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Study OverviewFREEDOM-EV TRIAL—designed with a composite primary endpoint to assess the effect of Orenitram on time to first clinical worsening event1,2

FREEDOM-EV was an international, multicenter, randomized, double-blind, placebo-controlled, event-driven study1,2

Freedom EV PAH sequential combination therapy trail
  • Patients received Orenitram or placebo starting at 0.125 mg TID and titrated to a maximum dose of 12 mg TID1
  • Randomization was stratified by type of background therapy and baseline 6MWD2

Primary Endpoint

Clinical Assessments Summary

Time to First Adjudicated Clinical Worsening Event2:

or
Unsatisfactory long-term clinical response*
or
Disease progression†
or
Initiation of inhaled/infused prostacyclin
or
Hospitalization due to worsening PAH
Death (all causes)

Selected Secondary Endpoints

Change from baseline measured at week 242:

  • Exercise capacity as assessed by 6MWD
  • Right ventricle dysfunction as indicated by NT-proBNP
  • Symptom improvement as indicated by WHO FC

Vital Status Substudy

  • Patients who participated in FREEDOM-EV and agreed to be followed were a part of the vital status substudy2‡
  • Decrease in 6MWD at week 24 and beyond, and sustained WHO FC III/IV symptoms for ≥24 weeks, consecutively.2
  • Defined as a ≥15% decrease in 6MWD and increase in WHO FC, or a ≥15% decrease in 6MWD and appearance or worsening of symptoms of right heart failure.2
  • The initial data collection plan stopped following participants 30 days after discontinuing randomized treatment unless they consented to participate in an open-label follow-up study. An amended protocol later included a vital status substudy; vital status was assessed every 6 months for consenting participants until closure of the randomized study in October 2018.2

The FREEDOM-EV study population was relatively young and recently diagnosed, with the majority of patients at FC II1,2

Patient Profile in FREEDOM-EV1,2
Patient profile in FREEDOM-EV PAH study
  • Patients in FREEDOM-EV included 3% FC I, 63% FC II, 34% FC III, and 0.1% FC IV.2

The majority of patients had idiopathic or heritable PAH (63%)1,2

  • 26% had PAH associated with connective tissue disease
  • 7% had PAH associated with a congenital heart defect
  • 1% had PAH associated with HIV infection
  • 3% had PAH from other causes

Important Safety Information

Contraindications

  • Avoid use of Orenitram in patients with severe hepatic impairment (Child Pugh Class C) due to increases in systemic exposure.

Warnings and Precautions

  • Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms.
  • The Orenitram tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum.

Adverse Reactions

  • In the 12-week, placebo-controlled, monotherapy study, and an event-driven, placebo-controlled, combination therapy study, adverse reactions that occurred at rates at least 5% higher on Orenitram than on placebo included headache, diarrhea, nausea, vomiting, flushing, pain in jaw, pain in extremity, hypokalemia, abdominal discomfort, and upper abdominal pain.

Drug Interactions

  • Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil increases exposure to treprostinil; therefore, Orenitram dosage reduction may be necessary in these patients.

Specific Populations

  • Animal reproductive studies with Orenitram have shown an adverse effect on the fetus. There are no adequate and well-controlled studies with Orenitram in pregnant women.
  • It is not known whether treprostinil is excreted in human milk or if it affects the breastfed infant or milk production.
  • Safety and effectiveness of Orenitram in pediatric patients have not been established.
  • Use of Orenitram in patients aged 65 years and over demonstrated slightly higher absolute and relative adverse event rates compared to younger patients. Caution should be used when selecting a dose for geriatric patients.
  • There is a marked increase in the systemic exposure to treprostinil in hepatically impaired patients.

Indication

Orenitram is a prostacyclin mimetic indicated for treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to delay disease progression and to improve exercise capacity. The studies that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (66%) or PAH associated with connective tissue disease (26%).

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Please see Full Prescribing Information and Patient Information for Orenitram.

For additional information, call 1-877-UNITHER (1-877-864-8437).

6MWD=6-minute walk distance; ERA=endothelin receptor antagonist; FC=functional class; HIV=human immunodeficiency virus; NT-proBNP=N-terminal pro–B-type natriuretic peptide; OLE=open-label extension; PAH=pulmonary arterial hypertension; PDE-5i=phosphodiesterase type 5 inhibitor; sGCS=soluble guanylate cyclase stimulator; TID=3 times daily; WHO=World Health Organization.

References: 1. Orenitram [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2019. 2. Data on file. United Therapeutics Corporation. Research Triangle Park, NC.