Published online April 1, 2005
PEDIATRICS Vol. 115 No. 4 April 2005, pp. 1018-1029 (doi:10.1542/peds.2004-2183)
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A Multicenter, Randomized, Masked, Comparison Trial of Lucinactant, Colfosceril Palmitate, and Beractant for the Prevention of Respiratory Distress Syndrome Among Very Preterm Infants

Fernando R. Moya, MD*, Janusz Gadzinowski, MD, PhD{ddagger}, Eduardo Bancalari, MD§, Vicente Salinas, MD||, Benjamin Kopelman, MD, Aldo Bancalari, MD#, Maria Katarzyna Kornacka, MD, PhD**, T. Allen Merritt, MD{ddagger}{ddagger}, Robert Segal, MD§§, Christopher J. Schaber, PhD§§, Huei Tsai, PhD§§, Joseph Massaro, PhD||||, Ralph d'Agostino, PhD¶¶ for the International Surfaxin Collaborative Study Group

* Department of Pediatrics, University of Texas Health Science Center at Houston, Houston, Texas
{ddagger} University of Medical Sciences, Poznan, Poland, and Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
§ Jackson Memorial Hospital, University of Miami, Miami, Florida
|| National Institute of Perinatology, Mexico City, Mexico
Hospital São Paulo, University of Sao Paulo, Paulista School of Medicine, Sao Paulo, Brazil
# Regional Clinical Hospital Guillermo Grant-Benavente, University of Concepción, Concepción, Chile
** Neonatology Clinic, Warsaw Medical University, Warsaw, Poland
{ddagger}{ddagger} St Charles Medical Center, Bend, Oregon
§§ Discovery Laboratories, Doylestown, Pennsylvania
|||| Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
¶¶ Statistics and Consulting Unit, Department of Mathematics and Statistics, Boston University, Boston, Massachusetts


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background and Objective. Evidence suggests that synthetic surfactants consisting solely of phospholipids can be improved through the addition of peptides, such as sinapultide, that mimic the action of human surfactant protein-B (SP-B). A synthetic surfactant containing a mimic of SP-B may also reduce the potential risks associated with the use of animal-derived products. Our objective was to compare the efficacy and safety of a novel synthetic surfactant containing a functional SP-B mimic (lucinactant; Discovery Laboratories, Doylestown, PA) with those of a non–protein-containing synthetic surfactant (colfosceril palmitate; GlaxoSmithKline, Brentford, United Kingdom) and a bovine-derived surfactant (beractant; Abbott Laboratories, Abbott Park, IL) in the prevention of neonatal respiratory distress syndrome (RDS) and RDS-related death.

Methods. We assigned randomly (double-masked) 1294 very preterm infants, weighing 600 to 1250 g and of ≤32 weeks gestational age, to receive colfosceril palmitate (n = 509), lucinactant (n = 527), or beractant (n = 258) within 20 to 30 minutes after birth. Primary outcome measures were the rates of RDS at 24 hours and the rates of death related to RDS during the first 14 days after birth. All-cause mortality rates, bronchopulmonary dysplasia (BPD) rates, and rates of other complications of prematurity were prespecified secondary outcomes. Primary outcomes, air leaks, and causes of death were assigned by an independent, masked, adjudication committee with prespecified definitions. The study was monitored by an independent data safety monitoring board.

Results. Lucinactant reduced significantly the incidence of RDS at 24 hours, compared with colfosceril (39.1% vs 47.2%; odds ratio [OR]: 0.68; 95% confidence interval [CI]: 0.52–0.89). There was no significant difference in comparison with beractant (33.3%). However, lucinactant reduced significantly RDS-related mortality rates by 14 days of life, compared with both colfosceril (4.7% vs 9.4%; OR: 0.43; 95% CI: 0.25–0.73) and beractant (10.5%; OR: 0.35; 95% CI: 0.18–0.66). In addition, BPD at 36 weeks postmenstrual age was significantly less common with lucinactant than with colfosceril (40.2% vs 45.0%; OR: 0.75; 95% CI: 0.56–0.99), and the all-cause mortality rate at 36 weeks postmenstrual age was lower with lucinactant than with beractant (21% vs 26%; OR: 0.67; 95% CI: 0.45–1.00).

Conclusions. Lucinactant is a more effective surfactant preparation than colfosceril palmitate for the prevention of RDS. In addition, lucinactant reduces the incidence of BPD, compared with colfosceril palmitate, and decreases RDS-related mortality rates, compared with beractant. Therefore, we conclude that lucinactant, the first of a new class of surfactants containing a functional protein analog of SP-B, is an effective therapeutic option for preterm infants at risk for RDS.

Key Words: lucinactant • colfosceril palmitate • beractant • surfactant • respiratory distress syndrome

Abbreviations: RDS, respiratory distress syndrome • BPD, bronchopulmonary dysplasia • OR, odds ratio • CI, confidence interval • IVH, intraventricular hemorrhage • PVL, periventricular leukomalacia • PMA, postmenstrual age • SP, surfactant protein • DPPC, dipalmitoylphosphatidylcholine • FIO2, fraction of inspired oxygen

The lungs of preterm infants with respiratory distress syndrome (RDS) are deficient in pulmonary surfactant,1 and the administration of exogenous surfactants improves oxygenation and reduces neonatal mortality rates among affected newborn infants.2,3 Surfactants that have been used therapeutically include synthetic products that contain phospholipids but no surfactant proteins (SPs) and natural surfactants derived from human amniotic fluid or bovine and porcine sources, which contain phospholipids and variable amounts of SPs (primarily SP-B and -C).4

Synthetic surfactants may have certain advantages over animal-derived products, because the latter may be immunogenic,5,6 can contain proinflammatory mediators7 involved in the pathogenesis of respiratory disease,8,9 and are potentially capable of transmitting animal-borne infectious agents. The immunogenic potential of the animal-derived SPs and clinical implications have been the subject of controversy. Although some investigators failed to find antibodies (with an enzyme-linked immunosorbent assay) to SP-B and SP-C among very premature infants treated with beractant,10,11 Hamvas et al12 unequivocally demonstrated antibodies to bovine SP-B epitopes among infants. Antibodies generated against SP-B have been shown to inactivate in vitro and in vivo the porcine-derived surfactant poractant alfa13 and can lead to airway leakage of proteins and respiratory failure.14 In addition, respiratory failure was reported to be induced by antibodies raised against SP-B from poractant alfa.15

