Pediatric Pulmonology 14:16-22 (1992)
ExosurfB Treatment Investigational New Drug Phase: Effect of an Individualized Third Dose in Infants With Respiratory Distress Syndrome David Easa, MD,' Susan Pelke, R N , ~Kenneth T. Nakamura, MD,' Janet Barrett, B S , ~ Venkataraman Balaraman, MBBS,~Sherry W.H. Loo, M D , ~Elenita Ibarra-Pratt, R N , ~and Martha B. Smith, RR? Summary. Of 95 infants treated with the synthetic surfactant, ExosurfB, under a Treatment InvestigationalNew Drug protocol, 17 receivedone dose, 40 receivedtwo, and 38 receivedthree doses. Seventy-six (80%) of the infants were treated by rescue protocol. We retrospectively reviewed the clinical course of the 67 surviving rescue infants. We found that, compared to oneand two-dose infants, those treated with three doses of Exosurfm were more premature,smaller, required a longer ventilator course, and had more frequent complications,includingpatent ductus arteriosus (PDA), intraventricular hemorrhage, nosocomial pneumonia, and apnea. They required higher oxygen concentrations starting 8 hr after their first dose and higher mean airway pressure (MAP) from the time of their second dose. These trends continued during all subsequent time points, as compared to infants treated with two doses. The third dose was administered an average of 17 hr after the second, resulting in little change of MAP, but some reductionin oxygen requirements.By 24 hr after the last dose, only 4% of three-dose infants were extubated compared with 30% of the two-dose and 71% of one-dose infants. In conclusion, repeated administrationof Exosurf@is not equally effective in every treated infant with respiratorydistress syndrome (RDS) and complications of prematurity may affect or accompany poor response. We speculate that (1) the group of infants treated with three doses of ExosurfWhad a greater degree of surfactant deficiency than the other groups, (2) PDA may account for this refractory response to surfactant, and (3) the three-dose group might have responded better to earlier treatment and/or more surfactant doses, or to earlier PDA closure. Pediatr Pulmonol. 1992;14:1622. G) 1992 Wiley-Liss. Inc. Key words: Oxygen requirement; mean airway pressure; survival rate, complications; Patent ductus arteriosus.
INTRODUCTION
Randomized, prospective, controlled studies of surfactant replacement therapy in neonatal RDS have confirmed reductions in severity and some complications in treated infants. '-I4 Although most of the trials have provided surfactant as a single dose, it has been suggested that either very large single doses, multiple doses or very large sample sizes would be required to demonstrate convincing reductions in mortality and incidence of bronchopulmonary dysplasia (BPD) after surfactant replacement Recently, a very large trial did demonstrate convincing reductions in BPD after two doses of a synthetic surfactant.I4 Outcome may also be dependent upon the surfactant preparation used, since it is not known which surfactant preparation is most appropriate or what dosing schedules are optimal. ''.I6 A third possibility is that other concomitant problems such as patent ductus arteriosus (PDA) may affect the response to surfactant and, thus, clinical outcome. A synthetic surfactant invented by Clements at the University of California ( E x o s u f l Neonatal, Burroughs 6 1992 Wiley-Liss, Inc.
Wellcome Co., Research Triangle Park, NC) was the first to receive U.S. Food and Drug Administration From the Departmentsof Pediatrics' and Respiratory Care,' Kapiolani Medical Center for Women and Children, John A. Burns School of Medicine, Honolulu, Hawaii and Burroughs Wellcome Co., Research Triangle Park, North Carolina.' Received August 27, 1991; (revision) accepted lor publicationApril 7. 1992. Janet Barrett, B.S., i s an ernployec of Burroughs Wellcome Co. and the only author who holds stock in the holding company which wholly owns Burroughs Wellcome, Wellcome plc. The University of Hawaii received formal grants from Burroughs Wellcome (USA) for conduct of earlier randomized, placebo-controlled studies, but no funding was provided lor this study. None of the investigators derived personal incornc from those grants. No formal financial relationship exists b e tween any of the coauthors (except for Ms. Barrett) o r investigatorsand any arm of Wellcome. Financial considerations have not colored either the conduct, analysis, or presentation olthe results of this trial. Address correspondence and reprint requests to Dr. D. Easa, Kapiolani Medical Center for Women and Children, 1319 Punahou St.. Honolulu, HI 96826.
