Clinical trial NCT03496623: A Phase 3 Adaptive Study to Evaluate the Safety and Efficacy of Inhaled Treprostinil in Participants With Pulmonary Hypertension (PH) Due to Chronic Obstructive Pulmonary Disease (COPD)
Official title: A Phase 3, Randomized, Placebo-controlled, Double-blind, Adaptive Study to Evaluate the Safety and Efficacy of Inhaled Treprostinil in Patients With Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease (PH-COPD)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Pulmonary Hypertension
Chronic Obstructive Pulmonary Disease
Keywords: Pulmonary Hypertension
COPD
Inhaled Treprostinil
6-Minute Walk Test
Tyvaso
Lead sponsor: United Therapeutics
Sponsor class: INDUSTRY
First posted: 2018-04-12
Enrollment: 188
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to demonstrate the efficacy of inhaled treprostinil compared to placebo in improving exercise ability as measured by change from baseline in 6-Minute Walk Distance (6MWD) following 12 weeks of active treatment in participants with PH-COPD.

Detailed description: This is a multicenter, randomized, double-blind, placebo-controlled, 34-week, cross-over study, with a Treatment Period of approximately 26 weeks under the Original Crossover Design or, if applicable, a 21-week parallel study, with a Treatment Period of approximately 14 weeks under the Contingent Parallel Design.

Eligibility criteria: Inclusion Criteria:

Participants who meet the following criteria may be included in the study:

1. Participant voluntarily gives informed consent to participate in the study.
2. Males and females 18 years of age and above at the time of informed consent.

   1. Women of childbearing potential (defined as less than 1 year post-menopausal and not surgically sterile) must agree to practice abstinence or use 2 highly effective methods of contraception (defined as a method of birth control that results in a low failure rate, \[\<1% per year\], such as approved hormonal contraceptives, barrier methods \[such as condom or diaphragm\] used with a spermicide, or an intrauterine device) for the duration of study treatment and for 48 hours after discontinuing study drug. Participants must have a negative pregnancy test at the Screening Visit 1 (urine \[prior to the first dose of study medication\] and serum) and Baseline Visit (Study Week 1) (urine).
   2. Males with a partner of childbearing potential must agree to use a barrier method (condom) with a spermicide for the duration of treatment and for at least 48 hours after discontinuing study drug.
3. Diagnosis of PH-COPD (World Heath Organization \[WHO\] Group 3).
4. Clinical diagnosis of COPD will be made using the Global Initiative for Chronic

   Obstructive Lung Disease (GOLD) diagnostic criteria (GOLD Criteria 2020) and spirometry with the following documented parameters measured during Screening Visit 1 (prior to start of low-dose inhaled treprostinil):
   1. Forced expiratory volume in 1 second (FEV1) \<80% predicted
   2. FEV1/Forced vital capacity (FVC) \<70
5. The participant has a resting saturation peripheral capillary oxygenation (SpO2) greater than or equal to 90%, with or without supplemental oxygen, but not to exceed 10 liters (L)/min oxygen supplementation by any mode of delivery during Screening Visit 1.
6. During Screening Visit 1 prior to start of low-dose inhaled treprostinil, a 6MWD greater than or equal to 100 meters.
7. Have a right heart catheterization (RHC) performed during Screening Visit 1. (A previous RHC obtained within 12 months prior to the start of Screening Visit 1 is acceptable for determining eligibility, even if done without oxygen or vasodilator challenge, and a repeat RHC is not required.) The following parameters must be documented for eligibility:

   1. Pulmonary vascular resistance (PVR) greater than or equal to 4 Wood units
   2. A pulmonary artery wedge pressure (PAWP) or left ventricular end-diastolic pressure (LVEDP) of less than or equal to 15 millimeters of mercury (mmHg)
   3. A Pulmonary artery pressure mean (PAPm) of greater than or equal to 30 mmHg
8. Participants must be on a stable and optimized dose of chronic COPD medications for greater than or equal to 30 days prior to start of Screening Visit 1 and remain on the same dose throughout the Screening Period.
9. In the opinion of the Investigator, the participant can communicate effectively with study personnel and is considered reliable, willing, and likely to be cooperative with protocol requirements, including attending all study visits.

