SUPER-1 (NCT00644605) -Sildenafil monotherapy [20 mg, 40 mg, and 80 mg three times a day]
A randomized, double-blind, placebo-controlled study of sildenafil (SUPER-1) was conducted in 277 patients with PAH (defined as a mean pulmonary artery pressure ≥25 mmHg at rest with a pulmonary capillary wedge pressure <15 mmHg). Patients were predominantly WHO Functional Classes II-III. Allowed background therapy included a combination of anticoagulants, digoxin, calcium channel blockers, diuretics, and oxygen. The use of prostacyclin analogues, endothelin receptor antagonists, and arginine supplementation were not permitted. Patients who had failed to respond to bosentan were also excluded. Patients with left ventricular ejection fraction less than 45% or left ventricular shortening fraction less than 0.2 also were not studied.
Patients were randomized to receive placebo (n = 70) or sildenafil 20 mg (n = 69), 40 mg (n = 67) or 80 mg (n = 71) three times a day for a period of 12 weeks. They had either primary pulmonary hypertension (PPH) (63%), PAH associated with CTD (30%), or PAH following surgical repair of left-to-right congenital heart lesions (7%). The study population consisted of 25% men and 75% women with a mean age of 49 years (range: 18 to 81 years) and baseline 6-minute walk distance between 100 and 450 meters (mean 343).
The primary efficacy endpoint was the change from baseline at Week 12 (at least 4 hours after the last dose) in the 6-minute walk distance. Placebo-corrected mean increases in walk distance of 45 to 50 meters were observed with all doses of sildenafil. These increases were significantly different from placebo, but the sildenafil dose groups were not different from each other (see Figure 3), indicating no additional clinical benefit from doses higher than 20 mg three times a day. The improvement in walk distance was apparent after 4 weeks of treatment and was maintained at Week 8 and Week 12.
Figure 3. Change from Baseline in 6-Minute Walk Distance (meters) at Weeks 4, 8, and 12 in SUPER-1: Mean (95% Confidence Interval)
Figure 4. Placebo-Corrected Change From Baseline in 6-Minute Walk Distance (meters) at Week 12 by Study Subpopulation in SUPER-1: Mean (95% Confidence Interval)
Key: PAH = pulmonary arterial hypertension; CTD = connective tissue disease; PH = pulmonary hypertension; PAP = pulmonary arterial pressure; PVRI = pulmonary vascular resistance index; TID = three times daily.
SUPER-2 (NCT00159887) Long-term Treatment of PAH
In a long-term follow-up of patients who were treated with sildenafil (n=277), K-M estimates of survival at 1, 2, and 3 years were 94%, 88% , and 79%, respectively. These uncontrolled observations do not allow comparison with a group not given sildenafil and cannot be used to determine the long term-effect of sildenafil on mortality.
PACES-1 (NCT00159861) - Sildenafil Co-administered with Epoprostenol
Arandomized, double-blind, placebo-controlled study (PACES-1) was conducted in 267 patients with PAH who were taking stable doses of intravenous epoprostenol. Patients had to have a mean pulmonary artery pressure (mPAP) greater than or equal to 25 mmHg and a pulmonary capillary wedge pressure (PCWP) less than or equal to 15 mmHg at rest via right heart catheterization within 21 days before randomization, and a baseline 6-minute walk test distance greater than or equal to 100 meters and less than or equal to 450 meters (mean 349 meters). Patients were randomized to placebo or sildenafil (in a fixed titration starting from 20 mg to 40 mg and then 80 mg, three times a day) and all patients continued intravenous epoprostenol therapy.
At baseline patients had PPH (80%) or PAH secondary to CTD (20%); WHO Functional Class I (1%), II (26%), III (67%), or IV (6%); and the mean age was 48 years, 80% were female, and 79% were Caucasian.
There was a statistically significant greater increase from baseline in 6-minute walk distance at Week 16 (primary endpoint) for the sildenafil group compared with the placebo group. The mean change from baseline at Week 16 (last observation carried forward) was 30 meters for the sildenafil group compared with 4 meters for the placebo group giving an adjusted treatment difference of 26 meters (95% CI: 10.8, 41.2) (p = 0.0009).
Patients on sildenafil achieved a statistically significant reduction in mPAP compared to those on placebo. A mean placebo-corrected treatment effect of -3.9 mmHg was observed in favor of sildenafil (95% CI: -5.7, -2.1) (p = 0.00003).
