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

NCT03497689 | Completed Phase 4 Results FDA Drug

• 1 other identifier: TDE-PH-402
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 11

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).

Conditions

Pulmonary Arterial Hypertension

Keywords

Pulmonary hypertension; Treprostinil; Pulmonary arterial hypertension; Remodulin; Orenitram

Outcome Measures

Primary Outcomes (1)

• Number of Subjects Achieving Oral Treprostinil Dose

  The number of subjects that achieved an oral treprostinil dose of ≥4 mg TID (or a total daily dose \[TDD\] of 12 mg) at Week 16 (or a dose of ≥0.057 mg/kg TID \[TDD of 0.171 mg/kg\] for subjects \<70 kg).

  Assessed at Week 16

Secondary Outcomes (25)

• Change in 6-minute Walk Distance (6MWD)

  From Baseline to Week 16

• Change in Borg Dyspnea Score

  From Baseline to Week 16

• Number of Subjects With Changes in WHO FC

  From Baseline to Week 16

• Change in Serum N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Levels

  From Baseline to Week 16

• Change in Echocardiogram Parameters (Change in Cardiac Output)

  At Baseline and Week 16

Study Arms (1)

Intravenous/Subcutaneous Treprostinil; Oral Treprostinil

EXPERIMENTAL

Subjects began Remodulin at 2 ng/kg/min subcutaneously (SC) or intravenously (IV) and were optimized to their maximum tolerated dose (MTD) of Remodulin. Subjects were then transitioned to Orenitram XR tablets (oral) based upon their Remodulin dose. Subjects were optimized on Orenitram therapy to a MTD. There were no maximum Remodulin or Orenitram doses specified during the study.

Drug: Intravenous/Subcutaneous Treprostinil; Oral Treprostinil

Interventions

Intravenous/Subcutaneous Treprostinil; Oral Treprostinil DRUG

Short-term course of IV or SC treprostinil continuous infusion followed by transition to oral treprostinil extended-release (XR) tablets taken 3 times daily (TID)

Also known as: Remodulin, Orenitram

Intravenous/Subcutaneous Treprostinil; Oral Treprostinil

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects who voluntary gave written informed consent to participate in study.
• Males and female subjects aged 18 to 75 years at Screening (date the subject provided written informed consent to participate in study).
• 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.
• Subjects with WHO functional class (FC) II or III symptoms at Baseline.
• Subjects with 6MWD \>250 m at Baseline.
• 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.
• 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.
• 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).
• 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.
• 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.
• Subjects who agreed to follow the specified precautions to avoid pregnancy as follows:
• 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).
• 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.
• 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.
• 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.

You may not qualify if:

• Female subjects who were pregnant, lactating, or planning to become pregnant during the study.
• Subjects with a current diagnosis of uncontrolled sleep apnea, as defined by their physician.
• 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.
• 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.
• Subjects with anemia, as defined by Screening hemoglobin \<9 g/dL.
• Subjects with an active infection or condition that interfered with interpretation of study assessments.
• 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%.
• Subjects with uncontrolled systemic hypertension, as evidenced by systolic blood pressure \>160 mmHg or diastolic blood pressure \>100 mmHg at Baseline.
• Subjects with severe hypotension, as evidenced by systolic blood pressure \<90 mmHg or diastolic blood pressure \<50 mmHg at Baseline.
• 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.
• Subjects with chronic musculoskeletal disorder or any other disease that limited ambulation, or who were connected to a machine that was not portable.
• 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.
• Subjects with any other concomitant disease with life expectancy of \<12 months from Baseline.
• 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.
• 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.

Sponsors & Collaborators

• United Therapeutics: lead

Study Sites (11)

University of California San Francisco - Fresno

Fresno, California, 93701, United States

Location

Harbor-UCLA Medical Center

Torrance, California, 90502, United States

Location

Florida Hospital

Orlando, Florida, 32803, United States

Location

Piedmont Healthcare Pulmonary and Critical Care Research

Austell, Georgia, 30106, United States

Location

St. Vincent Medical Group

Indianapolis, Indiana, 46260, United States

Location

University of Nebraska Medical Center

Omaha, Nebraska, 68198, United States

Location

University of New Mexico Health Sciences Center

Albuquerque, New Mexico, 87131, United States

Location

University of Cincinnati Health

Cincinnati, Ohio, 45267, United States

Location

The Ohio State University Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

Integris Baptist Medical Center

Oklahoma City, Oklahoma, 73112, United States

Location

UPMC Presbytarian Hospital

Pittsburgh, Pennsylvania, 15213, United States

Location

Related Publications (1)

• Miller CE, Franco V, Smith JS, Balasubramanian V, Kingrey J, Zolty R, Melendres-Groves L, Huston J, Elwing JM, Ravichandran A, Cella D, Shen E, Seaman S, Thrasher CM, Broderick M, Oudiz RJ. Parenteral treprostinil induction for rapid attainment of therapeutic doses of oral treprostinil. Respir Med. 2023 Nov;218:107374. doi: 10.1016/j.rmed.2023.107374. Epub 2023 Aug 1.

  PMID: 37532157 DERIVED

MeSH Terms

Conditions

Pulmonary Arterial Hypertension; Hypertension, Pulmonary

Interventions

treprostinil

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Global Medical Information
• Organization: United Therapeutics Corp.

clinicaltrials@unither.com

919-485-8350

Study Officials

• Chad E Miller, MD

  Piedmont Healthcare Pulmonary and Critical Care Research

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 20, 2018
• First Posted: April 13, 2018
• Study Start: January 31, 2019
• Primary Completion: May 11, 2022
• Study Completion: May 11, 2022
• Last Updated: August 7, 2023
• Results First Posted: August 7, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (11)