PERFECT: 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)

Sponsor

United Therapeutics (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03496623

Collaborator

(none)

314

Enrollment

Locations

Arms

49.1

Anticipated Duration (Months)

4.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Hypertension Chronic Obstructive Pulmonary Disease	Drug: Inhaled treprostinil solution Drug: Placebo solution	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

314 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Jun 27, 2018

Anticipated Primary Completion Date :

Jul 31, 2022

Anticipated Study Completion Date :

Jul 31, 2022

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Change from Baseline to Week 12 in Moderate to Vigorous Physical Activity (MVPA) [Baseline, Week 12]
MVPA measured by actigraphy
Change from Baseline to Week 12 in Overall Activity [Baseline, Week 12]
Activity measured by actigraphy
Change from Baseline to Week 12 in Borg Dyspnea Score [Baseline, Week 12]
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).
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) [Baseline, Week 12]
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.
Change from Baseline to Week 12 in QOL measured by the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) [Baseline, Week 12]
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"
Change from Baseline to Week 12 in Plasma Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Levels [Baseline, Week 12]
The NT-proBNP concentration is a biomarker associated with changes in right heart morphology and function.
Change from Baseline to Week 12 in Patient Global Assessment (PGA) [Baseline, Week 12]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

Participant voluntarily gives informed consent to participate in the study.
Males and females 18 years of age and above at the time of informed consent.
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).
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.
Diagnosis of PH-COPD (World Heath Organization [WHO] Group 3).
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):

Forced expiratory volume in 1 second (FEV1) <80% predicted
FEV1/Forced vital capacity (FVC) <70
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.
During Screening Visit 1 prior to start of low-dose inhaled treprostinil, a 6MWD greater than or equal to 100 meters.
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:
Pulmonary vascular resistance (PVR) greater than or equal to 4 Wood units
A pulmonary artery wedge pressure (PAWP) or left ventricular end-diastolic pressure (LVEDP) of less than or equal to 15 millimeters of mercury (mmHg)
A Pulmonary artery pressure mean (PAPm) of greater than or equal to 30 mmHg
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.
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:

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.
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.