In systematic reviews, however, non–protein-containing synthetic surfactants appeared to be inferior to animal-derived products in improving pulmonary function and clinical outcomes,3 a difference that has been attributed to the absence of SP-B and SP-C in the synthetic products.16 Of the 4 known SPs (SP-A, SP-B, SP-C, and SP-D), the hydrophobic SPs SP-B and SP-C are known to act in a critical manner to stabilize and enhance the ability of phospholipids to lower surface tension. Of the 2, SP-B appears to play the dominant role, because infants who are congenitally deficient in SP-B17 develop lethal respiratory failure shortly after birth, whereas those deficient in SP-C tend to develop chronic lung disease in early adulthood.18 Recognition of the importance of SP-B led to the development of lucinactant, a new surfactant that contains not only phospholipids but also high concentrations of sinapultide, a 21-amino acid synthetic peptide consisting of lysines (K) and leucines (L) arranged in the sequence KLLLLKLLLLKLLLLKLLLLK, which mimics the actions of human SP-B.19 Although it has been suggested that this peptide forms a transmembrane helix and therefore more likely mimics SP-C, this structural orientation is seen only in phospholipid bilayers20,21 and not in the physiologic phospholipid monolayer in vivo, where the sinapultide spatial structure resembles 1 of the amphipathic domains of SP-B.22 Sinapultide is more resistant than naturally occurring SP-B to inhibition by serum proteins and reactive oxygen species.23,24 Lucinactant reduces surface tension as well as or better than animal-derived surfactants25 and has been shown to improve oxygenation and ventilation among preterm infants with established RDS.26 Therefore, we hypothesized that lucinactant would be more effective in the prevention of RDS than a synthetic surfactant containing only phospholipids and would have a clinical effect at least comparable to that observed with administration of an animal-derived surfactant. We also intended to use this trial for global regulatory approval of lucinactant.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Patients
Infants at risk for developing RDS were eligible for the study if they had a gestational age between 24 and 32 weeks, had a birth weight between 600 and 1250 g, and had undergone endotracheal intubation. Infants were not allowed to participate if they had an Apgar score of <3 at 5 minutes; a major congenital malformation or chromosomal abnormality; circulatory instability in the delivery room, as evidenced by the need for chest compression, epinephrine, bicarbonate, or fluid bolus; or had a mother with rupture of membranes of >2 weeks. Infants were recruited from 50 tertiary NICUs in Europe and Latin America. The institutional review boards of all 50 participating institutions approved the protocol. Written informed consent was obtained from the parents of all patients before randomization.

Study Surfactants
Lucinactant is manufactured by Discovery Laboratories. The 2 surfactants used for comparison were acquired commercially (colfosceril palmitate; GlaxoSmithKline, Brentford, United Kingdom; and beractant; Abbott Laboratories, Abbott Park, IL) and distributed to participating sites by a central independent distributor. According to manufacturers' recommendations, lucinactant and beractant were stored refrigerated and colfosceril palmitate was stored at room temperature. Before administration, lucinactant was placed in a specially designed warming cradle, set at 44°C, for 15 minutes and was shaken vigorously to ensure a uniform, free-flowing, liquid instillate. Beractant was allowed to come to room temperature over 20 minutes and was swirled gently before administration. Colfosceril palmitate was prepared with sterile water and shaken gently. The doses used were lucinactant at 175 mg of phospholipid per kg (5.8 mL/kg, 30 mg/mL), colfosceril palmitate at 67.5 mg of phospholipids per kg (5.0 mL/kg, 13.5 mg/mL), and beractant at 100 mg of phospholipid per kg (4.0 mL/kg, 25 mg/mL). The composition of lucinactant is as follows: each milliliter contains 30 mg of total phospholipids including 22.5 mg of dipalmitoylphosphatidylcholine (DPPC), 7.5 mg of palmitoyloleyl-phosphatidyl glycerol sodium salt, 4.05 mg of palmitic acid, and 0.801 mg of sinapultide (KL4) in tromethamine sodium chloride buffer.27 Colfosceril palmitate is a protein-free synthetic surfactant that contains a single phospholipid, DPPC, cetyl alcohol, and tyloxapol. When reconstituted according to manufacturer's instructions, each milliliter contains 13.5 mg of DPPC, 1.5 mg of cetyl alcohol, and 1 mg of tyloxapol.28 Beractant is an organic extract of bovine lung extract that contains phospholipids, neutral lipids, fatty acids, and bovine SPs, to which DPPC, palmitic acid, and tripalmitin are added. The composition provides 25 mg/mL phospholipids, 0.5 to 1.75 mg/mL triglycerides, 1.4 to 3.5 mg/mL free fatty acids, and <1.0 mg/mL total SPs (SP-B and/or SP-C).29

Study Design
Sites were selected individually by an independent steering committee that consisted of neonatal, clinical trial, and statistical experts in addition to the sponsor, Discovery Laboratories, to ensure proper conduct and execution of the trial. All sites underwent on-site inspections by members of the steering committee and the sponsor. An independent, international, data safety and monitoring board oversaw the trial. The primary end points, air leaks and deaths, were evaluated by an independent adjudication committee (see below). Ventilator management guidelines were established by the steering committee, to encourage use of a uniform approach to treating patients across the 50 participating multinational sites. In addition to frequent good clinical practice monitoring of the sites by the sponsor during the entire course of the study, a team of local expert neonatologists provided oversight of compliance with the protocol and ventilator strategies used during the trial, reporting back to the steering committee. These approaches all ensured the rigorous oversight of the execution of the study, with strict adherence to the protocol.

Randomization occurred after birth if entry criteria were met (Fig 1) and written informed consent had been obtained from the parent(s) before delivery. Infants were randomized, in a masked manner, to receive lucinactant, colfosceril palmitate, or beractant in a 2:2:1 ratio, with randomization stratified according to birth weight (600–800 g, 801–1000 g, or 1001–1250 g). Treatment was initiated within 20 to 30 minutes after birth.


