In patients with pulmonary arterial hypertension (PAH) receiving background double combination therapy in the GRIPHON study, the addition of selexipag reduced the risk of the primary composite endpoint of morbidity/mortality, consistent with that observed for the overall population. |
The beneficial effect of selexipag when added as a third agent to patients receiving an endothelin receptor antagonist and phosphodiesterase-5 inhibitor was consistent in patients with World Health Organization functional class II or III symptoms at baseline. |
These findings support escalation of treatment to triple oral combination therapy to improve outcomes for patients with PAH receiving double combination therapy. |
1 Introduction
2 Methods
2.1 Study Population
2.2 Study Design
2.3 Outcome Measures
2.4 Statistical Analyses
3 Results
3.1 Patient Characteristics
Characteristic | Overallb | WHO FC II symptoms at baseline | WHO FC III symptoms at baseline | |||
---|---|---|---|---|---|---|
Selexipag (N = 179) | Placebo (N = 197) | Selexipag (N = 55) | Placebo (N = 60) | Selexipag (N = 122) | Placebo (N = 133) | |
Female sex | 143 (79.9) | 156 (79.2) | 46 (83.6) | 48 (80.0) | 96 (78.7) | 105 (78.9) |
Age (years) | 50.6 ± 15.00 | 50.7 ± 14.24 | 47.6 ± 15.69 | 46.6 ± 13.75 | 51.8 ± 14.57 | 52.2 ± 14.19 |
Geographical region | ||||||
Asia | 12 (6.7) | 17 (8.6) | 6 (10.9) | 6 (10.0) | 6 (4.9) | 11 (8.3) |
Eastern Europe | 8 (4.5) | 11 (5.6) | 0 (0) | 2 (3.3) | 8 (6.6) | 9 (6.8) |
Latin America | 10 (5.6) | 12 (6.1) | 5 (9.1) | 10 (16.7) | 4 (3.3) | 2 (1.5) |
North America | 57 (31.8) | 50 (25.4) | 20 (36.4) | 16 (26.7) | 37 (30.3) | 33 (24.8) |
Western Europe/Australia | 92 (51.4) | 107 (54.3) | 24 (43.6) | 26 (43.3) | 67 (54.9) | 78 (58.6) |
Time since PAH diagnosisc (years) | 4.0 ± 4.39 | 3.6 ± 3.33 | 4.3 ± 4.31 | 3.6 ± 3.00 | 3.9 ± 4.47 | 3.6 ± 3.49 |
PAH classification | ||||||
Idiopathic | 106 (59.2) | 118 (59.9) | 32 (58.2) | 40 (66.7) | 72 (59.0) | 74 (55.6) |
Heritable | 9 (5.0) | 9 (4.6) | 6 (10.9) | 2 (3.3) | 3 (2.5) | 7 (5.3) |
Associated with CTD | 40 (22.3) | 56 (28.4) | 10 (18.2) | 11 (18.3) | 30 (24.6) | 45 (33.8) |
Associated with corrected congenital shunts | 10 (5.6) | 10 (5.1) | 4 (7.3) | 3 (5.0) | 6 (4.9) | 7 (5.3) |
Associated with HIV infection | 2 (1.1) | 2 (1.0) | 1 (1.8) | 2 (3.3) | 1 (0.8) | 0 (0) |
Associated with drug/toxin exposure | 12 (6.7) | 2 (1.0) | 2 (3.6) | 2 (3.3) | 10 (8.2) | 0 (0) |
6-min walk distance (m) | 359.7 ± 80.97 | 358.7 ± 79.73 | 398.9 ± 55.45 | 392.9 ± 61.44 | 342.4 ± 84.94 | 348.8 ± 76.88 |
3.2 Selexipag Exposure and Dose
3.3 Primary Endpoint
