Table 2.
Primary and Secondary Efficacy Endpoints
| Endpoint | Oral Treprostinil (n = 346) | Placebo (n = 344) | Treatment Effect (95% CI) |
|---|---|---|---|
| Primary endpoint: adjudicated clinical worsening event, n (%) | |||
| All events | 90 (26.0) | 124 (36.0) | HR, 0.74 (0.56 to 0.97); P = 0.028*; P = 0.039† |
| Death (all causes) | 15 (4.3) | 14 (4.1) | |
| Hospitalization due to PAH and/or right heart failure | 35 (10.1) | 35 (10.2) | |
| Initiation of inhaled or infused prostacyclin | 2 (0.6) | 5 (1.5) | |
| Disease progression | 19 (5.5) | 50 (14.5) | |
| Unsatisfactory long-term clinical response | 19 (5.5) | 20 (5.8) | |
| Secondary endpoints (at Week 24) | |||
| 6MWD, LS mean change, m | 16 | 8.03 | 7.96 (−2 to 17.92); P = 0.117‡ |
| NT-proBNP, concentration ratio to baseline, LS mean change | 0.82 | 1.16 | 0.71 (0.61 to 0.82); P < 0.001§ |
| Borg dyspnea score, shift from baseline, n (%) | P = 0.014‖ | ||
| Improved | 126 (36.5) | 105 (30.5) | |
| No change | 128 (37.1) | 113 (32.8) | |
| Deteriorated | 91 (26.4) | 126 (36.6) | |
| Combined ranking of 6MWD and Borg dyspnea score | — | — | P = 0.006¶ |
| WHO functional class, shift from baseline, n (%) | P = 0.017‖ | ||
| Improved | 51 (14.7) | 37 (10.8) | |
| No change | 256 (74) | 244 (70.9) | |
| Deteriorated | 39 (11.3) | 63 (18.3) | |
| Deaths (all causes), n (%) | |||
| Deaths during study | 17 (4.9) | 18 (5.2) | HR, 1.00 (0.52 to 1.95); P = 0.992*; P = 0.978† |
| Deaths at closure of study** | 38 (11.0) | 60 (17.4) | HR, 0.63 (0.42 to 0.95); P = 0.026*; P = 0.032† |
Definition of abbreviations: 6MWD = 6-minute-walk distance; CI = confidence interval; HR = hazard ratio; LS = least squares; MMRM = mixed-model repeated measurement; NT-proBNP = N-terminal pro–brain natriuretic peptide; PAH = pulmonary arterial hypertension; WHO = World Health Organization.
Hazard ratio, 95% CI, and P value were calculated with proportional hazard model with explanatory variables of treatment, background PAH therapy, and baseline 6MWD as a continuous variable.
P value was obtained from log-rank test stratified by background PAH therapy and baseline 6MWD category.
LS mean, P value, estimated difference, and its 95% CI were from the MMRM with the change from baseline in 6MWD as the dependent variable, treatment, week, treatment-by-week interaction, and background PAH therapy as the fixed effects, and baseline 6MWD as the covariate. An unstructured variance/covariance structure shared across treatment groups was used to model the within-subject errors.
LS mean, P value, estimated difference, and its 95% CI were from the MMRM with the change from baseline in log-transformed data in NT-proBNP as the dependent variable, treatment, week, and treatment-by-week interaction as the fixed effects, and log-transformed baseline NT-proBNP as the covariate. An unstructured variance/covariance structure shared across treatment groups was used to model the within-subject errors.
P value was obtained from Fisher’s exact test.
P value obtained from nonparametric analysis of covariance.
Vital status was collected at the study closure for all subjects including subjects who rolled over to extension study and who discontinued early from the study. For subjects whose vital status was not available at the study closure, their time to death was censored at the subjects’ last known date to be alive. Subjects who were alive at the study closure have their time to death censored at the last contact date.