Figure 1
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  		Fig 1. Enrollment flow diagram. This flow chart diagrams the patient flow through screening for eligibility, enrollment, and allocation. The asterisk indicates patients not receiving study drug.

 
Randomization codes according to birth weight stratum were computer-generated by an independent, university-based, statistical analysis center. Each institution received sealed envelopes with randomization codes, to be opened sequentially as each new patient was randomized. To maintain masking, the identity of the medication assignment was not known by the neonatologists or staff members caring for the infants or by the infants' families but was known only by those who prepared and administered the drugs. These individuals, who were from other areas of the hospital, included pharmacists, respiratory therapists, and nurses trained to deliver surfactant therapy. After drug preparation and/or dosing, these individuals were not involved in the infant's medical management and did not reveal the identity of the study medications to the health care providers treating the infants. All surfactant doses were administered in 4 aliquots with syringes covered with adhesive opaque paper, via a 5-French, end-hole catheter passed through a Bodai Neo2-Safe valve (B&B Medical Technologies, Orangevale, CA) or a Swivel-Valve (DHD Healthcare, Wampsville, NY) attached to the endotracheal tube, to a point just past the tube's tip and above the carina. All drugs (including sham air) were administered as a bolus as rapidly as possible, generally in a few seconds, with the infant being positioned sequentially to ensure homogeneous distribution of material throughout the lungs. During administration, positive pressure in the circuit was maintained with manual or mechanical ventilation.

After initial dosing, infants were treated according to the best judgment of their physicians and received all appropriate treatments other than open-label surfactants. Infants who required mechanical ventilation were treated with time-cycled, pressure-limited ventilators according to specific guidelines developed for the study, which attempted to maintain a partial pressure of oxygen in arterial blood of 50 to 80 mm Hg, a partial pressure of carbon dioxide in arterial blood of 40 to 50 mm Hg, and oxygen saturations between 88% and 95%. Trained personnel at each site ensured that ventilator settings were adjusted rapidly to changing physiologic conditions, to minimize the risk of pulmonary injury (eg, volutrauma or barotrauma). Furthermore, at 6, 12, 18, and 24 hours after the initial dose, the clinical status and respiratory status of each infant were reassessed, to determine whether additional surfactant therapy was needed. These time points were chosen to maintain masking, because the interval for retreatment varies among surfactants. Infants received additional doses of their randomized surfactant if they required continued mechanical ventilation with a mean airway pressure of ≥6 cm H2O, required a fraction of inspired oxygen (FIO2) of ≥0.30 to maintain a partial pressure of oxygen in arterial blood between 50 and 80 mm Hg, and had radiographic evidence of RDS. According to manufacturer' recommendations, infants could receive up to 3 retreatments with lucinactant or beractant (at 6-hour intervals) or up to 2 retreatments with colfosceril palmitate (at 12-hour intervals). To maintain masking, infants not scheduled to receive active treatment at a specified time would receive a "sham" administration of a matching volume of air in a covered syringe. No crossover between treatment groups was allowed. After treatment, patients were evaluated on an ongoing basis for complications associated with RDS, prematurity, and mechanical ventilation, up to 36 weeks postmenstrual age (PMA) or discharge.

Study End Points
The prespecified adjudicated primary end points of the study were the development of RDS at 24 hours and the occurrence of death related to RDS through 14 days of age.30 The protocol indicated that, to merit a conclusion that the trial had reached its objectives, both end points had to be achieved with P values of <.05; therefore, no adjustment was made for the specification of 2 end points. Both primary end points, plus the incidence of air leaks through 7 days of age and causes of death, were adjudicated with prespecified definitions by an independent committee of neonatologists and pediatric radiologists, who, while masked to the treatment assignments, reviewed the chest radiographs and other pertinent clinical and laboratory data for all infants through these time points. RDS was defined as the need for FIO2 of ≥0.30, combined with the demonstration of a reticulogranular pattern on a chest radiograph obtained at 24 ± 4 hours of age. RDS-related deaths included deaths associated with RDS through the first 14 days of life, excluding other causes of respiratory failure leading to death and other causes of death. RDS-associated deaths included deaths resulting from pulmonary hemorrhage if the RDS had not resolved before the development of this complication, from severe respiratory failure, or from air leaks that occurred in the presence of severe RDS. Deaths attributable to sepsis, pneumonia, or pulmonary hypoplasia were assigned as not related to RDS. Secondary outcome measures included all-cause mortality rates, bronchopulmonary dysplasia (BPD) (defined as the need for supplemental oxygen to maintain saturations of 88–96% at 28 days or 36 weeks PMA), and other specific complications of prematurity, RDS, and mechanical ventilation, eg, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), retinopathy of prematurity, pulmonary hemorrhage, and sepsis.

The prespecified primary comparison of interest was that of lucinactant and colfosceril palmitate. Therefore, the study was powered to test differences between these 2 products. The hypothesis being tested was that a synthetic surfactant containing a peptide mimicking the function of SP-B (lucinactant) would be superior to that of a non–protein-containing synthetic surfactant (colfosceril palmitate). On the basis of a recommendation by the Food and Drug Administration, an animal-derived, protein-containing surfactant was added to anchor the results with those that might be observed with a commonly used surfactant. Therefore, beractant was included as a reference arm, and the comparison between lucinactant and beractant was of secondary interest. To keep the trial at a workable size, a 2:2:1 randomization scheme was used, meaning that one half the number of patients were to be enrolled in the beractant treatment arm. The trial was designed to be event-driven, and the expected frequency of events was based on the observations reported in an earlier trial comparing synthetic and animal-derived surfactants.30 Accordingly, we anticipated that the frequency of RDS would be ~40% for colfosceril palmitate but only 30% for lucinactant and the frequency of death related to RDS up to 14 days would be 7.5% for colfosceril palmitate but only 3.5% for lucinactant. On the basis of these assumptions, the trial would continue until 420 infants had developed RDS and 66 infants had died from RDS-related causes. This number of events would provide 94% power to detect the prespecified difference between lucinactant and colfosceril palmitate for the occurrence of RDS at 24 hours and 83% power for the occurrence of death related to RDS by 14 days.