Effect of a Third Exosurf@Dose
(FDA) approval for general use in neonatal RDS. Prior to this approval in August 1990, the multicenter clinical trials of ExosurP included 1762 infants treated prophylactically and 1656 infants treated for established RDS. Prophylactic treatment involved dosing high-risk infants (700-1,350 g) within the first 10 min of life. Prenatal exclusion criteria included proven fetal pulmonary maturity, fetal growth retardation, anomalies, hydrops, maternal heroin addiction, and unequivocal chorioamnionitis. Studies were performed using zero, one, or three doses; the two additional doses of the three-dose group were administered at 12 and 24 hr of life. l 7 Infants ventilated for RDS alone and fulfilling arterial/ alveolar Po, ratio (a/A) entry criteria were treated between 2 and 24 hr of life. Infants were excluded from participation if they demonstrated fetal pulmonary maturity, major congenital or chromosomal anomalies, hydrops, or pulmonary disease in addition to or other than RDS. After qualifying, 419 infants weighing 700-1,350 g13 and 1,237 infants 2 1,250 gI4 with established RDS were treated with two doses of Exosufl 12 hr apart or air placebo. Each of these clinical protocols'.'0*13.'4required strict adherence to inclusion and exclusion criteria, with blood gas analysis, laboratory tests, radiologic evaluations, and follow-up studies performed according to specific schedules.l 8 A Treatment Investigational New Drug (TIND) protocol, involving over 1 1,000 patients, was conducted for 12 months prior to commercial release of the drug. During this TIND phase, some flexibility was permitted in inclusion/exclusioncriteria, number of total doses (maximum of three), and dosing regimens, but most centers followed the one prophylactic dose and two rescue dose protocols. Acceptable deviations from recommended procedures required documentation of revised parental informed consent. We treated 95 infants during the TIND phase. We performed a retrospective analysis of the clinical characteristics and treatment response of these infants in order to document the variation in response to Exosurfm and to characterize those neonates in apparent need of multiple doses.
17
Exosurf@is composed of dipalmitoylphosphatidylcholine (DPPC), hexadecanal, tyloxapol, and sodium chloride in lyophilized powder form. It is stored under vacuum at room temperature and thoroughly mixed with 8 mL sterile, preservative-free water immediately before use. The suspension contains 13.5 mg/mL DPPC, 1.5 mg/mL cetyl alcohol, and 1 mg/mL tyloxapol in 0. I N sodium chloride. Each dose of 5 mL/kg birthweight was administered in two aliquots through a special endotracheal tube sideport adapter with the infant in supine position. Between aliquots, the infant was rotated 45" to alternating sides and held there for 30 seconds." A physician and nurse remained at the bedside to carefully monitor the infant and adjust oxygen and ventilator settings as appropriate for at least 1 hr postdose. Continuous electrographic heart rate and transcutaneous oxygen saturation monitors were employed. Although specific time windows were not protocol-dictated, arterial blood gases were done frequently and roentgenograms of the chest were ordered as needed. The prophylactic treatment protocol involved a single (5 mWkg birthweight) dose of Exosurf@administered immediately after birth. A second or a second and third dose was permitted at the discretion of the treating neonatologist. Criteria for prophylactic treatment included birthweights of 700 to 1,100 g age less than 30 min, and mechanical ventilation for respiratory distress. Infants with congenital anomalies, chromosomal abnormalities, hydrops, or absent heart rate at birth could be enrolled if the investigator deemed Exosurfm administration in the patient's best interest. Infants were excluded from this protocol if they had proven fetal pulmonary maturity by amniotic fluid analysis. Infants in the rescue treatment protocol received two ( 5 mL/kg) doses of ExosurP 12 k 1 hr apart. A third dose was administered at the discretion of the treating neonatologist. Rescue TIND-eligible infants weighed 2700 g, were between 2 and 24 hr of age with established RDS, on intermittent mandatory ventilation (IMV), and with a documented a/A ratio (0.22. The a/A ratio was calculated from the following formula:
MATERIALS AND METHODS
The medical records and Burroughs Wellcome case report forms of 95 infants enrolled in the Exosurf@TIND program from September 1989 to August 1990 were retrospectively reviewed and analyzed. Written informed consent was obtained from parents of all enrolled infants. The study was approved by the Institutional Review Board at Kapiolani Medical Center for Women and Children. *
*Exosufl Neonatal was supplied by Burroughs Wellcome Co., Research Triangle Park, North Carolina.
