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A Safety and Efficacy Study of Pulsed Inhaled Nitric Oxide in Pulmonary Hypertension Associated With Pulmonary Fibrosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03267108
Recruitment Status : Active, not recruiting
First Posted : August 30, 2017
Last Update Posted : June 16, 2020
Sponsor:
Collaborator:
Bellerophon
Information provided by (Responsible Party):
Bellerophon ( Bellerophon Pulse Technologies )

Tracking Information
First Submitted Date  ICMJE August 27, 2017
First Posted Date  ICMJE August 30, 2017
Last Update Posted Date June 16, 2020
Actual Study Start Date  ICMJE December 29, 2017
Estimated Primary Completion Date June 16, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 11, 2020)
  • Change in Moderate to Vigorous Physical Activity (MVPA) as Measured by Actigraphy [ Time Frame: Baseline of Blinded Treatment to Month 4 ]
    Part 1 - Blinded Treatment Period
  • Adverse Events and Serious Adverse Events with Long Term Therapy will be Summarized [ Time Frame: Baseline of OLE to Month 4 ]
    Part 2 - Open Label Extension (OLE)
Original Primary Outcome Measures  ICMJE
 (submitted: August 27, 2017)
6 Minute Walk Distance (6MWD) [ Time Frame: 8 weeks ]
Change in 6MWD from baseline to Week 8
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 12, 2020)
  • Change in Overall Activity as Measured by Actigraphy [ Time Frame: Baseline of Blinded Treatment to Month 4 ]
    Part 1 - Blinded Treatment Period
  • Change in University of California San Diego (UCSD) Shortness of Breath Questionnaire (SOBQ) [ Time Frame: Baseline of Blinded Treatment to Month 4 ]
    Part 1 - Blinded Treatment Period: The UCSD SOBQ is a 24-item questionnaire developed to measure breathlessness associated with activities of daily living, on a scale between zero and five where 0 is not at all breathless and 5 is maximally breathless or too breathless to do the activity. The responses to all items are summed up to provide the overall score that can range from 0 (best outcome) to 120 (worst outcome).
  • Change in St. George Respiratory Questionnaire (SGRQ) - Activity, Impacts & Total [ Time Frame: Baseline of Blinded Treatment to Month 4 ]
    Part 1 - Blinded Treatment Period: SGRQ is a tool for assessing quality of life that has previously been validated for the use with patients with interstitial lung disease. It is a responsive tool that has three domains: symptoms, activity and impact (on daily life)
  • Clinical Worsening - defined as first clinically adjudicated event of either death (all cause), Need for Hospitalization due to cardiopulmonary worsening, Reduction in 6 Minute Walk Distance (6MWD) [ Time Frame: Baseline of Blinded Treatment to Month 4 ]
    Part 1 - Blinded Treatment Period
  • Clinical Deterioration - defined as the 1st event observed at 2 sequential visits or at Month 4 of either St. George Respiratory Quest., U of Cal San Diego Shortness of Breath Quest., Six Minute Walk Distance, Moderate Vigorous Physical Activity [ Time Frame: Baseline of Blinded Treatment to Month 4 ]
    Part 1 - Blinded Treatment Period
  • Clinical Improvement - defined as the 1st event observed at 2 sequential visits or at Month 4 of either St. George Respiratory Quest., U of Cal San Diego Shortness of Breath Quest., Six Minute Walk Distance, Moderate Vigorous Physical Activity [ Time Frame: Baseline of Blinded Treatment to Month 4 ]
    Part 1 - Blinded Treatment Period
  • Change in 6 Minute Walk Distance [ Time Frame: Baseline of Blinded Treatment to Month 4 ]
    Part 1 - Blinded Treatment Period
Original Secondary Outcome Measures  ICMJE
 (submitted: August 27, 2017)
Right Ventricular Function (RVF) [ Time Frame: 8 weeks ]
Change in RVF as measured by RV Tei index and RV free wall longitudinal strain from baseline to Week 8
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: August 27, 2017)
  • Nadir SpO2 [ Time Frame: 8 weeks ]
    Difference in Nadir SpO2 during 6MWT from baseline to Week 8
  • Oxygen desaturation [ Time Frame: 8 weeks ]
    Difference in oxygen desaturation during 6MWT from baseline to Week 8
  • Distance Saturation Product (DSP) [ Time Frame: 8 weeks ]
    Difference in DSP from baseline to Week 8
  • Integral Distance Saturation Product (IDSP) [ Time Frame: 8 weeks ]
    Difference in IDSP from baseline to Week 8
  • Activity [ Time Frame: 8 weeks ]
    Difference in Activity as measured by activity monitoring from baseline to Week 8
  • Dyspnea [ Time Frame: 8 weeks ]
    Difference in Dyspnea as measured by UCSD Shortness of Breath (SOB) questionnaire from baseline to Week 8
  • Quality of Life [ Time Frame: 8 weeks ]
    Difference in disease-specific Quality of Life as measured by St. George Respiratory questionnaire (SGRQ) from baseline to Week 8
 
