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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02630316
Other study ID # RIN-PH-201
Secondary ID
Status Completed
Phase Phase 2/Phase 3
First received
Last updated
Start date February 3, 2017
Est. completion date December 26, 2019

Study information

Verified date July 2022
Source United Therapeutics
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This was a multicenter, randomized (1:1 inhaled treprostinil: placebo), double-blinded, placebo-controlled trial to evaluate the safety and efficacy of inhaled treprostinil in subjects with pre-capillary pulmonary hypertension (PH) associated with interstitial lung disease (ILD) including combined pulmonary fibrosis and emphysema (CPFE). The study included 326 patients at approximately 120 clinical trial centers. The treatment phase of the study lasted approximately 16 weeks. Patients who completed all required assessments were eligible to enter an open-label, extension study (RIN-PH-202).


Description:

Study RIN-PH-201 was a multicenter, randomized, double-blind, placebo controlled, 16 week, parallel group study designed to investigate the safety and efficacy of inhaled treprostinil in subjects with PH-ILD. Subjects initiated inhaled treprostinil or placebo at a dose of 3 breaths (18 mcg) 4 times daily (QID) (during waking hours). Study drug doses were maximized throughout the study. Dose escalations (additional 1 breath QID) could occur up to every 3 days with a target dosing regimen of 9 breaths (54 mcg) QID and a maximum dose of 12 breaths (72 mcg) QID, as clinically tolerated. Subjects were assessed during Screening and Baseline to determine eligibility for the study. Once eligible, 5 Treatment Phase visits to the clinic were required at Week 4, Week 8, Week 12, Week 15, and Week 16 (final study visit). An Early Termination (ET) Visit was conducted for subjects who discontinued prior to Week 16; all assessments planned for the final Week 16 Visit were conducted during the ET Visit, if applicable. Subjects were contacted at least weekly by telephone or email to assess tolerance to study drug, AEs, and changes to concomitant medications. Efficacy assessments consisted of 6-minute walk distance (6MWD), plasma N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentration, and incidence of clinical worsening. Exploratory endpoints included change in St. George's Respiratory Questionnaire (SGRQ), change in distance saturation product (DSP), time to exacerbation of underlying lung disease, and pulmonary function tests (PFT). Safety assessments consisted of the development of AEs, vital signs, clinical laboratory parameters, ECG parameters, hospitalizations due to cardiopulmonary indications, exacerbations of underlying lung disease, and oxygenation. Subjects who remained on study drug, completed all assessments during the 16-week Treatment Phase, and met all eligibility criteria were eligible for the open-label extension study (RIN-PH-202). Additionally, subjects who withdrew from study drug prior to Week 16 due to clinical worsening and returned to the clinic for scheduled visits (excluding the Week 15 Visit) were eligible for RIN PH-202.


Recruitment information / eligibility

Status Completed
Enrollment 326
Est. completion date December 26, 2019
Est. primary completion date December 26, 2019
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: 1. Subject voluntarily gave informed consent to participate in the study. 2. Males and females aged 18 years or older at the time of informed consent. a. Females of reproductive potential were non-pregnant (as confirmed by a urine pregnancy test at screening) and non-lactating, and: i. Abstained from intercourse (when in line with their preferred and usual lifestyle), or ii. Used 2 medically acceptable, highly effective forms of contraception for the duration of study, and at least 30 days after discontinuing study drug. b. Males with a partner of childbearing potential used condoms for the duration of treatment and for at least 48 hours after discontinuing study drug. 3. The subject had a confirmed diagnosis of WHO Group 3 PH based on computed tomography (CT) imaging which was performed within 6 months prior to randomization and demonstrated evidence of diffuse parenchymal lung disease. Subjects had any form of ILD or CPFE. 4. Subjects were required to have a right heart catheterization (RHC) within 1 year prior to randomization with the following documented parameters: 1. Pulmonary vascular resistance (PVR) >3 Wood Units (WU) and 2. A pulmonary capillary wedge pressure (PCWP) of <15 mmHg and 3. A mean pulmonary arterial pressure (mPAP) of >25 mmHg 5. Baseline 6MWD =100 m. 6. Subjects on a chronic medication for underlying lung disease (ie, pirfenidone, nintedanib, etc) were on a stable and optimized dose for =30 days prior to randomization. 7. In the opinion of the Investigator, the subject was able to communicate effectively with study personnel, and was considered reliable, willing and likely to be cooperative with protocol requirements, including attending all study visits. 8. Subjects with connective tissue disease (CTD) had a Baseline forced vital capacity (FVC) of <70%. Exclusion criteria: 1. The subject had a diagnosis of PAH or PH for reasons other than WHO Group 3 PH ILD as outlined in Inclusion Criterion 3. 2. The subject showed intolerance or significant lack of efficacy to a prostacyclin or prostacyclin analogue that resulted in discontinuation or inability to effectively titrate that therapy. 3. The subject received any PAH-approved therapy including: prostacyclin therapy (ie, epoprostenol, treprostinil, iloprost, or beraprost; except for acute vasoreactivity testing), prostacyclin (IP) receptor agonist (selexipag), endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor (PDE5-I), or soluble guanylate cyclase (sGC) stimulator within 60 days of randomization. 4. The subject had evidence of clinically significant left-sided heart disease as defined by: 1. PCWP >15 mmHg 2. Left ventricular ejection fraction <40%. Note: Subjects with abnormal left ventricular function attributable entirely to impaired left ventricular filling due to the effects of right ventricular overload (ie, right ventricular hypertrophy and/or dilatation) were not excluded. 5. The subject was receiving >10 L/min of oxygen supplementation by any mode of delivery at rest at Baseline. 6. Current use of any inhaled tobacco/marijuana products or significant history of drug abuse at the time of informed consent. 7. Exacerbation of underlying lung disease or active pulmonary or upper respiratory infection within 30 days of randomization. 8. Initiation of pulmonary rehabilitation within 12 weeks prior to randomization. 9. In the opinion of the Investigator, the subject had any condition that would interfere with the interpretation of study assessments or has any disease or condition (ie, peripheral vascular disease, musculoskeletal disorder, morbid obesity) that would likely be the primary limit to ambulation (as opposed to PH). 10. Use of any investigational drug/device, or participation in any investigational study with therapeutic intent within 30 days prior to randomization. 11. Severe concomitant illness limiting life expectancy (<6 months). 12. Acute pulmonary embolism within 90 days of randomization.

