Clinical trial NCT03497689: EXPEDITE: A Study of Remodulin Induction Followed by Orenitram Optimization to Treat Pulmonary Arterial Hypertension
Official title: EXPEDITE: A 16-Week, Multicenter, Open-label Study of Remodulin Induction Followed by Orenitram Optimization in Subjects With Pulmonary Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary hypertension
Treprostinil
Pulmonary arterial hypertension
Remodulin
Orenitram
Lead sponsor: United Therapeutics
Sponsor class: INDUSTRY
First posted: 2018-04-13
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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).

Detailed description: Subjects were initiated on subcutaneous (SC) or intravenous (IV) treprostinil and titrated to a dose that improved the symptoms of PAH while minimizing excessive pharmacologic effects. After achieving a minimum SC/IV treprostinil dose of 20 ng/kg/min, subjects began a transition to oral treprostinil at the Transition Visit, which occurred at the Week 2, 4, or 8 study visit. After the Transition Visit, oral treprostinil titration continued through Week 16 to reach the maximum tolerated dose (MTD).

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.

Primary outcomes:
measure: Number of Subjects Achieving Oral Treprostinil Dose
timeFrame: Assessed at Week 16
Secondary outcomes:
measure: Change in 6-minute Walk Distance (6MWD)
timeFrame: From Baseline to Week 16
measure: Change in Borg Dyspnea Score
timeFrame: From Baseline to Week 16
measure: Number of Subjects With Changes in WHO FC
timeFrame: From Baseline to Week 16
measure: Change in Serum N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Levels
timeFrame: From Baseline to Week 16
measure: Change in Echocardiogram Parameters (Change in Cardiac Output)
timeFrame: At Baseline and Week 16
measure: Change in Echocardiogram Parameters (Heart Rate)
timeFrame: At Baseline and Week 16
measure: Change in Echocardiogram Parameters (Left Ventricular Outflow Track Dimension)
timeFrame: At Baseline and Week 16
measure: Change in Echocardiogram Parameters (LVOT Velocity Time Integral)
timeFrame: At Baseline and Week 16
measure: Change in Echocardiogram Parameters (LV Diameter)
timeFrame: At Baseline and Week 16
measure: Change in Echocardiogram Parameters (LV Eccentricity Index [Diastole])
timeFrame: At Baseline and Week 16
measure: Change in Echocardiogram Parameters (LV Eccentricity Index [Systole])
timeFrame: At Baseline and Week 16
measure: Change in Echocardiogram Parameters (Pulmonary Valve Acceleration Time)
timeFrame: At Baseline and Week 16
measure: Change in Echocardiogram Parameters (RV/LV Ratio)
timeFrame: At Baseline and Week 16
measure: Change in Echocardiogram Parameters (Right Atrial Area)
timeFrame: At Baseline and Week 16
measure: Change in Echocardiogram Parameters (RV Diameter)
timeFrame: At Baseline and Week 16
measure: Change in Echocardiogram Parameters (RV Free Wall Strain)
timeFrame: At Baseline and Week 16
measure: Change in Echocardiogram Parameters (RV Myocardial Performance Index)
timeFrame: At Baseline and Week 16
measure: Change in Echocardiogram Parameters (Tricuspid Annular Plane Systolic Excursion)
timeFrame: At Baseline and Week 16
measure: Change in PAH Symptom Score
timeFrame: At Baseline and Week 16
measure: Change in Patient-reported Outcomes (Health-related Quality of Life)
timeFrame: At Baseline and Week 16
measure: Change in Treatment Satisfaction
timeFrame: At Baseline and Week 16
measure: Improvement From Baseline in Clinical Risk Category
timeFrame: At Baseline and Week 16
measure: Achievement of Low Risk Category in Clinical Parameters
timeFrame: At Week 16
measure: Overall Achievement
timeFrame: At Week 16
measure: Transition and Maintenance of Orenitram Therapy
timeFrame: At Week 16
Other outcomes:
Locations:
city: Fresno
country: United States
facility: University of California San Francisco - Fresno
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Medical Center
state: California
city: Orlando
country: United States
facility: Florida Hospital
state: Florida
city: Austell
country: United States
facility: Piedmont Healthcare Pulmonary and Critical Care Research
state: Georgia
city: Indianapolis
country: United States
facility: St. Vincent Medical Group
state: Indiana
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Albuquerque
country: United States
facility: University of New Mexico Health Sciences Center
state: New Mexico
city: Cincinnati
country: United States
facility: University of Cincinnati Health
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: Integris Baptist Medical Center
state: Oklahoma
city: Pittsburgh
country: United States
facility: UPMC Presbytarian Hospital
state: Pennsylvania
Study officials:
affiliation: Piedmont Healthcare Pulmonary and Critical Care Research
name: Chad E Miller, MD
role: PRINCIPAL_INVESTIGATOR
References: