Journal of Perinatology (2009) 29, S38–S43 r 2009 Nature Publishing Group All rights reserved. 0743-8346/09 $32 www.nature.com/jp REVIEW Animal-derived surfactants: where are we? The evidence from randomized, controlled clinical trials

R Ramanathan Division of Neonatal Medicine, Department of Pediatrics, Women’s and Children’s Hospital and Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

production of a surface-active agent, namely, surfactant. Surfactant Animal-derived surfactants, as well as synthetic surfactants, have been is the first drug developed specifically for treatment of preterm extensively evaluated in the treatment of respiratory distress syndrome neonates with RDS. Surfactant therapy has become the standard of (RDS) in preterm infants. Three commonly available animal-derived care in the management of RDS. Human surfactant is primarily surfactants in the United States include beractant (BE), calfactant (CA) and composed of dipalmitoylphosphatidylcholine (DPPC) and poractant alfa (PA). Multiple comparative studies have been performed surfactant proteins (SP), SP-A, SP-B, SP-C and SP-D. Among these using these three surfactants. Prospective as well as retrospective studies four surfactant proteins, two hydrophobic proteins, SP-B and SP-C, comparing BE and CA have shown no significant differences in clinical or play a crucial role in the adsorption and spread of the DPPC at the economic outcomes. Randomized, controlled clinical trials have shown that air–liquid interphase in the lungs. In addition, an antioxidant treatment with PA is associated with rapid weaning of oxygen and phospholipid, plasmalogen, has been shown to work synergistically ventilatory pressures, fewer additional doses, cost benefits and survival with surfactant-associated hydrophobic proteins in the spreading of advantage when compared with BE or CA. Recently, a study using an DPPC, thus maintaining lower surface tension and alveolar administrative database that included over 20 000 preterm infants has stability at the end of expiration.3,4 SP-A and SP-D are lectin shown a significant decrease in mortality and cost benefits in favor of PA, proteins that help to maintain sterility in the lung, whereas SP-B when compared with BE or CA. Differences in outcomes between these and SP-C help to maintain stability in the lung. None of the animal-derived surfactants may be related to a higher amount of surfactant preparations contain SP-A or SP-D. Natural, modified phospholipids and plasmalogens in PA. To date, animal-derived surfactants surfactants derived from bovine or porcine lungs contain different seem to be better than synthetic surfactants during the acute phase of RDS amounts of SP-B, SP-C and plasmalogens. Animal-derived as well and in decreasing neonatal mortality. Further studies are needed comparing as synthetic surfactants, which are completely devoid of SP-B, SP-C animal-derived surfactants with the newer generation of synthetic and plasmalogens, have been extensively evaluated in preterm surfactants. infants with RDS. Three animal-derived surfactant preparations Journal of Perinatology (2009) 29, S38–S43; doi:10.1038/jp.2009.31 used worldwide include beractant (BE) (Survanta, Abbott Keywords: preterm; respiratory distress syndrome; surfactant; animal Laboratories Inc., Columbus, OH, USA), calfactant (CA) (Infasurf, derived; synthetic; mortality Forest Laboratories, St Louis, MO, USA) and poractant alfa (PA) (Curosurf, Dey, LP, Napa, CA, USA). Synthetic surfactants that have been evaluated in comparative trials include colfosceril palmitate Introduction (Exosurf, Research Triangle Park, NC, USA), pumactant (ALEC, Significant advances in perinatal care have been achieved over the Britannia Pharmaceuticals, Crawley, UK) and past three decades. Despite this, preterm birth rates continue to (Surfaxin, Discovery Laboratories, Doylestown, PA, USA). increase in the United States.1,2 Respiratory distress syndrome (RDS) is the leading cause of respiratory insufficiency and is a major cause of mortality and morbidity in preterm infants. Natural vs synthetic-surfactant studies Incidence of RDS is inversely proportional to gestational age at birth. Pathophysiology of RDS is characterized by insufficient Fourteen trials comparing animal-derived surfactants with synthetic surfactants have been published (Table 1).5–18 To date, Correspondence: Dr R Ramanathan, Division of Neonatal Medicine, Department of treatment with animal-derived surfactant preparations has been Pediatrics, Women’s and Children’s Hospital and Childrens Hospital Los Angeles, Keck School shown to result in better clinical response during the acute phase of Medicine, University of Southern California, 1240, North Mission Road, Room L-919, Los Angeles, CA 90033, USA. of RDS as evidenced by rapid weaning of inspired oxygen, mean E-mail: [email protected] airway pressure and lower air leaks when compared with treatment Animal-derived surfactants R Ramanathan S39

