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)

Chronic Obstructive Pulmonary Disease Clinical Trial

— PERFECT  

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03496623
• Other study ID #: RIN-PH-304
• Status: Terminated
• Phase: Phase 3
• Start date: May 8, 2018
• Est. completion date: October 13, 2022

Study information

• Verified date: November 2023
• Source: United Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 188
• Est. completion date: October 13, 2022
• Est. primary completion date: October 13, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Obstructive Pulmonary Disease
• Hypertension
• Hypertension, Pulmonary
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive
• Pulmonary Hypertension

Intervention

Drug:
• Inhaled treprostinil solution
Treprostinil inhalation solution
• Placebo solution
Placebo solution

Locations

Country	Name	City	State
Argentina	El Cruce Hospital	Buenos Aires
Argentina	Hospital Britanico de Buenos Aires	Buenos Aires
Argentina	Fundacion Favaloro	Ciudad Autonoma Buenos Aires
Argentina	Hospital Italiano de Buenos Aires	Ciudad Autonoma Buenos Aires
Argentina	Hospital Italiano de Cordoba	Cordoba
Argentina	Centro Medico 21 de Diciembre	Santa Fe
Israel	Lady Davis Carmel Medical Centre	Haifa
Israel	Hadassah-Hebrew University Hospital	Jerusalem
Israel	Rabin Medical Center	Petah Tiva
Israel	The Chaim Sheba Medical Center	Tel Hashomer
Puerto Rico	CardioPulmonary Research Center	Guaynabo
United States	Albany Medical College	Albany	New York
United States	The University of New Mexico	Albuquerque	New Mexico
United States	Pulmonary & Critical Care of Atlanta	Atlanta	Georgia
United States	University of Colorado Health Sciences Center	Aurora	Colorado
United States	Georgia Clinical Research	Austell	Georgia
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	The University of Alabama at Birmingham	Birmingham	Alabama
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
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	University of Illinois Medical Center	Chicago	Illinois
United States	The Carl and Edyth Lindner Research Center at the Christ Hospital	Cincinnati	Ohio
United States	University of Cincinnati	Cincinnati	Ohio
United States	St. Francis Medical Institute	Clearwater	Florida
United States	Cleveland Clinic	Cleveland	Ohio
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Detroit Medical Center Lung Institute	Detroit	Michigan
United States	Henry Ford Health System	Detroit	Michigan
United States	Clinical Research Associates of Central PA, LLC	DuBois	Pennsylvania
United States	Duke University Medical Center	Durham	North Carolina
United States	Texas Tech	El Paso	Texas
United States	Advocate Aurora Health Care	Elmhurst	Illinois
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	University of Florida Clinical Research Center	Gainesville	Florida
United States	Spectrum Health	Grand Rapids	Michigan
United States	Hartford Hospital	Hartford	Connecticut
United States	Indiana University Healh North Hospital	Indianapolis	Indiana
United States	St. Vincent Medical Group, Inc.	Indianapolis	Indiana
United States	Mayo Clinic - Jacksonville	Jacksonville	Florida
United States	St. Vincent's Lung, Sleep, and Critical Care Specialists	Jacksonville	Florida
United States	Pulmonary Disease Specialists	Kissimmee	Florida
United States	Statcare Pulmonary Consultants	Knoxville	Tennessee
United States	University of Kentucky Medical Center	Lexington	Kentucky
United States	Advocate Condell Medical Center	Libertyville	Illinois
United States	South Denver Cardiology	Littleton	Colorado
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	West Los Angeles VA Healthcare Center	Los Angeles	California
United States	Kentuckiana Pulmonary Associates	Louisville	Kentucky
United States	University of Louisville Research Foundation	Louisville	Kentucky
United States	University of Wisconsin School of Medicine and Public Health	Madison	Wisconsin
United States	University of Miami Hospital	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	The Mount Sinai Hospital	New York	New York
United States	Advocate Heart Institute & Pulmonology	Normal	Illinois
United States	Edward Heart Hospital	Oakbrook Terrace	Illinois
United States	Temple Lung Center	Philadelphia	Pennsylvania
United States	Banner University Medical Center	Phoenix	Arizona
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania
United States	University of Pittsburgh Medical Center - Montefiore	Pittsburgh	Pennsylvania
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Pulmonary Associates of Richmond, Inc.	Richmond	Virginia
United States	Carilion Clinic	Roanoke	Virginia
United States	University of Rochester Medical Center	Rochester	New York
United States	University of California Davis Medical Center	Sacramento	California
United States	Santa Barbara Pulmonary Associates	Santa Barbara	California
United States	University of South Florida	Tampa	Florida
United States	Beaumont Health	Troy	Michigan
United States	University of Arizona Clinical and Translational Science (CATS) Research Center	Tucson	Arizona
United States	MedStar Washington Hospital Center	Washington	District of Columbia
United States	Clear Lake Specialties/Tranquility Research	Webster	Texas