All interim and final analyses were conducted by the university-based, statistical center, independent of the sponsor. The independent data and safety monitoring board periodically reviewed the unmasked results and was empowered to recommend early termination of the study if it observed a major safety issue.

Statistical Analyses
Differences between the 2 groups in the occurrence of each of the 2 primary end points and the occurrence of all secondary end points were assessed with logistic regression analyses, adjusted for study center and birth weight stratum. This method was chosen to allow for adjustment in covariates. These analyses included all randomized patients, and all fatal and nonfatal events that occurred during the planned duration of treatment were assigned to the patient's randomized treatment group (according to the intention-to-treat principle), whether or not patients received the study medication. Differences in mortality risk were also evaluated with a time-to-first-event approach; cumulative survival curves were constructed with Kaplan-Meier survivorship methods. The baseline characteristics of the 2 treatment groups were compared (adjusted for study center) with the Wilcoxon test (for continuous and ordinal variables) and the Cochran-Mantel-Haenszel test (for categorical variables). Differences between treatment groups in the distribution of categorical responses (primary end point) were tested for significance with the use of the Cochran-Mantel-Haenszel test and Fisher's exact test. Statistical analyses were performed with SAS software, version 8.1 (SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Enrollment and Demographic Characteristics
Between July 2001 and December 2003, 6551 infants were evaluated for eligibility, of whom 1294 were randomized into the trial, 527 to lucinactant, 509 to colfosceril palmitate, and 258 to beractant (Fig 1). Screening failures included infants who did not meet inclusion criteria and/or for whom consent was not obtained (Table 1). More than one half of all infants received only a single dose of surfactant (55%, 53%, and 62% of the lucinactant, colfosceril palmitate, and beractant groups, respectively). Six infants (0.46%; 3 in the lucinactant group and 3 in the colfosceril group) did not receive any surfactant, and 4 patients received the incorrect agent inadvertently (2 beractant patients, 1 of whom received lucinactant and the other colfosceril, and 2 colfosceril patients, who received beractant). However, as prespecified, the patients were included in the intention-to-treat analysis. The mean time (± SD) for administration of the initial dose of each surfactant was 27 ± 2.9 minutes for lucinactant, 26 ± 3.0 minutes for colfosceril, and 26 ± 3.0 minutes for beractant (not significant). Study completers were defined as patients who were monitored through the 36-week PMA evaluation or had died before this visit and for whom complete information was available. A total of 522 of 527 patients (99.1%) in the lucinactant group and 505 of 509 patients (99.2%) in the colfosceril group were study completers; only 1 patient was lost to follow-up monitoring with respect to survival status through the final evaluation at 36 weeks PMA. Data for all beractant patients were available. The 3 groups were similar with respect to their baseline demographic and clinical characteristics (Table 2).


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  		TABLE 1. Patient Screening and Enrollment

 

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  		TABLE 2. Maternal and Neonatal Demographic Features

 
Primary Outcomes
Among the randomized infants, 47.2% of the colfosceril palmitate group but only 39.1% of the lucinactant group had RDS at 24 hours (odds ratio [OR]: 0.68; 95% confidence interval [CI]: 0.52–0.89; P = .005) (Fig 2). In addition, 9.4% of infants in the colfosceril palmitate group but only 4.7% of those in the lucinactant group died as a result of RDS-related causes by 14 days (OR: 0.43; 95% CI: 0.25–0.73; P = .002). Although the effects of lucinactant and beractant on the occurrence of RDS at 24 hours were not statistically different (39.1 vs 33.3%, P = .108), the risk of death resulting from RDS-related causes was significantly lower with lucinactant, compared with beractant (4.7% vs 10.5%; OR: 0.35; 95% CI: 0.18–0.66; P = .001). Analyses of the coprimary end points with the number of actual treated infants yielded results that were essentially identical to those for the intention-to-treat population.


Figure 2
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  		Fig 2. Primary outcome variables. ORs and 95% CIs for treatment differences between lucinactant and colfosceril palmitate (top) and between lucinactant and beractant (bottom) are shown. The box size is proportional to the event rate. The data reflect the number of events in each treatment group for each variable; the percentage of randomized infants is shown in parentheses. The P values denote the significance of the between-group difference for each end point.

 
Death, BPD, and Other Complications of Prematurity
More infants were alive and without BPD at 28 days and 36 weeks PMA in the lucinactant group than in the colfosceril palmitate group (P = .052 at 28 days and P = .021 at 36 weeks PMA) (Fig 3). This benefit resulted from both a reduction in the all-cause mortality rate and a reduced frequency of BPD. Specifically, the incidence of BPD was lower among infants treated with lucinactant than among those treated with colfosceril palmitate (OR: 0.75; 95% CI: 0.56–0.99; P = .045 at 36 weeks PMA). Postnatal steroid use did not differ among the groups (28.6%, 32%, and 31.4% for lucinactant, colfosceril palmitate, and beractant, respectively). In addition, the all-cause mortality rate at 36 weeks PMA was lower for the lucinactant group than for the colfosceril palmitate group (OR: 0.80; 95% CI: 0.58–1.11), although this difference was not statistically significant (P = .182). When lucinactant was compared with beractant, the incidences of BPD were similar at both 28 days and 36 weeks PMA, but the all-cause mortality rate at 36 weeks PMA was lower among infants treated with lucinactant (OR: 0.67; 95% CI: 0.45–1.00; P = .051) (Fig 4).


Figure 3
Figure 3
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  		Fig 3. Secondary outcome variables, namely, complications of prematurity. ORs and 95% CIs for treatment differences between lucinactant and colfosceril palmitate (A) and between lucinactant and beractant (B) are shown. The box size is proportional to the event rate. The data reflect the number of events in each treatment group for each variable; the percentage of randomized infants is shown in parentheses. IVH values represent the overall worst case at any given time. The P values denote the significance of the between-group difference for each end point. ROP indicates retinopathy of prematurity; PIE, pulmonary interstitial emphysema.

 

Figure 4
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  		Fig 4. All-cause mortality rates for the duration of the follow-up period. Kaplan-Meier survival plots, through a 36-week follow-up period, for infants treated with lucinactant, colfosceril palmitate, and beractant are shown. The all-cause mortality rates at 36 weeks PMA were 111 of 527 infants (21.1%) for lucinactant, 121 of 509 infants (23.8%) for colfosceril palmitate, and 68 of 258 infants (26.4%) for beractant (OR according to prespecified logistic regression: 0.80; 95% CI: 0.58–1.11; P = .182, for lucinactant versus colfosceril; OR: 0.67; 95% CI: 0.0.45–1.00; P = .051, for lucinactant versus beractant).

 
The frequencies for all other prespecified secondary outcome variables (eg, air leaks, IVH, PVL, retinopathy of prematurity, pulmonary hemorrhage, and sepsis) were similar across the 3 treatment groups (Fig 3), as were the overall rates of patent ductus arteriosus (37%), necrotizing enterocolitis (17%), and apnea (52%). IVH (grade III or IV) or PVL occurred at 21.8%, 22.0%, and 21.3% in the lucinactant, colfosceril, and beractant treatment groups, respectively. Necrotizing enterocolitis (stage 2 or 3) occurred at 6.5%, 8.3%, and 13.6% in the lucinactant, colfosceril, and beractant treatment groups, respectively (P < .001 for lucinactant versus beractant).

Dosing and Ventilatory Support
The mean number of doses (± SD) did not differ between groups (lucinactant: 1.9 ± 1.2; colfosceril: 2.1 ± 1.4; beractant: 1.7 ± 1.2). Transient peridosing events (common to treatment with surfactants) observed during administration of any dose occurred at higher rates for both lucinactant and beractant, compared with colfosceril. These included transient pallor (12.4% and 12.8% vs 7.1%; P < .05, lucinactant and beractant versus colfosceril), transient dose interruption (11.8% and 9.7% vs 7.3%; P < .05, lucinactant versus colfosceril), and transient endotracheal obstruction (8.4% and 6.6% vs 3.8%; P < .05, lucinactant versus colfosceril). Rates of endotracheal tube reflux were not significantly different among the groups (25.2%, 20.9%, and 26.9% for lucinactant, beractant, and colfosceril, respectively). These results represent peridosing events observed with all attempts to administer surfactant, including events reported during sham-air dosing, which was required to maintain the masking in the colfosceril group (see Methods).

The FIO2 and mean airway pressure needed to maintain adequate oxygenation decreased progressively in all 3 treatment groups during the first 72 hours, but the decrease in both respiratory variables at 24 hours was greater with both lucinactant and beractant, compared with colfosceril palmitate. Areas under the curve for 0 to 72 hours for FIO2 were 0.38 ± 0.19 and 0.37 ± 0.19 for lucinactant and beractant, respectively, compared with 0.40 ± 0.20 for colfosceril (P < .05). Areas under the curve (0–72 hours) for mean airway pressure showed similar trends among groups (4.43 ± 3.47 and 4.13 ± 3.49 vs 4.66 ± 3.47) but did not reach statistical significance for any comparison.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
This study demonstrated that a surfactant containing a synthetic peptide that mimics the function of SP-B (lucinactant) reduced the occurrence and consequences of RDS among very preterm infants more effectively than did a synthetic surfactant devoid of SPs (colfosceril palmitate). Infants treated with lucinactant were less likely to develop RDS and less likely to die of causes related to RDS than were those treated with colfosceril palmitate. We selected these primary outcomes because they were used in the only previously reported trial comparing prophylactic use of colfosceril versus calfactant.30 However, our trial is the only one that has involved completely independent adjudication of all major outcomes. In addition, the need for ventilatory support decreased more rapidly with lucinactant, and more infants were alive without BPD in the lucinactant group than in the colfosceril palmitate group. This latter benefit was related to both a reduction in the all-cause mortality rate and a reduced frequency of BPD. These results suggest that the addition of a peptide that mimics the function of SP-B, such as sinapultide, to a mixture of surfactant phospholipids improves the efficacy of synthetic surfactants for the prevention and treatment of RDS.

The results of this study are consistent with those of earlier trials that compared synthetic surfactants lacking SPs with animal-derived surfactants containing variable quantities of SP-B and SP-C.3,30,31 Of those studies, only the trial by Hudak et al30 used a prophylactic approach. In those studies, infants treated with animal-derived surfactants experienced more rapid improvement in oxygenation and lung compliance. This improvement in pulmonary function probably reflected a lower risk for development of RDS and also lesser disease severity. In keeping with these previous observations, infants in our study who received beractant had less RDS at 24 hours (colfosceril: 47.2%; beractant: 33.3%; P < .01) and were weaned to a lower FIO2 than were those exposed to colfosceril. However, as in previous trials comparing beractant and colfosceril, these improvements did not translate into a lower mortality rate or a reduced incidence of BPD.3,32,33

The superiority of animal-derived surfactants over non–protein-containing synthetic surfactants seemed consistent with the importance of SP-B, but animal-derived surfactants also contain SP-C, which might have contributed importantly to the observed benefits.31 Several experimental lines of evidence have supported a more important role for SP-B over SP-C in the effectiveness of exogenous surfactants. SP-B promotes the rapid absorption and stabilization of phospholipids at the air-liquid interface and accounts for the sustained low surface-tension activity after dynamic compression.34,35 Although SP-C is also highly hydrophobic, it seems to contribute less than SP-B to the surface tension-lowering properties of natural surfactant.36 Preterm infants with RDS are deficient in SP-B for several days after birth, and infants with the lowest levels of SP-B are most likely to die as a result of the syndrome.37 The importance of SP-B is supported by the observation that SP-B gene-knockout mice and human infants born with a genetic deficiency of SP-B exhibit severe fulminant respiratory failure, whereas the congenital absence of SP-C is usually not lethal.17,18,38 Addition of peptides that mimic the function of SP-B, such as sinapultide, to a mixture of surfactant phospholipids enhanced gas exchange and pulmonary function in experimental RDS and among preterm infants with established RDS.26,39 However, it was not clear whether this improvement in pulmonary function would translate into reductions in the risks of major adverse clinical events in a large, controlled, clinical study. The current trial, when taken together with evidence from earlier comparative studies and the aforementioned biochemical data, supports the hypothesis that SP-B is the critical element in determining the enhanced benefit of animal-derived surfactant therapy and that the selective addition of a peptide that mimics the function of SP-B is sufficient to improve the major clinical outcomes targeted by surfactant therapy.

