Pulmonary Arterial Hypertension
Conditions
Keywords
pulmonary arterial hypertension, pulmonary hypertension, PAH, sildenafil, revatio
Brief summary
This is a blinded study in adult patients with PAH evaluating the relative effects of sildenafil on mortality when administered at the three doses (80 mg, 20 mg or 5 mg, all three times per day \[TID\]). In addition, the relative effects on clinical worsening and 6-minute walking distance (6MWD) will be assessed.
Interventions
DRUGsildenafil citrate
sildenafil citrate (PDE-5 inhibitor) 5 mg tablet TID until study treatment discontinued or end of study
Sponsors
Pfizer's Upjohn has merged with Mylan to form Viatris Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
Subjects ≥ 18 \<75 years of age with any of the following conditions: * Idiopathic Primary Pulmonary Arterial Hypertension (IPAH) * PAH secondary to connective tissue disease * PAH with surgical repair (at least 5 years previously) of atrial septal defect (ASD),ventricular septal defect (VSD), patent ductus arteriosus (PDA) and aorto-pulmonary window * PAH diagnosis confirmed by right heart catheterization performed within 12 months prior to randomization * Functional Class II-IV; Baseline 6MWD ≥ 50 m.
Exclusion criteria
* Significant (ie, \>2+) valvular disease other than tricuspid regurgitation or pulmonary regurgitation * History of cardiac arrest, respiratory arrest, hemodynamic collapse, CPR, ventricular tachycardia, ventricular fibrillation, or uncontrolled atrial fibrillation * History of pulmonary embolism; History of chronic lung disease / restrictive lung disease (eg, chronic obstructive pulmonary disease (COPD) or scleroderma) with impairment of lung function * No prior long term treatment with PDE-5 inhibitors * Treatment with bosentan OR riociguat within 3 months of randomization * Current treatment with nitrates or nitric oxide
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Day 1 of study treatment up to date of death (within a maximum duration of 2102 days) | In this outcome measure number of deaths during the study were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Worsening Events | Day 1 of study treatment up to date of clinical worsening event (within a maximum duration of 2080 days) | Clinical worsening was defined as all-cause mortality, non-elective hospital stay for worsening pulmonary arterial hypertension (PAH) (including but not limited to right heart failure \[RHF\], initiation of intravenous (IV) prostanoids, lung transplantation, or septostomy) or disease progression. Disease progression was defined as a reduction from baseline in the 6-Minute Walk Distance (6MWD) test by 15% and worsening functional class from baseline, both confirmed by second test within 2 weeks of study treatment. |
| Change From Baseline in 6-Minute Walk Distance (6MWD) at Month 6 | Baseline, Month 6 | 6MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Analysis was performed using mixed model for repeated measures (MMRM), adjusted for baseline 6MWD and for randomization stratification factors: PAH treatment at study entry and etiology of PAH. |
| Change From Baseline in 6-Minute Walk Distance (6MWD) at Month 12 | Baseline, Month 12 | 6MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Analysis was performed using mixed model for repeated measures (MMRM), adjusted for baseline 6MWD and for randomization stratification factors: PAH treatment at study entry and etiology of PAH. |
Countries
Australia, Belgium, Bosnia and Herzegovina, Croatia, Czechia, Germany, Greece, Hong Kong, Israel, Latvia, Malaysia, Mexico, Poland, Romania, Russia, Serbia, Singapore, South Africa, Spain, Thailand, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
This was a randomized, double-blind, parallel-group, multinational and multicenter study to assess the effects of oral sildenafil on mortality in adult participants with pulmonary arterial hypertension (PAH). The study was conducted at 68 active sites in 23 countries.
Participants by arm
| Arm | Count |
|---|---|
| Sildenafil 5 mg Participants received a single tablet of sildenafil at a dose of 5 mg along with two tablets of placebo matching 20 mg and 80 mg sildenafil orally TID until discontinuation of study treatment or end of study. The maximum duration of study treatment was 2080 days approximately. Participants were followed up for at least 28 days after last dose of study treatment. | 129 |
| Sildenafil 20 mg Participants received a single tablet of sildenafil at a dose of 20 mg along with two tablets of placebo matching 5 mg and 80 mg sildenafil orally TID until discontinuation of study treatment or end of study. The maximum duration of study treatment was 1984 days approximately. Participants were followed up for at least 28 days after last dose of study treatment. | 128 |
| Sildenafil 80 mg Participants received a single tablet of sildenafil at a dose of 20 mg along with two tablets of placebo matching 5 mg and 80 mg sildenafil orally TID on day 1 for 2 weeks and then titrated up to 80 mg at week 2 along with two tablets of placebo matching 5 mg and 20 mg sildenafil orally TID until discontinuation of study treatment or end of study. The maximum duration of study treatment was 2073 days approximately. Participants were followed up for at least 28 days after last dose of study treatment. | 128 |
| Total | 385 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Death | 34 | 25 | 19 |
| Overall Study | Lack of Efficacy | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 3 | 0 | 2 |
| Overall Study | Other | 1 | 2 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 1 |
| Overall Study | Randomized in error | 1 | 0 | 0 |
| Overall Study | Study Terminated By Sponsor | 87 | 89 | 100 |
| Overall Study | Withdrawal by Subject | 3 | 10 | 4 |
Baseline characteristics
| Characteristic | Total | Sildenafil 5 mg | Sildenafil 20 mg | Sildenafil 80 mg |
|---|---|---|---|---|
| Age, Continuous | 51.6 Years STANDARD_DEVIATION 15.16 | 51.4 Years STANDARD_DEVIATION 15.02 | 51.2 Years STANDARD_DEVIATION 15.81 | 52.1 Years STANDARD_DEVIATION 14.72 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 5 Participants | 4 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 373 Participants | 124 Participants | 124 Participants | 125 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 56 Participants | 23 Participants | 14 Participants | 19 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 325 Participants | 104 Participants | 113 Participants | 108 Participants |
| Sex: Female, Male Female | 297 Participants | 97 Participants | 102 Participants | 98 Participants |
| Sex: Female, Male Male | 88 Participants | 32 Participants | 26 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 34 / 129 | 25 / 128 | 19 / 128 |
| other Total, other adverse events | 108 / 129 | 107 / 128 | 111 / 128 |
| serious Total, serious adverse events | 66 / 129 | 49 / 128 | 51 / 128 |
Outcome results
Primary
Overall Survival
In this outcome measure number of deaths during the study were reported.