Table 1 Summary of 14 trials comparing animal-derived surfactants with synthetic surfactants for RDS in preterm infants

Trials (n ¼ 14) Surfactant Number of Type Patients Results patients

5 Horbar et al. Beractant vs colfosceril 617 Treatment 500–1500 g Beractant: lower 0–72 h FiO2 and MAP palmitate 6 Alvarado et al. Beractant vs colfosceril 66 Treatment <1500 g Beractant: decreased duration of PPV, O2, LOS palmitate Pearlman et al.7 Beractant vs colfosceril 121 Treatment Any with No differences in any outcomes palmitate RDS Sehgal et al.8 Beractant vs colfosceril 41 Treatment 600–1750 g No differences in any outcomes palmitate 9 VON Beractant vs colfosceril 1296 Treatment 501–1500 g Beractant: lower FiO2 at 72 h, lower 0–72 h MAP, fewer air leaks palmitate 10 Hudak et al. Calfactant vs colfosceril 1126 Treatment All with RDS Calfactant: lower 0–72 h FiO2 and MAP, fewer air leaks palmitate 11 Hudak et al. Calfactant vs colfosceril 846 Prophylaxis <29 weeks Calfactant: less RDS, lower 0–72 h FiO2 and MAP, fewer air leaks, palmitate more intraventricular hemorrhage

Modanlou Beractant vs colfosceril 122 Treatment <1500 g Beractant: lower FiO2, MAP and OI et al.12 palmitate da Costa et al.13 Beractant vs colfosceril 89 Treatment <37 weeks, No difference palmitate 1000 g 14 Rollins et al. Poractant alfa vs colfosceril 66 Treatment All with RDS Poractant alfa: lower FiO2, and improved a/A ratio palmitate

Kukkonen Poractant alfa vs colfosceril 228 Treatment All with RDS Poractant alfa: lower FiO2, and MAP et al.15 palmitate Ainsworth Poractant alfa vs pumactant 212 Treatment <30 weeks Poractant alfa: decreased mortality (trial stopped after interim et al.16 analysis) Moya et al.17 Lucinactant vs colfosceril 1294 Prophylaxis 600–1250 g Lucinactant more effective than colfosceril palmitate and similar to palmitote vs beractant beractant Sinha et al.18 Lucinactant vs poractant alfa 252 Prophylaxis 600–1250 g Non-inferiority trial, early trial closure, original sample size 496, no differences in any outcomes

Abbreviations: RDS, respiratory distress syndrome; FiO2, fraction of inspired oxygen; MAP, mean airway pressure; PPV, positive pressure ventilation; LOS, length of stay; OI, oxygenation index.