The doses of phospholipids administered varied among the groups, but this was a function of the fact that we were using the products appropriately at doses that are used typically in clinical practice and have been approved by regulatory agencies around the world. These doses were also used in several other controlled trials comparing these surfactants (reviewed in ref 3). Moreover, at least for colfosceril, no additional clinical improvements were demonstrated with a 50% higher dose of phospholipids.40 Most of the argument in favor of the clinical advantage of animal-derived surfactants over synthetic surfactants has been based on the presence of SPs and not on the fact that the former products provide more phospholipids than does colfosceril (approximately one third more and up to 3 times more for high-dose poractant).34,35,41 The idea that the amount of phospholipids may not be the determining factor in the clinical efficacy of surfactants was substantiated by the recent comparison of pumactant, a mixture of 2 phospholipids used at a dose of 100 mg/kg (one third more than colfosceril), and 100 mg/kg poractant, which contains SP-B and SP-C.42 The study was stopped early because overall mortality rates were higher with pumactant (31%) than with poractant (14%).

Because we hypothesized that SP-B was the primary SP contributing to the effectiveness of animal-derived surfactants, we anticipated that lucinactant (containing only a peptide that mimics the function of SP-B) would prove at least similar to beractant (an animal-derived surfactant containing small quantities of SP-B and a predominance of SP-C35,43,44) across outcome variables related to RDS in the current trial. In contrast, if SP-C was more important, then lucinactant would be expected to be inferior to beractant. We found that infants treated with lucinactant, compared with beractant, had a significantly lower rate of death attributable to causes related to RDS up to 14 days after birth (P < .001) and also a lower rate of death for any reason at 36 weeks PMA (P = .051). Although the comparison between lucinactant and beractant was not the primary objective of this study, the observed difference in the risk of death between the 2 treatments is difficult to ignore, because previous large comparison trials failed to find differences in mortality rates or the incidence of BPD among infants treated with a synthetic surfactant or beractant.32,33 What could account for this difference? The concentration of sinapultide in lucinactant is consistently much higher26 than the SP-B concentration in beractant, which is low and variable, as well as that in other animal-derived surfactants.35,43 In fact, beyond batch-to-batch variations, the concentration of hydrophobic SPs in animal-derived products may be too low to support effectively the rapid absorption of phospholipids to the air-liquid interface.34,35 Furthermore, compared with beractant, the engineered hydrophobic peptide sinapultide was designed without tyrosine residues, which makes it more resistant to endogenous inactivation by reactive oxygen species and serum proteins23,45 known to contribute to the severity of RDS among preterm infants. It is also important to note that lucinactant does not alter human type II cell physiologic processes and does not down-regulate SP gene expression.46 Therefore, our finding that lucinactant may be superior to beractant in reducing the mortality rate associated with RDS (but not its occurrence) is consistent with this trial's original hypothesis concerning the central role of SP-B or of peptides that mimic its function.

Earlier studies comparing animal-derived and synthetic surfactants reported incidences of pneumothorax between 4 and 22%, although most studies involved rescue administration of surfactant (reviewed in ref 3). Infants who received animal-derived surfactants had a lower risk of air leaks in those studies, but no such difference was seen in the current study. The lack of difference may be related to prenatal steroid use (infrequent in earlier trials) and to the prospective implementation of ventilatory guidelines aimed to reduce the risk of volutrauma. Moreover, trial outcomes such as air leaks have seldom been adjudicated independently, and several studies did not report the occurrence of pulmonary interstitial emphysema, the most common form of air leak in this population.32,33,42 In the current trial, infants treated with lucinactant had a lower risk of BPD than did those treated with colfosceril palmitate. Infants who received lucinactant had improved chances of being alive without BPD at 28 days and 36 weeks PMA, compared with those who received colfosceril palmitate. Such a benefit has not been observed previously in trials comparing animal-derived and synthetic surfactants.3 In a sister trial of similar design reported in this issue of Pediatrics,47 lucinactant was compared with poractant alfa (Chiesi Pharmaceuticals, Parma, Italy), a porcine-derived surfactant used extensively in Europe. Poractant alfa is purported to have more SP-B than beractant, but this is less than the relative amount of sinapultide in lucinactant. Being alive without BPD at 28 days, the primary outcome in the study, occurred for 37.8% of infants given lucinactant, compared with 33.1% of those given poractant alfa. The all-cause mortality rate was also lower with lucinactant (11.8%) than with poractant alfa (16.1%) at 28 days of age, although neither of these outcome differences reached statistical significance. Therefore, evidence from these 2 controlled trials suggests that using an exogenous surfactant with a greater relative amount of a peptide that mimics the function of SP-B, ie, sinapultide, may provide additional benefits in the prevention and treatment of RDS.

Earlier comparative trials also noted some disadvantages of animal-derived surfactants, ie, potentially greater risks of sepsis,48 IVH,30 and PVL, compared with synthetic surfactants. These risks have been ascribed to the immunomodulating properties and extremely rapid onset of action of some animal-derived products (the latter leading to sudden changes in blood flow to and hydrostatic pressure in the fragile neonatal cerebral circulation).49 However, no increase in the risk of sepsis or neuroimaging abnormalities was seen in the lucinactant group, compared with the colfosceril palmitate and beractant groups, in the current study.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Lucinactant prophylaxis offers very preterm infants at high risk for RDS important advantages, compared with colfosceril palmitate, by reducing RDS and RDS-related mortality rates and improving rates of survival without BPD. Although the effects of lucinactant and beractant on the occurrence of RDS and BPD at 36 weeks PMA were similar, RDS-related mortality rates were reduced with lucinactant therapy, as were all-cause mortality rates by 36 weeks PMA. These benefits were achieved without compromising overall safety. Our data indicate that synthetic surfactants consisting solely of phospholipids can be improved by adding peptides (such as sinapultide) that mimic the function of human SP-B. Lucinactant, the first of a new class of surfactants to contain a functional protein analog of SP-B, is an effective therapeutic option for preterm infants at risk for RDS, without the potential risks associated with animal-derived products.