Endpoint | Overallb | WHO FC II symptoms at baseline | WHO FC III symptoms at baseline | |||
---|---|---|---|---|---|---|
Selexipag (N = 179) | Placebo (N = 197) | Selexipag (N = 55) | Placebo (N = 60) | Selexipag (N = 122) | Placebo (N = 133) | |
Primary composite endpoint of morbidity/mortality up to the end of the treatment periodc | ||||||
All events | 47 (26.3) | 80 (40.6) | 6 (10.9) | 18 (30.0) | 41 (33.6) | 59 (44.4) |
Hospitalization for PAH worsening | 27 (15.1) | 43 (21.8) | 3 (5.5) | 8 (13.3) | 24 (19.7) | 33 (24.8) |
Disease progression | 11 (6.1) | 22 (11.2) | 1 (1.8) | 5 (8.3) | 10 (8.2) | 16 (12.0) |
Death from any cause | 4 (2.2) | 3 (1.5) | 0 | 1 (1.7) | 4 (3.3) | 2 (1.5) |
Initiation of parenteral prostanoid therapy or long-term oxygen therapy for worsening PAH | 5 (2.8) | 10 (5.1) | 2 (3.6) | 3 (5.0) | 3 (2.5) | 7 (5.3) |
Need for lung transplantation or balloon atrial septostomy for worsening PAH | 0 | 2 (1.0) | 0 | 1 (1.7) | 0 | 1 (0.75) |
Secondary composite endpoint of death due to PAH or hospitalization for worsening of PAH up to the end of the treatment periodc | ||||||
All events | 29 (16.2) | 51 (25.9) | 3 (5.5) | 11 (18.3) | 26 (21.3) | 38 (28.6) |
Hospitalization for worsening of PAH | 29 (100) | 49 (96.1) | 3 (100) | 11 (100) | 26 (100) | 36 (94.7) |
Death due to PAH | 0 | 2 (3.9) | 0 | 0 | 0 | 2 (5.3) |
3.4 Secondary Endpoints
3.4.1 Death due to PAH or Hospitalization due to PAH Worsening
3.4.2 All-Cause Death up to the End of the Study
3.5 Safety and Tolerability
Variable | Overallb | WHO FC II symptoms at baseline | WHO FC III symptoms at baseline | |||
---|---|---|---|---|---|---|
Selexipag (N = 179) | Placebo (N = 197) | Selexipag (N = 55) | Placebo (N = 60) | Selexipag (N = 122) | Placebo (N = 133) | |
Exposure to double-blind treatment (weeks) | 63.1 (30.3–104.0) | 63.7 (38.0–102.1) | 66.3 (44.7–124.1) | 70.2 (46.0–101.0) | 61.3 (25.7–103.0) | 60.1 (31.7–104.3) |
AEs, n | 1783 | 1693 | 496 | 462 | 1259 | 1181 |
Patients with ≥ 1 AE | 175 (97.8) | 195 (99.0) | 53 (96.4) | 58 (96.7) | 120 (98.4) | 133 (100) |
Patients with ≥ 1 SAE | 80 (44.7) | 104 (52.8) | 18 (32.7) | 29 (48.3) | 60 (49.2) | 72 (54.1) |
Premature discontinuations due to an AE | 34 (19.0) | 15 (7.6) | 9 (16.4) | 5 (8.3) | 24 (19.7) | 10 (7.5) |
AEc | ||||||
Headache | 136 (76.0) | 76 (38.6) | 43 (78.2) | 18 (30.0) | 91 (74.6) | 57 (42.9) |
Diarrhea | 100 (55.9) | 52 (26.4) | 32 (58.2) | 8 (13.3) | 66 (54.1) | 41.(30.8) |
Nausea | 85 (47.5) | 49 (24.9) | 30 (54.5) | 12 (20.0) | 53 (43.4) | 36 (27.1) |
Pain in jaw | 74 (41.3) | 20 (10.2) | 21 (38.2) | 3 (5.0) | 52 (42.6) | 16 (12.0) |