Time to clinical worsening of PAH was defined as the time from randomization to the first occurrence of a clinical worsening event (death, lung transplantation, initiation of bosentan therapy, or clinical deterioration requiring a change in epoprostenol therapy). Table 4 displays the number of patients with clinical worsening events in PACES-1. Kaplan-Meier estimates and a stratified log-rank test demonstrated that placebo-treated patients were 3 times more likely to experience a clinical worsening event than sildenafil-treated patients and that sildenafil-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p = 0.0074). Kaplan-Meier plot of time to clinical worsening is presented in Figure 5.
Table 4. Clinical Worsening Events in PACES-1
| ||Placebo |
(N = 131)
(N = 134)
|Number of patients with clinical worsening first event ||23 ||8 |
| ||First Event ||All Events ||First Event ||All Events |
|Death, n ||3 ||4 ||0 ||0 |
|Lung transplantation, n ||1 ||1 ||0 ||0 |
|Hospitalization due to PAH, n ||9 ||11 ||8 ||8 |
|Clinical deterioration resulting in: |
Change of Epoprostenol Dose, n
Initiation of Bosentan, n
|Proportion worsened |
95% Confidence Interval
(0.12 - 0.26)
(0.02 - 0.10)
Figure 5. Kaplan-Meier Plot of Time (in Days) to Clinical Worsening of PAH in PACES-1
Improvements in WHO Functional Class for PAH were also demonstrated in patients on sildenafil compared to placebo. More than twice as many sildenafil-treated patients (36%) as placebo-treated patients (14%) showed an improvement in at least one functional New York Heart Association (NYHA) class for PAH.
Study A1481243 (NCT00323297) - Sildenafil Added to Bosentan Therapy – Lack of Effect on Exercise Capacity
A randomized, double-blind, placebo-controlled study was conducted in 103 patients with PAH who were on bosentan therapy for a minimum of 3 months. The PAH patients included those with primary PAH and PAH associated with CTD. Patients were randomized to placebo or sildenafil (20 mg three times a day) in combination with bosentan (62.5 to 125 mg twice a day). The primary efficacy endpoint was the change from baseline at Week 12 in 6-minute walk distance (6MWD). The results indicate that there is no significant difference in mean
change from baseline on 6MWD observed between sildenafil 20 mg plus bosentan and bosentan alone.
STARTS-1 (NCT00159913) - Sildenafil in Treatment-Naive Children, Aged 1 to 17 Years, With Pulmonary Arterial Hypertension
A total of 234 patients with PAH aged 1 to 17 years were treated in a randomized, double-blind, multi-center, placebo-controlled parallel group, dose-ranging study. Patients (38% male and 62% female) had body weight ≥8 kg and had idiopathic pulmonary arterial hypertension (33%), or PAH associated with congenital heart disease (systemic-to-pulmonary shunt 37%, surgical repair 30%). In this trial, 27% of patients were <7 years old. Patients were WHO Functional Class I (32%), II (51%), III (15%), or IV (0.4%).
Patients were naïve for specific PAH therapy and the use of prostacyclin, prostacyclin analogues and endothelin receptor antagonists were not permitted in the study, and neither were arginine supplementation, nitrates, alpha-blockers and potent CYP450 3A4 inhibitors.
The primary objective of the study was to assess the effect of sildenafil on percent change from baseline in PVO2, normalized to body weight, from baseline to week 16 as measured by the Cardiopulmonary Exercise Test (CPET) (patients who were developmentally able to perform the test, n = 115). Secondary endpoints included hemodynamic monitoring, symptom assessment, WHO Functional Class, change in background treatment, and quality of life measurements (n = 234).
Patients were allocated to one of three sildenafil treatment groups (low, medium, or high) or placebo. Actual doses administered were dependent on body weight (see Table 5).
Table 5. Treatment Allocation by Dose and Body Weight in Pediatric Study
| ||Placebo||Low Dose||Medium Dose||High Dose|
|Body Weight (kg)||N||Dose||N||Dose||N||Dose||N|
|≥8 to 20 ||18 || ||na ||10 mg ||15 ||20 mg ||35 |
|>20 to 45 ||32 ||10 mg ||31 ||20 mg ||30 ||40 mg ||31 |
|>45 ||10 ||10 mg ||11 ||40 mg ||10 ||80 mg ||11 |
The proportion of patients receiving supportive medicinal products at baseline (anticoagulants, digoxin, calcium channel blockers, diuretics and/or oxygen) was similar in the combined sildenafil treatment group (48%) and the placebo treatment group (42%).
