Safety and Efficacy of Inhaled Treprostinil in Adult PH With ILD Including CPFE

Pulmonary Hypertension Clinical Trial

Official title:

A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Inhaled Treprostinil in Subjects With Pulmonary Hypertension Due to Parenchymal Lung Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02630316
• Other study ID #: RIN-PH-201
• Status: Completed
• Phase: Phase 2/Phase 3
• 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
• 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.

Related Conditions & MeSH terms

• Combined Pulmonary Fibrosis and Emphysema
• Emphysema
• Hypertension
• Hypertension, Pulmonary
• Interstitial Lung Disease
• Lung Diseases
• Lung Diseases, Interstitial
• Pulmonary Fibrosis
• Pulmonary Hypertension

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