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 PROTOCOL NO.: A1481134 PROTOCOL TITLE: A randomised, multicentre, double-blind, placebo-controlled, doseranging, parallel group study of intravenous sildenafil in the treatment of children, aged 0 to 17 with pulmonary hypertension after corrective cardiac surgery. Study Center(s): A total of 6 centers took part in the study, including 2 in France and 4 in the United States. Study Initiation Date and Completion Dates: 14 September 2003 to 4 March 2005. The study was terminated prematurely due to low enrollment because of the rarity of clinically significant post-operative pulmonary hypertension associated with current treatment practices. Phase of Development: Phase 2/3 Study Objective(s): Primary: To assess the efficacy of intravenous (IV) sildenafil, over 24 hours of treatment, on pulmonary hypertension during the post-operative period in children aged 0 (34 weeks gestational age) to 17 years with congenital heart disease who have undergone corrective cardiac surgery. Secondary: To assess the safety and tolerability of IV sildenafil in children with pulmonary hypertension after corrective cardiac surgery, as assessed by clinical laboratory parameters, physical examination, vital signs and frequency and severity of adverse events To establish an effective dose range of IV sildenafil in the treatment of pulmonary hypertension in children following corrective cardiac surgery To investigate the pharmacokinetic (PK)-effect relationship To determine the population PK parameters and to evaluate the healthcare resource utilisation associated with the use of sildenafil compared to alternate therapies. Page 1
METHODS Study Design: This was a randomised, multi-centre, double-blind, placebo-controlled, dose-ranging, parallel group study to be conducted in approximately 252 subjects aged 0 to 17 years, receiving one of three doses (low, medium or high dose) of IV sildenafil or placebo for a minimum of 24 hours. Randomisation of subjects was to be stratified by age (neonate or non-neonate) and by study centre. No more than 25% of subjects were to be greater than one year old. Baseline echocardiograms were performed to verify presence of pulmonary hypertension. Baseline haemodynamic parameters (in subjects with a pulmonary artery, left atrial, and/or right atrial/central venous catheters), inotrope score, and vital signs were measured, and blood samples collected for serum lactate measurement. After 30 minutes of study drug infusion, additional therapy for pulmonary hypertension was to be initiated if clinically indicated based on protocol-defined rules. If the subject was judged clinically stable at 24 or more hours after randomisation, the infusion was discontinued. Number of Subjects: A total of 252 subjects were planned, 63 per treatment group. A total of 87 subjects were screened, 18 were enrolled and 17 were treated. Diagnosis and Main Criteria for Inclusion: Male or female subjects aged 0 (34 weeks gestational age) to 17 years (up to one day before 18 th birthday). Subjects undergoing corrective cardiac surgery (2 ventricle repair), for at least one of the lesions or procedures specified in the protocol and subjects who had a clinical diagnosis of post-operative pulmonary hypertension and a systolic pulmonary artery pressure >50% of the systolic arterial blood pressure (>75% for neonates 28 days) confirmed by qualifying Doppler echocardiogram or pulmonary artery (PA) catheter at baseline were included in the study. Study Treatment: Three intravenous sildenafil dosage regimens were selected to achieve target sildenafil plasma concentrations of approximately 40, 120, and 360 ng/ml, respectively, for the three dosage regimens. Each regimen consisted of a bolus loading dose infused over five minutes, followed by a maintenance infusion for 24 to 72 hours, the infusion of study drug continued for a minimum of 24 and maximum of 72 hours. Sildenafil was provided in 50 ml vials containing sildenafil 1.0 mg/ml. Placebo was supplied in bags as 5% dextrose in water. Efficacy Evaluations: The efficacy evaluations included: receipt of additional therapy for the treatment of post-operative complication of pulmonary hypertension within 24 hours of the start of study drug infusion. Time to first extubation, length of hospital stay, length of stay in intensive care unit, total duration of administration of additional therapy for pulmonary hypertension and deaths assessed up to 28-day follow-up. Change from baseline in post-operative inotrope scores, change from baseline in serum lactate levels (as a surrogate for cardiac output evaluation) and change from baseline in haemodynamic parameters at post-baseline assessment times. Plasma concentration data for sildenafil and its metabolite (UK-103,320) was obtained from all subjects in this study. Safety Evaluations: Safety evaluations included clinical monitoring, vital signs (heart rate, blood pressure), adverse events, and safety laboratory tests. Page 2
