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) (PERFECT)

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)

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.

Study Overview

• Status: Terminated
• Conditions: Chronic Obstructive Pulmonary Disease; Pulmonary Hypertension
• Intervention / Treatment: Drug: Inhaled treprostinil solution; Drug: Placebo solution

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.

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1280AEB
    • Hospital Britanico de Buenos Aires
  • Buenos Aires, Argentina
    • El Cruce Hospital
  • Ciudad Autonoma Buenos Aires, Argentina, C1093AAS
    • Fundacion Favaloro
  • Ciudad Autonoma Buenos Aires, Argentina, C1093AAS
    • Hospital Italiano de Buenos Aires
  • Cordoba, Argentina
    • Hospital Italiano de Cordoba
  • Santa Fe, Argentina
    • Centro Medico 21 de Diciembre
• Israel
  • Haifa, Israel, 34362
    • Lady Davis Carmel Medical Centre
  • Jerusalem, Israel, 9112001
    • Hadassah-Hebrew University Hospital
  • Petah Tiva, Israel, 49100
    • Rabin Medical Center
  • Tel Hashomer, Israel, 52621
    • The Chaim Sheba Medical Center
• Puerto Rico
  • Guaynabo, Puerto Rico, 00968
    • CardioPulmonary Research Center
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • The University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Banner University Medical Center
    • Tucson, Arizona, United States, 85724
      • University of Arizona Clinical and Translational Science (CATS) Research Center
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University Medical Center
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90073
      • West Los Angeles VA Healthcare Center
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • Santa Barbara, California, United States, 93102
      • Santa Barbara Pulmonary Associates
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Health Sciences Center
    • Littleton, Colorado, United States, 80120
      • South Denver Cardiology
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Hartford Hospital
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • MedStar Washington Hospital Center
  • Florida
    • Clearwater, Florida, United States, 33765
      • St. Francis Medical Institute
    • Gainesville, Florida, United States, 32610
      • University of Florida Clinical Research Center
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville
    • Jacksonville, Florida, United States, 32204
      • St. Vincent's Lung, Sleep, and Critical Care Specialists
    • Kissimmee, Florida, United States, 34741
      • Pulmonary Disease Specialists
    • Miami, Florida, United States, 33136
      • University of Miami Hospital
    • Tampa, Florida, United States, 33606
      • University of South Florida
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Pulmonary & Critical Care of Atlanta
    • Austell, Georgia, United States, 30106
      • Georgia Clinical Research
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois Medical Center
    • Elmhurst, Illinois, United States, 60126
      • Advocate Aurora Health Care
    • Libertyville, Illinois, United States, 60048
      • Advocate Condell Medical Center
    • Normal, Illinois, United States, 06176
      • Advocate Heart Institute & Pulmonology
    • Oakbrook Terrace, Illinois, United States, 60181
      • Edward Heart Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • St. Vincent Medical Group, Inc.
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Healh North Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Medical Center
    • Louisville, Kentucky, United States, 40202
      • Kentuckiana Pulmonary Associates
    • Louisville, Kentucky, United States, 40202
      • University Of Louisville Research Foundation
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • Detroit, Michigan, United States, 48201
      • Detroit Medical Center Lung Institute
    • Grand Rapids, Michigan, United States, 49546
      • Spectrum Health
    • Troy, Michigan, United States, 48085
      • Beaumont Health
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • The University of New Mexico
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
    • New York, New York, United States, 10029
      • The Mount Sinai Hospital
    • Rochester, New York, United States, 14623
      • University of Rochester Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27517
      • University of North Carolina at Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Cincinnati, Ohio, United States, 45219
      • The Carl and Edyth Lindner Research Center at The Christ Hospital
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexner Medical Center
  • Pennsylvania
    • DuBois, Pennsylvania, United States, 15801
      • Clinical Research Associates of Central Pa, LLC
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple Lung Center
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center - Montefiore
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Knoxville, Tennessee, United States, 37909
      • Statcare Pulmonary Consultants
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • El Paso, Texas, United States, 79905
      • Texas Tech
    • Webster, Texas, United States, 77598
      • Clear Lake Specialties/Tranquility Research
  • Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Fairfax Hospital
    • Richmond, Virginia, United States, 23230
      • Pulmonary Associates of Richmond, Inc.
    • Roanoke, Virginia, United States, 24014
      • Carilion Clinic
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin School of Medicine and Public Health
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

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:

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Inhaled Treprostinil; Inhaled treprostinil delivered via an ultrasonic nebulizer with a target dosing regimen of 12 breaths (72 micrograms [mcg]) 4 times daily (QID)	Drug: Inhaled treprostinil solution; Treprostinil inhalation solution
PLACEBO_COMPARATOR: Placebo; Placebo delivered via an ultrasonic nebulizer for QID administration	Drug: Placebo solution; Placebo solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline to Week 12 in 6MWD at Peak Exposure (10 to 60 minutes after Dosing)	The intent of the 6-Minute Walk Test (6MWT) is a validated and reliable measure of exercise ability in participants with chronic respiratory diseases.	Baseline, Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from Baseline to Week 12 in Moderate to Vigorous Physical Activity (MVPA)	MVPA measured by actigraphy	Baseline, Week 12
Change from Baseline to Week 12 in Overall Activity	Activity measured by actigraphy	Baseline, Week 12
Change from Baseline to Week 12 in Borg Dyspnea Score	The Borg dyspnea score is a 10 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).	Baseline, Week 12
Change from Baseline to Week 12 in 6MWD/Borg Dyspnea Composite Score		Baseline, Week 12
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 impact on overall health, daily life, and perceived well-being in participants with obstructive airways disease. Scores range from 0 to 100, with higher scores indicating more limitations.	Baseline, Week 12
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"	Baseline, Week 12
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.	Baseline, Week 12
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.	Baseline, Week 12

Collaborators and Investigators

• Sponsor: United Therapeutics

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 27, 2018
• Primary Completion (ACTUAL): October 13, 2022
• Study Completion (ACTUAL): October 13, 2022

Study Registration Dates

• First Submitted: March 29, 2018
• First Submitted That Met QC Criteria: April 5, 2018
• First Posted (ACTUAL): April 12, 2018

Study Record Updates

• Last Update Posted (ACTUAL): February 8, 2023
• Last Update Submitted That Met QC Criteria: February 7, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: COPD; Pulmonary Hypertension; Tyvaso; Inhaled Treprostinil; 6-Minute Walk Test
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Hypertension; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Hypertension, Pulmonary; Antihypertensive Agents; Pharmaceutical Solutions; Treprostinil
• Other Study ID Numbers: RIN-PH-304

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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