PFIZER INC. These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert. For publications based on this study, see associated bibliography. PROPRIETARY DRUG NAME /GENERIC DRUG NAME: Revatio / Sildenafil citrate THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See USPI. NCT NO.: N/A PROTOCOL NO.: A1481157 PROTOCOL TITLE: A 7-Day, Open-Label, Multicentre, Pharmacokinetic Study (Part 1) Followed by A 7-Day, Randomised, Multicentre, Double-Blind, Placebo-Controlled, Dose-Ranging, Parallel Group Study (Part 2) of IV Sildenafil in the Treatment of Neonates With Persistent Pulmonary Hypertension of the Newborn (PPHN) or Hypoxic Respiratory Failure and at Risk for PPHN Study Center(s): Six (6) centers in the US (3), France (2) and the UK (1) Study Initiation and Completion Dates: 02 November 2003 to 16 May 2005 (Part 1 only; study terminated prematurely) Phase of Development: Phase 2 Study Objective(s) (Part 1 of study): Primary: To evaluate the pharmacokinetics of intravenous (IV) sildenafil in near term and full term newborns with PPHN or with hypoxic respiratory failure and at risk for PPHN Secondary: To assess the safety and tolerability of IV sildenafil as measured by clinical laboratory parameters, physical examination, vital signs [blood pressure, heart rate, respiratory rate and oxygen (O 2 ) saturation], oxygenation index (OI), and the frequency and severity of adverse events (AEs), and to characterize the pharmacokinetics of sildenafil in newborns with PPHN or hypoxic respiratory failure and at risk of developing PPHN METHODS Study Design: The study was planned as a two-part study. The first part (Part 1) was a small pharmacokinetics study conducted at only a few sites. The pharmacokinetic results of Part 1 were to be used to determine doses and infusion rates for the second part (Part 2) of the study. However, Part 2 of the study was not performed and is not reported here. This was a 7 day, open-label, multicenter study in 36 neonatal subjects who had PPHN or had hypoxic respiratory failure and were at risk of developing PPHN. Page 1
The study was comprised of 3 phases; a screening phase (up to 72 hours of age), a treatment phase (during which subjects received study drug for at least 48 hours and for up to 7 days [168 hours, inclusive of times off study drug infusion] with or without the addition of standard treatment), and a follow-up phase (which consisted of 2 visits, one conducted at 7 ± 3 days after the final termination of study treatment or at the time of hospital discharge, whichever came first, and the other on Day 28 ± 3 days). For the purpose of this study, standard treatment was inhaled nitric oxide (ino) and/or extracorporeal membrane oxygen (ECMO). Immediately after screening, eligible subjects were started on open-label study drug treatment (Day 1). They received a loading IV dose of study medication to bring the plasma concentration of sildenafil to a targeted level, followed by a maintenance infusion for the remainder of the study. Number of Subjects (Planned and Analyzed): Planned: 20 to 25 subjects After reviewing data from the initial 3 treatment groups, which had not achieved the target plasma concentration as planned (40, 120 and 360 ng/ml), the number of planned subjects was shown to be underestimated. Therefore, as the loading dose was carefully increased, more subjects were needed to achieve the target plasma concentrations, and hence the number of subjects was increased accordingly. Analyzed: 36 subjects Diagnosis and Main Criteria for Inclusion: Subjects were males or females, 72 hours of age and 34 weeks gestational age, who had PPHN or hypoxic respiratory failure associated with one of the following: idiopathic PPHN, meconium aspiration syndrome, respiratory distress syndrome, sepsis, and/or pneumonia. They also had to have an OI 15 on 2 separate occasions, calculated using arterial blood gas taken at least 30 minutes apart. Study Treatment: Sildenafil was supplied in 50 ml vials containing sildenafil 1 mg/ml, for IV administration. Study drug infusion started with an IV loading dose for 5 minutes. After the first 2 subjects, the loading dose infusion was extended to 30 minutes. For subjects in Group 7, no loading dose was administered and for subjects in Group 8, the duration of the loading dose was extended to 3 hours (180 minutes). Following the loading dose infusion, a maintenance dose infusion was administered at a constant infusion rate. This continued for