Infants were excluded if fetal pulmonary maturity was documented or 4 hr or more had elapsed since the qualifying a/A ratio was obtained. As with the prophylactic protocol, investigators were allowed discretion in enrolling infants with both RDS and one or more of the conditions described above or infants with potential infection. However, to be eligible for enrollment in the rescue protocol, infants required at least a confirmed diagnosis of RDS. This was based on respiratory distress not attrib-
18
Easaet al. TABLE 1-Characteristics
of Rescue Survivors'
~
Characteristic Gestational age (wk) Birthweight (g) Apgar (mean scores) I min 5 min IMV hr (first 28 days) Extubated (94,) (24 hr after last dose) 0, days (first 2X days) Length of stay
One dose (n = 7 ) 35 2149
* Ih * 271
Two dosc
Three dose
(n = 33)
(n = 27)
32 2 0 . 5 1824 ? I10
31 -C 0.5 1496 k 114'
0.005 0.03
6
5
8
7
161 f 32
266 & 42
0. I 6 0.10 0.01
30
4
7 9 32
* Xb
71 6 + 24
Ih
*7
15
P
0.0005*
22
16 & 2
0.04
43 f 5
49 f 6
0.14
"Values are mean ? SE except wherc marked otherwise; IMV, intcrinittent mandatory ventilation; 0,. oxygen supplcrnentation. "One dose different from two dose and thrce dose. 'Three dose different lrom one dose. dDifferences between all groups.
utable to other causes and chest roentgenogram findings on the first day of life. As mentioned, the second or second and third dose (prophylactic) and the third dose (rescue) were administered at the discretion of the treating neonatologist. When administered, extra doses were provided because of a perceived lack of response to previous doses and/or continued high ventilator and oxygen requirements. Although no specific guidelines were established for administration of extra doses, the principal investigator of the TIND study (DE) was consulted in all cases when deviations from the prescribed protocol were considered. Distinct criteria defined patient entry into prophylactic or rescue groups. Comparisons were made between groups receiving one vs. two vs. three doses in both prophylactic and rescue treated babies. Data were analyzed using Student's t test and one way analysis of variance with Duncan's post hoc multiple comparison procedure. Chi-square and the Kruskal-Wallis Test were used for nonparametric data. A P value of
ExosurfB Treatment Investigational New Drug Phase: Effect of an Individualized Third Dose in Infants With Respiratory Distress Syndrome David Easa, MD,' Susan Pelke, R N , ~Kenneth T. Nakamura, MD,' Janet Barrett, B S , ~ Venkataraman Balaraman, MBBS,~Sherry W.H. Loo, M D , ~Elenita Ibarra-Pratt, R N , ~and Martha B. Smith, RR? Summary. Of 95 infants treated with the synthetic surfactant, ExosurfB, under a Treatment InvestigationalNew Drug protocol, 17 receivedone dose, 40 receivedtwo, and 38 receivedthree doses. Seventy-six (80%) of the infants were treated by rescue protocol. We retrospectively reviewed the clinical course of the 67 surviving rescue infants. We found that, compared to oneand two-dose infants, those treated with three doses of Exosurfm were more premature,smaller, required a longer ventilator course, and had more frequent complications,includingpatent ductus arteriosus (PDA), intraventricular hemorrhage, nosocomial pneumonia, and apnea. They required higher oxygen concentrations starting 8 hr after their first dose and higher mean airway pressure (MAP) from the time of their second dose. These trends continued during all subsequent time points, as compared to infants treated with two doses. The third dose was administered an average of 17 hr after the second, resulting in little change of MAP, but some reductionin oxygen requirements.By 24 hr after the last dose, only 4% of three-dose infants were extubated compared with 30% of the two-dose and 71% of one-dose infants. In conclusion, repeated administrationof Exosurf@is not equally effective in every treated infant with respiratorydistress syndrome (RDS) and complications of prematurity may affect or accompany poor response. We speculate that (1) the group of infants treated with three doses of ExosurfWhad a greater degree of surfactant deficiency than the other groups, (2) PDA may account for this refractory response to surfactant, and (3) the three-dose group might have responded better to earlier treatment and/or more surfactant doses, or to earlier PDA closure. Pediatr Pulmonol. 1992;14:1622. G) 1992 Wiley-Liss. Inc. Key words: Oxygen requirement; mean airway pressure; survival rate, complications; Patent ductus arteriosus.
