EXPEDITE: A Study of Remodulin Induction Followed by Orenitram Optimization to Treat Pulmonary Arterial Hypertension
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: Intravenous/Subcutaneous Treprostinil; Oral Treprostinil
Intervention description: Short-term course of IV or SC treprostinil continuous infusion followed by transition to oral treprostinil extended-release (XR) tablets taken 3 times daily (TID)
Intervention MeSH terms: Treprostinil
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 36.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Pulmonary hypertension; Treprostinil; Pulmonary arterial hypertension; Remodulin; Orenitram

Summary:

      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).
    

Eligibility criteria:

        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.