Surfactant Trials

(1)

LETTERS TO THE EDITOR

Statements appearing here are those of the writers and do not represent the ofﬁcial position of the American Academy of Pediatrics or its Committees. Comments on any topic, including the contents of PEDIATRICS, are invited from all members of the profession; those accepted for publication will not be subject to major editorial revision but generally must be no more than 400 words in length. The editors reserve the right to publish replies and may solicit responses from authors and others.

Please see www.pediatrics.org for instructions on submitting letters.

Surfactant Trials

To the Editor.—

We read with interest Dr Kattwinkel’s commentary1_on

our recently published studies2,3_{comparing the new}

sur-factant, lucinactant, to current commercially available surfactants. We write to address specific comments and explicate our purpose in undertaking this research.

As Dr Kattwinkel points out, the simplistic approach of delivering only phospholipids to infants with surfac-tant deficiency did not prevent or ameliorate respiratory distress syndrome (RDS). It was only with modifications of the formulation, including the addition of alcohols to facilitate the spreading of surfactant proteins (animal-derived in current formulations), that an improvement in the clinical performance of surfactants was noted. As these newer formulations were developed and tested, surfactants became one of the most studied therapies in neonatology. Yet, there are many myths regarding these data. For example, the perception that the data “consis-tently favored” animal-derived protein-containing “nat-ural” surfactants is only true as they relate to reductions in the incidence of pneumothorax. This advantage has been observed across most of the head-to-head trials, and in a meta-analysis it translated into a number needed to treat of⬃20.4_{In contrast, a significant}

reduc-tion in neonatal mortality with animal-derived protein-containing surfactants versus synthetic, non–protein-containing surfactants was observed in only 1 of the 10 comparison trials,5_{and in the results of the}

meta-anal-ysis comparing these 2 classes of surfactants, it was only marginally significant.4_{The latter trial, which compared}

poractant alfa with the non–protein-containing syn-thetic surfactant Pumactant, was halted prematurely and led to the withdrawal of Pumactant. It is important to highlight that this trial enrolled fewer infants than our trial comparing lucinactant to poractant alfa (STAR). None of the 8 surfactant-comparison trials reporting on bronchopulmonary dysplasia or chronic lung disease showed any significant difference between the 2 classes

of surfactants either alone or after pooled analyses.4_An

increase in the risk of intraventricular hemorrhage was observed in a trial that compared calfactant with colfos-ceril and overall with animal-derived surfactants as a class in the systematic review, translating into a number needed to harm of 36.4 _{Unfortunately, none of these}

trials reported the competing outcomes of death or in-traventricular hemorrhage or the occurrence of periven-tricular leukomalacia, an important contributor to ad-verse neurodevelopmental outcome. Moreover, there is no information on outcomes beyond the neonatal period for any of these trials.

The search for an alternative to animal-derived sur-factants has been the focus of our group for more than a decade, culminating in the conduct of our 2 global trials of lucinactant, SELECT and STAR. These trials were designed to evaluate how this novel peptide-based sur-factant would perform across a variety of regions and neonatal practices in a “real-world” environment com-pared with other commercially available surfactants. The SELECT and STAR trials were conducted according to current and contemporary clinical-trial standards. The merits of clinical studies should be judged based on how well they are designed and conducted, not on precon-ceived notions of acceptability depending on their origin. Many well-conducted studies addressing crucial issues in neonatal and perinatal medicine have been conducted primarily or exclusively in countries outside the United States, including the OSIRIS trial of colfosceril and trials of delivery-room management of infants with meconi-um-stained amniotic fluid.6 _{These studies have had a}

major impact on current neonatal practice, not only in the United States but worldwide. Implying that only studies conducted in the United States are worthy of consideration would limit contributions to the scientific literature.

The approaches taken in the conduct of our trials exceeded in detail and quality any of the previously published studies that compared surfactants. Both trials were designed with internationally recognized

neonatol-PEDIATRICS Volume 117, Number 1, January 2006 245 at Viet Nam:AAP Sponsored on August 29, 2020

www.aappublications.org/news

(2)

ogists who served as members of the respective study steering committees that provided oversight of the trials. A single data-safety–monitoring board was established to monitor both trials. The principal investigators of both trials were intimately involved throughout the trials and conducted investigator meetings in addition to visiting most individual sites to ensure adherence to the proto-col. In contrast to the majority of previous surfactant-comparison trials, which were not blinded, we focused on strict adherence to blinding procedures and used a central adjudication process for the primary outcomes in our pivotal SELECT trial. Given the significant lack of agreement in establishing important neonatal diagnoses described in the literature, we felt very strongly that the use of strict adjudication methods would improve assess-ment of the primary and key secondary end points. Ventilatory-management guidelines that reflect evi-dence-based current practice were also developed (see addendum of ref 3 for distinguished committee mem-bership), used, and monitored throughout the trial. The US Food and Drug Administration (FDA) also provided guidance and, on completion of the pivotal SELECT study, formally audited the data and reviewed the trial’s execution.