The primary endpoint was a percentage change in VO 2peak from baseline to week 16 assessed by CPET. Mean baseline peak volume of oxygen consumed (VO 2) values were similar across the sildenafil treatment groups (17 to 18 ml/kg/min), and slightly higher for the placebo treatment group (20 ml/kg/min). See Figure 6.
A total of 45% of patients were evaluable for CPET, which comprised those children ≥7 years old and developmentally able to perform the test. Children <7 years were evaluable only for the secondary endpoints.
Mean increases in VO 2peak percentage change from baseline at Week 16, were observed with all 3 sildenafil doses (range of 6% to 13%, Figure 6), with little change with placebo (0.5%).
Figure 6. Percentage Change from Baseline in VO2Peak: Mean (95% ConfidenceIntervals)
The estimated difference between the combined sildenafil doses and placebo was 8% (95% CI: - 0.2 to 16). The results of the main analysis (combined dose groups versus placebo) were not statistically significant (p=0.056).
The estimated difference between the sildenafil medium dose group and placebo was 11±5% (95% CI: 2 to 21).
Impact on Hemodynamic Parameters
Dose related improvements were observed with PVRI and mPAP. Statistically significant PVRI reductions compared to placebo were seen with the sildenafil medium and high dose groups (18% [95% CI: -32% to -2%] and 27% [95% CI: -39% to -14%], respectively) but not the low dose group (2% (95% CI: -20%, 20%). The sildenafil medium and high dose groups displayed mPAP changes from baseline compared to placebo, of -3.5 mmHg (95% CI: -8.9, 1.9) and -7.3 mmHg (95% CI: -12.4, -2.1), respectively; while the low dose group showed little difference from placebo (difference of 1.6 mmHg [95% CI: -4.5, 7.6]). Improvements were observed with cardiac index with all three sildenafil groups over placebo, 10%, 4%, and 15% for the low, medium, and high dose groups, respectively [see Clinical Pharmacology (12.2)].
STARTS-2 (NCT00159874) - Long-Term Survival with Oral Sildenafil Monotherapy in Treatment-Naïve Pediatric Pulmonary Arterial Hypertension
Of the 234 pediatric patients treated in the short-term, placebo-controlled study, 220 patients entered the long-term extension study. Patients who had been in the placebo group in the short-term study were randomly reassigned to sildenafil treatment; patients weighing ≤20 kg entered the medium or high dose groups (1:2), while patients weighing >20 kg entered the low, medium, or high dose groups (1:1:1). Of the total 229 patients who received sildenafil, there were 55, 74, and 100 patients in the low, medium, and high dose groups, respectively. Across the short-term and long-term studies, the overall duration of treatment from start of double-blind for individual patients ranged from 3 to 3,129 days. By sildenafil treatment group, median duration of sildenafil treatment was 1,696 days (excluding the 5 patients who received placebo in double-blind and were not treated in the long-term extension study).
Peak VO 2 was assessed 1 year after the start of the placebo-controlled study. Of sildenafil-treated patients developmentally able to perform the CPET 59/114 patients (52%) had not shown any deterioration in PVO 2 from start of sildenafil. Similarly, 191 of 229 patients (83%)who had received sildenafil had either maintained or improved their WHO Functional Class at 1 year assessment.
Kaplan-Meier estimates of survival at 3 years in patients >20 kg in weight at baseline were 94%, 93%, and 85% in the low, medium, and high dose groups, respectively; for patients ≤20 kg in weight at baseline, the survival estimates were 94% and 93% for patients in the medium and high dose groups, respectively [see Use in Specific Populations (8.4) and Adverse Reactions (6.1)].
Study A1481324 (NCT02060487) - Study to Assess the Effects of Sildenafil on Mortality in Adults with PAH
A study to assess the effects of multiple doses of sildenafil on mortality in adults with PAH was conducted following the observation of a higher risk of mortality in pediatric patients taking a high dose of sildenafil TID, based on body weight, compared to those taking a lower dose of sildenafil in the long-term extension of the pediatric clinical trial.
The study was a randomized, double-blind, parallel-group study in 385 adults with PAH. Patients were randomly assigned 1:1:1 to one of three treatment groups (5, 20, and 80 mg TID). Most patients were PAH treatment naïve (83%). For most patients the etiology of PAH was idiopathic (72%). The most common WHO Functional Class was Class III (58% of patients). Treatment groups were well balanced with respect to baseline demographics of strata history of PAH treatment and etiology of PAH, as well as the WHO Functional Class categories.
The primary objective of the study was to compare sildenafil 80 mg TID versus 5 mg TID for mortality, with success defined by ruling out twice the mortality at 80 mg.
