TY - JOUR

T1 - Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension

T2 - A Double-Blind Placebo-controlled Clinical Trial

AU - White, R James

AU - Jerjes-Sanchez, Carlos

AU - Bohns Meyer, Gisela Martina

AU - Pulido, Tomas

AU - Sepulveda, Pablo

AU - Wang, Kuo Yang

AU - Grünig, Ekkehard

AU - Hiremath, Shirish

AU - Yu, Zaixin

AU - Gangcheng, Zhang

AU - Yip, Wei Luen James

AU - Zhang, Shuyang

AU - Khan, Akram

AU - Deng, C Q

AU - Grover, Rob

AU - Tapson, Victor F

AU - FREEDOM-EV Investigators

AU - Svetliza, Graciela Noemi

AU - Lescano, Adrian Jose

AU - Bortman, Guillermo Roberto

AU - Carlsen, Jørn

AU - McDonough, Clark

AU - White, James R

AU - Rischard, Franz

PY - 2020

Y1 - 2020

N2 - 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).

AB - 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).

KW - Administration, Oral

KW - Adolescent

KW - Adult

KW - Aged

KW - Antihypertensive Agents/administration & dosage

KW - Double-Blind Method

KW - Epoprostenol/analogs & derivatives

KW - Female

KW - Humans

KW - Male

KW - Middle Aged

KW - Placebos/therapeutic use

KW - Pulmonary Arterial Hypertension/drug therapy

KW - Young Adult

U2 - 10.1164/rccm.201908-1640OC

DO - 10.1164/rccm.201908-1640OC

M3 - Journal article

C2 - 31765604

VL - 201

SP - 707

EP - 717

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 6

ER -