A Dose Response Study of UT-15C SR in Patients With Exercise-Induced Pulmonary Hypertension

Study Overview
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Brief Summary
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This is a prospective, randomized, parallel group study to assess the hemodynamic effect of three different dose regimens of a sustained release (SR) tablet of UT-15C in patients with exercise-induced pulmonary hypertension (PH), as measured by the change in peak total pulmonary resistance index (TPRI) during exercise from Baseline to Week 12.

Detailed Description
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Prospective, randomized, parallel group study with two periods: a 10 week, dose titration period, followed by a 2 week, dose maintenance period in patients with exercise-induced PH. The study population will be randomized into Dose Group 1, Dose Group 2, or an Individual Maximum Tolerated Dose (iMTD) of UT-15C SR by Week 10 and maintained through Week 12. Patients may be either currently receiving an approved oral background therapy for their PH (phosphodiesterase-5 [PDE-5] inhibitor, OR endothelin receptor antagonist [ERA]) (no dual background therapy), or not currently receiving therapy for PH.

Official Title
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A 12-Week, Randomized, Dose Response Study of UT-15C (Treprostinil Diethanolamine) SR in Patients With Exercise-Induced Pulmonary Hypertension

Conditions
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Pulmonary Hypertension

Intervention / Treatment
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* Drug: UT-15C


