Published online May 28, 2007
PEDIATRICS Vol. 119 No. 6 June 2007, pp. e1361-e1370 (doi:10.1542/peds.2006-0149)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow An erratum has been published
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Moya, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Moya, F.
Related Collections
Right arrow Premature & Newborn

ARTICLE

One-Year Follow-up of Very Preterm Infants Who Received Lucinactant for Prevention of Respiratory Distress Syndrome: Results From 2 Multicenter Randomized, Controlled Trials

Fernando Moya, MDa, Sunil Sinha, MD, PhDb, Janusz Gadzinowski, MD, PhDc,d, Ralph D'Agostino, PhDe, Robert Segal, MDf, Carlos Guardia, MDf, Jan Mazela, MD, PhDc,f, Genzhou Liu, PhDf on behalf of the SELECT and STAR Study Investigators

a Department of Neonatology, Coastal Area Health Education Center, Wilmington, North Carolina
b Department of Pediatrics, James Cook University Hospital, Middlesbrough, United Kingdom
c Department of Neonatology, University of Medical Sciences, Poznan, Poland
d Department of Neonatology, Mother's Memorial Hospital Research Institute, Lodz, Poland
e Department of Mathematics, Boston University, Boston, Massachusetts
f Medical Affairs, Discovery Laboratories, Inc, Warrington, Pennsylvania


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
BACKGROUND. The benefits of exogenous surfactants for prevention or treatment of respiratory distress syndrome are well established, but there is a paucity of long-term follow-up data from surfactant-comparison trials.

OBJECTIVE. We sought to determine and compare survival and pulmonary and neurodevelopmental outcomes through 1 year corrected age of preterm infants who received lucinactant and other surfactants in the SELECT (Safety and Effectiveness of Lucinactant Versus Exosurf in a Clinical Trial) and STAR (Surfaxin Therapy Against Respiratory Distress Syndrome) trials individually and, secondarily, from analysis using combined data from these 2 trials.

METHODS. All infants from both trials who were randomly assigned to administration of lucinactant (175 mg/kg), colfosceril palmitate (67.5 mg/kg), beractant (100 mg/kg), or poractant alfa (175 mg/kg) were prospectively followed through 1 year corrected age, at which point masked assessment of outcomes was performed for surviving infants. One-year survival was a key outcome of interest. Other parameters assessed included rates of rehospitalization and respiratory morbidity and gross neurologic status. Data were analyzed by comparing the different surfactants within each trial and, in secondary analysis, combining data from both trials to compare lucinactant versus the animal-derived surfactants (beractant and poractant) used in these trials. Survival rates over time were compared by using the Wilcoxon test for survival through 1 year corrected age and logistic regression for comparison of fixed time points. The latter analyses were performed by using the prespecified approach, where loss to follow-up or withdrawal of consent was imputed as a death, and also using raw data. Other outcomes were analyzed by using the Cochran-Mantel-Haenszel test or logistic regression for categorical data, and analysis of variance on ranks was used for continuous data.

RESULTS. Very few cases were lost to follow-up in either trial (29 of 1546 enrolled in both trials [1.9%]). In the primary analysis of the SELECT trial comparing lucinactant to either colfosceril or beractant, there were no significant differences in the proportion of infants who were alive through 1 year corrected age. Fixed-time-point estimates of mortality at 1 year corrected age imputing loss to follow-up as a death were 28.1% for lucinactant, 31.0% for colfosceril, and 31.0% for beractant. By using raw data without imputing loss to follow-up as a death, mortality estimates at 1 year corrected age were computed to be 26.6%, 29.1%, and 28.3%, respectively. In the primary analysis of the STAR trial, significantly more infants treated with lucinactant were alive through 1 year corrected age compared with those who received poractant alfa. Fixed time estimates of mortality at 1 year corrected age imputing loss to follow-up as a death were 19.4% for lucinactant and 24.2% for poractant. These estimates using raw data that did not impute loss to follow-up as a death were 18.6% and 21.9%, respectively. In the combined analysis, survival through 1 year corrected age was higher for infants in the lucinactant group versus that of the infants in the animal-derived surfactants (beractant and poractant) group. The fixed-time-point estimates of mortality at 1 year corrected age imputing loss to follow-up as a death for lucinactant and animal-derived surfactants were 26.0% and 29.4%, respectively. However, the 1-year-corrected-age estimates using combined raw data were 24.6% for the lucinactant group and 26.7% for the animal-derived surfactant group. The incidence of postdischarge rehospitalizations, total number of rehospitalizations, incidence of respiratory illnesses, and total number of respiratory illnesses were generally similar among those in the treatment groups. Neurologic status at 1 year corrected age was essentially similar between infants who received lucinactant and those who received all other surfactants used in these 2 trials.

CONCLUSIONS. Findings from this 1-year follow-up of both lucinactant trials indicate that this new peptide-based synthetic surfactant is at least as good, if not superior, to animal-derived surfactants for prevention of respiratory distress syndrome and may be a viable alternative to animal-derived products.

