Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: Remodulin
Intervention description: Treatment will be initiated whilst hospitalized at approximately 2.0 ng/kg/min with dose increments of 1- 2 ng/kg/min approximately every 12 hours according to clinical response and tolerability. Following subject discharge, the dose rate is increased by 1-2 ng/kg/min with dose increments separated by at least 24 hours. When a dose rate of 20 ng/kg/min is achieved dose increments can be increased at a rate of up to 4 ng/kg/min with dose increments separated by at least 24 hours depending on tolerability. The aim is to achieve a dose rate of at least 10, 20 and 30 ng/kg/min by the end of weeks 1, 4 and 12, respectively and a dose rate by the end of week 16 that achieves pre-defined treatment goals subject to clinical response and tolerability.
Intervention MeSH terms: Treprostinil
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 39.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The purpose of the study is to evaluate the safety and tolerability of a rapid dose titration
      regimen of subcutaneous Remodulin® therapy in patients with PAH.
    

Eligibility criteria:

        Inclusion Criteria:

          1. The subject is at least 18 years of age at screening.

          2. The subject weigh a minimum of 40 kg with a body mass index less than 40 kg/m^2 at
             screening.

          3. Sexually active women of childbearing potential must use two different forms of highly
             effective contraception. Males participating in the study must use a condom during the
             length of the study, and for at least 64 days after discontinuing study drug.

          4. The subject has a diagnosis of symptomatic idiopathic or heritable PAH (IPAH or HPAH).

          5. A Baseline 6MWD between 150 and 550 metres is required, in the absence of a concurrent
             injury, illness (other than PAH or a PAH related condition), or other confounding
             factors that would effect the subject's exercise capacity.

          6. The subject is either treatment naïve or receiving an approved PDE-5 inhibitor and /
             or an approved ERA for at least 60 days prior to screening and is on a stable dose for
             30 days and is willing to remain on a PDE-5 inhibitor and / or an ERA at the same dose
             for the duration of the 16-week treatment phase.

          7. The subject must be optimally treated with conventional pulmonary hypertension therapy
             (e.g., oral vasodilators, oxygen, digoxin, etc.) with no additions, discontinuations,
             or dose changes for at least 14 days prior to screening (excluding diuretics and
             anticoagulant dose adjustments).

          8. The subject has undergone right heart catheterisation at screening (or within 8 weeks
             before screening) and has been documented to have a mean pulmonary artery pressure
             (PAPm) of greater than or equal to 25 mmHg, a pulmonary capillary wedge pressure
             (PCWP) of less than or equal to 15 mmHg, and pulmonary vascular resistance (PVR) of
             more than 3 Wood units.

          9. The subject has undergone echocardiography at screening with evidence of clinically
             normal left systolic and diastolic ventricular function, absence of any clinically
             significant left sided heart disease (e.g., mitral valve stenosis) and absence of
             unrepaired congenital heart disease.

         10. The subject has a previous ventilation perfusion lung scan and / or high resolution
             computerised tomography scan of the chest and / or pulmonary angiography that is
             consistent with the diagnosis of PAH (e.g., low probability of pulmonary embolism;
             absence of major perfusion defects).

         11. The subject has pulmonary function tests done within 9 months of screening with the
             following:

               -  Total lung capacity (TLC) was at least 60% (of predicted value)

               -  Forced expiratory volume in one second/forced vital capacity (FEV1/FVC) ratio is
                  at least 50%

         12. In the opinion of the Principal Investigator, the subject is able to communicate
             effectively with study personnel, was considered reliable, willing and likely to be
             cooperative with protocol requirements.

         13. The subject voluntarily gives written informed consent to participate in the study.

        Exclusion Criteria:

          1. The subject is pregnant or lactating.

          2. The subject has received epoprostenol, treprostinil, intravenous iloprost, or
             beraprost within 30 days prior to screening (except if used during acute
             vasoreactivity testing).

          3. The subject has had previous intolerance or significant lack of efficacy to
             prostacyclin or a prostacyclin analogue that resulted in discontinuation or inability
             to titrate that therapy effectively.

          4. The subject has any disease associated with PH other than idiopathic PAH or heritable
             PAH or had had an atrial septostomy.

          5. The subject is in WHO functional class IV.

          6. The subject has a current diagnosis of uncontrolled sleep apnoea as defined by their
             physician.

          7. The subject has liver function tests (aspartate transaminase (AST) or alanine
             transaminase (ALT)) greater than three times the upper limit of the laboratory
             reference range and / or an international normalised ratio (INR) greater than 3 units
             at screening.

          8. The subject has a history of active gastro-intestinal ulcer, intracranial haemorrhage,
             injury or other cause of clinically significant bleeding episode within 6 months
             before screening, or has any other disease / condition that would either jeopardise
             the safety of the subject and / or interfere with the interpretation of study
             assessments in the opinion of the Investigator.

          9. The subject has a history of ischemic heart disease including previous myocardial
             infarction or symptomatic coronary artery disease within 6 months of screening, or
             history of left sided myocardial disease as evidenced by a PCWP (or Left Ventricular
             End-Diastolic Pressure (LVEDP)) greater than 15 mmHg or left ventricular ejection
             fraction (LVEF) less than 40%.

         10. The subject has uncontrolled systemic hypertension as evidenced by systolic blood
             pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg.

         11. The subject has a musculoskeletal disorder (e.g., arthritis affecting the lower limbs,
             recent hip or knee joint replacement, artificial leg) or any other disease that is
             likely to limit ambulation, or is connected to a machine that is not portable.

         12. The subject has an unstable psychiatric condition or is mentally incapable of
             understanding the objectives, nature, or consequences of the trial.

         13. The subject is receiving an investigational drug, has an investigational device in
             place or has participated in an investigational drug or device study within 30 days
             prior to screening.