Statistical Methods: As the study was terminated early, the statistical analysis plan was amended prior to unblinding the study and the efficacy data were listed, however, no statistical analysis was done. RESULTS Subject Disposition and Demography: One subject was randomised but did not receive study drug because receipt of other treatment for pulmonary hypertension before initiation of study drug. One subject randomised to placebo died due to pulmonary hypertension related to the disease under study during follow-up and one subject randomised to sildenafil IV medium was withdrawn during active treatment due to lack of efficacy. Subject disposition is summarized in Table 1 and subject demographics are summarized in Table 2. Table 1. Subject disposition and Subjects analyzed Number of Subjects Placebo Sildenafil Assigned to treatment IV Low IV Medium IV High Randomised 5 4 5 4 Treated 5 4 4 4 Completed 4 4 3 4 Discontinued 0 0 2 0 Died 1 0 0 0 Analyzed Analysed for Adverse events 5 4 4 4 Analysed for Laboratory data 5 4 4 4 Table 2. Demographic characteristics Placebo Sildenafil IV Low IV Medium IV High Male Female Male Female Male Female Male Female Number of subjects 4 1 2 2 2 2 1 3 Mean Weight (kg) 18.4 3.9 6.3 9.7 5.7 8.2 5.2 5.2 Mean Height (cm) 78.1 49.0 62.0 111.8 56.0 70.8 59.5 65.3 Efficacy Results: Four of the seventeen treated subjects, two each on sildenafil (17%) and placebo (40%), received additional therapy for treatment of post-operative pulmonary hypertension within 24 hours of start of study drug infusion. No subject from the sildenafil IV high treatment group received additional therapy and nitric oxide was the most frequently received additional therapy. The time to first extubation ranged from 4 to 11 days for the subjects on placebo and 1 to 11 days for subjects on sildenafil. Eight of the seventeen treated subjects; five (42%) on sildenafil and three (60%) on placebo, received additional therapy to Day 28 follow-up. The duration of therapy ranged from 6 to 601 hours. The time to first discharge from intensive care unit ranged from 5 to 15 days for the placebo group and from 1 to 12 days for subjects Page 3
on sildenafil therapy. Post baseline serum lactate values ranged from 0.5 mmol/l to 3.13 mmol/l. Pharmacokinetic Results: Pharmacokinetic-pharmacodynamic (PK-PD) analyses were not reported since limited pharmacokinetic and efficacy data were available. Safety Results: Of 17 subjects, 15 (88.2%) reported 45 adverse events (presented in Table 3 below), none were treatment related. The most frequently reported all causality adverse events by body system were respiratory, thoracic and mediastinal disorders and most commonly reported adverse event was pulmonary hypertension due to the disease under study. Six subjects reported severe adverse events. There were no permanent discontinuations due to adverse events. One subject reported temporary discontinuation of study drug due to severe pulmonary hypertension aggravated by the disease under study. Page 4
Table 3. Incidence of all causality adverse events Placebo Sildenafil IV Low Sildenafil IV Medium Sildenafil IV High Anaemia 0 1 0 0 0 0 0 0 0 0 0 0 Bradycardia 0 0 0 0 0 0 0 0 0 1 0 0 Nodal arrhythmia 0 0 0 1 0 0 0 0 0 0 0 0 Constipation 0 0 0 0 0 0 1 0 0 0 0 0 Drug withdrawal syndrome 0 1 0 0 1 0 0 0 0 0 0 0 Oedema 0 0 0 0 0 0 1 0 0 0 0 0 Pyrexia 0 0 0 0 1 0 1 1 0 0 0 0 Bronchial infection 0 0 0 0 0 0 0 0 0 0 1 0 Enterobacter sepsis 0 1 0 0 0 0 0 0 0 0 0 0 Pneumonia 0 0 1 0 0 0 0 0 0 0 0 0 Respiratory tract infection 0 2 0 0 0 0 0 0 0 0 0 0 Staphylococcal infection 0 1 0 0 0 0 0 0 0 0 0 0 ALT increased 0 1 0 0 0 0 0 0 0 0 0 0 AST increased 0 1 0 0 0 0 0 0 0 0 1 0 Bacteria blood identified 0 0 0 0 0 0 0 0 0 1 0 0 Bacterial culture positive 0 0 0 0 0 0 0 0 0 1 0 0 Blood HCO 3 increased 0 0 0 0 0 0 1 0 0 0 0 0 Blood chloride decreased 0 0 0 0 0 0 1 0 0 0 0 0 Oxygen (O 2 ) saturation decreased 0 0 0 0 0 0 0 0 0 1 0 0 Acidosis 0 0 0 0 0 0 1 0 0 0 0 0 Hyperglycaemia 0 1 0 0 0 0 0 0 0 0 0 0 Hypoglycaemia 1 0 0 0 0 0 0 0 0 0 0 0 Hypokalaemia 1 0 0 0 1 0 0 0 0 0 0 0 Anuria 0 0 1 0 0 0 0 0 0 0 0 1 Apnoeic attack 0 0 0 0 0 1 0 0 0 0 0 0 Atelectasis 0 0 0 0 0 0 1 0 0 0 0 0 Pleural effusion 0 1 0 0 1 0 0 0 0 0 0 0 Pulmonary hypertension 0 0 1 0 0 0 0 1 0 0 0 1 Stridor 0 0 0 0 0 0 1 0 0 0 0 0 Rash 0 0 0 0 0 0 1 0 0 0 0 0 Arterial thrombosis limb 0 0 0 0 0 0 0 0 0 1 0 0 Haemorrhage 0 0 0 0 0 1 0 0 0 0 0 0 Hypotension 0 1 0 0 0 0 1 0 0 0 0 0 Superior vena caval occlusion 0 0 1 0 0 0 0 0 0 0 0 0 Total Events 2 11 4 1 4 2 10 2 0 5 2 2 Two subjects reported treatment emergent serious adverse events that were not related to treatment (severe apnoeic attack and severe pulmonary hypertension) ten subjects reported serious non-treatment emergent adverse events. The non-treatment emergent serious adverse events are provided in Table 4. Page 5