with synthetic preparations. Furthermore, neonatal mortality has compared two different synthetic preparations, bronchopulmonary also been shown to be lower among infants treated with a porcine- dysplasia was significantly lower with lucinactant therapy when derived surfactant when compared with those treated with compared with colfosceril palmitate. In this prophylaxis trial, BE pumactant, a synthetic preparation.16 Ainsworth et al.16 compared was included as a reference arm. A total of 1294 preterm infants, the porcine-derived surfactant, PA, with pumactant. This trial was weighing 600 to 1250 g, were included; 509 infants received stopped by the data and safety monitoring committee, because colfosceril palmitate, 527 received lucinactant and 258 infants mortality assumed greater importance than the primary outcome. received BE, within 20 to 30 min of birth. Even though the trial Mortality was significantly lower (14.1 vs 31%, P ¼ 0.006; odds was designed as a prophylaxis trial, investigators allowed up to ratio 0.37; 95% confidence interval [0.18, 0.76]) in the PA-treated 30 min for administration of surfactants. This is because of the fact infants. This difference was sustained after adjusting for gestational that lucinactant is a gel at both room and body temperature, and age, birth weight, gender, center, plurality and use of antenatal had to be warmed in a special warming cradle to 44 1C for 15 min. steroids. This was the first randomized, controlled trial that showed In all earlier, randomized, controlled prophylaxis trials, surfactant a survival advantage for an animal-derived surfactant preparation was typically administered within 10 to 15 min of birth. In the true over that for a synthetic surfactant. However, survival advantage sense, this trial17 is an early rescue trial. Furthermore, comparison was a secondary endpoint in this trial. The incidence of of outcomes between BE and lucinactant was of secondary interest, bronchopulmonary dysplasia was not different with either and this trial was not powered to detect efficacy against BE. Despite animal-derived or synthetic surfactants. In the only trial17 that these limitations, there were no differences in the 14 variables that

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Table 2 Composition of animal-derived surfactant preparations

Surfactant Preparation/Composition Phospholipids Plasmalogens SP-B SP-C a b (%) (mol%) (mg per mM PL) (mg per mM PL)

Beractant Minced bovine lung extract+DPPC++ 84 1.5 0–1.3 1–20 Calfactant Bovine lung lavage+DPPC+cholesterol 95 NA 5.4 8.1 Poractant alfa Minced porcine lung extract (Liquid gel chromatography) 99 3.8 2–3.7 5–11.6

Abbreviations: DPPC, dipalmitoylphosphatidylcholine; SP-B, surfactant protein B; SP-C, surfactant protein-C; NA, not available. aAdapted from Dargaville et al.21 bAdapted from Taeush et al.22 and Rudiger et al.23