INTRODUCTION
Randomized, prospective, controlled studies of surfactant replacement therapy in neonatal RDS have confirmed reductions in severity and some complications in treated infants. '-I4 Although most of the trials have provided surfactant as a single dose, it has been suggested that either very large single doses, multiple doses or very large sample sizes would be required to demonstrate convincing reductions in mortality and incidence of bronchopulmonary dysplasia (BPD) after surfactant replacement Recently, a very large trial did demonstrate convincing reductions in BPD after two doses of a synthetic surfactant.I4 Outcome may also be dependent upon the surfactant preparation used, since it is not known which surfactant preparation is most appropriate or what dosing schedules are optimal. ''.I6 A third possibility is that other concomitant problems such as patent ductus arteriosus (PDA) may affect the response to surfactant and, thus, clinical outcome. A synthetic surfactant invented by Clements at the University of California ( E x o s u f l Neonatal, Burroughs 6 1992 Wiley-Liss, Inc.
Wellcome Co., Research Triangle Park, NC) was the first to receive U.S. Food and Drug Administration From the Departmentsof Pediatrics' and Respiratory Care,' Kapiolani Medical Center for Women and Children, John A. Burns School of Medicine, Honolulu, Hawaii and Burroughs Wellcome Co., Research Triangle Park, North Carolina.' Received August 27, 1991; (revision) accepted lor publicationApril 7. 1992. Janet Barrett, B.S., i s an ernployec of Burroughs Wellcome Co. and the only author who holds stock in the holding company which wholly owns Burroughs Wellcome, Wellcome plc. The University of Hawaii received formal grants from Burroughs Wellcome (USA) for conduct of earlier randomized, placebo-controlled studies, but no funding was provided lor this study. None of the investigators derived personal incornc from those grants. No formal financial relationship exists b e tween any of the coauthors (except for Ms. Barrett) o r investigatorsand any arm of Wellcome. Financial considerations have not colored either the conduct, analysis, or presentation olthe results of this trial. Address correspondence and reprint requests to Dr. D. Easa, Kapiolani Medical Center for Women and Children, 1319 Punahou St.. Honolulu, HI 96826.
Effect of a Third Exosurf@Dose
(FDA) approval for general use in neonatal RDS. Prior to this approval in August 1990, the multicenter clinical trials of ExosurP included 1762 infants treated prophylactically and 1656 infants treated for established RDS. Prophylactic treatment involved dosing high-risk infants (700-1,350 g) within the first 10 min of life. Prenatal exclusion criteria included proven fetal pulmonary maturity, fetal growth retardation, anomalies, hydrops, maternal heroin addiction, and unequivocal chorioamnionitis. Studies were performed using zero, one, or three doses; the two additional doses of the three-dose group were administered at 12 and 24 hr of life. l 7 Infants ventilated for RDS alone and fulfilling arterial/ alveolar Po, ratio (a/A) entry criteria were treated between 2 and 24 hr of life. Infants were excluded from participation if they demonstrated fetal pulmonary maturity, major congenital or chromosomal anomalies, hydrops, or pulmonary disease in addition to or other than RDS. After qualifying, 419 infants weighing 700-1,350 g13 and 1,237 infants 2 1,250 gI4 with established RDS were treated with two doses of Exosufl 12 hr apart or air placebo. Each of these clinical protocols'.'0*13.'4required strict adherence to inclusion and exclusion criteria, with blood gas analysis, laboratory tests, radiologic evaluations, and follow-up studies performed according to specific schedules.l 8 A Treatment Investigational New Drug (TIND) protocol, involving over 1 1,000 patients, was conducted for 12 months prior to commercial release of the drug. During this TIND phase, some flexibility was permitted in inclusion/exclusioncriteria, number of total doses (maximum of three), and dosing regimens, but most centers followed the one prophylactic dose and two rescue dose protocols. Acceptable deviations from recommended procedures required documentation of revised parental informed consent. We treated 95 infants during the TIND phase. We performed a retrospective analysis of the clinical characteristics and treatment response of these infants in order to document the variation in response to Exosurfm and to characterize those neonates in apparent need of multiple doses.
