, Poland); Spain: E. Domenech, Hospital Universitario de Canarias (Santa Cruz de Tenerife, Spain); J. Lopez Sastre, Hospital Central de Asturias (Oviedo, Spain); M. Sanchez Luna, Hospital General Gregorio Maranon (Madrid, Spain); A. Valls i Soler, Hospital de Cruces (Bizkaia, Spain); and Xavier Kruel, Hospital S. Joan de Deu (Barcelona, Spain); Portugal: M. Guimaraes, Hospital de Sao Joao (Oporto, Portugal); and A. Costa, Hospital Garcia de Orta (Almada, Portugal); France: T. Lacaze-Masmonteil, Hopital Antoine Beclere, Assistance Publique/Hopitaux de Paris (Paris, France); P. Kuhn, Hôpital Universitaire de Strasbourg (Strasbourg, France); O. Claris, Hôpital Edouard Herriot (Lyon, France); and R. Lenclen, Centre Hospitalaire Intercommunal de Poissy (Poissy, France); United States: G. Bernstein, Sharp Mary Birch Hospital for Women (San Diego, CA); Canada: K. Sankaran, Royal University Hospital (Saskatoon, Canada).
Data Analysis Center: Joseph Massaro and Ralph d'Agostino, Boston University (Boston, MA).
Study Coordination Center: Robert Segal, Christopher J. Schaber, Vince Benn, Timothy Gregory, Valerie Parker, and Allison Evans, Discovery Laboratories (Doylestown, PA); Jan Mazela, University of Medical Sciences (Poznan, Poland); Biostatistics: Huei Tsai, Genzhou Liu, and Steve Chen, Discovery Laboratories (Doylestown, PA).
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FOOTNOTES |
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Address correspondence to Sunil K. Sinha, MD, PhD, Department of Paediatrics and Neonatal Medicine, University of Durham and the James Cook University Hospital, Marton Rd, Middlesbrough TS4 3BW, United Kingdom. E-mail: sunil.sinha{at}stees.nhs.uk
Conflict of interest: Members of the scientific advisory committee received payments from Discovery Laboratories for consulting in relation to this trial. The members of the steering committee received travel and subsistence expenses for attending committee meetings and scientific conferences in relation to this trial. Dr Thomas Wiswell retains an equity position in Discovery Laboratories, granted when he was an employee of the company. Drs Robert Segal and Christopher J. Schaber are employees of Discovery Laboratories Inc.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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