   ACKNOWLEDGMENTS
 
This study was funded by Discovery Laboratories (Warrington, PA).

The Safety and Effectiveness of Lucinactant Versus Exosurf in a Clinical Trial of RDS in Premature Infants (SELECT) Study Organization was as follows.

Steering Committee: Fernando Moya (chair), University of Texas-Houston School of Medicine (Houston, TX); Janusz Gadzinowski (lead investigator, Europe), Poznan University of Medical Sciences (Poznan, Poland) and Polish Mother's Memorial Hospital Research Institute (Lódz, Poland); Eduardo Bancalari, Jackson Memorial Hospital (Miami, FL); Ralph D'Agostino, Boston University (Boston, MA); José F. Gómez-Rosales, Hospital Enrique C. Sotomayor (Guayaquil, Ecuador); Benjamin Kopelman, Hospital São Paulo Universidade de São Paulo Escola Paulista de Medicina, Sao Paulo, Brazil; Joseph Massaro, Boston University School of Public Health (Boston, MA); T. Allen Merritt, St Charles Medical Center (Bend, OR); Jorge Torres-Pereyra, University of Chile (Santiago, Chile); Nestor Vain, Sanatorio de la Trinidad (Buenos Aires, Argentina); Thomas E. Wiswell, State University of New York (Stony Brook, NY); and Jaime Zegarra, Camacho-La Molina (Lima, Peru).

Data Safety Monitoring Board: Ian Gross, Yale University School of Medicine (New Haven, CT); David DeMets, University of Wisconsin Medical School (Madison, WI); and Edmund Hey (Newcastle on Tyne, United Kingdom).

Adjudication Committee: Soraya Abbasi, Pennsylvania Hospital (Philadelphia, PA); Geoffrey Agrons, Pennsylvania Hospital (Philadelphia, PA); Sherry Courtney, Schneider Children's Hospital, Long Island Jewish Medical Center (New Hyde Park, NY); Jacqueline Evans, Children's Hospital of Philadelphia (Philadelphia, PA); Margaret Fernandes, Our Lady of Lourdes Hospital (Camden, NJ); Richard Markowitz, Children's Hospital of Philadelphia (Philadelphia, PA); and Kerry Weiss, St Peter's University Medical Center (New Brunswick, NJ).

Independent Data Analysis Center: Joseph Massaro, Boston University School of Public Health (Boston, MA); and Ralph d'Agostino, Boston University (Boston, MA).

Scientific Advisory Board: Fernando Moya (chair), University of Texas-Houston School of Medicine (Houston, TX); Steven M. Donn, University of Michigan (Ann Arbor, MI); Ralph D'Agostino, Boston University (Boston, MA); Neil Finer, University of California, San Diego (San Diego, CA); Janusz Gadzinowski, Poznan University of Medical Sciences (Poznan, Poland) and Polish Mother's Memorial Hospital Research Institute (Lódz, Poland); Bill Longmore, St Louis University School of Medicine (St Louis, MO); T. Allen Merritt, St Charles Medical Center (Bend, OR); Thomas E. Wiswell, State University of New York (Stony Brook, NY); and Milton Packer, Columbia University College of Physicians and Surgeons (New York, NY).

Ventilatory Guidelines Committee: Fernando Moya (lead), University of Texas-Houston School of Medicine (Houston, TX); Eduardo Bancalari; Jackson Memorial Hospital (Miami, FL); Jorge Torres-Pereyra, University of Chile (Santiago, Chile); Nestor Vain, Sanatorio de la Trinidad (Buenos Aires, Argentina); Carlos Guardia, Discovery Laboratories Latin America (Santa Cruz, Bolivia); Thomas E. Wiswell, State University of New York (Stony Brook, NY); Jan Mazela, Discovery Laboratories Europe (Poznan, Poland); José F. Gómez-Rosales, Hospital Enrique C. Sotomayor (Guayaquil Ecuador); Jaime Zegarra, Camacho-La Molina (Lima, Peru); Neil Finer, University of California, San Diego (San Diego, CA); Steven Donn, University of Michigan (Ann Arbor, MI); T. Allen Merritt, St Charles Medical Center (Bend, OR); and Janusz Gadzinowski, Poznan University of Medical Sciences (Poznan, Poland) and Polish Mother's Memorial Hospital Research Institute (Lódz, Poland).

Ventilatory Management Assessors: Carlos Guardia (global coordinator, Santa Cruz, Bolivia); Jan Mazela (regional coordinator, Europe), Discovery Laboratories Europe (Poznan, Poland); Krzysztof Zieba (regional coordinator, Poznan, Poland); Katarzyna Kowalska (Warsaw, Poland); Ela Lerch (Lódz, Poland); Dmitri Orliv (Russia); Katalin Bogdanyi (Hungary); Anges Till (Hungary); Agnes Mernyi (Hungary); Gergely Sarkozy (Hungary); Andres Maturana (regional coordinator); Margarita Samame (Chile); Maria Teresa Henriquez; Ana Cristina Monteiro Tancredi Pinheiro (Brazil); Guadalupe Cordero; Guadalupe Garcia; Eduardo Duenas (Mexico); Cecilia Garcia (Uruguay); and Maria Teresa Iovane (Panama).

Study Coordination Center: Robert Segal, Christopher J. Schaber, Vince Benn, and Valerie Parker, Discovery Laboratories (Warrington, PA); Biostatistics: Huei Tsai, Genzhue Liu, and Steven Chen, Discovery Laboratories (Warrington, PA); regional coordination: Carlos Guardia, Discovery Laboratories, Latin America (Santa Cruz, Bolivia), and Jan Mazela, Discovery Laboratories, Eastern Europe (Poznan, Poland).