17
Exosurf@is composed of dipalmitoylphosphatidylcholine (DPPC), hexadecanal, tyloxapol, and sodium chloride in lyophilized powder form. It is stored under vacuum at room temperature and thoroughly mixed with 8 mL sterile, preservative-free water immediately before use. The suspension contains 13.5 mg/mL DPPC, 1.5 mg/mL cetyl alcohol, and 1 mg/mL tyloxapol in 0. I N sodium chloride. Each dose of 5 mL/kg birthweight was administered in two aliquots through a special endotracheal tube sideport adapter with the infant in supine position. Between aliquots, the infant was rotated 45" to alternating sides and held there for 30 seconds." A physician and nurse remained at the bedside to carefully monitor the infant and adjust oxygen and ventilator settings as appropriate for at least 1 hr postdose. Continuous electrographic heart rate and transcutaneous oxygen saturation monitors were employed. Although specific time windows were not protocol-dictated, arterial blood gases were done frequently and roentgenograms of the chest were ordered as needed. The prophylactic treatment protocol involved a single (5 mWkg birthweight) dose of Exosurf@administered immediately after birth. A second or a second and third dose was permitted at the discretion of the treating neonatologist. Criteria for prophylactic treatment included birthweights of 700 to 1,100 g age less than 30 min, and mechanical ventilation for respiratory distress. Infants with congenital anomalies, chromosomal abnormalities, hydrops, or absent heart rate at birth could be enrolled if the investigator deemed Exosurfm administration in the patient's best interest. Infants were excluded from this protocol if they had proven fetal pulmonary maturity by amniotic fluid analysis. Infants in the rescue treatment protocol received two ( 5 mL/kg) doses of ExosurP 12 k 1 hr apart. A third dose was administered at the discretion of the treating neonatologist. Rescue TIND-eligible infants weighed 2700 g, were between 2 and 24 hr of age with established RDS, on intermittent mandatory ventilation (IMV), and with a documented a/A ratio (0.22. The a/A ratio was calculated from the following formula:
MATERIALS AND METHODS
The medical records and Burroughs Wellcome case report forms of 95 infants enrolled in the Exosurf@TIND program from September 1989 to August 1990 were retrospectively reviewed and analyzed. Written informed consent was obtained from parents of all enrolled infants. The study was approved by the Institutional Review Board at Kapiolani Medical Center for Women and Children. *
*Exosufl Neonatal was supplied by Burroughs Wellcome Co., Research Triangle Park, North Carolina.
Infants were excluded if fetal pulmonary maturity was documented or 4 hr or more had elapsed since the qualifying a/A ratio was obtained. As with the prophylactic protocol, investigators were allowed discretion in enrolling infants with both RDS and one or more of the conditions described above or infants with potential infection. However, to be eligible for enrollment in the rescue protocol, infants required at least a confirmed diagnosis of RDS. This was based on respiratory distress not attrib-
18
Easaet al. TABLE 1-Characteristics
of Rescue Survivors'
~
Characteristic Gestational age (wk) Birthweight (g) Apgar (mean scores) I min 5 min IMV hr (first 28 days) Extubated (94,) (24 hr after last dose) 0, days (first 2X days) Length of stay
One dose (n = 7 ) 35 2149
* Ih * 271
Two dosc
Three dose
(n = 33)
(n = 27)
32 2 0 . 5 1824 ? I10
31 -C 0.5 1496 k 114'
0.005 0.03
6
5
8
7
161 f 32
266 & 42
0. I 6 0.10 0.01
30
4
7 9 32
* Xb
71 6 + 24
Ih
*7
15
P
0.0005*
22
16 & 2
0.04
43 f 5
49 f 6
0.14
"Values are mean ? SE except wherc marked otherwise; IMV, intcrinittent mandatory ventilation; 0,. oxygen supplcrnentation. "One dose different from two dose and thrce dose. 'Three dose different lrom one dose. dDifferences between all groups.
utable to other causes and chest roentgenogram findings on the first day of life. As mentioned, the second or second and third dose (prophylactic) and the third dose (rescue) were administered at the discretion of the treating neonatologist. When administered, extra doses were provided because of a perceived lack of response to previous doses and/or continued high ventilator and oxygen requirements. Although no specific guidelines were established for administration of extra doses, the principal investigator of the TIND study (DE) was consulted in all cases when deviations from the prescribed protocol were considered. Distinct criteria defined patient entry into prophylactic or rescue groups. Comparisons were made between groups receiving one vs. two vs. three doses in both prophylactic and rescue treated babies. Data were analyzed using Student's t test and one way analysis of variance with Duncan's post hoc multiple comparison procedure. Chi-square and the Kruskal-Wallis Test were used for nonparametric data. A P value of