Key Words: long-term survival • respiratory distress syndrome • surfactant • survival rate • 1-year outcome

Abbreviations: RDS—respiratory distress syndrome • SP—surfactant protein • BPD—bronchopulmonary dysplasia • SELECT—Safety and Effectiveness of Lucinactant Versus Exosurf in a Clinical Trial • STAR—Surfaxin Therapy Against Respiratory Distress Syndrome • PMA—postmenstrual age • OR—odds ratio • CI—confidence interval

Intratracheal administration of animal-derived and synthetic exogenous surfactant preparations improves respiratory status and decreases mortality and morbidity rates among premature infants at risk of or with respiratory distress syndrome (RDS).1 Currently available animal-derived surfactants from bovine or porcine sources contain phospholipids and variable, yet relatively small, quantities of surfactant proteins (SPs) B and C,2 whereas currently available synthetic surfactants contain phospholipids but no SPs. Although these synthetic surfactants have potential safety advantages over animal-derived products, they seem to be inferior to animal-derived surfactants in improving clinical outcomes.1

A meta-analysis of 11 controlled trials that compared these 2 classes of surfactants demonstrated a marginally significant lower mortality rate and a lower risk of pneumothorax with animal-derived surfactants when surfactant was administered as a rescue therapy.1 However, no reductions in the incidence of bronchopulmonary dysplasia (BPD) were demonstrated. None of these surfactant-comparison trials reported findings beyond the initial hospital stay in the NICU. The limitation of synthetic non–protein-containing surfactants has been attributed to the lack of SP-B and SP-C.3–5 The absence of SP-B seems to be particularly important: animals or humans lacking SP-B because of a genetic mutation develop a fatal form of respiratory failure during the neonatal period.4,5 In contrast, individuals with mutations in SP-C develop interstitial lung disease as adults rather than neonatal RDS.6

Lucinactant (Surfaxin; Discovery Laboratories, Inc, Warrington, PA) is a new-generation synthetic surfactant that contains phospholipids and a high concentration of the synthetic 21-amino acid hydrophobic peptide (sinapultide, also known as KL4 peptide). This peptide resembles the hydrophobic-hydrophilic amino acid pattern of the tail end of SP-B.7 The concentration of sinapultide in lucinactant is higher than the concentration of SP-B in current animal-derived products, which approximates the concentration of SP-B in normal lungs. Lucinactant has greater resistance to oxidation and peroxidation than the bovine-derived surfactant beractant (Survanta; Ross Products Division, Abbott Laboratories, Columbus, OH)8 and has been shown to improve pulmonary function and alveolar expansion in an animal model of RDS9 and in a pilot study that involved preterm infants with RDS.10

We recently reported the results of 2 multicenter, phase III, double-blind, randomized, controlled trials, which demonstrated the efficacy of lucinactant in the prevention of neonatal RDS.11,12 The SELECT (Safety and Effectiveness of Lucinactant Versus Exosurf in a Clinical Trial) study compared lucinactant with the synthetic non–protein-containing surfactant, colfosceril palmitate (Exosurf; GlaxoSmithKline, Brentford, United Kingdom); beractant was used in the trial as a reference arm.11 The STAR (Surfaxin Therapy Against Respiratory Distress Syndrome) trial compared lucinactant with the porcine-derived surfactant poractant alfa (Curosurf; Chiesi Farmaceutici, Parma, Italy).12 Inclusion criteria, approach to surfactant administration, and time periods when the studies were conducted were fairly similar for both trials. In the SELECT trial, RDS-related mortality through 14 days of age was significantly (P < .01) reduced with lucinactant compared with both beractant and colfosceril palmitate, and proportionally more patients were alive at 36 weeks' postmenstrual age (PMA) compared with beractant (odds ratio [OR]: 0.67; 95% confidence interval [CI]: 0.45–1.00). In the STAR trial, the primary outcome of alive without BPD at 28 days was not significantly different between lucinactant and poractant alfa.12 To evaluate outcomes beyond the initial hospital stay and examine further the safety of lucinactant, both trials included planned follow-up of participating infants to 1 year corrected age.

The primary objective for this study was to report the outcome results of the planned follow-up to 1 year corrected age of infants participating in the SELECT and STAR trials. Furthermore, given the similarity of these trials in the populations studied, treatment approach, end points, and contemporary nature, a secondary goal of this analysis was to compare the outcome of infants who received lucinactant versus those who received other classes of surfactants after combining data from both trials.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Study Design
Methods for both RDS-prevention trials have been described previously in detail.11,12 In summary, within 30 minutes of birth, infants between 600 and 1250 g were randomly assigned to receive lucinactant, colfosceril palmitate, or beractant in a 2:2:1 ratio in the SELECT trial and lucinactant or poractant alfa in a 1:1 ratio in the STAR trial. In both trials, infants were randomly assigned by stratification on the basis of birth weight at each site. Clinicians who were caring for participating infants remained blinded to the surfactant assigned at randomization throughout their stay in the NICU and up to 1 year corrected age for prematurity (ie, chronologic age minus the number of weeks premature). Study protocols were approved by the institutional review boards of all participating centers, and signed informed consent was obtained for all participants. An independent data-safety board reviewed the study design and data for both trials. Both studies were conducted under the auspices of independent steering committees, which were chaired by the respective principal investigators.

From birth to 1 year corrected age, we recorded the occurrence of rehospitalization after discharge from the NICU, the number and type of respiratory illnesses that occurred after 36 weeks' PMA (eg, wheezing, pneumonia, cough), and deaths. In addition, at the 1-year-corrected-age visit, weight, length, and head circumference were obtained and a physical examination, including a gross neurologic assessment, was performed. The neurologic examination assessed, at minimum, gross motor tone, reflex abnormalities, presence of unilateral or bilateral deafness, unilateral or bilateral blindness, and history of seizures that required treatment with anticonvulsant agents. The clinicians involved in the follow-up assessment phase of the studies also remained blind to the assigned surfactant treatment throughout the study.