at least 48 hours, and for up to 7 days (168 hours, inclusive of times off study drug infusion). The rate of study drug infusion was weight dependent. The dose of study drug administered in the first 2 treatment groups was based on pharmacokinetic parameters of IV sildenafil in adults scaled for various neonatal body weights using allometric methods. As a conservative approach, these 2 groups were administered a fraction of the dose that was derived on the basis of scaling adult pharmacokinetic parameters by neonatal body weight, and targeting a plasma concentration of 40 ng/ml. Therefore, sildenafil plasma concentrations would be higher than 40 ng/ml if clearance in neonates was several fold lower than in adults. Dose escalation for the Page 2
subsequent treatment groups was based upon the pharmacokinetic data from the previous treatment group(s) and based on toleration by the previous group. Doses were not to be escalated if the average steady-state plasma sildenafil concentration for a treatment group was similar to the highest targeted concentration of approximately 360 ng/ml. Efficacy Evaluations: Part 1 of the study was a safety and pharmacokinetic study and no analysis of efficacy data was planned. However, the following study treatment endpoints were recorded in Part 1: Subject support (ie, receipt and duration of ino, ECMO, mechanical ventilation and supplemental O 2 ) Duration of hospital stay Death during the study Pharmacokinetic Evaluations: Blood samples for pharmacokinetic assay were collected at: 5 and 30 minutes after the end of the loading dose infusion, every 24 hours from the start of the study drug infusion, just prior to the end of the study drug infusion and at 1, 4, 8, 12, 24, 48, and 72 hours after the end of the study drug infusion. If the subject stopped and re-started study medication then no pharmacokinetic sampling was performed after the subject had re-started study drug infusion. As there was no loading dose in Group 7, blood samples for pharmacokinetic assay were collected at 6 and 12 hours after the start of study drug infusion instead of at 5 and 30 minutes after the end of the loading dose infusion. As the duration of the loading dose in Group 8 was 3 hours blood samples for pharmacokinetic assay were collected at 30 minutes after the start of study drug infusion and just before the loading dose was completed. Safety Evaluations: Adverse event recording, physical examinations, laboratory tests, OI measurements (partial pressure of arterial oxygen, fraction of inspired oxygen, mean airway pressure and OI), and vital signs (blood pressure, heart rate, respiratory rate and O 2 saturation) were performed at intervals throughout the study. Statistical Methods: Two study populations were defined. The safety population consisted of all subjects who had received study medication (any amount of infusion). This population was used for analyses of the safety data and for descriptive analyses of the study treatment assessment endpoints. The laboratory population consisted of all subjects who had received study medication (any amount of infusion), and who had a post-screening, on-treatment laboratory data measurement. Study treatment assessment endpoints: These were listed and summarized. No hypothesis testing was performed. Pharmacokinetics: Sildenafil plasma concentration-time data from previous treatment groups were analyzed prior to dose escalation for the next treatment group. The pharmacokinetic analysis reported here was performed at the end of the study, using plasma concentration-time data for sildenafil and its active (N-desmethyl) metabolite (UK-103,320) from 35 of the 36 subjects enrolled. Page 3
The population pharmacokinetic analysis was performed using the Nonlinear Mixed Effects Modeling software. Mixed-effects pharmacokinetic models were used to simultaneously describe the natural log-transformed plasma concentration-time data for sildenafil and UK-103,320. Since biotransformation to UK-103,320 is the primary route of elimination of sildenafil in adults, it was assumed for purposes of model development, that sildenafil was completely metabolized to UK-103,320 in neonates. One- and two-compartmental pharmacokinetic models, parameterized in terms of sildenafil clearance (Clpar), central volume of distribution of sildenafil (V1par), inter-compartmental clearance of sildenafil (Qpar), peripheral volume of distribution of sildenafil (V2par), UK-103,320 clearance (Clmet), central volume of distribution of UK-103,320 (V1met), inter-compartmental clearance of UK-103,320 (Qmet), and peripheral volume of distribution of UK-103,320 (V2met) were evaluated, in order to select a base pharmacokinetic model. Covariates such as body weight, age, gender, and concomitant administration of other CYP3A4 substrates were included in the base model to form the full model. The Wald s approximation method procedure was applied to the full model to identify the final covariate model. Model selection and covariate inclusion was based on the change in the minimum objective function value, evaluation of model diagnostic plots, and clinical significance of the covariate effect. RESULTS Subject Disposition and Demography: A summary of subject disposition is presented in Table S1. Table S1 Subject Disposition Sildenafil N= 36 n (%) Assigned to study treatment Treated 36 (100.0) Completed 31 (86.1) Discontinued 5 (13.9) Adverse events 4 (11.1) Died 1 (2.8) Analyzed for safety Adverse events 36 (100.0) Laboratory data a 33 (91.7) Safety population 36 (100.0) a No post-screening, on-treatment laboratory measurements were recorded for 3 subjects. Page 4
A summary of subject demographic characteristics is presented in Table S2. Table S2 Demographic Characteristics Sildenafil Male Female Total Number of subjects 17 19 36 Age (hours) a Mean (SD) 35.5 (17.0) 33.2 (16.8) 34.3 (16.7) Range 12 71 11-70 11-71 Gestational age (weeks) Mean (SD) 39.0 (1.6) 39.5 (1.6) 39.3 (1.6) Range 36.0 41.0 37.0 42.0 36.0 42.0 N 17 19 36 Race: W / B / A / H / O 5 / 4 / 2 / 4 / 2 5 / 7 / 1 / 4 / 2 10 / 11 / 3 / 8 / 4 Weight (kg) Mean (SD) 3.6 (0.5) 3.3 (0.5) 3.4 (0.5) Range 2.9 4.4 2.5 4.2 2.5 4.4 N 17 19 36 Length (cm) Mean (SD) 49.6 (4.9) 50.2 (2.4) 49.9 (3.9) Range 34.5 54.5 46.5 53.5 34.5 54.5 N 14 12 26 a Time from birth until the start of the study drug infusion. SD = standard deviation W / B / A / H / O = White / Black / Asian / Hispanic / Other Thirty-two (32) subjects had PPHN and 4 subjects had hypoxic respiratory failure. A summary of primary diagnosis is given in Table S3. Table S3 Summary of Primary Diagnosis Primary Diagnosis Associated Disease Sildenafil N= 36 Hypoxic respiratory failure Pneumonia Respiratory distress syndrome 1 3 Idiopathic PPHN Not Applicable 2 PPHN Sepsis Pneumonia Respiratory distress syndrome Meconium aspiration syndrome 4 1 5 20 Efficacy Results: There were no efficacy evaluations undertaken in Part 1 of this study. Study Treatment Results: Six (17%) subjects completed the treatment period without the need for standard therapy (ino or ECMO). Furthermore, they remained in the study until Day 28 without the need for any standard therapy. The remaining 30 subjects (83%) all received ino within the treatment period. Oxygenation index values were calculated for 35 of the 36 subjects. All of the OI values improved during the course of study treatment in subjects irrespective of whether concomitant ino therapy was administered. Only 1 subject required additional ECMO therapy. Although ECMO started on the same day as study medication had started (Day 1), Page 5
the study drug infusion had been discontinued approximately 4 hours prior to the initiation of ECMO. The duration of ECMO treatment was from Day 1 (approximately 17:30 hours) until Day 6 (approximately 15:30 hours). Pharmacokinetic Results: The number of plasma concentration values obtained from the 35 subjects included in the pharmacokinetic analysis was 406 for both sildenafil and its active metabolite UK-103,320. In total, 93 (23%) sildenafil and 90 (22%) UK-103,320 plasma concentration values were below the lower limit of quantification (BLQ). Approximately 90% of the sildenafil concentrations that were BLQ occurred during the terminal elimination phase because blood sampling was performed up to 120 hours after the end of the infusion in anticipation of a long half-life. The BLQ data were excluded from the final analysis. A pharmacokinetic model with 2-compartmental elimination of both parent and metabolite was identified as the base model. The final model included post-natal age as a covariate on sildenafil clearance. Mean pharmacokinetic parameter estimates (standard errors) from the final model were: Clpar (for 3.5 day old) = 1.720 (0.192) L/hr, V1par = 10.40 (0.964) L, Qpar = 0.188 (0.053) L/hr, V2par = 12.00 (5.190) L, Clmet = 3.800 (0.466) L/hr, V1met = 7.560 (3.360) L, Qmet = 3.260 (0.888) L/hr, and V2met = 25.90 (6.950) L. Based