Descriptive Information
Brief Title  ICMJE A Safety and Efficacy Study of Pulsed Inhaled Nitric Oxide in Pulmonary Hypertension Associated With Pulmonary Fibrosis
Official Title  ICMJE Randomized, Double-Blind, Placebo-Controlled Dose Escalation and Verification Study to Assess the Safety and Efficacy of Pulsed iNO in Subjects at Risk of Pulmonary Hypertension Associated With Pulmonary Fibrosis on Long Term Oxygen Therapy
Brief Summary A randomized, double-blind, placebo-controlled dose escalation and verification study to assess the safety and efficacy of pulsed iNO versus placebo in subjects at risk for pulmonary hypertension associated with pulmonary fibrosis on long term oxygen therapy.
Detailed Description A phase 3, randomized, double-blind, placebo-controlled dose escalation clinical study to assess the safety and efficacy of pulsed inhaled nitric oxide (iNO) versus placebo in subjects with pulmonary fibrosis on long term oxygen therapy.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Pulmonary Fibrosis
  • Pulmonary Hypertension
Intervention  ICMJE
  • Combination Product: iNOpulse
    Subjects will be treated by means of an iNOpulse device using an iNOpulse nasal cannula.
  • Combination Product: Placebo
    Subjects will be treated by means of an iNOpulse device using an iNOpulse nasal cannula.
  • Combination Product: Open Label Extension
    Subjects will be treated by means of an iNOpulse device using an iNOpulse nasal cannula.
Study Arms  ICMJE
  • Active Comparator: Inhaled Nitric Oxide (iNO)
    Pulsed inhaled iNO45 mcg/kg Ideal Body Weight (IBW)/hour (hr)
    Intervention: Combination Product: iNOpulse
  • Placebo Comparator: Placebo
    Pulsed inhaled N2, 99.999% gas
    Intervention: Combination Product: Placebo
  • Open Label Extension
    Open Label Therapy iNO45 mcg/kg IBW/hr
    Intervention: Combination Product: Open Label Extension
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 Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: June 11, 2020)
300
Original Estimated Enrollment  ICMJE
 (submitted: August 27, 2017)
40
Estimated Study Completion Date  ICMJE March 23, 2023
Estimated Primary Completion Date June 16, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Part 1: Blinded Treatment Period

Inclusion criteria: Subjects must meet all of the following inclusion criteria to be enrolled and eligible to participate in the study:

  1. Signed Informed Consent Form (and assent as appropriate) prior to the initiation of any study mandated procedures or assessments.
  2. Diagnosed with pulmonary fibrosis by high resolution CT scan performed in the 6 months prior to screening associated with one of the following conditions and confirmed using guidelines, as per American Thoracic Society (ATS) / European Respiratory Society (ERS) / Japanese Respiratory Society (JRS) / Latin American Thoracic Association (ALAT): Major IIPs (idiopathic interstitial pneumonias) diagnosis or suspected as one of the following:

    • Idiopathic pulmonary fibrosis
    • Idiopathic nonspecific interstitial pneumonia
    • Respiratory bronchiolitis-interstitial lung disease
    • Desquamative interstitial pneumonia
    • Cryptogenic organizing pneumonia
    • Acute interstitial pneumonia

    Rare IIPs diagnosis by one of the following:

    • Idiopathic lymphoid interstitial pneumonia
    • Idiopathic pleuroparenchymal fibroelastosis

    Unclassifiable idiopathic interstitial pneumonias

    • Chronic hypersensitivity pneumonitis
    • Occupational lung disease
  3. Low or Intermediate/high probability of pulmonary hypertension (PH) by echocardiogram as assessed by local

    Radiologist/Investigator, or PH as determined by a right heart catheterization (RHC) within 3 years prior to Baseline with the following parameters:

    1. Pulmonary vascular resistance (PVR) ≥ 3 Wood Units (WU) (320 dynes.sec.cm-5)
    2. A left ventricular end diastolic pressure (LVEDP) or pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg
    3. A mean pulmonary arterial pressure (mPAP) of ≥ 21 mmHg