Statistical Analyses
In this 1-year-corrected-age follow-up analysis, all randomly assigned infants were included on the basis of the intent-to-treat principle across both studies. In the STAR trial, the short-term results through 36 weeks' PMA were previously reported on the basis of the per-protocol population (all infants who received any surfactant [N = 243]), which is typical for noninferiority studies.13,14 For all survival comparisons, we used a prespecified imputation approach, with which loss to follow-up or withdrawal of consent was counted as a death. However, we also compared survival between groups using raw data without imputing loss to follow-up or consent withdrawal as death. The overall survival rate through 1 year corrected age for all randomly assigned infants within each study was estimated by using a standard Kaplan-Meier approach for long-term survival analysis. The Kaplan-Meier curves for lucinactant versus animal-derived surfactants in the combined analysis were estimated by using meta-analysis methods in which the overall Kaplan-Meier curves were constructed on the basis of the weighted average of the individual curves from the studies, weighted by study size.15 Also, when comparing lucinactant with animal-derived surfactants, we used meta-analysis methodology for analyzing data across studies with different sample sizes between and within these studies.1,15 This statistical method was chosen to compare these surfactants because simple pooling of data from the STAR and SELECT trials is not appropriate given that the randomization ratios in the 2 studies were unequal (lucinactant/colfosceril palmitate/beractant, randomization ratio: 2:2:1 [SELECT]; lucinactant/poractant alfa, randomization ratio: 1:1 [STAR]). Survival rates through 1 year corrected age for individual studies and the meta-analysis were compared by using the Wilcoxon test adjusting for study, birth weight strata, country, gender, and race. In addition to using the standard Kaplan-Meier approach for survival comparisons, we determined fixed-time-point estimates of mortality by imputing loss to follow-up as a death and also using raw data and compared them by using logistic regression adjusting for pooled center and birth weight stratum.

The incidence of rehospitalizations was analyzed by using logistic regression, and the total number of postdischarge rehospitalizations was compared by using analysis of variance. Data on respiratory morbidity through 1 year corrected age were collected for those patients who were alive at 36 weeks' PMA. The incidence of respiratory illnesses was compared by using logistic regression. The total number of respiratory illnesses through 1 year corrected age was compared by using analysis of variance. Neurologic outcomes at 1 year corrected age were only assessed for surviving infants in whom the data were captured; the data were compared by using the Cochran-Mantel-Haenszel test. All analyses described above were adjusted for pooled center and birth weight stratum. No missing data imputation was performed unless clearly specified.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patient Population and Disposition
In the SELECT study, 527, 509, and 258 preterm infants between 24 and 32 weeks' gestational age and between 600 and 1250 g birth weight were randomly assigned to receive lucinactant, colfosceril palmitate, and beractant, respectively. In the STAR study, 124 and 128 preterm infants in the same weight range were randomly assigned to receive lucinactant and poractant alfa, respectively. The upper limit for gestational age in the STAR trial was <29 weeks. Complete maternal and neonatal demographics for the STAR and SELECT study populations have been reported.11,12 A summary of the main demographic characteristics of both studies is given in Table 1. The study populations were fairly similar; small, nonsignificant differences in Apgar scores, birth weight, and prenatal steroid use were observed among infants enrolled in the 2 trials. In total, 651 infants were randomly assigned to lucinactant and 386 to animal-derived surfactants (beractant and poractant alfa).


View this table:
[in this window]
[in a new window]

  		TABLE 1 Summary of the Main Demographic Characteristics

 
In both trials and subsequent follow-up, 6 infants (0.9%) who received lucinactant and 8 (1.6%) and 6 (1.6%) infants who received colfosceril palmitate and an animal-derived surfactant, respectively, were lost to follow-up (Fig 1). Consent after randomization was withdrawn for 3 infants (0.5%) who received lucinactant and 2 (0.4%) and 4 (1.5%) infants who received colfosceril palmitate and an animal-derived surfactant, respectively. Per the prespecified rules (see "Methods"), these losses to follow-up were counted as deaths. Nonetheless, overall survival comparisons were also conducted only on infants for whom data were available (ie, without imputation for loss to follow-up as a death).


Figure 1
View larger version (13K):
[in this window]
[in a new window]

  		FIGURE 1 Enrollment and disposition of infants in the SELECT and STAR trials through 1 year corrected age. a Did not receive study medication.

