Pulmonary Arterial Hypertension
Conditions
Keywords
pulmonary arterial hypertension, PAH
Brief summary
The AC-065A302 (GRIPHON) study is an event-driven Phase 3 study to demonstrate the effect of selexipag on time to first morbidity or mortality event in patients with pulmonary arterial hypertension.
Interventions
DRUGSelexipag
Selexipag 200 µg tablets
DRUGPlacebo
Placebo tablets matching selexipag
Sponsors
Actelion
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 75 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients 18-75 years old, with symptomatic PAH * PAH belonging to the following subgroups of the updated Dana Point Clinical Classification Group 1 (Idiopathic, or Heritable, or Drug or toxin induced, or Associated (APAH) with Connective tissue disease, Congenital heart disease with simple systemic-to-pulmonary shunt at least 1 year after surgical repair, or HIV infection) * Documented hemodynamic diagnosis of PAH by right heart catheterization, performed at any time prior to Screening * Six minute walk distance (6MWD) between 50 and 450 m at Screening within 2 weeks prior to the Baseline Visit * Signed informed consent
Exclusion criteria
* Patients with pulmonary hypertension (PH) in the Updated Dana Point Classification Groups 2-5, and PAH Group 1 subgroups that are not covered by the inclusion criteria * Patients who have received prostacyclin or its analogs within 1 month before Baseline Visit, or are scheduled to receive any of these compounds during the trial * Patients with moderate or severe obstructive lung disease * Patients with moderate or severe restrictive lung disease * Patients with moderate or severe hepatic impairment (Child-Pugh B and C) * Patients with documented left ventricular dysfunction * Patients with severe renal insufficiency * Patients with BMI \<18.5 Kg/m2 * Patients who are receiving or have been receiving any investigational drugs within 1 month before the Baseline Visit * Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements, in particular with 6MWT * Recently conducted or planned cardio-pulmonary rehabilitation program based on exercise training * Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements * Life expectancy less than 12 months * Females who are lactating or pregnant or plan to become pregnant during the study * Known hypersensitivity to any of the excipients of the drug formulations
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake | Up to 7 days after end of double-blind treatment (maximum: 4.3 years) | Time from randomization to the first occurrence of a morbidity event or death (all causes) was analyzed with the Kaplan-Meier method (event-free KM estimates at different time points). Morbidity event was defined as any of the following events confirmed by the Critical Event committee: * Hospitalization for worsening of pulmonary arterial hypertension (PAH), * Worsening of PAH resulting in need for lung transplantation or balloon atrial septostomy, * Initiation of parenteral prostanoid therapy or chronic oxygen therapy due to worsening of PAH, * Disease progression which was defined by a decrease in 6-minute walk distance from baseline (\>=15%, confirmed by a 2nd test on a different day) combined with worsening of WHO FC for patients belonging to WHO FC II/III at baseline, or combined with the need for additional PAH-specific therapy for patients belonging to WHO FC III/IV at baseline. Note: The number of patients at risk decreased over time but this cannot be captured below |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) at Trough | Week 26 | The 6-minute walk distance test (6MWD) is a non-encouraged test performed in a 30 m long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. If the patient was used to taking bronchodilators before a walk, he/she was given them 5 to 30 min before the test. Also if the patient was on chronic oxygen therapy, oxygen was given at their standard rate during the test. Absolute change from baseline to Week 26 in 6MWD was measured at trough, i.e., either on the next day after the last study drug administration or at least 12 hours after study drug administration if on the same day. |
| Absence of Worsening From Baseline to Week 26 in Modified NYHA/WHO Functional Class (WHO FC) | Week 26 | — |
Countries
Argentina, Australia, Austria, Belarus, Belgium, Canada, Chile, China, Colombia, Czechia, Denmark, France, Germany, Greece, Hungary, India, Ireland, Israel, Italy, Malaysia, Mexico, Netherlands, Peru, Poland, Romania, Russia, Serbia, Singapore, Slovakia, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
A total of 1351 patients were screened from 181 sites in 39 countries worldwide. Of these, 1156 were randomized
Pre-assignment details
Screening assessments were performed up to a maximum of 28 days before baseline
Participants by arm
| Arm | Count |
|---|---|