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria- A subject was eligible for inclusion in this study if all of the following criteria applied: Was between the ages of 18 and 75 years of age at Screening Weighed a minimum of 40 kilograms with a body mass index less than 40 kg/m2 at Screening Agreed to have right heart catheterization with exercise performed at Baseline and Week 12, or at the time of early discontinuation of study drug Had exercise-induced PH at Baseline (defined as a PAPm ≥ 30 mmHg during exercise). Note: eligible subjects may or may not have had a PAPm ≥ 25 mmHg at rest Exercise-induced PH may have been: Idiopathic, heritable, drug- or toxin-induced PAH, or PAH associated with connective tissue diseases or HIV infection Due to ILD Due to sarcoidosis Had a Baseline pulmonary function tests as follows: Forced vital capacity (FVC) ≥ 50% (predicted) If FVC <50% (predicted), total lung capacity (TLC) must be ≥ 50% (predicted) Forced expiratory volume / forced vital capacity (FEV / FVC) ratio ≥ 50% Had a Baseline 6MWD between 150 and 450 meters, inclusive Was 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 Baseline (excluding anticoagulants). Oral diuretics may have been adjusted, but not discontinued or added, within 14 days of Baseline May or may not have been receiving an approved PDE-5 inhibitor OR an approved ERA. Subjects receiving an approved ERA or an approved PDE-5 inhibitor must have been on a stable dose for 30 days prior to Baseline, and were willing to remain on a PDE-5 inhibitor or an ERA and at the same dose for the duration of the 12-week Treatment Phase. If a subject chose to discontinue their PDE-5 or ERA prior to entering this study, they must have had a ≥30 day washout period between the last dose of the PDE-5 or ERA and start of the screening phase. If female, was physiologically incapable of childbearing or practicing an acceptable method of birth control as deemed appropriate by the physician or institution. Women of childbearing potential had a negative serum pregnancy test at Screening Was able to communicate effectively with study personnel, and considered reliable, willing and likely to be cooperative with protocol requirements, including attending all study visits, in the opinion of the Principal Investigator Voluntarily gave informed consent to participate in the study. Exclusion Criteria- A subject was not eligible for inclusion in this study if any of the following criteria applied: Had received epoprostenol, treprostinil, iloprost, beraprost, or any other prostacyclin therapy within 30 days of Baseline (except if used during acute vasoreactivity testing) Had previous intolerance or significant lack of efficacy to an oral or parenteral prostacyclin or prostacyclin analogue that resulted in discontinuation or inability to effectively titrate that therapy Had a concurrent injury, illness (other than PH or a PH related condition), or other confounding factor that would prevent the accurate assessment of the subject's exercise capacity Had a musculoskeletal disorder (e.g. recent hip replacement, artificial leg, etc.) or any other disease that was likely to limit ambulation, or was connected to a machine that was not portable Had portal hypertension Had congenital heart disease (repaired or unrepaired) Had a history or current evidence of left-sided heart disease including myocardial infarction in the previous 3 years or mitral valve stenosis, or evidence of current left-sided heart disease as defined by mean resting pulmonary capillary wedge pressure (PCWPm) or left ventricular end diastolic pressure (LVEDP) > 15 mmHg or left ventricular ejection fraction (LVEF) < 45% (as assessed by either multigated acquisition [MUGA] scan, angiography or echocardiography), or symptomatic coronary artery disease (i.e., demonstrable ischemia either at rest or during exercise) Had acute pulmonary embolism (less than 6 months), chronic thromboembolic disease, pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis Had an atrial septostomy Had a current diagnosis of uncontrolled sleep disordered breathing Had PH associated with: chronic obstructive lung disease (COPD), cystic fibrosis, emphysema, alveolar hypoventilation disorders, chronic exposure to high altitude, developmental abnormalities, schistosomiasis, or chronic hemolytic anemia hematologic disorders (myeloproliferative disorders, splenectomy) metabolic disorders (glycogen storage disease, Gaucher disease, thyroid disorders pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis tumoral obstruction, fibrosing mediastinitis, or extensive loss of lung tissue from surgery or trauma Had chronic renal insufficiency as defined by either a Screening creatinine value greater than 2.5 mg/dL (221 μmol/L) or the requirement for dialysis. Had liver function tests (AST or ALT) greater than three times the upper limit of normal at Screening. Had anemia as defined by a Screening hemoglobin value of less than 10 g/dL, active infection, or any other condition that would interfere with the interpretation of study assessments. Had uncontrolled systemic hypertension as evidenced by systolic blood pressure greater than 160 mmHg or diastolic blood pressure greater than 100 mmHg. Was pregnant or nursing. Had an unstable psychiatric condition or was mentally incapable of understanding the objectives, nature, or consequences of the trial, or had any condition which in the Investigator's opinion would constitute an unacceptable risk to the subject's safety. Was receiving an investigational drug, had an investigational device in place or had participated in an investigational drug or device study within 30 days prior to Screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dose Group 1<br>UT-15C 0.25 mg twice daily | Drug: UT-15C<br>* oral<br>* Other names: treprostinil diethanolamine, sustained release;|
| Active Comparator: Dose Group 2<br>UT-15C 1.25 mg twice daily | Drug: UT-15C<br>* oral<br>* Other names: treprostinil diethanolamine, sustained release;|
| Active Comparator: Dose Group 3<br>UT-15C individual Maximum Tolerated Dose | Drug: UT-15C<br>* oral<br>* Other names: treprostinil diethanolamine, sustained release;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Peak Total Pulmonary Resistance Index (TPRI) During Exercise From Baseline to Week 12 | The effects of 12-week treatment with different doses of UT-15C on peak TPRI during exercise will be evaluated by comparing the change from Baseline to Week 12 at peak wattage on a pairwise basis between treatment groups. The primary measure of efficacy was the change from Baseline to Week 12 in peak TPRI during exercise assessed 3 to 6 hours after the subject's morning dose of UT-15C to obtain measurements at peak concentrations of treprostinil. The equation used to determine the Total Pulmonary Resistance Index (TPRI) (mmHg/[L/min/m^2]) is Mean Pulmonary Artery Pressure (PAPm)/ Cardiac Index (CI). | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Pulmonary Artery Pressure (PAPm) From Baseline to Week 12 | Pulmonary hypertension (PH) is an increase in pressure in the pulmonary vasculature defined as a mean pulmonary artery pressure (PAPm) greater than 25 mmHg at rest or greater than 30 mmHg with exercise, as measured by right heart catheterization. The PAPm values and their respective changes from Baseline to Week 12 at peak exercise will be summarized by treatment group and measured by Swan-Ganz right heart catheterization. | Baseline and Week 12 | 
| Change in Cardiac Index (CI) From Baseline to Week 12 | Cardiac Index (CI) relates the cardiac output (CO) from left ventricle to body surface area (BSA), thus relating heart performance to the size of the individual. The CI values and their respective changes from Baseline to Week 12 at peak exercise will be summarized by treatment group and measured by Swan-Ganz right heart catheterization. | Baseline and Week 12 | 
| Change in 6-minute Walk Distance (6MWD) From Baseline to Week 12 | The intent of the 6MWD test is to evaluate exercise capacity associated with carrying out activities of daily living. Change in 6MWD from Baseline to Week 12, correlates with the current clinical standard for assessing patient functional status in the treatment of PH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS). Subjects were instructed to walk down a corridor at a comfortable speed as far as they could manage for six minutes. Distance <500 meters suggests considerable exercise limitation; Distance 500-800 meters suggests moderate limitation; Distance >800 meters (with no rests) suggests mild or no limitation. | Baseline and Week 12 | 
| Change in Borg Dyspnea Score (Following 6MWT) From Baseline to Week 12 | The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea (difficulty in breathing) experienced during the six-minute walk test (6MWT). The Borg dyspnea score was assessed immediately following the 6MWT. Scores ranged from 0 (for no shortness of breath) to 10 (for the greatest shortness of breath ever experienced). | Baseline and Week 12 | 
| Change in PH Symptoms From Baseline to Week 12 | Symptoms of PH including fatigue, dyspnea, edema, dizziness, syncope, chest pain and orthopnea were assessed and severity grade values (i.e., 0, 1, 2 or 3) for each symptom were assigned for subjects. A severity of 0 indicated no symptoms, the maximum severity was 3, indicating severe symptoms. Median change in symptom severity from Baseline to Week 12 is described. | Change from Baseline at 12 Weeks | 
| Number of Participants With a Change From Baseline World Health Organization (WHO) Functional Classification at Week 12 | The WHO Functional Class of pulmonary hypertension is a physical activity rating scale as follows: Class I: No limitation of physical activity. Class II: Slight limitation of physical activity. Class III: Marked limitation of physical activity. Class IV: Inability to carry out any physical activity without symptoms. Only participants who experienced a change in WHO functional classification from Baseline to Week 12 are described by class change below; all other participants maintained their Baseline WHO functional classification at Week 12. | Change from Baseline at Week 12 | 
| Change in N-terminal Pro-B-type Natriuretic Peptide (NT-proBNP) Concentrations From Baseline to Week 12 | The N-terminal pro-BNP (NT-proBNP) serum concentration was assessed to compare the severity of heart failure at Baseline and Week 12. | Baseline and Week 12 |