Sponsors (1)

Lead Sponsor	Collaborator
United Therapeutics

Countries where clinical trial is conducted

United States,  Argentina,  Israel,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline to Week 12 in 6-Minute Walk Distance (6MWD)	6 MWD was calculated at peak exposure (10 to 60 minutes after dosing). 6MWT was performed by standardized procedures for all participants. Participants were asked to walk a set course for 6 minutes (timed) and the distance walked (in meters) was recorded. Statistical analyses were not performed due to lack of appropriate sample size.	Baseline, Week 12
Secondary	Change From Baseline to Week 12 in Moderate to Vigorous Physical Activity (MVPA)	MVPA was defined as the number of minutes spent in moderate to vigorous physical activity as measured via a wrist-worn medical grade physical activity monitor. The screening data were used to establish a baseline level of physical activity.	Baseline, Week 12
Secondary	Change From Baseline to Week 12 in Overall Activity	Overall activity was defined as the number of minutes spent in overall activity (non-sedentary activity) as measured via a wrist-worn medical grade physical activity monitor. The screening data will be used to establish a baseline level of physical activity.	Baseline, Week 12
Secondary	Change From Baseline to Week 12 in Borg Dyspnea Score	The Borg Dyspnea Score was a 11-point scale rating the maximum level of dyspnea experienced during the 6-minute walking test (6MWT). Scores range from 0 (no dyspnea at all) to 10 (very, very severe dyspnea), with lower scores indicating a less exertion (a better outcome). The Borg Dyspnea Score was to be evaluated immediately after the 6MWT.	Baseline, Week 12
Secondary	Change From Baseline to Week 12 in 6MWD/Borg Dyspnea Composite Score	6MWD was calculated at peak exposure (10 to 60 minutes after dosing). 6MWT was performed by standardized procedures for all participants. Participants were asked to walk a set course for 6 minutes (timed) and the distance walked (in meters) was recorded. The Borg Dyspnea Score was an 11-point scale rating the maximum level of dyspnea experienced during the 6MWT. Scores range from 0 (no dyspnea at all) to 10 (very, very severe dyspnea), with lower scores indicating less exertion (a better outcome). The Borg Dyspnea Score was to be evaluated immediately after the 6MWT. The average 6WMWD data and the average Borg Dyspnea Composite Score data were summed and reported as the composite score.	Baseline, Week 12
Secondary	Change From Baseline to Week 12 in Quality of Life (QOL) Measured by St. George's Respiratory Questionnaire (SGRQ)	The SGRQ is a designed to measure how breathing impacts overall health, daily life, and perceived well-being in participants with obstructive airways disease. Scores range from 0 to 100, with lower scores indicating a better QoL.	Baseline, Week 12
Secondary	Change From Baseline to Week 12 in QOL Measured by the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ)	The UCSD SOBQ is a self-administered rating of dyspnea associated with activities of daily living. The questionnaire uses a 6-point scale where 0 = "not at all" and 5 = "maximal or unable to do because of breathlessness". Lower scores indicate a better QoL.	Baseline, Week 12
Secondary	Change From Baseline to Week 12 in Plasma Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Levels	The NT-proBNP concentration is a biomarker associated with changes in right heart morphology and function. Improvement is defined as a decrease in the NT-proBNP plasma concentration.	Baseline, Week 12
Secondary	Change From Baseline to Week 12 in Patient Global Assessment (PGA)	The PGA is used to rate participant fatigue and shortness of breath. Participants will use the Sponsor-provided smart device for at-home capture of PGA data. The PGA used a 5-point response scale of: "never," "rarely," "sometimes," "often," or "always" with higher scores indicating a worse symptom rating.	Baseline, Week 12