We wish to clarify, as clearly stated in our article, that the SELECT trial was designed as a superiority trial that compared lucinactant to colfosceril, with beractant serv-ing as a reference arm in the study. The hypothesis tested was that sinapultide, the novel synthetic peptide that mimics human surfactant protein B (SP-B), when added to a formulation of phospholipids (the surfactant preparation, lucinactant) would confer superiority over a colfosceril surfactant formulation of phospholipid only, which contains no proteins. We applied uniformly rig-orous clinical design, execution, and statistical method-ology to all aspects of the study, including developing the primary study hypothesis, obtaining the study data, and testing the statistical comparisons on the primary outcomes measures. The sample size of the SELECT study and the statistical assumptions of a power of 94% to detect differences between these 2 primary compara-tors are clearly much more robust than those of any previous surfactant trial. The comment that the SELECT study was “designed as [a] ‘noninferiority’” study and was “underpowered” is not accurate. The beractant treatment group was included as a reference arm per request by the FDA so that it could be used for internal validation of the clinical trial. In fact, our data provide the only comparative information in the literature on the prophylactic use of colfosceril and beractant and are consistent with observations from treatment trials of colfosceril and the animal-derived surfactant, beractant, in which no major outcome differences were otherwise seen except for air leak. Moreover, our SELECT study of RDS prophylaxis (N⫽ 1294) and the Vermont Oxford Network rescue study, which used colfosceril and

berac-tant (N⫽1296), are the 2 largest surfactant-comparison trials conducted to date.

We also wish to clarify that, as stated clearly in our article, the STAR trial was a study designed to demon-strate noninferiority of lucinactant compared with po-ractant. Noninferiority of lucinactant was established even with only half of the planned patients. From a statistical point of view, early termination of the study with only half of the planned patients being enrolled could reduce its power. Any statistically insignificant findings resulting from analysis of this reduced sample could be attributed to the smaller sample. However, any statistically significant result would be valid and is even more convincing, because it is based on a smaller sample size. Power of the study is a concept that is more appro-priate for study design and is meaningful before final analyses of the data. After a study is completed and final analysis is performed, power is not a factor that has an impact on the interpretation of statistically significant results.

Consistent with other large multicenter international clinical trials, the number of patients per center in our trials varied from one center to another. In addition, although there were many centers from outside the United States, the quality of the clinical trial was not compromised; the study sites passed rigorous inspection by regulatory agencies (the FDA and European Agency for the Evaluation of Medicinal Products). In addition, the statistical analysis, after adjusting for center effect, still demonstrated the superiority of lucinactant com-pared with colfosceril in the SELECT trial and noninfe-riority of lucinactant compared with poractant in the STAR trial. The diversity of the centers is not a “fault” in the design of these studies but rather is an indication of the generalizability of the results.

Administration of animal-derived surfactants results in a more rapid decrease of ventilatory requirements and supplemental oxygen than older-generation synthetic surfactants such as colfosceril. This faster response has been attributed primarily to the presence of surfactant proteins, particularly SP-B, although none of the trials that compared animal-derived surfactants to colfosceril used similar doses of phospholipids. In our study, more rapid reductions of oxygen requirements were also ob-served among infants who received lucinactant than those in the colfosceril group, which is in keeping with in vitro data demonstrating rapid reductions of surface tension by a mixture of phospholipids and the KL4 pep-tide (sinapulpep-tide). The same response was seen for in-fants who received beractant. In follow-up comments about the need to know more about the fate of the KL-4 peptide, we believe that we addressed this in the article. We referred to recently published data demonstrating that sinapultide is not only taken up slowly by human type II pneumocytes, but, more importantly, it does not interfere with endogenous surfactant protein

expres-246 LETTERS TO THE EDITOR

at Viet Nam:AAP Sponsored on August 29, 2020

(3)

sion, the formation of lamellar bodies, or other surfac-tant-related functions of type II cells.7

Data from our trials and supporting in vitro studies clearly demonstrate that the synthetic peptide, si-napultide, mimics the most important function of SP-B. When added to surfactant phospholipids, sinapultide re-sults in a novel surfactant that outperforms non–pro-tein-containing synthetic surfactants and functions at least as well, if not better, than some animal-derived surfactants. Widespread availability of this surfactant will potentially obviate the need for use of animal-de-rived products and hence reduce any potential risk as-sociated with such products. These considerations do not even address the issues related to the ethical and reli-gious concerns of administering animal-derived thera-peutics when a suitable alternative exists. We can only wonder what parental choices would be if appropriate information were provided regarding not only the com-parative data from the lucinactant trials but also the origin of the surfactant preparations commonly in use, in the context of availability of this new alternative.8_In

our opinion, data from our clinical trials supporting the use of lucinactant as an alternative therapy for prevent-ing and treatprevent-ing RDS represent a major breakthrough.

Fernando R. Moya, MD Department of Neonatology Coastal Area Health Education Center Wilmington, NC 28402-9025

Sunil K. Sinha, MD, PhD, FRCP, FRCPCH Department of Paediatrics South Cleveland Hospital Middlesbrough TS4 3BW , United Kingdom

Ralph D’Agostino, PhD Department of Mathematics Boston University Boston, MA 02215 on behalf of the SELECT and STAR Investigators

REFERENCES

1. Kattwinkel J. Synthetic surfactants: the search goes on [com-mentary].Pediatrics.2005;115:1075–1076

2. Sinha SK, Lacaze-Masmonteil T, Valls i Soler A, et al. A ran-domized, controlled trial of lucinactant versus poractant alfa among very premature infants at high risk for respiratory dis-tress syndrome.Pediatrics.2005;115:1030 –1038

3. 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 dis-tress syndrome among very preterm infants. Pediatrics. 2005; 115:1018 –1029

4. Soll RF, Blanco F. Natural surfactant extract versus synthetic surfactant for neonatal respiratory distress syndrome [Cochrane review]. In: The Cochrane Library. Issue 2. Oxford, United Kingdom: Update Software; 2004

5. Ainsworth SB, Beresford MW, Milligan DW, 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 inLancet. 2000;356:600].Lancet.

2000;355:1387–1392

6. Wiswell TE, Gammon CM, Jacol J, et al. Delivery room man-agement of the apparently vigorous meconium-stained neonate: results of the multicenter, international collaborative trial. Pedi-atrics.2000;105:1–7

7. Romero EJ, Moya FR, Tuvim MJ, Alcorn JL. Interaction of an artificial surfactant in human pulmonary epithelial cells.Pediatr Pulmonol.2005;39:167–177

8. Adappa R, Benson R, Oddie S, Wyllie J. Use of animal surfactant: should we seek consent?Arch Dis Child Fetal Neonatal Ed.2003;88:F351

doi:10.1542/peds.2005-1927

In Reply.—

Drs Moya et al are concerned with comments related to the following issues concerning their recently reported trials with the new synthetic surfactant lucinactant:

1. whether previous studies have shown natural surfac-tants to be superior to previously developed synthetic surfactants;

2. whether lucinactant is superior or equivalent to ex-isting synthetic surfactants; and

3. whether lucinactant is superior or equivalent to ex-isting natural surfactants.

The answer to concern 1 has been examined in sev-eral meta-analyses and in vitro studies that have con-cluded convincingly that the natural surfactants are more effective biophysically, physiologically, and clini-cally (numerous reviews on this subject are available1–4_).

Superiority of natural surfactants is supported by the discontinuance of previously developed synthetic surfac-tants in the United States and United Kingdom.

The answer to the second concern seems to be “yes,” as evidenced from in vitro studies and the SELECT trial. However, as my commentary pointed out, approved synthetic surfactants are no longer used in the United States or United Kingdom. The SELECT trial may well justify the use of lucinactant over the existing synthetic surfactants in those parts of the world in which synthetic surfactants are still in use and may justify its use in the United States and United Kingdom under circumstances in which natural surfactant is deemed by clinicians or parents to be contraindicated for religious or theoretical infectious or immunologic reasons. However, questions about the metabolism of sinapultide compared with sur-factant proteins B and C and the ultimate fate of the sinapultide protein remain to be answered.

Concern 3 is still an open question. Moya et al are correct that power analysis is most important for defin-ing the appropriate sample size before the study is initi-ated and that sample size is less important when signif-icant differences are detected after a predefined interim analysis has been conducted. However, direct compari-son of lucinactant with poractant in the STAR trial found no significant differences (P⬍.05). In the SELECT trial, comparing lucinactant to beractant, there was no

differ-PEDIATRICS Volume 117, Number 1, January 2006 247 at Viet Nam:AAP Sponsored on August 29, 2020

(4)

DOI: 10.1542/peds.2005-1927

2006;117;245

Pediatrics

Fernando R. Moya, Sunil K. Sinha and Ralph D'Agostino

Surfactant Trials

Services

Updated Information &

http://pediatrics.aappublications.org/content/117/1/245 including high resolution figures, can be found at:

References

http://pediatrics.aappublications.org/content/117/1/245#BIBL This article cites 7 articles, 5 of which you can access for free at:

Subspecialty Collections

sub

http://www.aappublications.org/cgi/collection/fetus:newborn_infant_

Fetus/Newborn Infant

following collection(s):

This article, along with others on similar topics, appears in the

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtml in its entirety can be found online at:

Information about reproducing this article in parts (figures, tables) or

Reprints

http://www.aappublications.org/site/misc/reprints.xhtml Information about ordering reprints can be found online:

(5)

DOI: 10.1542/peds.2005-1927

2006;117;245

Pediatrics

Fernando R. Moya, Sunil K. Sinha and Ralph D'Agostino

Surfactant Trials

http://pediatrics.aappublications.org/content/117/1/245

located on the World Wide Web at:

The online version of this article, along with updated information and services, is

the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2006 has been published continuously since 1948. Pediatrics is owned, published, and trademarked by Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it