Table 4. Non treatment emergent serious adverse events SAE Study Day Subject outcome Persistent pulmonary hypertension Pulmonary hypertension crisis Cardiac arrest 19 Death Increased work of breathing 13 Recovered Left ventricular failure 12 Acute renal failure 16 Respiratory arrest 12 Seizure disorder 12 Fungal sepsis Respiratory insufficiency 50 Tenkoff catheter replacement 54 Consbacteremia MRSA trachitis Varicella zoster Cardiac arrest 64 Death Resistant pulmonary hypertension Death Hemorragia intrathoracic and diffuse Recovered Bronchiolitis 14 Recovered Supraventricular tachycardia Recovered Sternal dysjunction Recovered Hemorragia intrathoracic and diffuse Recovering Death, cause unknown Death Days are relative to the day of starting active therapy (Day 1) Study days were not available for all subjects There were four deaths reported. Of these, two subjects died pre-randomisation and two were on placebo. A six-month-old white female subject received placebo therapy via intravenous infusion from 28 May 2004 (Study Day 1) to 31 May 2004 (Study Day 3), a total of four days. On 15 June 2004, the subject was intubated and mechanically ventilated to treat respiratory failure, secondary to bronchopulmonary dysplasia and congestive heart failure. On the afternoon of 15 June 2004, the subject suffered from multiple desaturation episodes and a cardiac arrest. It was believed that the subject suffered a pulmonary hypertensive crisis or a series of pulmonary hypertensive crises leading to the arrest. The subject expired at 04:15 on 16 Jun 2004, during the 28-day follow-up. The cause of death was captured as pulmonary hypertension not related to treatment. An 11-month-old female subject reported resistant pulmonary hypertension on 11 August 2004 during the pre-randomisation phase. On 12 August 2004, the subject was to undergo surgery (unspecified) but prior to the scheduled surgery, the subject expired on the operating table. The cause of death was reported to be resistant pulmonary hypertension not related to treatment and due to the disease under study. Page 6
A 15-month-old female subject was enrolled in the study but had not yet received treatment. On 02 July 2004, the subject expired before cardiac surgery. Death was not related to study treatment. On 21 April 2004, a 14-year-old white male was admitted to the hospital for a mitral valve repair and was randomised to placebo treatment. On 11 June 2004 (Study Day 50), the subject suffered from respiratory insufficiency, which resulted in a tracheostomy. On 8 May 2004 (Study Day 16), the subject suffered from acute renal failure, which required dialysis. The subject also suffered from coagulase-negative Staphylococcus bacteremia, methicillin-resistant Staphylococcus aureus trachitis, varicella zoster, and fungemia. On 25 June 2004, the subject experienced cardiac arrest and was successfully resuscitated. On 26 June 2004, life support was withdrawn and the subject expired. The cause of death was fungal sepsis and was not related to treatment. CONCLUSION(S): Four of the seventeen treated subjects, two each on sildenafil (17%) and placebo (40%), received additional therapy for treatment of post-operative pulmonary hypertension within 24 hours of start of study drug infusion. Eight of the seventeen treated subjects, five on sildenafil (42%) and three on placebo (60%), received additional therapy to Day 28 follow-up. The duration ranged from 6 to 601 hours. Post baseline serum lactate values ranged from 0.5 mmol/l to 3.13 mmol/l. Fifteen (88.2%) subjects reported adverse events; none were treatment related. There were three discontinuations; one subject (Placebo) died due to pulmonary hypertension related to the disease under study, one subject (IV medium) was withdrawn during active treatment due to lack of efficacy and one subject was randomised but was withdrawn before being treated. Six subjects reported severe adverse events, two subjects reported serious treatment emergent adverse events and ten subjects reported serious non treatment emergent adverse events. One subject reported temporary discontinuation of study drug due to severe pulmonary hypertension aggravated by the disease under study. Four deaths were reported (including one subject above), two occurred pre-randomisation, one was during the 28-day follow-up period; none were treatment related. Page 7