Study Design


Intervention

Drug:
Inhaled Treprostinil
Inhaled treprostinil (6 mcg/breath) administered four times daily
Placebo
Placebo administered four times daily

Locations

Country Name City State
Puerto Rico Auxilio Mutuo Hospital Guaynabo
United States Albany Medical College Albany New York
United States The University of New Mexico Clinical and Translational Science Center Albuquerque New Mexico
United States AnMed Health Medical Center Anderson South Carolina
United States The Emory Clinic Atlanta Georgia
United States University of Colorado Hospital - Cardiac and Vascular Center Aurora Colorado
United States Piedmont - Georgia Lung Associates Austell Georgia
United States Johns Hopkins University Pulmonary and Critical Care Medicine Baltimore Maryland
United States University of Maryland Medical Center Baltimore Maryland
United States Cedars-Sinai Medical Center, Advanced Health Sciences Pavilion Beverly Hills California
United States University of Alabama at Birmingham Birmingham Alabama
United States Brigham & Women's Hospital Boston Massachusetts
United States Massachusetts General Hospital Boston Massachusetts
United States Tufts Medical Center Boston Massachusetts
United States New York Methodist Hospital Brooklyn New York
United States Florida Lung, Asthma & Sleep Specialists, P.A. Celebration Florida
United States University of North Carolina at Chapel Hill Chapel Hill North Carolina
United States Medical University of South Carolina Charleston South Carolina
United States Northwestern University School of Medicine Chicago Illinois
United States Rush University Medical Center Chicago Illinois
United States University of Chicago Medical Center Chicago Illinois
United States University of Illinois at Chicago Hospital Chicago Illinois
United States The Lindner Research Center at The Christ Hospital Cincinnati Ohio
United States University of Cincinnati Health Cincinnati Ohio
United States St. Francis Sleep, Allergy and Lung Institute Clearwater Florida
United States Cleveland Clinic Cleveland Ohio
United States University Hospitals Cleveland Medical Center Cleveland Ohio
United States Vermont Lung Center Colchester Vermont
United States The Ohio State University Medical Center Columbus Ohio
United States Baylor University Medical Center Dallas Texas
United States UT Southwestern Medical Center Dallas Texas
United States National Jewish Health Denver Colorado
United States Duke University Medical Center-Duke South Clinic Durham North Carolina
United States Texas Tech University Health Sciences Center El Paso Texas
United States Inova Fairfax Medical Campus Fairfax Virginia
United States University of California San Francisco - Fresno Fresno California
United States University of Florida Clinical Research Center Gainesville Florida
United States Spectrum Health Heart and Lung Specialized Care Clinic Grand Rapids Michigan
United States Houston Methodist Houston Texas
United States Memoral Hermann Hospital - Texas Medical Center Houston Texas
United States Michael E. DeBakey VA Medical Center Houston Texas
United States Community Heart and Vascular Hospital East Indianapolis Indiana
United States St. Vincent Medical Group, Inc. Indianapolis Indiana
United States U Health Physicians Advanced Heart and Lung Clinic Indianapolis Indiana
United States University of Iowa Hospitals & Clinics Iowa City Iowa
United States University of Mississippi Medical Center Jackson Mississippi
United States Mayo Clinic Jacksonville Jacksonville Florida
United States St. Vincent's Health System Jacksonville Florida
United States University of Florida College of Medicine, Jacksonville Jacksonville Florida
United States Saint Luke's Hospital of Kansas City Kansas City Missouri
United States University of Kansas Medical Center Kansas City Kansas
United States Statcare Pulmonary Consultants Knoxville Tennessee
United States University of California San Diego La Jolla California
United States University of Kentucky Medical Center Lexington Kentucky
United States VA Long Beach Healthcare System Long Beach California
United States Department of Veterans Affairs Greater Los Angeles Healthcare System Los Angeles California
United States University of Southern California Health Sciences Los Angeles California
United States University of Louisville Clinical Trials Unit Louisville Kentucky
United States University of Wisconsin School of Medicine and Public Health Madison Wisconsin
United States Wellstar Medical Group - Pulmonary Medicine Marietta Georgia
United States Loyola University Medical Center Maywood Illinois
United States University of Miami Miami Florida
United States Aurora St. Luke's Medical Center Milwaukee Wisconsin
United States Medical College of Wisconsin/Froedtert Hospital Milwaukee Wisconsin
United States University of Minnesota Minneapolis Minnesota
United States IMC-Diagnostic & Medical Clinic Mobile Alabama
United States Yale New Haven Hospital New Haven Connecticut
United States Northwell Health New Hyde Park New York
United States Louisiana State University Health Sciences Center New Orleans New Orleans Louisiana
United States Mount Sinai Medical Center New York New York
United States New York Presbyterian - Weill Cornell Medical Center New York New York
United States NYU Langone Medical Center New York New York
United States Sentara Norfolk General Hospital Norfolk Virginia
United States INTEGRIS Baptist Medical Center Oklahoma City Oklahoma
United States Florida Hospital Orlando Florida
United States Penn Medicine University City Philadelphia Pennsylvania
United States Arizona Pulmonary Specialists, Ltd. Phoenix Arizona
United States St. Joseph's Hospital and Medical Center Phoenix Arizona
United States Pinehurst Medical Clinic, Inc. Pinehurst North Carolina
United States Allegheny General Hospital Pittsburgh Pennsylvania
United States UPMC Montifiore University Hospital Pittsburgh Pennsylvania
United States Pulmonary Associates of Richmond Richmond Virginia
United States Pacific Pulmonary Medical Group Riverside California
United States Mayo Clinic Rochester Minnesota
United States Kaiser Permanente - Roseville Roseville California
United States University of California Davis Medical Center Sacramento California
United States Washington University School of Medicine Saint Louis Missouri
United States The University of Texas Health Science Center at San Antonio San Antonio Texas
United States Kaiser Permanente San Francisco California
United States University of Washington Medical Center Seattle Washington
United States South Miami Heart Specialists South Miami Florida
United States Chest Medicine Associates South Portland Maine
United States Tampa General Hospital Center of Research Excellence Tampa Florida
United States University of Arizona Tucson Arizona
United States Medstar Georgetown University Hospital Washington District of Columbia
United States MedStar Washington Hospital Center Washington District of Columbia
United States Cleveland Clinic Florida Weston Florida

