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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)

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ClinicalTrials.gov Identifier: NCT03496623
Recruitment Status : Recruiting
First Posted : April 12, 2018
Last Update Posted : June 23, 2021
Sponsor:
Information provided by (Responsible Party):
United Therapeutics

Tracking Information
First Submitted Date  ICMJE March 29, 2018
First Posted Date  ICMJE April 12, 2018
Last Update Posted Date June 23, 2021
Actual Study Start Date  ICMJE June 27, 2018
Estimated Primary Completion Date July 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 10, 2020)
Change from Baseline to Week 12 in 6MWD at Peak Exposure (10 to 60 minutes after Dosing) [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: April 5, 2018)
Change in 6-Minute Walk Distance (6MWD) from Baseline to Week 12 [ Time Frame: Baseline to Week 12 ]
The intent of the 6-Minute Walk Test (6MWT) is a validated and reliable measure of exercise ability in patients with chronic respiratory diseases.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 10, 2020)
  • Change from Baseline to Week 12 in Moderate to Vigorous Physical Activity (MVPA) [ Time Frame: Baseline, Week 12 ]
    MVPA measured by actigraphy
  • Change from Baseline to Week 12 in Overall Activity [ Time Frame: Baseline, Week 12 ]
    Activity measured by actigraphy
  • Change from Baseline to Week 12 in Borg Dyspnea Score [ Time Frame: 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 [ Time Frame: Baseline, Week 12 ]
  • Change from Baseline to Week 12 in Quality of Life (QOL) Measured by St. George's Respiratory Questionnaire (SGRQ) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 5, 2018)
  • Change in Borg dyspnea score from Baseline to Week 12 [ Time Frame: Baseline to 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 in quality of life (QOL) measured by St. George's Respiratory Questionnaire (SGRQ) from Baseline to Week 12 [ Time Frame: Baseline to Week 12 ]
    The SGRQ is a designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Scores range from 0 to 100, with higher scores indicating more limitations.
  • Change in QOL measured by the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) from Baseline to Week 12 [ Time Frame: Baseline to 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 in plasma concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) levels from Baseline to Week 12 [ Time Frame: Baseline to Week 12 ]
    The NT-proBNP concentration is a biomarker associated with changes in right heart morphology and function.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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)
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Pulmonary Hypertension
  • Chronic Obstructive Pulmonary Disease
Intervention  ICMJE
  • Drug: Inhaled treprostinil solution
    Treprostinil inhalation solution
  • Drug: Placebo solution
    Placebo solution
Study Arms  ICMJE
  • 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)
    Intervention: Drug: Inhaled treprostinil solution
  • Placebo Comparator: Placebo
    Placebo delivered via an ultrasonic nebulizer for QID administration
    Intervention: Drug: Placebo solution
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 5, 2018)
314
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 31, 2022
Estimated Primary Completion Date July 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Prakash Sista, Ph.D. 240-821-1661 304perfectstudy@lungbiotechnology.com
Contact: Mary Lou Tomson, M.A. 240-821-1881 304perfectstudy@lungbiotechnology.com
Listed Location Countries  ICMJE Argentina,   Israel,   Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03496623
Other Study ID Numbers  ICMJE RIN-PH-304
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party United Therapeutics
Study Sponsor  ICMJE United Therapeutics
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account United Therapeutics
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP