A MULTINATIONAL, MULTICENTER, MASKED, RANDOMIZED, CONTROLLED
STUDY TO ASSESS THE SAFETY AND EFFICACY OF LUCINACTANT FOR
INHALATION IN PRETERM NEONATES 26 TO 32 WEEKS GESTATIONAL AGE
WITH RESPIRATORY DISTRESS SYNDROME.

Preterm neonates are often surfactant deficient and receive surfactant
replacement therapy (SRT) to treat respiratory distress syndrome
(RDS).Currently, SRT is instilled directly into the neonate*s lung through an
endotracheal tube usually while receiving positive pressure mechanical
ventilation (MV). However, data from studies in animal models of RDS suggest
that positive pressure MV administered by an endotracheal tube
may be injurious to the preterm lung. In an attempt to avoid endotracheal
intubation and MV, to support preterm newborns with mild to moderate
RDS, nasal continuous positive airway pressure (nCPAP) has become a widely
accepted practice. However, use of nCPAP precludes delivery of
SRT and deterioration in over one-third to one-half of preterm neonates
receiving nCPAP has been observed in large multicenter trials, with most
requiring endotracheal intubation, MV, and in many cases delayed administration
of SRT. Meta-analyses of clinical surfactant studies indicate
that SRT is most effective when administered early in the course of RDS, and
the therapeutic benefit of SRT can diminish substantially when
administered late. Therefore, the inability to administer SRT in preterm
neonates with RDS who are initially supported with nCPAP and then
deteriorate, requiring endotracheal intubation and delayed SRT results in
suboptimal timing for SRT to treat RDS.

To evaluate the safety and efficacy of lucinactant for inhalation, in
comparison to nasal continuous positive airway pressure (nCPAP) alone, in
preterm neonates with RDS, as assessed by the time to, and incidence of,
respiratory failure and/or death due to RDS, incidence of
bronchopulmonary dysplasia (BPD), and change in physiologic parameters
(fraction of inspired oxygen [FiO2] and partial pressure of carbon dioxide
[PCO2]) over the first 72 hours of life.

This study is a multinational, multicenter, masked, randomized, controlled
study to evaluate the safety and efficacy of 2 different doses of lucinactant
for inhalation (40 mg TPL/kg and 80 mg TPL/kg) in conjunction with nCPAP
compared with nCPAP alone, in preterm neonates 26 to
32 completed weeks PMA who are being cared for in a neonatal intensive care
unit (NICU) and who are within the first 20 hours after birth, who had
successful implementation of controlled nCPAP within 90 minutes of birth, and
who are candidates for SRT. Neonates will be enrolled by strata: 26 to 28
completed weeks PMA and 28 to 32 completed weeks PMA; approximately 2/3 of
enrolled subjects will be in the 26 to 28 completed weeks PMA strata. There
will be 2 phases in the study, a primary phase through 36 weeks PMA and a
longer-term follow-up phase through 1-year corrected age. Before study
enrollment, legal guardians will provide a signed written informed consent form
(ICF) for each potential subject. Qualification for study enrollment will be
established after confirmation that the subject has met all of the inclusion
criteria and none of the exclusion criteria. The clinical criteria for
enrollment may be met prior to informed consent being obtained; however, no
study-specific procedures that are not part of the usual standard care of the
subject at the institution may be performed until the informed consent has been
provided by a legally authorized representative of the subject. Inclusion
criteria to be met within the first 20 hours after birth include respiratory
insufficiency with a requirement for nCPAP of 5 to 6 cm H2O for at least 30
minutes to maintain oxygen saturation measured by pulse oximetry (SpO2) of 90%
to 95%, with a fraction of inspired oxygen (FiO2) within a range of 0.25 to
0.45, also for at least 30 minutes. As soon as study eligibility has been
confirmed and the informed consent is signed, subjects will be randomized to 1
of 2 active treatment groups or the control group (nCPAP only). Study therapy
(lucinactant for inhalation or control) must be initiated as soon as possible
after randomization, with the caveat that all subjects must continue to meet
entry criteria at the time of initiation of study therapy (lucinactant for
inhalation, or control).
Subjects may be eligible to receive up to 2 repeat doses. Repeat doses will be
allowed 2 hours from completion of the previous dose up to 36 hours after
completion of randomization if subjects meet repeat dosing criteria, as
described in the *Treatment Groups* section. Subjects randomized to the control
group will be continued on nCPAP alone. All subjects in the active treatment
groups will receive the same drug
concentration of lucinactant for inhalation at the same rate delivery. The dose
will vary by the volume of the nominal dose of lucinactant (30 mg
TPL/mL) aerosolized and introduced into the nCPAP circuit, given over a
predetermined time for each dose. The lucinactant for inhalation delivery will
be facilitated by the investigational ADS device in conjunction with a
commercially available nCPAP generator and patient interface.
Dose assignments will be masked to the principal investigator (PI); study staff
(eg, site coordinator), as applicable; sponsor; and subject*s
parents/legal guardians. All enrolled subjects will receive study treatment in
a NICU, a specialized care center staffed by neonatologists, nurses, and
respiratory therapists who are experienced in the delivery of emergent care to
the preterm neonatal population. Neonates in the NICU are continuously
monitored using advanced and sophisticated monitoring equipment, and there is
ready and immediate access to equipment, medications, and skilled personnel
that may be needed to address emergent developments. Interventions such as
endotracheal intubation, MV, and surfactant administration will be readily
available to all study subjects if clinically indicated in accordance with the
high level standard of care customary in the NICU. Neonates will be followed
through the primary phase efficacy and safety evaluations through 36 weeks PMA,
NICU discharge, hospital transfer, or death, whichever occurs first. For the
longer-term follow-up phase, neonates will be followed up to 1-year corrected
age, at which time a physical examination will be performed, including an
abbreviated neurologic assessment.

This clinical study is intended for preterm neonates 26 to 32 completed weeks
postmenstrual age (PMA). Currently, preterm neonates 29 to
34 weeks PMA have been studied in Protocol 03-CL-1201 in a dose escalation of
25, 50, and 75 mg total phospholipids (TPL)/kg (with an
extension currently ongoing, which continues the dose escalation up to 150 mg
TPL/kg and also allows a repeat dose if repeat dosing criteria are
met). Similarly, a dose escalation study in preterm infants 26 to 28 weeks PMA
has been initiated (Protocol 03-CL-1401). To date, lucinactant for
inhalation has been generally well tolerated and there have been generally no
safety signals of concern with escalating doses.

The inability to administer SRT without the need for endotracheal intubation
represents an important unmet medical need. Aerosolized
surfactant delivery potentially addresses this unmet medical need by providing
a means to deliver SRT noninvasively to preterm neonates with
RDS supported with nCPAP, thereby providing SRT early in the disease course
while avoiding the need for endotracheal intubation.
This clinical study is intended for preterm neonates 26 to 32 completed weeks
postmenstrual age (PMA). Currently, preterm neonates 29 to
34 weeks PMA have been studied in Protocol 03-CL-1201 in a dose escalation of
25, 50, and 75 mg total phospholipids (TPL)/kg (with an
extension currently ongoing, which continues the dose escalation up to 150 mg
TPL/kg and also allows a repeat dose if repeat dosing criteria are
met). Similarly, a dose escalation study in preterm infants 26 to 28 weeks PMA
has been initiated (Protocol 03-CL-1401). To date, lucinactant for
inhalation has been generally well tolerated and there have been generally no
safety signals of concern with escalating doses.