Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension. A Double-Blind Placebo-controlled Clinical Trial

Abstract

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown.Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy.Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response.Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56-0.97; P = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro-brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil-assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12-60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting.Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.Clinical trial registered with www.clinicaltrials.gov (NCT01560624).

Keywords: clinical study; combination therapy; oral treprostinil; pulmonary arterial hypertension; sequential therapy.

Figures

Figure 1.

Patient disposition. *Includes one subject in the oral treprostinil group and one subject in the placebo group who experienced clinical worsening events due to urgent hospitalization for treatment of worsening pulmonary arterial hypertension. †Includes one subject in the oral treprostinil group and one subject in the placebo group who experienced clinical worsening events due to fatal serious adverse events, and one subject in the oral treprostinil group who discontinued treatment due to an adverse event, but remained in the study until death (which did not qualify as a clinical worsening event). ‡Includes one subject in the placebo group who died after discontinuation of study treatment due to clinical worsening.

Figure 2.

Kaplan-Meier plots of primary endpoint and primary endpoint by baseline risk stratification. (A) Time to adjudicated clinical worsening events. (B) Time to adjudicated clinical worsening events by baseline risk stratification. “Lower risk” is defined as subjects with two or three low-risk criteria met; “higher risk” is defined as subjects with zero or one low-risk criterion met. *P values were calculated with log-rank test stratified by background pulmonary arterial hypertension (PAH) therapy and baseline 6-minute-walk distance (6MWD) category. †Hazard ratios, 95% confidence intervals (CIs), and P values were calculated with proportional hazard model with explanatory variables of treatment, background PAH therapy, and baseline 6MWD as a continuous variable.

Figure 3.

Plasma N-terminal pro–brain natriuretic peptide (NT-proBNP) results by study visit. Per protocol, NT-proBNP values were not measured at Week 48. P value was obtained from the analysis of covariance with change from baseline in log-transformed data in NT-proBNP as the dependent variable, treatment as fixed effect, and log-transformed baseline NT-proBNP as a covariate. NT-proBNP assay centrally performed by Covance via the Immulite 2000 on a Seimens platform. The normal range for both sexes less than 75 years of age is less than 125 pg/ml. The normal range for both sexes over 75 years of age is less than 450 pg/ml. IQR = interquartile range; LS = least squares; PBO = placebo; TRE = oral treprostinil.

Figure 4.

Categorical changes from baseline in World Health Organization (WHO) functional class, Borg dyspnea score, and risk stratification criteria. (A) WHO functional class categorical change from baseline by study visit; participants who had a missing assessment at Week 24 and had deteriorated were assigned functional class IV; P value was obtained from Fisher’s exact test. (B) Borg dyspnea score categorical change from baseline by study visit; participants who had a missing assessment at Week 24 and had deteriorated were assigned worst case of 10; P value was obtained from Fisher’s exact test. (C) Risk categorical change from baseline through Week 60. Percentages are calculated based on the number of participants at each visit within each treatment group. Low-risk criteria are defined as WHO functional class I or II, 6-minute-walk distance >440 m, or N-terminal pro–brain natriuretic peptide <300 pg/ml. Low-risk criteria met were only counted for subjects with all three measures. “Improved” indicates any increase in the number of low-risk criteria met; “no change” indicates the same number of low-risk criteria met; and “deteriorated” indicates any decrease in the number of low-risk criteria met. P values were obtained from Fisher’s exact test. PBO = placebo; TRE = oral treprostinil.