 
Overall Survival
The Kaplan-Meier survival curves through 1 year corrected age for infants in the SELECT study, the STAR study, and the combined group of infants who received lucinactant compared with those who received animal-derived surfactants (beractant and poractant alfa) are presented in Fig 2 (A, B, and C, respectively). Comparisons of mortality data for lucinactant versus the individual comparator surfactants at both 28 days' and 36 weeks' PMA in the SELECT and STAR trials have already been provided in their original publications.11,12 However, the findings of the combined analysis at 36 weeks' PMA represent new data and are mentioned briefly below, because they provide a reference point for the 1-year-corrected-age data. There were no significant differences in the proportion of infants who were alive through 1 year corrected age comparing those given lucinactant with those who received colfosceril and beractant (Fig 2A). Fixed-time-point estimates of mortality at 1 year corrected age imputing loss to follow-up as a death were 28.1% for lucinactant, 31.0% for colfosceril, and 31.0% for beractant (OR: 0.81; 95% CI: 0.60–1.09 [lucinactant versus colfosceril]; OR: 0.84; 95% CI: 0.58–1.21 [lucinactant versus beractant]). In the STAR trial, significantly more infants who were treated with lucinactant were alive through 1 year corrected age compared with those who received poractant alfa (P = .04, Wilcoxon test; Fig 2B). Fixed-time-point estimates of mortality at 1 year corrected age imputing loss to follow-up as a death were 19.4% for lucinactant and 24.2% for poractant (OR: 0.64; 95% CI: 0.32–1.27). In the combined analysis, survival through 1 year corrected age of those infants who received lucinactant was higher compared with those who received animal-derived surfactants (P = .05, Wilcoxon test; Fig 2C). Fixed-time-point estimates using combined data from both trials imputing loss to follow-up as a death to compare lucinactant with the animal-derived surfactants demonstrated a lower mortality rate that favored infants who received lucinactant at 36 weeks' PMA (20.1% vs 24.7%; P = .045; OR: 0.70; 95% CI: 0.50–0.99). The fixed-time-point estimates of mortality at 1 year corrected age imputing loss to follow-up as a death for lucinactant and animal-derived surfactants were 26.0% vs 29.4%, respectively (OR: 0.80; 95% CI: 0.58–1.09).


Figure 2
View larger version (14K):
[in this window]
[in a new window]

  		FIGURE 2 Kaplan-Meier survival plots showing all-cause mortality through 1 year corrected age: A, data from the SELECT trial; B, data from the STAR trial; C, combined data from infants in both trials who received either lucinactant or animal-derived surfactants. All-cause mortality through 1 year corrected age favored lucinactant (Wilcoxon test) over poractant alfa (P = .04) and the animal-derived surfactants (P = .05).

 
Because very few infants from both trials were either lost to follow-up or had their consent withdrawn, estimations of overall survival using raw data without imputation for loss to follow-up as a death introduced minor variations to the findings described above but did not modify the trend of the results. Using raw data without imputing loss to follow-up as a death, fixed-time-point estimates of mortality at 1 year corrected age were 26.6%, 29.1%, and 28.3%, respectively (OR: 0.83; 95% CI: 0.61–1.12 [lucinactant versus colfosceril]; OR: 0.89; 95% CI: 0.61–1.32 [lucinactant versus beractant]). In the STAR trial, there was no loss to follow-up or withdrawal of consent before 36 weeks' PMA; therefore, estimates using raw data did not differ from those using a worst-case scenario approach.12 However, at 1 year corrected age, overall mortality estimates using raw data not imputing loss to follow-up as a death were 18.6% for the lucinactant group and 21.9% for the poractant group (OR: 0.69; 95% CI: 0.34–1.40). Mortality estimates using combined raw data at 1 year corrected age not imputing loss to follow-up as a death were 24.6% for the lucinactant group and 26.7% for the animal-derived surfactant group (OR: 0.85; 95% CI: 0.62–1.18).

Postdischarge Rehospitalization and Respiratory Morbidity
Although between one third and one half of the infants in both studies were rehospitalized during the first year, in general, readmission to the hospital occurred only once for most of them (Table 2). The incidence of postdischarge rehospitalization did not differ between surfactant groups in the SELECT trial (lucinactant: 43.4%; colfosceril: 43.4%; beractant: 50.8%) or the STAR trial (lucinactant: 34%; poractant alfa: 34.7%). Likewise, the number of postdischarge rehospitalizations through 1 year corrected age for all discharged infants did not differ between groups. Data on the number of respiratory illnesses (coughing, wheezing, and pneumonia) through 1 year corrected age were collected for infants from both studies who were alive at 36 weeks' PMA. There were no significant differences between the groups (Table 2).


View this table:
[in this window]
[in a new window]

  		TABLE 2 Postdischarge Rehospitalizations and Respiratory Illnesses From 36 Weeks' PMA to 1 Year Corrected Age

 
Neurologic Assessment
Neurologic evaluations at 1 year corrected age were performed for most surviving infants from the 2 studies. In the SELECT trial, 731 (81%) of the 908 infants alive at 1 year corrected age had neurologic evaluations (lucinactant: 306; colfosceril palmitate: 279; beractant: 146). In the STAR trial, neurologic evaluations were performed in 190 (96%) of the 197 infants alive at 1 year corrected age (lucinactant: 98; poractant alfa: 92; Table 3).


View this table:
[in this window]
[in a new window]

  		TABLE 3 Abnormal Gross Neurologic Findings: All Randomly Assigned Evaluated Survivors in Each Trial

 
Among survivors examined from the SELECT and STAR trials, there were generally no significant differences between groups with very few exceptions (Table 3). There were fewer muscle-tone abnormalities in the infants in the lucinactant group compared with those in the colfosceril and beractant groups and also a lower incidence of gross motor delay compared with the colfosceril group. There were no major differences in neurologic outcomes at 1 year corrected age when comparing infants who received lucinactant with those who received animal-derived surfactants (Table 4) despite the greater number of survivors in the lucinactant group.


View this table:
[in this window]
[in a new window]

  		TABLE 4 Pooled Analysis of Abnormal Gross Neurologic Findings: All Randomly Assigned Evaluated Survivors

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Surfactant therapy is associated with an absolute reduction of ~5% to 7% in neonatal mortality among preterm infants compared with those who receive placebo.16,17 This reduction in mortality rate translates into ~1 life saved for every 14 to 20 infants who receive surfactant. The other major benefit consistently shown in trials that have compared surfactant administration with placebo is a marked decrease in the occurrence of air leaks. On the basis of these findings, surfactant therapy has become widely used for the prevention and treatment of RDS.

There have been many randomized trials that compared the 2 major classes of surfactants, namely synthetic preparations devoid of SPs and animal-derived surfactants that contain variable amounts of SP-B and SP-C, although most have used a treatment rather than a prophylactic approach. Soll and Blanco1 conducted a systematic review of 11 trials and compared animal-derived surfactants versus synthetic surfactants. Ten of the trials included in that review compared colfosceril with beractant (7 trials),18–24 calfactant (2 trials),25,26 or poractant alfa (1 trial),27 whereas only 1 trial compared pumactant to poractant.28 These authors concluded that both types of surfactants are effective in the treatment and prevention of RDS. They also concluded that when taken together, use of animal-derived surfactants resulted in fewer deaths, greater early improvement in the requirement for ventilatory support, and a lower overall incidence of pneumothorax than synthetic products that contain only phospholipids. However, none of the studies that compared beractant to colfosceril, including large, well-conducted trials, have shown a significant difference in overall mortality rate favoring either surfactant, either singly or in combination. Furthermore, in the only trial that compared poractant alfa and colfosceril, the overall mortality rate was higher in the poractant group (20%) than in the colfosceril group (13%), but this difference was not significant, probably because of the relatively small sample size of the study (N = 228).27 No advantages in terms of reduction in the incidence of BPD were described in this systematic review or in any of the individual trials included in it. In addition, a small but significant increase in the incidence of intraventricular hemorrhage among infants who were treated with animal-derived surfactants was reported.

We recently reported the results of 2 multicenter, randomized, double-blind trials that compared the new-generation synthetic surfactant lucinactant, which contains a peptide that mimics the main function of human SP-B, with other synthetic or animal-derived surfactants for the prevention of RDS.11,12 In the largest of these trials, the SELECT study, lucinactant was shown to decrease the incidence of RDS, RDS-related mortality, and BPD compared with colfosceril, but no reduction in overall mortality rate compared with this surfactant was observed.11 These findings supported the hypothesis that the addition of a peptide that mimics the main action of SP-B to surfactant phospholipids improves short-term clinical outcomes compared with using a surfactant that contains only phospholipids. In this study, a reference arm of infants who were randomly assigned to receive beractant was included. Lucinactant reduced RDS-related deaths and the overall mortality rate at 36 weeks' corrected age compared with beractant, but there was no difference in BPD. It is notable that this is the only study to date that has compared prophylactic administration of colfosceril and beractant. Although this was not the comparison of primary interest in the SELECT trial, the findings of a lower incidence of RDS at 24 hours and more rapid weaning with beractant than with colfosceril parallel those of previous randomized comparison trials of these 2 types of surfactants for the treatment of established RDS.18,19 Similar to all previous trials that compared colfosceril and beractant, the SELECT trial did not demonstrate superiority of beractant over colfosceril in terms of BPD or overall mortality rate. The smaller of the 2 randomized trials of lucinactant, the STAR study, compared this surfactant with poractant alfa.12 This trial is the second largest study published to date to compare poractant alfa to another surfactant. In this trial, the phospholipid doses of both surfactants were similar (175 mg/kg) but were also higher than in other comparison trials of surfactants (for doses and administration in both trials, see the original publications11,12). Furthermore, both poractant alfa and lucinactant contain more SP-B (or its equivalent as sinapultide) than beractant. The primary outcome of being alive without BPD at 28 days was observed to be more frequent in the lucinactant group (37.8%) than in the poractant alfa group (33.1%), but without statistical significance. No differences in other secondary outcomes between groups were identified.

In these 2 lucinactant trials there were far fewer differences in study design and the populations studied than between those studies included in the systematic review by Soll and Blanco.1 Furthermore, most outcomes evaluated in the lucinactant trials were within the ranges reported in those studies included in the review by Soll and Blanco and data from the Vermont Oxford Network.29 In view of the relatively similar design of the lucinactant trials and considering that lucinactant is a different class of surfactant than previous synthetic and animal-derived preparations, we sought to compare overall survival between infants who received lucinactant versus those who received the other types of surfactants, not only within each trial but also by using combined data from both trials. We elected to present overall survival data by using the standard Kaplan-Meier approach, because it allows for comparison of survival between groups through the entire observation period (up to 1 year corrected age) and also because this methodology was used to report survival through 36 weeks' PMA in both of the original publications of the lucinactant trials.11,12 Using a similar approach to report the 1-year survival curves should facilitate comparison with previous data. Kaplan-Meier survival estimates do not falsely amplify treatment differences with respect to survival. Rather, they generally reveal unbiased estimates of survival rates for each treatment, hence yielding unbiased estimates of treatment differences. Nonetheless, because most of the surfactant benefit in mortality occurs in the neonatal period, in our survival analysis comparing treatments through 1 year corrected age we used the Wilcoxon test, which emphasizes earlier treatment differences. Using this approach for analysis, lucinactant administration resulted in better survival through 1 year corrected age than poractant in the STAR trial but no difference with colfosceril or beractant in the SELECT trial. In the combined analysis there was better survival at 1 year corrected age for lucinactant versus the animal-derived surfactants (beractant and poractant), which was of borderline statistical significance but potentially of clinical importance.