Participating Investigators and Study Centers: Brazil: Benjamin Israel Kopelman, Hospital São Paulo Universidade de São Paulo Escola Paulista de Medicina (Sao Paulo, Brazil); Bettina Barbosa Duque Figueira, Hospital Maternidade Leonor Mendes de Barros (Sao Paulo, Brazil); Manoel de Carvalho, Instituto Fernandes Figueiras (Rio de Janeiro, Brazil); Jefferson Guimarães de Resende, Hospital Regional da Asa Sul and Hospital Materno Infantil de Brasilia (Brasilia, Brazil); and Sérgio T. Martins Marba, CAISM-UNICAMP (Campinas, Brazil); Chile: Aldo Bancalari-Molina, Hospital Clínico Regional Guillermo Grant Benavente (Concepción, Chile); Jorge F. Ubilla Macias, Hospital Clínico San Borja Arriaran (Santiago, Chile); Alvaro José González Morandé, Hospital Clínico de la Pontificia Universidad Católica de Chile (Santiago, Chile); Salvador Miguel Roselló Larrain, Hospital Santiago Oriente Dr Luis Tisne Brousse (Santiago, Chile); Horacio Cox-Melane, Hospital San Jose (Santiago, Chile); Patricia I. Mena Nannig, Hospital Sotero del Rio (Santiago, Chile); Francisco Javier Correa Avendaño, Hospital Barros Luco Trudeau (Santiago, Chile); Jane E. Standen Herlitz, Hospital Dr Gustavo Fricke (Vina del Mar, Chile); María Elena Angélica Belmar Soto, Hospital Dr Hernan Henriquez Aravena de Temuco (Temuco, Chile); and María Isabel Saldes Ebensperger, Hospital Carlos Van Buren (Valparaiso, Chile); Mexico: Vicente Salinas Ramírez, Instituto Nacional de Perinatologia (Mexico City, Mexico); Luisa Sánchez García, Hospital de Gineco Obstretricia 3 (Mexico City, Mexico); Raúl Eguia-Líz Cedillo, Hospital de Gineco Obstetricia 4 (Mexico City, Mexico); and Victor Javier Lara-Díaz, Christus Muguerza Conchita SA de C.V. (Monterrey, Mexico); Ecuador: José F. Gómez-Rosales, Hospital Enrique C. Sotomayor (Guayaquil, Ecuador); and Guillermo Muñoz, Hospital Enrique C. Sotomayor (Guayaquil, Ecuador); Hungary: Márta Katona, Albert Szent-Gyorgi Medical and Pharmaceutical Center (Szeged, Hungary); Tibor Ertl, Szuleszeti es Nogyogyaszati Klinika (Pecs, Hungary); András T. Nobilis, Semmelweis University (Budapest, Hungary); György Balla, University of Debrecen (Debrecen, Hungary); Ferenc Dicso, Josa Andras County Hospital (Nyiregyhaza, Hungary); and Miklós Alexy, Petz Aladar Hospital (Gyor, Hungary); Panama: María Teresa Moreno, Hospital del Niño (Panama City, Panama); Poland: Janusz Gadzinowski, Poznan University of Medical Sciences (Poznan, Poland) and Polish Mother's Memorial Hospital Research Institute (Lódz, Poland); Maria Katarzyna Kornacka, Klinika Neonatologii Warsaw Medical University (Warsaw, Poland); Piotr Pawel Korbal, Jan Biziel Regional Hospital (Bydgoszcz, Poland); Ryszard Lauterbach, Department of Neonatology Medical College (Krakow, Poland); Maria Katarzyna Kornacka, Klinika Neonatologii Warsaw Medical University (Warsaw, Poland); Ewa Gulczynska, Instytut Centrum Zdrowia Matki Polki (Lódz, Poland); Ewa Helwich, Instytut Matki I Dziecka (Warsaw, Poland); Maria Beata Czeszynska, Instytut Poloznictwa I Ginekologii PAM (Szczecin, Poland); Jacek Rudnicki, Klinika Poloznictwa I Perinatologii and Oddzial Intensywnej Terapii Noworodka (Szczecin, Poland); Janusz S. Witalis, Specjalistyczny Szpital Wojewodzki Oddzial Noworodkow (Rzeszow, Poland); Marek Szczepanski, Klinika Neonatologii AM w Bialymstoku (Bialystok, Poland); Helena Slawska, Klinika Perinatologii i Ginekologii (Zabrze, Poland); Longin Marianowski, I Katedra Poloznictwa I Ginekologii (Warszaw, Poland); Jan Oleszczuk, Samodzielny Publiczny Szpital Kliniczny (Lublin, Poland); and Jerzy Szczapa, Instytut Poloznictwa I Chorob Kobiecych (Gdansk, Poland); Russia: Vjacheslav Andreevitch Lubimenko, City Children's Hospital 1 (St Petersburg, Russia); Faína V. Brusilóvskaya, Maternity Home 1 (St Petersburg, Russia); Galína S. Sheremét, Maternity Home 6 (St Petersburg, Russia); Marina I. Levadneva, Maternity Home 10 (St Petersburg, Russia); Larísa Pavlovna Djúnina, Maternity Home 15 (St Petersburg, Russia); Irina V. Myznikova, Maternity Home 16 (St Petersburg, Russia); Olga L'vovna Gulámova, Maternity Home 18 (St Petersburg, Russia); Anatóly M. Púlin, City Children's Hospital 17 (St Petersburg, Russia); Vyachesláv S. Shúlman, Saint Olga's Children's Hospital (St Petersburg, Russia); and Mikhail L. Finkel, Maternity Home 9 (St Petersburg, Russia); Uruguay: Ruben R. Panizza Varela, Centro Hospitalario Pereira Rossell (Montevideo, Uruguay).


   FOOTNOTES
 
Accepted Dec 6, 2004.

Reprint requests to (F.R.M.) Department of Pediatrics, University of Texas Health Science Center, 6431 Fannin St, Suite 3.242, Houston, TX 77030. E-mail: fernando.r.moya{at}uth.tmc.edu

This work was presented in part at the annual meeting of the Pediatric Academic Societies; May 1–4, 2004; San Francisco, CA

Conflict of interest: Drs Moya, Gadzinowski, E. Bancalari, Kopelman, Merritt, and D'Agostino are paid consultants for Discovery Laboratories. Drs Segal, Schaber, and Tsai are employees of Discovery Laboratories.


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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics

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