Clinical trial NCT02630316: Safety and Efficacy of Inhaled Treprostinil in Adult PH With ILD Including CPFE
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Pulmonary Hypertension
Interstitial Lung Disease
Combined Pulmonary Fibrosis and Emphysema
Keywords: Treprostinil
PH
ILD
CPFE
6 Minute Walk Test
Lead sponsor: United Therapeutics
Sponsor class: INDUSTRY
First posted: 2015-12-15
Enrollment: 326
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Change in 6-minute Walk Distance (6MWD) Measured at Peak Exposure From Baseline to Week 16
timeFrame: Baseline and Week 16
Secondary outcomes:
measure: Change in Plasma Concentration of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 16
timeFrame: Baseline and Week 16
measure: Incidence of Clinical Worsening
timeFrame: Baseline to Week 16
measure: Change in Peak 6-minute Walk Distance (6MWD) From Baseline to Week 12
timeFrame: Baseline and Week 12
measure: Change in Trough 6-minute Walk Distance (6MWD) From Baseline to Week 15
timeFrame: Baseline and Week 15
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Mobile
country: United States
facility: IMC-Diagnostic & Medical Clinic
state: Alabama
city: Phoenix
country: United States
facility: Arizona Pulmonary Specialists, Ltd.
state: Arizona
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center
state: Arizona
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: Beverly Hills
country: United States
facility: Cedars-Sinai Medical Center, Advanced Health Sciences Pavilion
state: California
city: Fresno
country: United States
facility: University of California San Francisco - Fresno
state: California
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Long Beach
country: United States
facility: VA Long Beach Healthcare System
state: California
city: Los Angeles
country: United States
facility: University of Southern California Health Sciences
state: California
city: Los Angeles
country: United States
facility: Department of Veterans Affairs Greater Los Angeles Healthcare System
state: California
city: Riverside
country: United States
facility: Pacific Pulmonary Medical Group
state: California
city: Roseville
country: United States
facility: Kaiser Permanente - Roseville
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: San Francisco
country: United States
facility: Kaiser Permanente
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital - Cardiac and Vascular Center
state: Colorado
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: New Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Washington
country: United States
facility: Medstar Georgetown University Hospital
state: District of Columbia
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: Celebration
country: United States
facility: Florida Lung, Asthma & Sleep Specialists, P.A.
state: Florida
city: Clearwater
country: United States
facility: St. Francis Sleep, Allergy and Lung Institute
state: Florida
city: Gainesville
country: United States
facility: University of Florida Clinical Research Center
state: Florida
city: Jacksonville
country: United States
facility: University of Florida College of Medicine, Jacksonville
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville
state: Florida
city: Jacksonville
country: United States
facility: St. Vincent's Health System
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Orlando
country: United States
facility: Florida Hospital
state: Florida
city: South Miami
country: United States
facility: South Miami Heart Specialists
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital Center of Research Excellence
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Atlanta
country: United States
facility: The Emory Clinic
state: Georgia
city: Austell
country: United States
facility: Piedmont - Georgia Lung Associates
state: Georgia
city: Marietta
country: United States
facility: Wellstar Medical Group - Pulmonary Medicine
state: Georgia
city: Chicago
country: United States
facility: Northwestern University School of Medicine
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago Hospital
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical Center
state: Illinois
city: Maywood
country: United States
facility: Loyola University Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: U Health Physicians Advanced Heart and Lung Clinic
state: Indiana
city: Indianapolis
country: United States
facility: Community Heart and Vascular Hospital East
state: Indiana
city: Indianapolis
country: United States
facility: St. Vincent Medical Group, Inc.
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals & Clinics
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky Medical Center
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville Clinical Trials Unit
state: Kentucky
city: New Orleans
country: United States
facility: Louisiana State University Health Sciences Center New Orleans
state: Louisiana
city: South Portland
country: United States
facility: Chest Medicine Associates
state: Maine
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University Pulmonary and Critical Care Medicine
state: Maryland
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Grand Rapids
country: United States
facility: Spectrum Health Heart and Lung Specialized Care Clinic
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Albuquerque
country: United States
facility: The University of New Mexico Clinical and Translational Science Center
state: New Mexico
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Brooklyn
country: United States
facility: New York Methodist Hospital
state: New York
city: New Hyde Park
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: New York Presbyterian - Weill Cornell Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center-Duke South Clinic
state: North Carolina
city: Pinehurst
country: United States
facility: Pinehurst Medical Clinic, Inc.
state: North Carolina
city: Cincinnati
country: United States
facility: The Lindner Research Center at The Christ Hospital
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati Health
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Medical Center
state: Ohio
city: Oklahoma City
country: United States
facility: INTEGRIS Baptist Medical Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Penn Medicine University City
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Montifiore University Hospital
state: Pennsylvania
city: Anderson
country: United States
facility: AnMed Health Medical Center
state: South Carolina
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Knoxville
country: United States
facility: Statcare Pulmonary Consultants
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: El Paso
country: United States
facility: Texas Tech University Health Sciences Center
state: Texas
city: Houston
country: United States
facility: Houston Methodist
state: Texas
city: Houston
country: United States
facility: Memoral Hermann Hospital - Texas Medical Center
state: Texas
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center
state: Texas
city: San Antonio
country: United States
facility: The University of Texas Health Science Center at San Antonio
state: Texas
city: Colchester
country: United States
facility: Vermont Lung Center
state: Vermont
city: Fairfax
country: United States
facility: Inova Fairfax Medical Campus
state: Virginia
city: Norfolk
country: United States
facility: Sentara Norfolk General Hospital
state: Virginia
city: Richmond
country: United States
facility: Pulmonary Associates of Richmond
state: Virginia
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Madison
country: United States
facility: University of Wisconsin School of Medicine and Public Health
state: Wisconsin
city: Milwaukee
country: United States
facility: Aurora St. Luke's Medical Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin/Froedtert Hospital
state: Wisconsin
city: Guaynabo
country: Puerto Rico
facility: Auxilio Mutuo Hospital
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.