Phase III Clinical Worsening Study of UT-15C in Subjects With PAH Receiving Background Oral Monotherapy
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: Treprostinil Diolamine; Placebo
Intervention description: Active; Placebo
Intervention MeSH terms: Treprostinil
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 690.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Pulmonary arterial hypertension (PAH); Pulmonary hypertension (PH); Clinical Worsening; Freedom; Freedom-EV; Treprostinil; UT-15C; 6 Minute walk test

Summary:

      This is an international, multicenter, randomized, double-blind, placebo-controlled, event
      driven study in subjects with pulmonary arterial hypertension.
    

Eligibility criteria:

        Subject Inclusion Criteria:

          1. Voluntarily gave informed consent to participate in the study.

          2. Are 18 to 75 years of age (inclusive) at Screening.

          3. Women of childbearing potential must practice abstinence from intercourse when in line
             with their preferred and usual lifestyle, or use 2 different forms of highly effective
             contraception for the duration of the study, and for at least 30 days after
             discontinuing study medication. A negative urine pregnancy test is required at
             Screening and Baseline prior to initiating study medication.

          4. Male subjects must consent to use a condom during intercourse for the duration of the
             study, and for at least 48 hours after discontinuing study medication.

          5. Have a diagnosis of symptomatic idiopathic or heritable PAH, PAH associated with
             connective tissue disease (CTD), PAH associated with HIV infection, PAH associated
             with repaired congenital systemic-to-pulmonary shunt, or PAH associated with appetite
             suppressant or toxin use.

          6. If known to be positive for HIV infection, have a CD4 lymphocyte count of at least 200
             cells/mm^3 assessed at Screening and are receiving current standard of care anti
             retroviral or other effective medication for the treatment of HIV infection.

          7. Have a baseline 6MWD greater than or equal to 150 m in the absence of a concurrent
             injury, illness, or other confounding factor including, but not limited to, use of an
             aid for ambulation or connection to a nonportable machine, that would have prevented
             the accurate assessment of the subject's exercise capacity.

          8. Are optimally treated with conventional pulmonary hypertension therapy with no
             additions, discontinuations, or dose changes for a minimum of 10 days prior to
             randomization. The exceptions are the discontinuation or dose changes of
             anticoagulants and/or dose change of diuretics.

          9. Are receiving a PAH-approved oral monotherapy at a minimum dose that complies with the
             approved prescribing information for the product for at least 30 days prior to
             randomization and are receiving a stable dose for at least 10 days prior to
             randomization.

         10. Have had previously undergone a cardiac catheterization within 3 years prior to the
             start of Screening or during the Screening Period, and the most recent assessment
             documented a pulmonary artery pressure mean of at least 25 mmHg, a pulmonary capillary
             wedge pressure (PCWP) (or in the event a PCWP could not be reliably obtained, a left
             ventricular end diastolic pressure [LVEDP]) less than or equal to 15 mmHg, and absence
             of unrepaired congenital heart disease (other than patent foramen ovale). If a
             reliable PCWP or LVEDP are unable to be obtained during cardiac catheterization,
             subjects with clinically normal left heart function and absence of clinically relevant
             mitral valve disease on echocardiography are eligible for enrollment.

         11. Undergo echocardiography with evidence of clinically normal systolic and diastolic
             left ventricular function and absence of any clinically significant left sided heart
             disease (eg, mitral valve disease). Subjects with clinically insignificant left
             ventricular diastolic dysfunction due to the effects of right ventricular overload
             (ie, right ventricular hypertrophy and/or dilatation) are eligible.

         12. Have a previous ventilation perfusion lung scan, high-resolution computerized
             tomography scan of the chest, and/or pulmonary angiography that are consistent with
             the diagnosis of PAH.

         13. Have pulmonary function tests conducted within 6 months before Screening or during the
             Screening Period to confirm the following:

               1. Total lung capacity is at least 60%

               2. Forced expiratory volume at 1 second is at least 50%

         14. In the opinion of the Principal Investigator, is able to communicate effectively with
             study personnel and is considered reliable, willing, and likely to cooperate with
             protocol requirements, including attending all study visits.

        Subject Exclusion Criteria:

          1. Is pregnant or lactating.

          2. Have previously received oral treprostinil.

          3. Have received a PGI2 (except if used during acute vasoreactivity testing) within 30
             days prior to randomization or have previous intolerance or significant lack of
             efficacy to any PGI2 or PGI2 analogue that resulted in discontinuation or inability to
             titrate that therapy effectively.

          4. Have any background conventional therapies for PAH added, removed, or dose-adjusted
             within 10 days prior to randomization. The exceptions are removal or dose adjustments
             of anticoagulants and/or dose adjustments of diuretics.

          5. Receive their first dose of a PAH-approved oral monotherapy less than 30 days prior to
             randomization, or have their PAH-approved oral monotherapy dose changed within 10 days
             prior to randomization, or the subject discontinues any PAH approved therapy within 30
             days prior to Screening, or the subject has previously received 2 PAH approved oral
             therapies at the same time (specifically, a PDE5-I, an ERA, or a sGC stimulator)
             concomitantly for more than 90 days cumulatively.

          6. Have any disease associated with PAH other than CTD, HIV infection, repaired (for at
             least 1 year) congenital systemic-to-pulmonary shunt, PAH associated with appetite
             suppressant/toxin use, or have an atrial septostomy.

          7. Have a current diagnosis of uncontrolled sleep apnea as defined by their physician.

          8. Have a history of ischemic heart disease, including a previous myocardial infarction
             or symptomatic coronary artery disease within 6 months prior to Screening or a history
             of left-sided myocardial disease as evidenced by a mean PCWP (or a LVEDP) greater than
             15 mmHg or left ventricular ejection fraction less than 40% as assessed by either
             multigated angiogram, angiography, or echocardiography.

          9. Have uncontrolled systemic hypertension as evidenced by systolic blood pressure (BP)
             greater than 160 mmHg or diastolic BP greater than 100 mmHg.

         10. Have alanine aminotransferase or aspartate aminotransferase levels at least 3 times
             greater than the upper limit of normal, clinically significant liver
             disease/dysfunction, or known Child-Pugh Class C hepatic disease at Screening.

         11. Have any other disease or condition that would interfere with the interpretation of
             study assessments.

         12. Have a musculoskeletal disorder, is using a device to assist walking, or any disease
             that is likely to limit ambulation, or is connected to a machine that is nonportable.

         13. Have an unstable psychiatric condition or is mentally incapable of understanding the
             objectives, nature, or consequences of the study, or has any condition which in the
             Investigator's opinion would constitute an unacceptable risk to the subject's safety.

         14. Is receiving an investigational drug, have an investigational device in place, or have
             participated in an investigational drug or device study within 30 days prior to
             Screening.

         15. Have chronic renal insufficiency as defined by either a Screening creatinine value
             greater than 2.5 mg/dL or the requirement for dialysis.

         16. Does not have 3 or more of the following left ventricular disease/dysfunction risk
             factors:

               1. Body mass index at least 30 kg/m^2

               2. History of essential hypertension

               3. Diabetes mellitus (any type)

               4. Historical evidence of significant coronary artery disease established by any 1
                  of the following: history of myocardial infarction, percutaneous coronary
                  intervention, or angiographic evidence of coronary artery disease; positive
                  stress test with imaging; previous coronary artery bypass graft; or stable
                  angina.