| Selexipag During the 12-week titration phase, treatment was initiated at 200 μg twice daily (b.i.d.) and up-titrated weekly in 200 μg b.i.d. increments to the maximum tolerated dose (MTD) for each individual patient but not above 1600 μg b.i.d. At Week 12, patients continued the treatment at their individual MTD up to Week 26. Thereafter the dose could be up-titrated at scheduled visits if needed for patients receiving a dose < 1600 μg b.i.d. The dose could be decreased at any time in case of tolerability issues. | 574 |
| Placebo Matching placebo was administered orally following the same administration schedule as described for selexipag | 582 |
| Total | 1,156 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative reason | 7 | 6 |
| Overall Study | Adverse Event | 78 | 42 |
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Morbidity or Mortality primary endpoint | 155 | 242 |
| Overall Study | Withdrawal by Subject | 43 | 37 |
Baseline characteristics
| Characteristic | Selexipag | Total | Placebo |
|---|---|---|---|
| 6-minute walk distance (6MWD) at baseline | 376 Meters | 372 Meters | 369 Meters |
| Age, Continuous | 48.2 Years STANDARD_DEVIATION 15.19 | 48.1 Years STANDARD_DEVIATION 15.37 | 47.9 Years STANDARD_DEVIATION 15.55 |
| Modified NYHA/WHO Functional class (FC) FC I | 4 Participants | 9 Participants | 5 Participants |
| Modified NYHA/WHO Functional class (FC) FC II | 274 Participants | 529 Participants | 255 Participants |
| Modified NYHA/WHO Functional class (FC) FC III | 293 Participants | 607 Participants | 314 Participants |
| Modified NYHA/WHO Functional class (FC) FC IV | 3 Participants | 11 Participants | 8 Participants |
| PAH etiology Associated with connective tissue disease | 167 Participants | 334 Participants | 167 Participants |
| PAH etiology Associated with drug or toxin exposure | 17 Participants | 27 Participants | 10 Participants |
| PAH etiology Associated with HIV infection | 5 Participants | 10 Participants | 5 Participants |
| PAH etiology Assoc. with corrected (>=12Mo) congenital shunts | 60 Participants | 110 Participants | 50 Participants |
| PAH etiology Heritable | 13 Participants | 26 Participants | 13 Participants |
| PAH etiology Idiopathic | 312 Participants | 649 Participants | 337 Participants |
| PAH medications at baseline Endothelin Receptor Agonists (ERA) | 94 Participants | 170 Participants | 76 Participants |
| PAH medications at baseline ERA and PDE5I in combination | 179 Participants | 376 Participants | 197 Participants |
| PAH medications at baseline None | 112 Participants | 236 Participants | 124 Participants |
| PAH medications at baseline Phosphodiesterase type 5 inhibitors (PDE5-I) | 189 Participants | 374 Participants | 185 Participants |
| Race/Ethnicity, Customized Asian | 125 Participants | 245 Participants | 120 Participants |
| Race/Ethnicity, Customized Black | 13 Participants | 27 Participants | 14 Participants |
| Race/Ethnicity, Customized Caucasion / White | 376 Participants | 751 Participants | 375 Participants |
| Race/Ethnicity, Customized Hispanic | 51 Participants | 114 Participants | 63 Participants |
| Race/Ethnicity, Customized Other | 9 Participants | 19 Participants | 10 Participants |
| Region of Enrollment Asia | 115 Participants | 228 Participants | 113 Participants |
| Region of Enrollment Eastern Europe | 149 Participants | 304 Participants | 155 Participants |
| Region of Enrollment Latin America | 54 Participants | 110 Participants | 56 Participants |
| Region of Enrollment North America | 95 Participants | 193 Participants | 98 Participants |
| Region of Enrollment Western Europe & Australia | 161 Participants | 321 Participants | 160 Participants |
| Sex: Female, Male Female | 457 Participants | 923 Participants | 466 Participants |
| Sex: Female, Male Male | 117 Participants | 233 Participants | 116 Participants |
| Time since PAH diagnosis | 0.9 Years | 1.0 Years | 1.1 Years |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 544 / 575 | 486 / 577 |
| serious Total, serious adverse events | 252 / 575 | 272 / 577 |
Outcome results
Primary
Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake
Time from randomization to the first occurrence of a morbidity event or death (all causes) was analyzed with the Kaplan-Meier method (event-free KM estimates at different time points). Morbidity event was defined as any of the following events confirmed by the Critical Event committee: * Hospitalization for worsening of pulmonary arterial hypertension (PAH), * Worsening of PAH resulting in need for lung transplantation or balloon atrial septostomy, * Initiation of parenteral prostanoid therapy or chronic oxygen therapy due to worsening of PAH, * Disease progression which was defined by a decrease in 6-minute walk distance from baseline (\>=15%, confirmed by a 2nd test on a different day) combined with worsening of WHO FC for patients belonging to WHO FC II/III at baseline, or combined with the need for additional PAH-specific therapy for patients belonging to WHO FC III/IV at baseline. Note: The number of patients at risk decreased over time but this cannot be captured below
