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

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

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).

Study Overview

• Status: Completed
• Conditions: Pulmonary Hypertension; Interstitial Lung Disease; Combined Pulmonary Fibrosis and Emphysema
• Intervention / Treatment: Drug: Inhaled Treprostinil; Drug: Placebo

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 326
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • Guaynabo, Puerto Rico, 00968
    • Auxilio Mutuo Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
    • Mobile, Alabama, United States, 36604
      • IMC-Diagnostic & Medical Clinic
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • St. Joseph's Hospital and Medical Center
    • Phoenix, Arizona, United States, 85012
      • Arizona Pulmonary Specialists, Ltd.
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Beverly Hills, California, United States, 90211
      • Cedars-Sinai Medical Center, Advanced Health Sciences Pavilion
    • Fresno, California, United States, 93701
      • University of California San Francisco - Fresno
    • La Jolla, California, United States, 92093
      • University of California San Diego
    • Long Beach, California, United States, 90822
      • VA Long Beach Healthcare System
    • Los Angeles, California, United States, 90073
      • Department of Veterans Affairs Greater Los Angeles Healthcare System
    • Los Angeles, California, United States, 90033
      • University of Southern California Health Sciences
    • Riverside, California, United States, 92505
      • Pacific Pulmonary Medical Group
    • Roseville, California, United States, 95825
      • Kaiser Permanente - Roseville
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • San Francisco, California, United States, 94115
      • Kaiser Permanente
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital - Cardiac and Vascular Center
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale New Haven Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • MedStar Washington Hospital Center
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Celebration, Florida, United States, 34747
      • Florida Lung, Asthma & Sleep Specialists, P.A.
    • Clearwater, Florida, United States, 33765
      • St. Francis Sleep, Allergy and Lung Institute
    • Gainesville, Florida, United States, 32610
      • University of Florida Clinical Research Center
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville
    • Jacksonville, Florida, United States, 32209
      • University of Florida College of Medicine, Jacksonville
    • Jacksonville, Florida, United States, 33204
      • St. Vincent's Health System
    • Miami, Florida, United States, 33136
      • University of Miami
    • Orlando, Florida, United States, 32804
      • Florida Hospital
    • South Miami, Florida, United States, 33143
      • South Miami Heart Specialists
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital Center of Research Excellence
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • The Emory Clinic
    • Austell, Georgia, United States, 30106
      • Piedmont - Georgia Lung Associates
    • Marietta, Georgia, United States, 30060
      • Wellstar Medical Group - Pulmonary Medicine
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
    • Chicago, Illinois, United States, 60611
      • Northwestern University School Of Medicine
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago Hospital
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • St. Vincent Medical Group, Inc.
    • Indianapolis, Indiana, United States, 46202
      • U Health Physicians Advanced Heart and Lung Clinic
    • Indianapolis, Indiana, United States, 46250
      • Community Heart and Vascular Hospital East
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals & Clinics
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Medical Center
    • Louisville, Kentucky, United States, 40202
      • University of Louisville Clinical Trials Unit
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Louisiana State University Health Sciences Center New Orleans
  • Maine
    • South Portland, Maine, United States, 04106
      • Chest Medicine Associates
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University Pulmonary and Critical Care Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's Hospital
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health Heart and Lung Specialized Care Clinic
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital of Kansas City
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • The University of New Mexico Clinical and Translational Science Center
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • Brooklyn, New York, United States, 11215
      • New York Methodist Hospital
    • New Hyde Park, New York, United States, 11040
      • Northwell Health
    • New York, New York, United States, 10016
      • NYU Langone Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • New York, New York, United States, 10065
      • New York Presbyterian - Weill Cornell Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center-Duke South Clinic
    • Pinehurst, North Carolina, United States, 28374
      • Pinehurst Medical Clinic, Inc.
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Health
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Research Center at The Christ Hospital
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
    • Columbus, Ohio, United States, 43221
      • The Ohio State University Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Integris Baptist Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Medicine University City
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Montifiore University Hospital
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • AnMed Health Medical Center
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Knoxville, Tennessee, United States, 37919
      • Statcare Pulmonary Consultants
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • El Paso, Texas, United States, 79905
      • Texas Tech University Health Sciences Center
    • Houston, Texas, United States, 77030
      • Michael E. DeBakey VA Medical Center
    • Houston, Texas, United States, 77030
      • Houston Methodist
    • Houston, Texas, United States, 77030
      • Memoral Hermann Hospital - Texas Medical Center
    • San Antonio, Texas, United States, 78229
      • The University of Texas Health Science Center at San Antonio
  • Vermont
    • Colchester, Vermont, United States, 05446
      • Vermont Lung Center
  • Virginia
    • Fairfax, Virginia, United States, 22042
      • Inova Fairfax Medical Campus
    • Norfolk, Virginia, United States, 23507
      • Sentara Norfolk General Hospital
    • Richmond, Virginia, United States, 23229
      • Pulmonary Associates of Richmond
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin School of Medicine and Public Health
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora St. Luke's Medical Center
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin/Froedtert Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo; Matching placebo inhaled using an ultrasonic nebulizer four times daily	Drug: Placebo; Placebo administered four times daily
ACTIVE_COMPARATOR: Inhaled Treprostinil; Active Treprostinil for inhalation solution (0.6 mg/mL) delivered via an ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath. Inhaled four times daily and titrated up to a maximum of 12 breaths four times daily	Drug: Inhaled Treprostinil; Inhaled treprostinil (6 mcg/breath) administered four times daily; Other Names: Tyvaso