Sponsors (1)

Lead Sponsor Collaborator
United Therapeutics

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type Measure Description Time frame Safety issue
Primary Change in 6-minute Walk Distance (6MWD) Measured at Peak Exposure From Baseline to Week 16 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 16, 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. Subjects will be instructed to walk down a corridor at a comfortable speed as far as they can manage for six minutes. Peak exposure 6MWD will occur by conducting 6-minute walk test (6MWT) within 10 to 60 minutes after the most recent dose of study drug dose. Baseline and Week 16
Secondary Change in Plasma Concentration of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 16 The NT-proBNP serum concentration is a useful biomarker associated with changes in right heart morphology and function. NT-proBNP serum concentration will be assessed to compare the severity of heart failure at Baseline and Week 16. Blood for NT-proBNP assessment must be drawn prior to conducting the 6MWT. Baseline and Week 16
Secondary Incidence of Clinical Worsening Subjects were monitored for clinical worsening from the time of randomization until 1 of the following criteria were met: hospitalization due to a cardiopulmonary indication; decrease in 6MWD >15% from Baseline directly related to the disease under study, at 2 consecutive visits and at least 24 hours apart; death (all causes); or lung transplantation. Baseline to Week 16
Secondary Change in Peak 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. Subjects will be instructed to walk down a corridor at a comfortable speed as far as they can manage for six minutes. Peak exposure 6MWD will occur by conducting 6MWT within 10 to 60 minutes after the most recent dose of study drug dose. Baseline and Week 12
Secondary Change in Trough 6-minute Walk Distance (6MWD) From Baseline to Week 15 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 15, 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. Subjects will be instructed to walk down a corridor at a comfortable speed as far as they can 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. Trough exposure 6MWD will occur by conducting 6-minute walk test (6MWT) at least four hours after the most recent study drug dose. Baseline and Week 15
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