      • If a right heart catheterization is negative for PH within the past year, subjects will be stratified to low probability of PH
  4. Have been using oxygen therapy by nasal cannula for at least 4 weeks prior to the screening run-in period.
  5. 6MWD ≥ 100 meters and ≤ 400 meters at screening and Baseline/Randomization visits.
  6. World Health Organization (WHO) Functional Class II-IV
  7. Forced Vital Capacity ≥ 40% predicted within last 6 months prior to screening the screening run-in period.
  8. Willingness to use INOpulse delivery device for at least 12 hours per day
  9. Female subjects of childbearing potential must have a negative pre-treatment pregnancy test (serum or urine). All female subjects should take adequate precaution to avoid pregnancy.
  10. Subjects must have completed at least 1 week of activity monitoring at time of the Baseline/Randomization visit.
  11. During the Screening Run-In period prior to Baseline/Randomization, subjects must demonstrate the ability to consistently use the INOpulse device greater than 12 hrs/day in the opinion of the investigator.
  12. Age between 18 and 80 years (inclusive)
  13. Subject should be clinically stable for at least 4 weeks prior to Baseline/Randomization in the opinion of the Principal Investigator.
  14. During the Screening Run-In period, subjects must demonstrate their ability to wear the activity monitor for at least 10 hours per day when awake at the time of the Baseline/Randomization visit in the opinion of the investigator.

Exclusion criteria: Subjects who meet any of the following criteria are not eligible for enrollment:

  1. Demonstrate symptomatic rebound defined as significant cardiopulmonary instability, such as systemic arterial oxygen desaturation, hypoxemia, bradycardia, tachycardia, systemic hypotension, shortness of breath, near-syncope, and syncope, occurring within 1 hour of acute iNO during rebound testing
  2. Episodes of disease worsening within 1 month prior to Baseline/Randomization
  3. Use of prostacyclin, guanylate cyclase stimulators, or endothelin receptor antagonists (ERA) pulmonary arterial hypertension (PAH)-specific medications regardless of reason for use (use of Phosphodiesterase-5 (PDE-5)) inhibitors regardless of reason for use is allowed)
  4. Acute or chronic physical impairment (other than dyspnea due to PF) that would limit the ability to comply with study procedures or adherence to therapy (i.e., 6MWT), including carrying and wearing the pulsed delivery INOpulse device per study protocol, or medical problem(s) likely to preclude completion of the study
  5. Pregnant or breastfeeding females at Screening
  6. Administered L-arginine within 1 month prior to Screening
  7. The concurrent use of the INOpulse device with a continuous positive airway pressure (CPAP), Bilevel positive airway pressure (BPAP), or any other positive pressure device.
  8. Use of investigational drugs or devices within 1 month prior to Screening (other than acute vasodilator testing with iNO)
  9. Any underlying medical or psychiatric condition that, in the opinion of the Investigator, makes the subject an unsuitable candidate for the study including unable to complete 6MWT
  10. Any subject who has been enrolled in any previous clinical study with inhaled NO administered through pulse delivery
  11. A definitive diagnosis of a connective tissue disease (eg, systemic sclerosis via American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria)
  12. The presence of emphysema unless the extent of fibrotic changes is greater than the extent of emphysema on the most recent HRCT scan in the opinion of the local radiologist/Investigator.
  13. A subject should not start a rehabilitation program during the study, not have started within 3 months of screening or change the nature of their rehabilitation program at any time during the blinded portion of the study.

Part 2: Open Label Period

Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be eligible to participate in Part 2 of the trial:

  1. All subjects must have completed Part 1- Blinded Treatment Period study assessments.
  2. In the opinion of the investigator, the subject would benefit from continued therapy with iNO 45. For Cohort 1 and 2 subjects, if investigator believes the subject's prior treatment dose of iNO 30 or iNO 75 mcg/kg IBW/hr is medically justified and would benefit the subject, agreement with the Sponsor's Medical Monitor should be obtained prior to enrollment.

Exclusion Criteria:

  1. Use of prostacyclin, guanylate cyclase stimulator or ERA PAH-specific medications regardless of reason for use (use of PDE-5 inhibitors regardless of reason for use is allowed).
  2. The concurrent use of the INOpulse device with CPAP/BiPAP, or any other positive pressure device.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03267108
Other Study ID Numbers  ICMJE PULSE-PHPF-001
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 Bellerophon ( Bellerophon Pulse Technologies )
Study Sponsor  ICMJE Bellerophon Pulse Technologies
Collaborators  ICMJE Bellerophon
Investigators  ICMJE
Study Director: Hunter Gillies, MD Bellerophon Therapeutics
PRS Account Bellerophon
Verification Date June 2020

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