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

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ClinicalTrials.gov Identifier: NCT03497689
Recruitment Status : Recruiting
First Posted : April 13, 2018
Last Update Posted : October 25, 2019
Sponsor:
Information provided by (Responsible Party):
United Therapeutics

Brief Summary:
This is 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).

Condition or disease Intervention/treatment Phase
Pulmonary Arterial Hypertension Drug: Intravenous/Subcutaneous Treprostinil; Oral Treprostinil Phase 4

Detailed Description:
Subjects will be initiated on subcutaneous (SC) or intravenous (IV) treprostinil and titrated to a dose that improves the symptoms of PAH while minimizing excessive pharmacologic effects. After achieving a minimum SC/IV treprostinil dose of 20 ng/kg/min, subjects may begin a transition to oral treprostinil at the Transition Visit, which can occur at the Week 2, 4, or 8 study visit. After the Transition Visit, oral treprostinil titration will continue through Week 16 to reach the maximum tolerated dose.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: EXPEDITE: A 16-Week, Multicenter, Open-label Study of Remodulin Induction Followed by Orenitram Optimization in Subjects With Pulmonary Arterial Hypertension
Actual Study Start Date : September 21, 2018
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : June 2020


Arm Intervention/treatment
Experimental: Intravenous/Subcutaneous Treprostinil; Oral Treprostinil
Intravenous (IV) or subcutaneous (SC) treprostinil induction followed by transition to oral treprostinil
Drug: Intravenous/Subcutaneous Treprostinil; Oral Treprostinil
Short term course of IV/SC treprostinil continuous infusion followed by transition to oral treprostinil extended-release tablets taken three times daily
Other Names:
  • Remodulin
  • Orenitram




Primary Outcome Measures :
  1. Oral treprostinil dose [ Time Frame: Assessed at Week 16 ]
    The percentage of subjects achieving an oral treprostinil dose of 4 mg three times daily (TID) (or a total daily dose of 12 mg) or higher at Week 16 (or a dose of 0.057 mg/kg TID [total daily dose of 0.171 mg/kg] or greater for subjects <70 kg) will be calculated and summarized


Secondary Outcome Measures :
  1. Prostanoid Adverse Events (AEs) [ Time Frame: Baseline through Week 16 ]
    Includes headache, diarrhea, nausea, flushing, jaw pain, extremity pain, and vomiting

  2. Echocardiograms [ Time Frame: At Baseline, Transition Visit (Week 2, 4, or 8), and Week 16 ]
    Echocardiograms provide information regarding cardiac structure and function. Echocardiographic parameters will be summarized at time points listed and will include but are not limited to the following: right atrial area, tricuspid annular plane systolic excursion, right ventricle (RV) strain, RV/left ventricular ratio at diastole, Eccentricity Index, strain imaging or speckle-tracking; RV Myocardial Performance Index or Tei index; Pulmonary Artery Acceleration Time and presence/timing of Notching; and cardiac output by left ventricular outflow tract diameter and time-velocity integral of aortic flow by pulse-wave Doppler.

  3. Change in 6-minute walk distance (6MWD) [ Time Frame: From Baseline to Transition Visit (Week 2, 4, or 8) and Week 16 ]
    The intent of the 6-Minute Walk Test (6MWT) is a validated and reliable measure of exercise ability in patients with chronic respiratory diseases.

  4. Change in Borg dyspnea score [ Time Frame: From Baseline to Transition Visit (Week 2, 4, or 8) and Week 16 ]
    The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea experienced during the 6MWT. Scores range from 0 (no shortness of breath) to 10 (worst shortness of breath you have ever had).

  5. Change in World Health Organization (WHO) functional class (FC) [ Time Frame: From Baseline to Transition Visit (Week 2, 4, or 8) and Week 16 ]
    The WHO functional classification ranges from I (subjects with pulmonary hypertension but without resulting limitation of physical activity) to IV (subjects with pulmonary hypertension with inability to carry out any physical activities without symptoms).

  6. Change in serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels [ Time Frame: From Baseline to Transition Visit (Week 2, 4, or 8) and Week 16 ]
    The NT-proBNP concentration is a biomarker associated with changes in right heart morphology and function.

  7. Impact of pulmonary hypertension on a person's life (health-related quality of life) [ Time Frame: At Baseline, Transition Visit (Week 2, 4, or 8), and Week 16 ]
    Will be assessed using the emPHasis-10 questionnaire

  8. Treatment satisfaction [ Time Frame: At Baseline, Transition Visit (Week 2, 4, or 8), and Week 16 ]
    Will be assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM)



Information from the National Library of Medicine

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Ages Eligible for Study:   17 Years to 85 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03497689


Contacts
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Contact: Bucky Turpin (919) 425-5492 bturpin@unither.com
Contact: Eric Shen, PharmD (919) 328-3528 eshen@unither.com

Locations
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United States, California
University of California San Francisco - Fresno Recruiting
Fresno, California, United States, 93701
Contact: Sonia Garcia    559-499-6639      
Principal Investigator: Vijay Balasubramanian, MD         
Harbor-UCLA Medical Center Recruiting
Torrance, California, United States, 90502
Contact: Bindu John    310-222-3560      
Principal Investigator: Ronald Oudiz, MD         
United States, Florida
Florida Hospital Recruiting
Orlando, Florida, United States, 32803
Contact: Kimberly Cawthon    407-303-7556      
Principal Investigator: James Tarver III, MD         
United States, Georgia
Piedmont Healthcare Pulmonary and Critical Care Research Recruiting
Austell, Georgia, United States, 30106
Contact: Stacy Beasley    770-745-1404      
Principal Investigator: Chad E Miller, MD         
United States, Indiana
St. Vincent Medical Group Recruiting
Indianapolis, Indiana, United States, 46260
Contact: Diane Slama, RN    317-338-6717      
Principal Investigator: Ashwin Ravichandran, MD         
United States, Ohio
University of Cincinnati Health Recruiting
Cincinnati, Ohio, United States, 45267
Contact: Jill Schulte    513-558-3415      
Principal Investigator: Jean Elwing, MD         
The Ohio State University Wexner Medical Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Joe Santiago    614-366-4593      
Principal Investigator: Veronica Franco, MD         
United States, Oklahoma
Integris Baptist Medical Center Recruiting
Oklahoma City, Oklahoma, United States, 73112
Contact: Kristin Mund    405-713-4413      
Principal Investigator: John Kingrey, MD         
United States, Pennsylvania
UPMC Presbytarian Hospital Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Janel Giovanneli    412-647-8305      
Principal Investigator: Marc Simon, MD         
Sponsors and Collaborators
United Therapeutics

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Responsible Party: United Therapeutics
ClinicalTrials.gov Identifier: NCT03497689     History of Changes
Other Study ID Numbers: TDE-PH-402
First Posted: April 13, 2018    Key Record Dates
Last Update Posted: October 25, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by United Therapeutics:
pulmonary hypertension
treprostinil
pulmonary arterial hypertension
PAH
Remodulin
Orenitram
Additional relevant MeSH terms:
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Familial Primary Pulmonary Hypertension
Hypertension
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases
Treprostinil
Antihypertensive Agents