We also calculated fixed estimates of mortality at defined time points to allow for crude estimations of the relative magnitude of change and its CIs by using both the prespecified worst-case scenario approach (imputing loss to follow-up as a death) and raw data. The impact of imputations on treatment differences is uncertain and depends on variations in the rate of censoring among treatment groups. When there are premature withdrawals from a study before the end of follow-up, a raw incidence estimate may be biased (ie, counting premature withdrawals as death will generally overestimate the event rate, whereas counting premature withdrawals as survival will generally underestimate the event rate). Not unexpectedly, results of the fixed-time-point estimates of mortality depended on whether imputation was used. Regardless of the methodology used, mortality estimates for infants who received lucinactant were either comparable or significantly lower than those observed for the other surfactants. Unfortunately, only short-term mortality data from the previously published surfactant-comparison trials are available, none of which evaluated survival at 1 year corrected age.

Several randomized trials that compared different animal-derived surfactants for prevention and treatment of RDS have been conducted in the past decade.30–34 Some of these surfactants contain more SP-B (calfactant, poractant) or have used higher doses of phospholipids than when beractant is administered.2,3 Therefore, it is not surprising that a faster improvement in oxygenation versus beractant has been observed in some of them.30,33,34 However, no differences in overall mortality rate have been reported in the 2 large RDS-prevention or -treatment trials that compared calfactant and beractant.30,31 Several relatively small trials have compared poractant with beractant only for treatment of RDS.35 These studies administered poractant using either a higher initial dose of phospholipids (200 mg/kg) or a similar amount (100 mg/kg) compared with beractant. In a preliminary meta-analysis of these trials, Halliday35 suggested that administration of poractant resulted in a lower neonatal mortality rate than beractant primarily when the higher initial dose was given, because no difference in mortality rate versus beractant was found in those trials that administered 100 mg/kg poractant initially. Using this lower initial dose for treatment of RDS, poractant administration resulted in a higher mortality rate (20%) than colfosceril (13%), although this difference did not achieve statistical significance, probably because of the study's sample size.27 At present, it is impossible to differentiate whether any potential benefits of the higher initial dose of poractant are a result of administration of more phospholipids, a higher amount of SP-B, a higher volume of drug (2.5 vs 1.25 mL/kg), which may improve lung distribution, or other alternative explanations. Nonetheless, Halliday concluded that for infants with moderate-to-severe RDS, the larger dose of poractant is more effective, but for prophylaxis a lower dose may be appropriate; however, this hypothesis has yet to be tested prospectively in a clinical trial.35 In keeping with this notion and because, to our knowledge, no randomized comparison of these 2 surfactants for prevention of RDS using any dose has ever been conducted, we combined data from infants who received beractant and poractant in both of the lucinactant trials for analysis. Furthermore, we used appropriate methodology for analyzing data across studies with different sample sizes and randomization schemes.1,15

To our knowledge, previous surfactant-comparison trials have not reported outcomes that were prospectively collected beyond the neonatal period. This may limit the ability to draw conclusions related to the impact of surfactants in long-term survival and other morbidity frequently observed in preterm infants after discharge from neonatal intensive care. Nonetheless, published follow-up data from studies that compared various surfactants with placebo demonstrate that the improved survival observed resulting from surfactant treatment is not associated with increased subsequent morbidity.36 Because lucinactant is a new-generation surfactant, we sought to determine postdischarge morbidity and outcome up to 1 year corrected age of infants who received this as well as the other surfactants used in these 2 trials. We successfully collected this information in nearly all of the participants or survivors from both trials. Our data indicate that rehospitalization of preterm infants after discharge from neonatal intensive care remains a frequent event and confirm the findings from previous follow-up studies of surfactant therapy.37 When we examined the incidences of respiratory morbidity and rehospitalization in each trial, no differences were detected between infants given the various surfactant preparations, including lucinactant. Similarly, neurologic assessment of these infants showed essentially no differences except for a lower occurrence of muscle-tone abnormalities and gross motor delay favoring the lucinactant group, even with a higher number of survivors in the lucinactant group. Although our data on neurologic evaluations have limitations, most infants from both trials were assessed at 1 year corrected age. In fact, the proportion of infants we were able to follow was similar or higher than many of the previous follow-up studies of infants treated with surfactant.38,39 An additional strength of these evaluations is that they were conducted by physicians who were unaware of group assignment.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
The findings of this 1-year follow-up study, as well as data from the original reports of the lucinactant trials, strongly suggest that administration of lucinactant to infants at risk for RDS results in neonatal survival that is at least comparable with, if not superior to, that of infants given the animal-derived surfactants beractant and poractant alfa. Furthermore, these data demonstrate that there is no difference in morbidity through 1 year corrected age in infants given lucinactant versus other animal-derived surfactants despite the proportionally higher number of survivors. These findings strongly support the long-term safety of using lucinactant for the prevention of neonatal RDS.