were analyzed in this study between BE and lucinactant. In the bovine or porcine lungs are the three commonly used surfactants second trial,18 designed as a non-inferiority trial, comparing worldwide. BE is a minced bovine lung extract that contains lower lucinactant with PA, no differences were found in 16 outcome amounts of phospholipids, plasmalogen and SP-B, compared with variables analyzed between lucinactant- and PA-treated infants. CA, which is a lavage preparation from bovine lungs. CA contains a There were several methodological problems with this trial. This higher amount of SP-B and phospholipids than does BE. study was stopped early because of slow recruitment after enrolling Plasmalogen content in CA is not known. A lung lavage only 50.8% of the original sample size (252 out of 496 patients); preparation from bovine lungs, used in Germany, namely, SF-RI1 mortality data chosen to assess non-inferiority was from a (alveofact), contains the lowest amount of plasmalogens. Poractant placebo-controlled treatment trial published 18 years before this alfa is a minced porcine surfactant that undergoes an additional trial; and the dose of PA used was not the dose used in the step, liquid gel chromatography. As a result, PA contains only polar placebo-controlled trial. Survival at 1 year of corrected age was not lipids and is more concentrated than the other animal-derived different among the BE-treated group; 178/258 infants (69%) surfactants. In addition, PA contains the highest amount of compared with 479/643 (75%) in the two trials17,18 with plasmalogens. Higher plasmalogen content in the tracheal lucinactant treatment.19 Similarly, survival at 1 year of corrected aspirates from preterm infants has been associated with a lower age among the PA-treated group was 97/124 infants (78%) incidence of bronchopulmonary dysplasia.24 Eight randomized, compared with 479/643 (75%) in the two trials17,18 treated with controlled clinical trials25–30 and two retrospective studies31,32 lucinactant.19 In a clinical report published in 2008,20 the comparing the three natural surfactants have been reported. Four American Academy of Pediatrics and the Committee of the Fetus of the eight trials compared BE with CA25,26 and the remaining and Newborn (COFN) issued the following statement: ‘FMore four trials27–30 compared BE with PA (Table 3). There are no analysis is needed before the findings from lucinactant studies can prospective studies published comparing CA with PA. be generalized because of questions about early trial closure and limited statistical power. Moreover, the metabolic fate of lucinactant and its component chemicals and potential risks Randomized trials comparing BE with CA introduced by the requirement to convert the lucinactant gel into In the four studies comparing BE with CA,25,26 treatment with CA liquid by using a special warming cradle immediately before was associated with a faster response during the acute phase of instillation need additional study.’20 In summary, results from RDS in the rescue trial published in 1997. In the prophylaxis trial25 randomized, controlled clinical trials show the superiority of comparing CA with BE published by the same investigators, animal-derived surfactant preparations over the synthetic mortality in infants <600 g in birth weight was significantly surfactants that have been studied. At the time of this writing, there higher in the CA group when compared with that in the BE group are no approved synthetic surfactants available for clinical use. (63 vs 26%, P ¼ 0.007). Overall mortality in the prevention trial was 8% in the BE group and 14% in the CA group (Figure 1). In the rescue trial,25 mortality rates were 17% and 18% in the BE- and Animal-derived vs animal-derived surfactant studies CA-treated groups, respectively (Figure 1). There were no Animal-derived surfactant preparations have been extensively significant differences in the percentage of infants requiring two or evaluated for the treatment of RDS in preterm infants. more surfactant doses in both these trials (Figure 2). In the Animal-derived surfactants differ in their source, method of remaining two large, but incomplete trials published in 2005, preparation, composition, viscosity, dosing volume, phospholipid involving a total of 2110 preterm infants, no differences in content, percentage of plasmalogens and amount of SP-B and mortality, need for additional doses, bronchopulmonary dysplasia SP-C21–23 (Table 2). Minced as well as lavage preparations from or any other outcomes were shown.26 Inadequate sample size from

Journal of Perinatology Animal-derived surfactants R Ramanathan S41

Table 3 Summary of eight comparative trials among animal-derived surfactants in preterm infants with respiratory distress syndrome

Eight trials Surfactant Number Prophy or Patient Characteristics Results Rescue

Bloom et al.25 Beractant vs calfactant 374 Prophy <1250 g No differences in any variables; increased mortality with calfactant in <600 g (63 vs 29%) 25 Bloom et al. Beractant vs calfactant 608 Rescue <2000 g Calfactant: lower average 0–72 h FiO2 and MAP Bloom et al.26 Beractant vs calfactant 749/2000 Prophy 23–29 weeks Early trial closure; original sample size 2000; Infants alive with BPD 34 vs 33%; no differences in any outcomes Bloom et al.26 Beractant vs calfactant 1361/2080 Rescue 401–2000 g Early trial closure; original sample size 2080; infants alive with BPD 31 vs 31%; no differences in any outcomes 27 Speer et al. Beractant vs poractant alfa 73 Rescue 700–1500 g Poractant alfa: lower FiO2, PIP and MAP at 12–24 h 28 Baroutis et al. Beractant vs poractant alfa vs 80 Rescue <2000 g Poractant alfa: fewer days on O2 and PPV; decreased LOS SF RI1 29 Ramanathan et al. Beractant vs poractant alfa 293 Rescue 750–1750 g Poractant alfa: lower FiO2, fewer doses, decreased mortality 30 Malloy et al. Beractant vs poractant alfa 58 Rescue <37 weeks with RDS Poractant alfa: lower FiO2 up to 48 h; fewer doses; lower volume of surfactant given; fewer PDA

Abbreviations: Prophy, prophylaxis; FiO2, fraction of inspired oxygen; MAP, mean airway pressure; PIP, peak inspiratory pressure; PPV, positive pressure ventilation; LOS, length of stay; OI, oxygenation index; PDA, patent ductus arteriosus; BPD, bronchopulmonary dysplasia; RDS, respiratory distress syndrome.

