EXPEDITE: A Study of Remodulin Induction Followed by Orenitram Optimization to Treat Pulmonary Arterial Hypertension

EXPEDITE: A 16-Week, Multicenter, Open-label Study of Remodulin Induction Followed by Orenitram Optimization in Subjects With Pulmonary Arterial Hypertension

This was a multicenter, open-label study to evaluate the dose of Orenitram® (treprostinil) Extended Release Tablets achieved at 16 weeks after a short-term course of Remodulin® (treprostinil) Injection in subjects with pulmonary arterial hypertension (PAH).

Subjects were initiated on subcutaneous (SC) or intravenous (IV) treprostinil and titrated to a dose that improved the symptoms of PAH while minimizing excessive pharmacologic effects. After achieving a minimum SC/IV treprostinil dose of 20 ng/kg/min, subjects began a transition to oral treprostinil at the Transition Visit, which occurred at the Week 2, 4, or 8 study visit. After the Transition Visit, oral treprostinil titration continued through Week 16 to reach the maximum tolerated dose (MTD).

Inclusion Criteria:

1. Subjects who voluntary gave written informed consent to participate in study.

2. Males and female subjects aged 18 to 75 years at Screening (date the subject provided written informed consent to participate in study).

3. Subjects with a diagnosis of World Health Organization (WHO) Group 1 pulmonary hypertension (PH): symptomatic idiopathic or heritable PAH; or PAH associated with connective tissue disease, human immunodeficiency virus (HIV) infection, repaired congenital systemic-to-pulmonary shunt (at least 1 year since repair with respect to the date of providing informed consent), or appetite suppressant/toxin use.

4. Subjects with WHO functional class (FC) II or III symptoms at Baseline.

5. Subjects with 6MWD >250 m at Baseline.

6. Subjects who were either not receiving PAH-targeted therapy or were currently being treated with 1 or 2 oral FDA-approved PAH therapies consisting of an endothelin receptor antagonist (ERA) and/or either a phosphodiesterase type-5 inhibitor (PDE5-I) or a soluble guanylate cyclase (sGC) stimulator for ≥45 days, and on a stable dose for ≥30 days prior to the Baseline Visit.

7. Subjects on stable doses of other medical therapies for at least 10 days prior to the Baseline Visit, with no dose adjustments, additions, or discontinuations, with the exception of discontinuation or dose changes of anticoagulants and/or diuretics. Subjects could not have recent changes to non-pharmacologic interventions, such as exercise, diet plans, pulmonary rehabilitation, or sleep apnea treatment, for at least 10 days prior to Baseline Visit.

8. Subjects with historical right heart catheterization (RHC) results consistent with WHO Group 1 PH, as demonstrated by pulmonary artery pressure mean of ≥25 mmHg, a pulmonary artery wedge pressure (PAWP) or left ventricular (LV) end-diastolic pressure ≤15 mmHg (if a PAWP measurement was not available) and a pulmonary vascular resistance (PVR) >3 Wood units, in the absence of unrepaired congenital heart disease (other than patent foramen ovale).

9. Subject underwent an RHC within 180 days of Baseline and had a cardiac index ≥2.0 L/min/m² with no changes in their PAH medication regimen (ie, both dosing and drug) since the RHC.

10. Subjects with most recent historical echocardiogram (ECHO) demonstrating clinically normal left systolic and diastolic ventricular function and absence of any clinically significant left-sided heart disease. Subjects with clinically insignificant LV diastolic dysfunction due to the effects of right ventricular (RV) overload (RV hypertrophy and/or RV dilation) were eligible.

11. Subjects who agreed to follow the specified precautions to avoid pregnancy as follows:

    1. For female subjects of childbearing potential, a negative urine pregnancy test was required at Screening and Baseline prior to initiating study drug. Female subjects of childbearing potential must have followed 1 of the following approaches: i. practice actual abstinence from intercourse, ii. had a partner with a vasectomy, iii. had an intrauterine device, or iv. must have used 2 different forms of highly effective contraception for the duration of the study, and for at least 48 hours after discontinuing study drug. Medically acceptable forms of effective contraception included approved hormonal contraceptives (such as birth control pills) or barrier methods (such as a condom or diaphragm).
    2. Male subjects with a partner of childbearing potential must have used a condom during intercourse for the duration of the study, and for 48 hours after discontinuing study drug.

12. HIV-positive subjects must have had a CD4 lymphocyte count of at least 200 cells/mm^3 within 30 days of Screening and been receiving current standard-of-care anti-retroviral or other effective medication for the treatment of HIV, with no changes for at least 8 weeks prior to enrollment.

13. Subjects who, in the opinion of the Investigator, were capable of communicating effectively with study personnel and were considered reliable, willing, and likely to be cooperative with protocol requirements and attend all required study visits.

14. Subjects who had the capability to answer surveys and questionnaires written in English.

Exclusion Criteria:

1. Female subjects who were pregnant, lactating, or planning to become pregnant during the study.
2. Subjects with a current diagnosis of uncontrolled sleep apnea, as defined by their physician.
3. Subjects with renal insufficiency, as defined by requiring dialysis or an estimated creatinine clearance of <30 mL/min, as calculated by the Cockcroft-Gault equation.
4. Subjects with liver dysfunction defined as elevated liver function tests (alanine aminotransferase or aspartate aminotransferase) ≥3 times the upper limit of normal at Screening, or subjects with Child-Pugh Class B or C hepatic disease.
5. Subjects with anemia, as defined by Screening hemoglobin <9 g/dL.
6. Subjects with an active infection or condition that interfered with interpretation of study assessments.
7. Subjects with a history of ischemic heart disease (defined as subjects who required anti-anginal therapy within 6 months of Screening or who had experienced a documented myocardial infarction within 6 months of Screening) or a history of left-sided myocardial dysfunction, as evidenced by a PAWP >15 mmHg or LV ejection fraction <50%.
8. Subjects with uncontrolled systemic hypertension, as evidenced by systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at Baseline.
9. Subjects with severe hypotension, as evidenced by systolic blood pressure <90 mmHg or diastolic blood pressure <50 mmHg at Baseline.
10. If a lung assessment was completed as per standard of care, any subject with 1 or more of the following signs of documented relevant lung disease within 180 days of Baseline: total lung capacity <60% of predicted or forced expiratory volume in 1 second <55% of predicted normal.
11. Subjects with chronic musculoskeletal disorder or any other disease that limited ambulation, or who were connected to a machine that was not portable.
12. Subjects with a history of alcohol abuse or illicit drug abuse within 12 months of Baseline which, in the Investigator's opinion, made the subject inappropriate for enrollment in a clinical study.
13. Subjects with any other concomitant disease with life expectancy of <12 months from Baseline.
14. Subjects with an unstable psychiatric condition or those not capable of understanding the objectives, nature, or consequences of the study, or who have any condition which, in the Investigator's opinion, constituted an unacceptable risk to the subject's safety.
15. Subjects who were currently receiving an investigational drug, had an investigational device in place, or who had participated in an investigational drug or device study within 180 days prior to Baseline. Participation in an observational study within 180 days prior to Baseline did not disqualify a subject from enrolling.
16. Subjects who had received a prostacyclin-class therapy within 28 days of Baseline.
17. Subjects who had a Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 Risk Score of ≥10.