   ACKNOWLEDGMENTS
 
This study was funded by Discovery Laboratories, Inc.

We acknowledge respective members of the SELECT and STAR Steering Committees, members of the Data Safety Monitoring Board, participating investigators and their staff, and Discovery Laboratories personnel, who monitored the study. Thomson Scientific Connections provided assistance with manuscript styling and graphics preparation.


   FOOTNOTES
 
Accepted Mar 1, 2007.

Address correspondence to Fernando Moya, MD, Coastal Area Health Education Center, Department of Neonatology, 2131 S 17th St, Wilmington, NC 28402-9025. E-mail: fernando.moya{at}coastalahec.org

Financial Disclosure: Drs Moya, Sinha, Gadzinowski, D'Agostino, Guardia, and Mazela received payments from Discovery Laboratories, Inc, for consulting in relation to this trial, and Drs Segal and Liu are employees of Discovery Laboratories, Inc.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Soll RF, Blanco F. Natural surfactant extract versus synthetic surfactant for neonatal respiratory distress syndrome. Cochrane Database Syst Rev. 2001;(2) :CD000144
  2. Notter RH, Wang Z, Egan EA, Holm BA. Component-specific surface and physiological activity in bovine-derived lung surfactants. Chem Phys Lipids. 2002;114 :21 –34[CrossRef][ISI][Medline]
  3. Curstedt T, Jörnvall H, Robertson B, Bergman T, Berggren P. Two hydrophobic low-molecular-mass protein fractions of pulmonary surfactant: characterization and biophysical activity. Eur J Biochem. 1987;168 :255 –262[ISI][Medline]
  4. Clark JC, Wert SE, Bachurski CJ, et al. Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice. Proc Natl Acad Sci USA. 1995;92 :7794 –7798[Abstract/Free Full Text]
  5. Nogee LM, Garnier G, Dietz HC, et al. A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds. J Clin Invest. 1994;93 :1860 –1863[ISI][Medline]
  6. Nogee LM, Dunbar AE III, Wert SE, Askin F, Hamvas A, Whitsett JA. Brief report: a mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 2001;344 :573 –579[Free Full Text]
  7. Cochrane CG, Revak SD. Pulmonary surfactant protein B (SP-B): structure-function relationships. Science. 1991;254 :566 –568[Abstract/Free Full Text]
  8. Andersson S, Kheiter A, Merritt TA. Oxidative inactivation of surfactants. Lung. 1999;177 :179 –189[CrossRef][ISI][Medline]
  9. Revak SD, Merritt TA, Cochrane CG, et al. Efficacy of synthetic peptide-containing surfactant in the treatment of respiratory distress syndrome in preterm infant rhesus monkeys. Pediatr Res. 1996;39 :715 –724[ISI][Medline]
  10. Cochrane CG, Revak SD, Merritt TA, et al. The efficacy and safety of KL4-surfactant in preterm infants with respiratory distress syndrome. Am J Respir Crit Care Med. 1996;153 :404 –410[Abstract]
  11. Moya FR, Gadzinowski J, Bancalari E, et al. A multicenter, randomized, masked, comparison trial of lucinactant, colfosceril palmitate, and beractant for the prevention of respiratory distress syndrome among very preterm infants. Pediatrics. 2005;115 :1018 –1029[Abstract/Free Full Text]
  12. Sinha SK, Lacaze-Masmonteil T, Valls i Soler A, et al. A multicenter, randomized, controlled trial of lucinactant versus poractant alfa among very preterm infants at high risk for respiratory distress syndrome. Pediatrics. 2005;115 :1030 –1038[Abstract/Free Full Text]
  13. D'Agostino RB Sr, Massaro JM, Sullivan LM. Non-inferiority trials: design concepts and issues—the encounters of academic consultants in statistics. Stat Med. 2003;22 :169 –186[CrossRef][ISI][Medline]
  14. International conference on harmonisation; guidance on statistical principles for clinical trials: availability—FDA. Notice. Fed Regist. 1998:63 :49583 –49598[Medline]
  15. Cupples LA, Gagnon DR, Ramaswamy R, D'Agostino RB. Age-adjusted survival curves with application in the Framingham study. Stat Med. 1995;14 :1731 –1744[CrossRef][ISI][Medline]
  16. Soll RF. Prophylactic natural surfactant extract for preventing morbidity and mortality in preterm infants. Cochrane Database Syst Rev. 1997;(4) :CD000511
  17. Soll RF. Synthetic surfactant for respiratory distress syndrome in preterm infants [Cochrane review]. In: The Cochrane Library. Issue 2. Chichester, United Kingdom: John Wiley & Sons, Ltd; 2004
  18. Horbar JD, Wright LL, Soll RF, et al. A multicenter randomized trial comparing two surfactants for the treatment of neonatal respiratory distress syndrome. J Pediatr. 1993;123 :757 –766[ISI][Medline]
  19. Vermont-Oxford Network. A multicenter, randomized trial comparing synthetic surfactant with modified bovine surfactant extract in the treatment of neonatal respiratory distress syndrome. Pediatrics. 1996;97 :1 –6[Abstract/Free Full Text]
  20. Alvarado M, Hingre R, Hakason D, Gross S. Clinical trial of Survanta versus Exosurf in infants <1500 g with respiratory distress syndrome [abstract]. Pediatr Res. 1993;33 :314A
