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

This is an interventional treatment trial for Pulmonary Arterial Hypertension focused on measuring Pulmonary hypertension, Treprostinil, Pulmonary arterial hypertension, Remodulin, Orenitram Read More

Inclusion Criteria:

1. Subjects who voluntary give written informed consent to participate in study
2. Males and female subjects aged 18 to 75 years at Screening (date the subject provides written informed consent to participate in study)
3. Subjects with a diagnosis of WHO Group 1 pulmonary hypertension: 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 FC II or III symptoms at Baseline
5. Subjects with 6MWD >250 meters at Baseline
6. Subjects who are either not receiving PAH-targeted therapy or are 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 should be on stable doses of other medical therapies for at least 10 days prior to the Baseline Visit, with no dose adjustments, additions, or discontinuations. Exceptions to this are discontinuation or dose changes of anticoagulants and/or diuretics. Subjects should not have experienced recent changes to non-pharmacologic interventions, such as exercise, diet plans, pulmonary rehabilitation, sleep apnea treatment, etc for at least 10 days prior to Baseline Visit.
8. Subjects with historical right-heart catheterization (RHC) with results consistent with WHO Group 1 PAH, as demonstrated by pulmonary artery pressure mean of ≥25 mmHg, a pulmonary artery wedge pressure (PAWP) or left ventricular end-diastolic pressure ≤15 mmHg if a PAWP measurement is not available, and a PVR >3 Wood units, in the absence of unrepaired congenital heart disease (other than patent foramen ovale)
9. Subject has undergone a RHC within 180 days of Baseline and had a cardiac index ≥2.0 L/min/m^2 with no changes in their PAH medication regimen (ie, both dosing and drug) since the RHC.
10. Subjects in whom their most recent historical echocardiography demonstrates clinically normal left systolic and diastolic ventricular function and absence of any clinically significant left-sided heart disease. Subjects with clinically insignificant left ventricular diastolic dysfunction due to the effects of right ventricle (RV) overload (RV hypertrophy and/or RV dilation) are eligible.

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

    • Subjects who are females of childbearing potential include any female subject who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea for at least 12 consecutive months). For female subjects of childbearing potential, a negative urine pregnancy test is required at Screening and Baseline prior to initiating study drug. Female subjects of childbearing potential must follow 1 of the following approaches:

      • Practice actual abstinence from intercourse
      • Have a partner with a vasectomy
      • Have an intrauterine device
      • Must use 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 include approved hormonal contraceptives (such as birth control pills) or barrier methods (such as a condom or diaphragm).
    • Male subjects with a partner of childbearing potential must use a condom during intercourse for the duration of the study, and for 48 hours after discontinuing study drug.
12. Human immunodeficiency virus-positive subjects must have a CD4 lymphocyte count of at least 200 cells/mm^3 within 30 days of Screening and be 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, are capable of communicating effectively with study personnel and are considered reliable, willing, and likely to be cooperative with protocol requirements and attend all required study visits
14. Subjects who have the capability to answer surveys and questionnaires written in English

Exclusion Criteria:

1. Female subjects who are 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 would interfere with interpretation of study assessments
7. Subjects with a history of ischemic heart disease (defined as subjects who require anti-anginal therapy within 6 months of Screening or who have 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 left ventricular 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 has been 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 would limit ambulation, or who are connected to a machine that is 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, would make 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, would constitute an unacceptable risk to the subject's safety
15. Subjects who are currently receiving an investigational drug, have an investigational device in place, or who have 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 does not disqualify a subject from enrolling.
16. Subjects who have received a prostacyclin-class therapy within 28 days of Baseline.
17. Subjects who have a Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0 Risk Score of 10 or greater.