Time frame: Up to 7 days after end of double-blind treatment (maximum: 4.3 years)
Population: The primary endpoint was analyzed using the full analysis set, which includes all randomized patients evaluated according to the study drug to which they have been randomized (intention-to treat analysis set).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Selexipag | Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake | KM estimate at Month 6 | 91.2 Percentage of patients free of events |
| Selexipag | Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake | KM estimate at Month 12 | 83.1 Percentage of patients free of events |
| Selexipag | Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake | KM estimate at Month 18 | 75.5 Percentage of patients free of events |
| Selexipag | Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake | KM estimate at Month 24 | 67.9 Percentage of patients free of events |
| Selexipag | Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake | KM estimate at Month 30 | 61.9 Percentage of patients free of events |
| Selexipag | Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake | KM estimate at Month 36 | 58.2 Percentage of patients free of events |
| Placebo | Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake | KM estimate at Month 30 | 49.3 Percentage of patients free of events |
| Placebo | Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake | KM estimate at Month 6 | 81.7 Percentage of patients free of events |
| Placebo | Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake | KM estimate at Month 24 | 53.9 Percentage of patients free of events |
| Placebo | Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake | KM estimate at Month 12 | 70.6 Percentage of patients free of events |
| Placebo | Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake | KM estimate at Month 36 | 41.7 Percentage of patients free of events |
| Placebo | Time From Randomization to the First Morbidity Event or Death (All Causes) up to 7 Days After the Last Study Drug Intake | KM estimate at Month 18 | 61.3 Percentage of patients free of events |
Comparison: The primary analysis was performed on the Full Analysis Set by a one-sided unstratified log-rank testp-value: <0.000199% CI: [0.46, 0.78]Log Rank
Secondary
Absence of Worsening From Baseline to Week 26 in Modified NYHA/WHO Functional Class (WHO FC)
Time frame: Week 26
Population: Full analysis set. Patients with WHO FC IV at baseline were excluded from this analysis as they could not shift to a worse category
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Selexipag | Absence of Worsening From Baseline to Week 26 in Modified NYHA/WHO Functional Class (WHO FC) | 77.8 Percentage of patients |
| Placebo | Absence of Worsening From Baseline to Week 26 in Modified NYHA/WHO Functional Class (WHO FC) | 74.9 Percentage of patients |
p-value: 0.284399% CI: [0.811, 1.664]Cochran-Mantel-Haenszel
Secondary
Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) at Trough
The 6-minute walk distance test (6MWD) is a non-encouraged test performed in a 30 m long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. If the patient was used to taking bronchodilators before a walk, he/she was given them 5 to 30 min before the test. Also if the patient was on chronic oxygen therapy, oxygen was given at their standard rate during the test. Absolute change from baseline to Week 26 in 6MWD was measured at trough, i.e., either on the next day after the last study drug administration or at least 12 hours after study drug administration if on the same day.
Time frame: Week 26
Population: Full analysis set
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Selexipag | Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) at Trough | 6MWD at baseline - Overall | 376 Meters |
| Selexipag | Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) at Trough | 6MWD at Week 26- Overall | 370 Meters |
| Selexipag | Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) at Trough | 6MWD Change from baseline at Week 26 | 4 Meters |
| Placebo | Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) at Trough | 6MWD at baseline - Overall | 369 Meters |
| Placebo | Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) at Trough | 6MWD at Week 26- Overall | 346 Meters |
| Placebo | Change From Baseline to Week 26 in 6-minute Walk Distance (6MWD) at Trough | 6MWD Change from baseline at Week 26 | -9 Meters |
Comparison: Non-parametric ANCOVA with 6MWD as covariate at baseline. Missing values were imputed based on the following imputation rules: 1) if patient was unable to walk at week 26, 0 meter was imputed, 2) if rule 1 did not apply, the second lowest observed 6MWD value (10 meters) at Week 26 was imputed. Missing values were imputed for 21.6% of the subjects.p-value: 0.002799% CI: [1, 24]ANCOVA