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

NCT ID: NCT02630316

Last Updated: 2022-07-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 326 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-02-03
• Study Completion Date: 2019-12-26

Brief 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).

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.

Conditions

Pulmonary Hypertension; Interstitial Lung Disease; Combined Pulmonary Fibrosis and Emphysema

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo

Matching placebo inhaled using an ultrasonic nebulizer four times daily

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo administered four times daily

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

Group Type: ACTIVE_COMPARATOR

Inhaled Treprostinil

Intervention Type: DRUG

Inhaled treprostinil (6 mcg/breath) administered four times daily

Interventions

Inhaled Treprostinil

Inhaled treprostinil (6 mcg/breath) administered four times daily

Intervention Type: DRUG

Placebo

Placebo administered four times daily

Intervention Type: DRUG

Other Intervention Names

Tyvaso

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

United Therapeutics

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

IMC-Diagnostic & Medical Clinic

Mobile, Alabama, United States

Arizona Pulmonary Specialists, Ltd.

Phoenix, Arizona, United States

St. Joseph's Hospital and Medical Center

Phoenix, Arizona, United States

University of Arizona

Tucson, Arizona, United States

Cedars-Sinai Medical Center, Advanced Health Sciences Pavilion

Beverly Hills, California, United States

University of California San Francisco - Fresno

Fresno, California, United States

University of California San Diego

La Jolla, California, United States

VA Long Beach Healthcare System

Long Beach, California, United States

University of Southern California Health Sciences

Los Angeles, California, United States

Department of Veterans Affairs Greater Los Angeles Healthcare System

Los Angeles, California, United States

Pacific Pulmonary Medical Group

Riverside, California, United States

Kaiser Permanente - Roseville

Roseville, California, United States

University of California Davis Medical Center

Sacramento, California, United States

Kaiser Permanente

San Francisco, California, United States

University of Colorado Hospital - Cardiac and Vascular Center

Aurora, Colorado, United States

National Jewish Health

Denver, Colorado, United States

Yale New Haven Hospital

New Haven, Connecticut, United States

Medstar Georgetown University Hospital

Washington D.C., District of Columbia, United States

MedStar Washington Hospital Center

Washington D.C., District of Columbia, United States

Florida Lung, Asthma & Sleep Specialists, P.A.

Celebration, Florida, United States

St. Francis Sleep, Allergy and Lung Institute

Clearwater, Florida, United States

University of Florida Clinical Research Center

Gainesville, Florida, United States

University of Florida College of Medicine, Jacksonville

Jacksonville, Florida, United States

Mayo Clinic Jacksonville

Jacksonville, Florida, United States

St. Vincent's Health System

Jacksonville, Florida, United States

University of Miami

Miami, Florida, United States

Florida Hospital

Orlando, Florida, United States

South Miami Heart Specialists

South Miami, Florida, United States

Tampa General Hospital Center of Research Excellence

Tampa, Florida, United States

Cleveland Clinic Florida

Weston, Florida, United States

The Emory Clinic

Atlanta, Georgia, United States

Piedmont - Georgia Lung Associates

Austell, Georgia, United States

Wellstar Medical Group - Pulmonary Medicine

Marietta, Georgia, United States

Northwestern University School of Medicine

Chicago, Illinois, United States

Rush University Medical Center

Chicago, Illinois, United States

University of Illinois at Chicago Hospital

Chicago, Illinois, United States

University of Chicago Medical Center

Chicago, Illinois, United States

Loyola University Medical Center

Maywood, Illinois, United States

U Health Physicians Advanced Heart and Lung Clinic

Indianapolis, Indiana, United States

Community Heart and Vascular Hospital East

Indianapolis, Indiana, United States

St. Vincent Medical Group, Inc.

Indianapolis, Indiana, United States

University of Iowa Hospitals & Clinics

Iowa City, Iowa, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

University of Kentucky Medical Center

Lexington, Kentucky, United States

University of Louisville Clinical Trials Unit

Louisville, Kentucky, United States

Louisiana State University Health Sciences Center New Orleans

New Orleans, Louisiana, United States

Chest Medicine Associates

South Portland, Maine, United States

University of Maryland Medical Center

Baltimore, Maryland, United States

Johns Hopkins University Pulmonary and Critical Care Medicine

Baltimore, Maryland, United States

Tufts Medical Center

Boston, Massachusetts, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Brigham & Women's Hospital

Boston, Massachusetts, United States

Spectrum Health Heart and Lung Specialized Care Clinic

Grand Rapids, Michigan, United States

University of Minnesota

Minneapolis, Minnesota, United States

Mayo Clinic

Rochester, Minnesota, United States

University of Mississippi Medical Center

Jackson, Mississippi, United States

Saint Luke's Hospital of Kansas City

Kansas City, Missouri, United States

Washington University School of Medicine

St Louis, Missouri, United States

The University of New Mexico Clinical and Translational Science Center

Albuquerque, New Mexico, United States

Albany Medical College

Albany, New York, United States

New York Methodist Hospital

Brooklyn, New York, United States

Northwell Health

New Hyde Park, New York, United States

NYU Langone Medical Center

New York, New York, 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

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States

Duke University Medical Center-Duke South Clinic

Durham, North Carolina, United States

Pinehurst Medical Clinic, Inc.

Pinehurst, North Carolina, United States

The Lindner Research Center at The Christ Hospital

Cincinnati, Ohio, United States

University of Cincinnati Health

Cincinnati, Ohio, United States

University Hospitals Cleveland Medical Center

Cleveland, Ohio, United States

Cleveland Clinic

Cleveland, Ohio, United States

The Ohio State University Medical Center

Columbus, Ohio, United States

INTEGRIS Baptist Medical Center

Oklahoma City, Oklahoma, United States

Penn Medicine University City

Philadelphia, Pennsylvania, United States

Allegheny General Hospital

Pittsburgh, Pennsylvania, United States

UPMC Montifiore University Hospital

Pittsburgh, Pennsylvania, United States

AnMed Health Medical Center

Anderson, South Carolina, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Statcare Pulmonary Consultants

Knoxville, Tennessee, United States

Baylor University Medical Center

Dallas, Texas, United States

UT Southwestern Medical Center

Dallas, Texas, United States

Texas Tech University Health Sciences Center

El Paso, Texas, 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

The University of Texas Health Science Center at San Antonio

San Antonio, Texas, United States

Vermont Lung Center

Colchester, Vermont, United States

Inova Fairfax Medical Campus

Fairfax, Virginia, United States

Sentara Norfolk General Hospital

Norfolk, Virginia, United States

Pulmonary Associates of Richmond

Richmond, Virginia, United States

University of Washington Medical Center

Seattle, Washington, United States

University of Wisconsin School of Medicine and Public Health

Madison, Wisconsin, United States

Aurora St. Luke's Medical Center

Milwaukee, Wisconsin, United States

Medical College of Wisconsin/Froedtert Hospital

Milwaukee, Wisconsin, United States

Auxilio Mutuo Hospital

Guaynabo, , Puerto Rico

Countries

United States; Puerto Rico

References

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. 2023 Feb;163(2):398-406. doi: 10.1016/j.chest.2022.09.007. Epub 2022 Sep 15.

Reference Type: DERIVED

PMID: 36115497 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34214475 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33440084 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

RIN-PH-201

Identifier Type: -

Identifier Source: org_study_id