on the estimated effect of age on CLpar, typical values of sildenafil clearance were estimated to increase from 0.83 L/hr at 1 day of age to 3.17 L/hr at 10 days of age. Coefficients of variation of CLpar, V1par, CLmet, and V1met between subjects were 54.7%, 41.1%, 66.1%, and 150%, respectively. Residual variability (coefficient of variation) in sildenafil and UK-103,320 concentrations were 39.8% and 29.3%, respectively. Based on these pharmacokinetic parameters, the predicted mean concentration of the active metabolite, UK-103,320, would be 11% of parent at the end of the 3 hour loading infusion (mean predicted sildenafil and UK-103,320 concentrations of 116ng/ml and 12.6ng/ml, respectively), and 76% of parent at the end of the maintenance infusion (mean predicted sildenafil and UK-103,320 concentrations of 75.8ng/ml and 57.4ng/ml, respectively). Since the in vitro potency of UK-103,320 is approximately 50% of that for sildenafil, UK-103,320 would be expected to contribute up to approximately 40% of the efficacy of sildenafil. Safety Results: Twenty subjects had a total of 41 treatment-emergent, all causality AEs. Only 5 treatment-related AEs were recorded for 5 subjects. Table S4, below, summarizes AEs reported in more than 1 subject. Page 6
Table S4 Adverse Events Reported in More Than One Subject Sildenafil N=36 n (%) Subjects with at least one adverse event 20 (55.6) Number of subjects with: Hypotension NOS 6 (16.7) Hyperbilirubinemia 3 (8.3) Drug withdrawal syndrome 2 (5.6) Edema NOS 2 (5.6) Labile blood pressure 2 (5.6) Pneumothorax NOS 2 (5.6) NOS = Not otherwise specified There was 1 death during the study. A 25-hour-old female died 2 hours after the start of study drug infusion from meconium aspiration, pulmonary hypertension, birth asphyxia and right tension pneumothorax. Four subjects reported treatment-emergent serious adverse events (SAEs), none of which were considered to be treatment-related. Two subjects had pneumothorax, 1 had hypotension and 1 had anomalous pulmonary venous connection and mediastinitis. Four subjects discontinued study treatment due to treatment-emergent AEs. These events were labile blood pressure in 2 subjects, hypotension in 1 subject and anomalous pulmonary venous connection in 1 subject. This latter event was also considered to be serious. One case of labile blood pressure and the hypotension was considered to be related to study treatment. There were no clinically significant changes from baseline to last observation in vital signs. CONCLUSION(S): A total of 36 subjects were recruited in an 8 step up: treatment group approach depending on the tolerability in each group. The initial target plasma concentrations ranged from 40 to 360 ng/ml but this was modified during the course of the study. The actual target plasma concentrations ranged from 18.5 to 150 ng/ml. The relatively long duration of a sildenafil infusion started soon after birth, allowed characterization of the maturation of sildenafil clearance in neonates during the early post-natal period, and was consistent with previous reports of the rapid maturation of CYP3A4 during this period of life. Sildenafil pharmacokinetics in neonates with PPHN was characterized by high inter-individual variability and moderately high residual variability. The inability to detect significant covariates, other than age, may be related to the small number of subjects in the study and the high variability. Therefore, other covariate effects on sildenafil and UK-103,320 pharmacokinetics could not be ruled out. Page 7
Six (17%) subjects completed the 7 day treatment period without the need for standard therapy (ino or ECMO). Furthermore, they remained in the study until Day 28 without the need for any standard therapy. The remaining 30 subjects (83%) all received ino within the treatment period. During the course of study treatment, OI values improved in all subjects irrespective of administration of concomitant ino therapy. Only 1 subject required additional ECMO therapy, which was started after study drug had been stopped. Sildenafil was given at increasing doses in this study. In total, 41 treatment-emergent AEs were reported. Although there was 1 death and there were 4 serious treatment-emergent AEs, none were considered to be related to study treatment. In total, 4 subjects withdrew from the study due to treatment-emergent AEs, 2 of which were treatment-related. The majority of AEs were mild or moderate in severity. Page 8