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.
The participant has a previous diagnosis of homozygous alpha-1 antitrypsin deficiency.
The participant has any prior intolerance to inhaled prostanoid therapy.
Inability to tolerate low-dose (3 breaths, 18 mcg) study drug and/or inability to follow dosing regimen during the Screening Period (pre-randomization).
Unwilling or unable to use Sponsor-provided devices (actigraph, spirometer, or smart device).
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.
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.
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.
The participant has any form of congenital heart disease (repaired or unrepaired; other than a patent foramen ovale).
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.
Use of any other investigational drug or device within 30 days prior to the start of Screening Visit 1.
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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Banner University Medical Center	Phoenix	Arizona	United States	85006
3	University of Arizona Clinical and Translational Science (CATS) Research Center	Tucson	Arizona	United States	85724
4	Loma Linda University Medical Center	Loma Linda	California	United States	92354
5	University of Southern California	Los Angeles	California	United States	90033
6	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
7	West Los Angeles VA Healthcare Center	Los Angeles	California	United States	90073
8	University of California Davis Medical Center	Sacramento	California	United States	95817
9	Santa Barbara Pulmonary Associates	Santa Barbara	California	United States	93102
10	University of Colorado Health Sciences Center	Aurora	Colorado	United States	80045
11	South Denver Cardiology	Littleton	Colorado	United States	80120
12	Hartford Hospital	Hartford	Connecticut	United States	06106
13	MedStar Washington Hospital Center	Washington	District of Columbia	United States	20010
14	St. Francis Medical Institute	Clearwater	Florida	United States	33765
15	University of Florida Clinical Research Center	Gainesville	Florida	United States	32610
16	St. Vincent's Lung, Sleep, and Critical Care Specialists	Jacksonville	Florida	United States	32204
17	Mayo Clinic - Jacksonville	Jacksonville	Florida	United States	32224
18	Pulmonary Disease Specialists	Kissimmee	Florida	United States	34741
19	University of Miami Hospital	Miami	Florida	United States	33136
20	University of South Florida	Tampa	Florida	United States	33606
21	Pulmonary & Critical Care of Atlanta	Atlanta	Georgia	United States	30342
22	Georgia Clinical Research	Austell	Georgia	United States	30106
23	University of Illinois Medical Center	Chicago	Illinois	United States	60612
24	Advocate Aurora Health Care	Elmhurst	Illinois	United States	60126
25	Advocate Condell Medical Center	Libertyville	Illinois	United States	60048
26	Advocate Heart Institute & Pulmonology	Normal	Illinois	United States	06176
27	Edward Heart Hospital	Oakbrook Terrace	Illinois	United States	60181
28	Indiana University Healh North Hospital	Indianapolis	Indiana	United States	46202
29	St. Vincent Medical Group, Inc.	Indianapolis	Indiana	United States	46260
30	University of Kentucky Medical Center	Lexington	Kentucky	United States	40536
31	Kentuckiana Pulmonary Associates	Louisville	Kentucky	United States	40202
32	University of Louisville Research Foundation	Louisville	Kentucky	United States	40202
33	University of Maryland Medical Center	Baltimore	Maryland	United States	21201
34	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
35	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
36	Detroit Medical Center Lung Institute	Detroit	Michigan	United States	48201
37	Henry Ford Health System	Detroit	Michigan	United States	48202
38	Spectrum Health	Grand Rapids	Michigan	United States	49546
39	Beaumont Health	Troy	Michigan	United States	48085
40	University of Minnesota	Minneapolis	Minnesota	United States	55455
41	The University of New Mexico	Albuquerque	New Mexico	United States	87106
42	Albany Medical College	Albany	New York	United States	12208
43	The Mount Sinai Hospital	New York	New York	United States	10029
44	University of Rochester Medical Center	Rochester	New York	United States	14623
45	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27517
46	Duke University Medical Center	Durham	North Carolina	United States	27710
47	The Carl and Edyth Lindner Research Center at the Christ Hospital	Cincinnati	Ohio	United States	45219
48	University of Cincinnati	Cincinnati	Ohio	United States	45267
49	Cleveland Clinic	Cleveland	Ohio	United States	44195
50	The Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43210
51	Clinical Research Associates of Central PA, LLC	DuBois	Pennsylvania	United States	15801
52	Temple Lung Center	Philadelphia	Pennsylvania	United States	19140
53	Allegheny General Hospital	Pittsburgh	Pennsylvania	United States	15212
54	University of Pittsburgh Medical Center - Montefiore	Pittsburgh	Pennsylvania	United States	15213
55	Rhode Island Hospital	Providence	Rhode Island	United States	02903
56	Medical University of South Carolina	Charleston	South Carolina	United States	29425
57	Statcare Pulmonary Consultants	Knoxville	Tennessee	United States	37909
58	UT Southwestern Medical Center	Dallas	Texas	United States	75390
59	Texas Tech	El Paso	Texas	United States	79905
60	Clear Lake Specialties/Tranquility Research	Webster	Texas	United States	77598
61	Inova Fairfax Hospital	Falls Church	Virginia	United States	22042
62	Pulmonary Associates of Richmond, Inc.	Richmond	Virginia	United States	23230
63	Carilion Clinic	Roanoke	Virginia	United States	24014
64	University of Wisconsin School of Medicine and Public Health	Madison	Wisconsin	United States	53792
65	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
66	Hospital Britanico de Buenos Aires	Buenos Aires		Argentina	1280AEB
67	El Cruce Hospital	Buenos Aires		Argentina
68	Fundacion Favaloro	Ciudad Autonoma Buenos Aires		Argentina	C1093AAS
69	Hospital Italiano de Buenos Aires	Ciudad Autonoma Buenos Aires		Argentina	C1093AAS
70	Hospital Italiano de Cordoba	Cordoba		Argentina
71	Centro Medico 21 de Diciembre	Santa Fe		Argentina
72	Lady Davis Carmel Medical Centre	Haifa		Israel	34362
73	Hadassah-Hebrew University Hospital	Jerusalem		Israel	9112001
74	Rabin Medical Center	Petah Tiva		Israel	49100
75	The Chaim Sheba Medical Center	Tel Hashomer		Israel	52621
76	CardioPulmonary Research Center	Guaynabo		Puerto Rico	00968