Exclusion Criteria:

The following will exclude participants from the study:

1. The participant has a diagnosis of either pulmonary arterial hypertension (PAH) or pulmonary hypertension (PH) due to reasons other than COPD. This would include, but is not limited to, chronic thromboembolic PH or acute/recent deep vein thrombosis or pulmonary embolism, untreated or inadequately treated obstructive sleep apnea, connective tissue disease (including but not limited to systemic sclerosis/scleroderma or systemic lupus erythematosus), sarcoidosis, human immunodeficiency virus-1 infection, and other conditions under WHO Group 1, 2, 4, and 5 classifications.
2. Based on chest computed tomography (CT) imaging during Screening Visit 1, the participant has a confirmed diagnosis of WHO Group 3 PH, other than COPD, such as idiopathic pulmonary fibrosis, combined pulmonary fibrosis and emphysema, diffuse parenchymal lung disease or interstitial lung disease. A previous chest CT scan performed within the 6 months prior to the start of Screening Visit 1 is also acceptable, and a repeat assessment is not required.

   A redacted CT scan report (from Screening Visit 1 or dated within prior 6 months) should be provided to the Medical Monitor with the Pre-Baseline Review Form to confirm eligibility.
3. The participant has received any Food and Drug Administration (FDA)-approved medication for the treatment of PAH (that is, prostacyclin, prostacyclin receptor agonist, endothelin receptor antagonist \[ERA\], phosphodiesterase type 5 inhibitor \[PDE5-I\], or soluble guanylate cyclase \[sGC\] stimulator) at Screening Visit 1 and thereafter, except if received for acute vasoreactivity testing.
4. The participant has a previous diagnosis of homozygous alpha-1 antitrypsin deficiency.
5. The participant has any prior intolerance to inhaled prostanoid therapy.
6. Inability to tolerate low-dose (3 breaths, 18 mcg) study drug and/or inability to follow dosing regimen during the Screening Period (pre-randomization).
7. Unwilling or unable to use Sponsor-provided devices (actigraph, spirometer, or smart device).
8. The participant has evidence of clinically significant left-sided heart disease (including but not limited to left ventricular ejection fraction \<40%, left ventricular hypertrophy,) or clinically significant cardiologic conditions, such as congestive heart failure, coronary artery disease, or valvular heart disease. Note: Participants with abnormal left ventricular function attributable to the effects of right ventricular overload will not be excluded, but a discussion with and approval by the Sponsor Medical Monitor is needed.
9. Any exacerbation of COPD (including hospitalization or outpatient therapy) or active pulmonary or upper respiratory infection 60 days prior to start of Screening Visit 1 through the Baseline Visit. This is defined as worsening of respiratory symptoms that required treatment with corticosteroids and/or antibiotics.
10. Initiation of pulmonary rehabilitation within 12 weeks prior to start of Screening Visit 1 or, in the opinion of the Investigator, pulmonary rehabilitation is likely to be needed during the study Treatment Period.
11. The participant has any form of congenital heart disease (repaired or unrepaired; other than a patent foramen ovale).
12. The participant has any musculoskeletal disorder (severe arthritis of the lower limbs which limits ambulation, recent hip or knee joint replacement, artificial leg) or any other condition that would likely be the primary limitation to ambulation.
13. Use of any other investigational drug or device within 30 days prior to the start of Screening Visit 1.
14. Any other clinically significant illness or abnormal laboratory value(s) measured during the Screening Period that, in the opinion of the Investigator, might adversely affect the interpretation of the study data or safety of the participant.