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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

Collaborators and Investigators

• Sponsor: United Therapeutics

Publications and helpful links

General Publications

• Nathan SD, Deng C, King CS, DuBrock HM, Elwing J, Rajagopal S, Rischard F, Sahay S, Broderick M, Shen E, Smith P, Tapson VF, Waxman AB. Inhaled Treprostinil Dosage in Pulmonary Hypertension Associated With Interstitial Lung Disease and Its Effects on Clinical Outcomes. Chest. 2022 Sep 15:S0012-3692(22)03725-4. doi: 10.1016/j.chest.2022.09.007. Online ahead of print.
• Nathan SD, Waxman A, Rajagopal S, Case A, Johri S, DuBrock H, De La Zerda DJ, Sahay S, King C, Melendres-Groves L, Smith P, Shen E, Edwards LD, Nelsen A, Tapson VF. Inhaled treprostinil and forced vital capacity in patients with interstitial lung disease and associated pulmonary hypertension: a post-hoc analysis of the INCREASE study. Lancet Respir Med. 2021 Nov;9(11):1266-1274. doi: 10.1016/S2213-2600(21)00165-X. Epub 2021 Jun 29.
• Waxman A, Restrepo-Jaramillo R, Thenappan T, Ravichandran A, Engel P, Bajwa A, Allen R, Feldman J, Argula R, Smith P, Rollins K, Deng C, Peterson L, Bell H, Tapson V, Nathan SD. Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease. N Engl J Med. 2021 Jan 28;384(4):325-334. doi: 10.1056/NEJMoa2008470. Epub 2021 Jan 13.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 3, 2017
• Primary Completion (ACTUAL): December 26, 2019
• Study Completion (ACTUAL): December 26, 2019

Study Registration Dates

• First Submitted: December 11, 2015
• First Submitted That Met QC Criteria: December 11, 2015
• First Posted (ESTIMATE): December 15, 2015

Study Record Updates

• Last Update Posted (ACTUAL): July 27, 2022
• Last Update Submitted That Met QC Criteria: July 21, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: ILD; PH; Treprostinil; 6 Minute Walk Test; CPFE
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Hypertension; Lung Diseases; Emphysema; Pulmonary Fibrosis; Hypertension, Pulmonary; Lung Diseases, Interstitial; Antihypertensive Agents; Treprostinil
• Other Study ID Numbers: RIN-PH-201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No