Time frame: Day 1 of study treatment up to date of death (within a maximum duration of 2102 days)
Population: The intent-to-treat population (ITT) included all randomized participants treated with study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sildenafil 5 mg | Overall Survival | 34 Participants |
| Sildenafil 20 mg | Overall Survival | 25 Participants |
| Sildenafil 80 mg | Overall Survival | 19 Participants |
99.7% CI: [0.31, 1.49]
99.7% CI: [0.22, 1.21]
99.7% CI: [0.3, 1.84]
Secondary
Change From Baseline in 6-Minute Walk Distance (6MWD) at Month 12
6MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Analysis was performed using mixed model for repeated measures (MMRM), adjusted for baseline 6MWD and for randomization stratification factors: PAH treatment at study entry and etiology of PAH.
Time frame: Baseline, Month 12
Population: ITT population included all randomized participants treated with study treatment. Here, overall number of participants analyzed signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sildenafil 5 mg | Change From Baseline in 6-Minute Walk Distance (6MWD) at Month 12 | 14.3 Meters |
| Sildenafil 20 mg | Change From Baseline in 6-Minute Walk Distance (6MWD) at Month 12 | 35.7 Meters |
| Sildenafil 80 mg | Change From Baseline in 6-Minute Walk Distance (6MWD) at Month 12 | 34.8 Meters |
p-value: 0.028695% CI: [2.25, 40.45]MMRM
p-value: 0.036495% CI: [1.3, 39.65]MMRM
p-value: 0.928395% CI: [-19.94, 18.19]MMRM
Secondary
Change From Baseline in 6-Minute Walk Distance (6MWD) at Month 6
6MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Analysis was performed using mixed model for repeated measures (MMRM), adjusted for baseline 6MWD and for randomization stratification factors: PAH treatment at study entry and etiology of PAH.
Time frame: Baseline, Month 6
Population: ITT population included all randomized participants treated with study treatment. Here, overall number of participants analyzed signifies number of participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sildenafil 5 mg | Change From Baseline in 6-Minute Walk Distance (6MWD) at Month 6 | 12.2 Meters |
| Sildenafil 20 mg | Change From Baseline in 6-Minute Walk Distance (6MWD) at Month 6 | 27.3 Meters |
| Sildenafil 80 mg | Change From Baseline in 6-Minute Walk Distance (6MWD) at Month 6 | 31.2 Meters |
p-value: 0.062795% CI: [-0.8, 30.81]MMRM
p-value: 0.020195% CI: [2.99, 34.86]MMRM
p-value: 0.625495% CI: [-11.85, 19.68]MMRM
Secondary
Number of Participants With Clinical Worsening Events
Clinical worsening was defined as all-cause mortality, non-elective hospital stay for worsening pulmonary arterial hypertension (PAH) (including but not limited to right heart failure \[RHF\], initiation of intravenous (IV) prostanoids, lung transplantation, or septostomy) or disease progression. Disease progression was defined as a reduction from baseline in the 6-Minute Walk Distance (6MWD) test by 15% and worsening functional class from baseline, both confirmed by second test within 2 weeks of study treatment.
Time frame: Day 1 of study treatment up to date of clinical worsening event (within a maximum duration of 2080 days)
Population: ITT population included all randomized participants treated with study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sildenafil 5 mg | Number of Participants With Clinical Worsening Events | 52 Participants |
| Sildenafil 20 mg | Number of Participants With Clinical Worsening Events | 36 Participants |
| Sildenafil 80 mg | Number of Participants With Clinical Worsening Events | 28 Participants |
p-value: 0.03599.7% CI: [0.33, 1.21]Wald test
p-value: <0.00199.7% CI: [0.22, 0.89]Wald test
p-value: 0.19599.7% CI: [0.34, 1.52]Wald test