PAH | 44 (24.6) | 74 (37.6) | 10 (18.2) | 21 (35.0) | 34 (27.9) | 50 (37.6) |
Vomiting | 42 (23.5) | 21 (10.7) | 13 (23.6) | 7 (11.7) | 28 (23.0) | 13 (9.8) |
Pain in extremity | 41 (22.9) | 20 (10.2) | 8 (14.5) | 4 (6.7) | 32 (26.2) | 16 (12.0) |
Dyspnea | 36 (20.1) | 46 (23.4) | 7 (12.7) | 9 (15.0) | 29 (23.8) | 36 (27.1) |
Flushing | 36 (20.1) | 16 (8.1) | 9 (16.4) | 5 (8.3) | 26 (21.3) | 11 (8.3) |
Dizziness | 33 (18.4) | 34 (17.3) | 11 (20.0) | 11 (18.3) | 21 (17.2) | 22 (16.5) |
URTI | 26 (14.5) | 29 (14.7) | 10 (18.2) | 10 (16.7) | 16 (13.1) | 19 (14.3) |
Nasopharyngitis | 26 (14.5) | 28 (14.2) | 8 (14.5) | 7 (11.7) | 17 (13.9) | 21 (15.8) |
Cough | 25 (14.0) | 31 (15.7) | 7 (12.7) | 9 (15.0) | 17 (13.9) | 21 (15.8) |
Myalgia | 24 (13.4) | 8 (4.1) | 8 (14.5) | 1 (1.7) | 16 (13.1) | 7 (5.3) |
Fatigue | 23 (12.8) | 23 (11.7) | 8 (14.5) | 6 (10.0) | 15 (12.3) | 17 (12.8) |
Edema peripheral | 21 (11.7) | 43 (21.8) | 6 (10.9) | 9 (15.0) | 15 (12.3) | 30 (22.6) |
Bronchitis | 21 (11.7) | 17 (8.6) | 7 (12.7) | 5 (8.3) | 14 (11.5) | 12 (9.0) |
Right ventricular failure | 14 (7.8) | 27 (13.7) | 1 (1.8) | 8 (13.3) | 13 (10.7) | 17 (12.8) |
Abdominal pain | 17 (9.5) | 15 (7.6) | 8 (14.5) | 5 (8.3) | 9 (7.4) | 9 (6.8) |
Arthralgia | 17 (9.5) | 20 (10.2) | 4 (7.3) | 4 (6.7) | 13 (10.7) | 16 (12.0) |
Syncope | 16 (8.9) | 24 (12.2) | 3 (5.5) | 8 (13.3) | 13 (10.7) | 15 (11.3) |
Decreased appetite | 10 (5.6) | 8 (4.1) | 6 (10.9) | 3 (5.0) | 4 (3.3) | 5 (3.8) |
Asthenia | 9 (5.0) | 13 (6.6) | 3 (5.5) | 7 (11.7) | 6 (4.9) | 5 (3.8) |
Variable | Titration period | Maintenance period | ||
---|---|---|---|---|
Selexipag (N = 179) | Placebo (N = 197) | Selexipag (N = 157) | Placebo (N = 174) | |
Exposure to double-blind treatment (weeks) | 12.4 (12.4–12.4) | 12.4 (12.4–12.4) | 59.7 (32.3–102.3) | 57.2 (39.6–94.6) |
Patients with one or more prostacyclin-associated AE | 167 (93.3) | 110 (55.8) | 133 (84.7) | 105 (60.3) |
AEb | ||||
Headache | 132 (73.7) | 62 (31.5) | 88 (56.1) | 48 (27.6) |
Diarrhea | 86 (48.0) | 28 (14.2) | 69 (43.9) | 39 (22.4) |
Nausea | 70 (39.1) | 35 (17.8) | 49 (31.2) | 26 (14.9) |
Pain in jaw | 70 (39.1) | 9 (4.6) | 55 (35.0) | 15 (8.6) |
Pain in extremity | 36 (20.1) | 11 (5.6) | 30 (19.1) | 14 (8.0) |
Vomiting | 35 (19.6) | 9 (4.6) | 17 (10.8) | 14 (8.0) |
Flushing | 31 (17.3) | 11 (5.6) | 30 (19.1) | 10 (5.7) |
Myalgia | 23 (12.8) | 8 (4.1) | 12 (7.6) | 4 (2.3) |
Dizziness | 22 (12.3) | 16 (8.1) | 21 (13.4) | 25 (14.4) |
Arthralgia | 9 (5.0) | 13 (6.6) | 15 (9.6) | 12 (6.9) |
Musculoskeletal pain | 9 (5.0) | 2 (1.0) | 7 (4.5) | 5 (2.9) |
Temporomandibular joint syndrome | 0 | 2 (1.0) | 0 | 1 (0.6) |