25 80 PA PA 70 20 BE BE CA 60 CA 15 50 40 10

Mortality (%) 30 * * 5 * 20 % of Infants > 2 doses 10 0 * #25 #25#26 #26 #27 #28 #29 #30 #31 #32 0 (P) (P) #25 (P) #25 #26 (P) #26 #29 #30^ Figure 1 Mortality differences among the three animal-derived surfactants Figure 2 Infants requiring>2 doses in the six comparative trials reported from reported in 10 studies between 1995 and 2007. Abbreviations: PA, poractant alfa; 1997 to 2005. Abbreviations: PA, poractant alfa; BE, beractant; CA, calfactant; BE, beractant; CA, calfactant; #references; (P), prophylaxis; *P<0.05. #references; (P), prophylaxis; ^, mean doses; *P<0.05. early trial closures prevented the investigators from accepting or Randomized trials comparing BE with PA rejecting null hypotheses. Sample sizes were calculated to show a Four randomized, controlled clinical treatment trials comparing BE difference of 6% in the primary outcome of infants alive at with PA have been published.27–30 Three of the four trials used 36 weeks post-menstrual age and not receiving supplemental 200 mg per kg of PA for the first dose and subsequent doses were oxygen. Prophylaxis study was stopped after enrolling 749 of the given at 100 mg kgÀ1. In the study by Baroutis et al.,28 three 2000 infants in the original sample size and the rescue trial was animal-derived surfactants (BE, PA and SF RI1) were compared also stopped after enrolling 1361 of 2080 infants. Overall mortality and these investigators used 100 mg kgÀ1 for the initial as well as rates in the prophylaxis trial were 12% and 13%, and 10% and 11% for subsequent doses in all three surfactant groups. All four trials in the treatment trial in the BE- and CA-treated groups, respectively showed a faster weaning of supplemental oxygen in the PA-treated (Figure 1). There were no significant differences in the percentage group when compared with treatment with BE. In the trial by of infants requiring two or more surfactant doses in both these Ramanathan et al.,29 infants were randomized to 100 or trials, similar to the earlier comparative trials published 8 years 200 mg kgÀ1 for the initial dose of PA and 100 mg kgÀ1 for the before these two studies (Figure 2). In summary, there were no initial dose of BE. All infants received 100 mg kgÀ1 of PA or BE differences in mortality or dosing requirements reported in the four for subsequent doses. The prespecified mortality at 36 weeks trials comparing BE with CA. post-menstrual age among preterm infants p32 weeks was

Journal of Perinatology Animal-derived surfactants R Ramanathan S42 significantly lower in the 200 mg per kg PA-treated group produce a synthetic surfactant that closely mimic the various compared with that in the BE-treated group (3% vs 11%, components, including plasmalogens that are present in P ¼ 0.034; OR 0.26, 95% CI 0.07, 0.98) (Figure 1). When mortality animal-derived surfactants, may be needed to achieve outcomes results from two of the four studies27,29 were combined in a that are equivalent to or better than animal-derived surfactants. meta-analysis, mortality was significantly lower in the PA-treated group when compared with that in the BE-treated group 33 (OR 0.35, 95% CI 0.13, 0.92). Need for additional doses were also Disclosure significantly lower in the PA-treated group when compared with that in the BE-treated group in two of the four trials29,30 R Ramanathan is a paid consultant for Dey, LP, but holds (Figure 2). In summary, results from randomized, controlled no equity. This paper was based on a talk presented at the clinical trials comparing animal-derived surfactants show survival Evidence vs Experience in Neonatal Practices Fifth Annual CME advantage, decreased need for additional doses and cost benefits in Conference that was supported by an unrestricted educational grant favor of PA when compared with BE. There were no differences from Dey, LP. observed in any of the trials comparing BE with CA.

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