The key secondary efficacy endpoint was time to first event of clinical worsening, defined as a composite endpoint of all-cause mortality, hospitalization for worsening PAH or disease progression. An additional secondary endpoint was 6MWD at Months 6 and 12.
At the time of a planned interim analysis (50% deaths) it was identified that the primary efficacy objective of this protocol was met and therefore the study was stopped. Based on the primary efficacy endpoint (mortality), the non-inferiority of sildenafil 80 mg TID arm versus 5 mg TID arm was met using a 2-sided significance level of 0.003 for the interim analysis. Primary comparison of the 80 mg TID group to the 5-mg TID group yielded the HR (99.7% CI) = 0.51 (0.22, 1.21); i.e., non-inferiority was established.
Table 6. Hazard Ratios for Overall Survival, Assessed in the Proportional Hazards Model – Intent To Treat Population
| ||Sildenafil |
N = 129
N = 128
N = 128
|Patient-years of follow-up ||329.8 ||340.5 ||356.7 |
|Number of deaths (%) ||34 (26) ||25 (20) ||19 (15) |
|On treatment deaths a (%) ||22 (17) ||13 (10) ||15 (12) |
|Off treatment deaths (%) ||12 (9) ||12 (9) ||4 (3) |
|Hazard ratio relative to sildenafil5 mg || || || |
|Hazard ratio estimate b|
| ||0.68 |
|Hazard ratio relative to sildenafil 20 mg || || || |
|Hazard ratio estimate |
| || ||0.74 |
a. On treatment deaths: Any death within 7 days of last dose was regarded as “On treatment”, thus might include deaths occurred after discontinuation from study treatment
b. Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH.
Kaplan-Meier estimates of survival at 3 years were 66%, 79%, and 85% in the 5-, 20-, and 80-mg TID dose groups, respectively
Sildenafil 80 mg was also superior to 5 mg for time to first event of clinical worsening with HR (99.7% CI) = 0.44 (0.22, 0.89).
Table 7. Hazard Ratios for Time to First Event of Clinical Worsening – Intent To Treat Population
| || Sildenafil |
N = 129
N = 128
N = 128
|Patient-years of follow-up ||249.6 ||276.4 ||306.5 |
|Number of patients with clinical |
|52 ||36 ||28 |
|First Event of clinical |
worsening a n (%)
| || || |
|Disease progression b||8 (6) ||2 (2) ||6 (5) |
|Hospitalization for PAH c||28 (22) ||23 (18) ||11 (9) |
| Death d||16 (12) ||11 (9) ||11 (9) |
|Hazard ratio relative to sildenafil |
| || || |
|Hazard ratio estimate e|| ||0.63 ||0.44 |
|99.7% CI || ||0.33, 1.21 ||0.22, 0.89 |
|p-value || ||0.035 ||<0.001 |
|Hazard ratio relative to |
sildenafil 20 mg
| || || |
|Hazard ratio estimate e|| || ||0.72 |
|99.7% CI || || ||0.34, 1.52 |
|p-value || || ||0.195 |
Note: Sildenafil 5 mg is not an approved dosage.
Abbreviations: 6MWD = 6-minute walk distance; CI = confidence interval; PAH = pulmonary arterial hypertension.
a. Clinical worsening events were defined as reduction from baseline in the 6MWD test by at least 15% and worsening functional class from baseline, both confirmed by a second test/evaluation within 2 weeks.
b. Count of cases of disease progression as the first event of clinical worsening.
c. Count of non-elective hospital stays for worsening PAH as the first event of clinical worsening.
d. Count of deaths as the first event of clinical worsening.
e. Hazard ratio estimates from the proportional Hazards model, stratified by actual previous PAH treatment and etiology of PAH. P-value from the Wald test.
6MWD at Months 6 and 12
At baseline, the median of 6MWD for the intent-to-treat (ITT) population was 332 to 352 m. At Month 6, the median change from baseline was highest for sildenafil 80 mg TID with 28 mcompared to 18 m and 19 m for sildenafil 5 mg TID and sildenafil 20 mg TID groups, respectively. The same was seen at Month 12, the median change from baseline for sildenafil 80 mg TID group was 33 m compared to 17 m for sildenafil 5 mg TID and 31 m in sildenafil 20 mg TID groups.
Overall, the safety data for sildenafil 20 mg TID and for the higher sildenafil 80 mg TID dose
were consistent with the established safety profile of sildenafil in previous adult PAH studies [ see Adverse Reactions (6.1)].