  21. da Costa DE, Pai MG, Al Khusaiby SM. Comparative trial of artificial and natural surfactants in the treatment of respiratory distress syndrome of prematurity: experiences in a developing country. Pediatr Pulmonol. 1999;27 :312 –317[CrossRef][ISI][Medline]
  22. Modanlou HD, Beharry K, Padilla G, Norris K, Safvati S, Aranda JV. Comparative efficacy of Exosurf and Survanta surfactants on early clinical course of respiratory distress syndrome and complications of prematurity. J Perinatol. 1997;17 :455 –460[Medline]
  23. Pearlman SA, Leef KH, Stefano JL, et al. A randomized trial comparing Exosurf versus Survanta in the treatment of neonatal RDS [abstract]. Pediatr Res. 1993;33 :340A
  24. Sehgal SS, Ewing CK, Richards T, Taeusch HW. Modified bovine surfactant (Survanta) versus a protein-free surfactant (Exosurf) in the treatment of respiratory distress syndrome in preterm infants: a pilot study. J Natl Med Assoc. 1994;86 :46 –52[Medline]
  25. Hudak ML, Farrell EE, Rosenberg AA, et al. A multicenter randomized, masked comparison trial of natural versus synthetic surfactant for the treatment of respiratory distress syndrome. J Pediatr. 1996;128 :396 –406[CrossRef][ISI][Medline]
  26. Hudak ML, Martin DJ, Egan EA, et al. A multicenter randomized masked comparison trial of synthetic surfactant versus calf lung surfactant extract in the prevention of neonatal respiratory distress syndrome. Pediatrics. 1997;100 :39 –50[Abstract/Free Full Text]
  27. Kukkonen AK, Virtanen M, Järvenpää AL, Pokela ML, Ikonen S, Fellman V. Randomized trial comparing natural and synthetic surfactant: increased infection rate after natural surfactant? Acta Paediatr. 2000;89 :556 –561[CrossRef][ISI][Medline]
  28. Ainsworth SB, Beresford MW, Milligan DWA, et al. Pumactant and poractant alfa for treatment of respiratory distress syndrome in neonates born at 25–29 weeks' gestation: a randomised trial [published correction appears in Lancet. 2000;356:600]. Lancet. 2000;355 :1387 –1392[CrossRef][ISI][Medline]
  29. Horbar JD, Badger GJ, Carpenter JH, et al. Trends in mortality and morbidity for very low birth weight infants, 1991–1999. Pediatrics. 2002;110 :143 –151[Abstract/Free Full Text]
  30. Bloom BT, Kattwinkel J, Hall RT, et al. Comparison of Infasurf (calf lung surfactant extract) to Survanta (beractant) in the treatment and prevention of respiratory distress syndrome. Pediatrics. 1997;100 :31 –38[Abstract/Free Full Text]
  31. Bloom BT, Clark RH; Infasurf Survanta Clinical Trial Group. Comparison of Infasurf (calfactant) and Survanta (beractant) in the prevention and treatment of respiratory distress syndrome. Pediatrics. 2005;116 :392 –399[Abstract/Free Full Text]
  32. Speer CP, Gefeller O, Groneck P, et al. Randomised clinical trial of two treatment regimens of natural surfactant preparations in neonatal respiratory distress syndrome. Arch Dis Child Fetal Neonatal Ed. 1995;72 :F8 –F13[Abstract]
  33. Ramanathan R, Rasmussen MR, Gerstmann DR, Finer N, Sekar K; North American Study Group. A randomized, multicenter masked comparison trial of poractant alfa (Curosurf) versus beractant (Survanta) in the treatment of respiratory distress syndrome in preterm infants. Am J Perinatol. 2004;21 :109 –119[CrossRef][ISI][Medline]
  34. Malloy CA, Nicoski P, Muraskas JK. A randomized trial comparing beractant and poractant treatment in neonatal respiratory distress syndrome. Acta Paediatr. 2005;94 :779 –784[CrossRef][ISI][Medline]
  35. Halliday HL. History of surfactant from 1980. Biol Neonate. 2005;87 :317 –322[CrossRef][Medline]
  36. Sinn JK, Ward MC, Henderson-Smart DJ. Developmental outcome of preterm infants after surfactant therapy: systematic review of randomized controlled trials. J Paediatr Child Health. 2002;38 :597 –600[CrossRef][ISI][Medline]
  37. Sell M, Cotton R, Hirata T, et al. One-year follow-up of 273 infants with birth weights of 700 to 1100 grams after prophylactic treatment of respiratory distress syndrome with synthetic surfactant or air placebo. American Exosurf Neonatal Study Group I. J Pediatr. 1995;126(5 pt 2) :S20 –S25
  38. Survanta Multidose Study Group. Two-year follow-up of infants treated for neonatal respiratory distress syndrome with bovine surfactant. J Pediatr. 1994;124 :962 –967[CrossRef][ISI][Medline]
  39. Robertson B, Curstedt T, Tubman R, et al. A 2-year follow up of babies enrolled in a European multicentre trial of porcine surfactant replacement for severe neonatal respiratory distress syndrome. Collaborative European Multicentre Study Group. Eur J Pediatr. 1992;151 :372 –376[CrossRef][ISI][Medline]
PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow An erratum has been published
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Moya, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Moya, F.
Related Collections
Right arrow Premature & Newborn