Primary outcomes:
measure: Change From Baseline to Week 12 in 6-Minute Walk Distance (6MWD)
timeFrame: Baseline, Week 12
Secondary outcomes:
measure: Change From Baseline to Week 12 in Moderate to Vigorous Physical Activity (MVPA)
timeFrame: Baseline, Week 12
measure: Change From Baseline to Week 12 in Overall Activity
timeFrame: Baseline, Week 12
measure: Change From Baseline to Week 12 in Borg Dyspnea Score
timeFrame: Baseline, Week 12
measure: Change From Baseline to Week 12 in 6MWD/Borg Dyspnea Composite Score
timeFrame: Baseline, Week 12
measure: Change From Baseline to Week 12 in Quality of Life (QOL) Measured by St. George's Respiratory Questionnaire (SGRQ)
timeFrame: Baseline, Week 12
measure: Change From Baseline to Week 12 in QOL Measured by the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ)
timeFrame: Baseline, Week 12
measure: Change From Baseline to Week 12 in Plasma Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Levels
timeFrame: Baseline, Week 12
measure: Change From Baseline to Week 12 in Patient Global Assessment (PGA)
timeFrame: Baseline, Week 12
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: The University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Banner University Medical Center
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Clinical and Translational Science (CATS) Research Center
state: Arizona
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: West Los Angeles VA Healthcare Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: Santa Barbara
country: United States
facility: Santa Barbara Pulmonary Associates
state: California
city: Aurora
country: United States
facility: University of Colorado Health Sciences Center
state: Colorado
city: Littleton
country: United States
facility: South Denver Cardiology
state: Colorado
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: Clearwater
country: United States
facility: St. Francis Medical Institute
state: Florida
city: Gainesville
country: United States
facility: University of Florida Clinical Research Center
state: Florida
city: Jacksonville
country: United States
facility: St. Vincent's Lung, Sleep, and Critical Care Specialists
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Kissimmee
country: United States
facility: Pulmonary Disease Specialists
state: Florida
city: Miami
country: United States
facility: University of Miami Hospital
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Pulmonary & Critical Care of Atlanta
state: Georgia
city: Austell
country: United States
facility: Georgia Clinical Research
state: Georgia
city: Chicago
country: United States
facility: University of Illinois Medical Center
state: Illinois
city: Elmhurst
country: United States
facility: Advocate Aurora Health Care
state: Illinois
city: Libertyville
country: United States
facility: Advocate Condell Medical Center
state: Illinois
city: Normal
country: United States
facility: Advocate Heart Institute & Pulmonology
state: Illinois
city: Oakbrook Terrace
country: United States
facility: Edward Heart Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Healh North Hospital
state: Indiana
city: Indianapolis
country: United States
facility: St. Vincent Medical Group, Inc.
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky Medical Center
state: Kentucky
city: Louisville
country: United States
facility: Kentuckiana Pulmonary Associates
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville Research Foundation
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Detroit Medical Center Lung Institute
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health
state: Michigan
city: Troy
country: United States
facility: Beaumont Health
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Albuquerque
country: United States
facility: The University of New Mexico
state: New Mexico
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: New York
country: United States
facility: The Mount Sinai Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester 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
state: North Carolina
city: Cincinnati
country: United States
facility: The Carl and Edyth Lindner Research Center at the Christ Hospital
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: DuBois
country: United States
facility: Clinical Research Associates of Central PA, LLC
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple Lung Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center - Montefiore
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
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: UT Southwestern Medical Center
state: Texas
city: El Paso
country: United States
facility: Texas Tech
state: Texas
city: Webster
country: United States
facility: Clear Lake Specialties/Tranquility Research
state: Texas
city: Falls Church
country: United States
facility: Inova Fairfax Hospital
state: Virginia
city: Richmond
country: United States
facility: Pulmonary Associates of Richmond, Inc.
state: Virginia
city: Roanoke
country: United States
facility: Carilion Clinic
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin School of Medicine and Public Health
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Hospital Britanico de Buenos Aires
city: Buenos Aires
country: Argentina
facility: El Cruce Hospital
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Fundacion Favaloro
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
city: Cordoba
country: Argentina
facility: Hospital Italiano de Cordoba
city: Santa Fe
country: Argentina
facility: Centro Medico 21 de Diciembre
city: Haifa
country: Israel
facility: Lady Davis Carmel Medical Centre
city: Jerusalem
country: Israel
facility: Hadassah-Hebrew University Hospital
city: Petah Tiva
country: Israel
facility: Rabin Medical Center
city: Tel Hashomer
country: Israel
facility: The Chaim Sheba Medical Center
city: Guaynabo
country: Puerto Rico
facility: CardioPulmonary Research Center
Study officials:
affiliation: United Therapeutics
name: Medical Director
role: STUDY_DIRECTOR
References: