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A Dose Escalation Study to Assess the Safety and Efficacy of Pulsed iNO in Subjects With Pulmonary Fibrosis

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ClinicalTrials.gov Identifier: NCT03267108
Recruitment Status : Recruiting
First Posted : August 30, 2017
Last Update Posted : January 10, 2019
Sponsor:
Collaborator:
Bellerophon
Information provided by (Responsible Party):
Bellerophon ( Bellerophon Pulse Technologies )

Brief Summary:
A phase 2b, 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 (Part 1 and Part 2).

Condition or disease Intervention/treatment Phase
Pulmonary Fibrosis Pulmonary Hypertension Drug: iNO Drug: Placebo Phase 2

Detailed Description:
A phase 2b, 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 and without pulmonary hypertension associated with pulmonary fibrosis on long term oxygen therapy (Part 1 and Part 2).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-Controlled Dose Escalation Study to Assess the Safety and Efficacy of Pulsed iNO in Subjects With Pulmonary Hypertension Associated With Pulmonary Fibrosis on Long Term Oxygen Therapy
Actual Study Start Date : December 29, 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort 1

Part 1: iNO or placebo 30 mcg/kg IBW/hr for a 1 week run-in period and 8 week treatment period

Part 2: Open Label Therapy iNO30 mcg/kg IBW/hr for 8 weeks, iNO45 mcg/kg IBW/hr for 8 weeks, iNO75 mg/kg IBW/hr for 8 weeks followed by long term open label therapy.

Drug: iNO
iNO30 mcg/kg IBW/hr, iNO45 mcg/kg IBW/hr, iNO75 mcg/kg IBW/hr
Other Name: inhaled nitric oxide

Drug: Placebo
Placebo

Experimental: Cohort 2

Part 1: iNO or placebo 45 mcg/kg IBW/hr for 1 week run-in period and a 16 week treatment period

Part 2: Open Label Therapy iNO45 mcg/kg IBW/hr for 8 weeks, iNO 75 mcg/kg/hr for 8 weeks followed by long term open label therapy

Drug: iNO
iNO30 mcg/kg IBW/hr, iNO45 mcg/kg IBW/hr, iNO75 mcg/kg IBW/hr
Other Name: inhaled nitric oxide

Drug: Placebo
Placebo

Experimental: Cohort 3

Part 1: iNO or placebo 75 mcg/kg IBW/hr for 1 week run-in period and a 16 week treatment period

Part 2: Open Label Therapy iNO75 mcg/kg IBW/hr for 8 weeks followed by long term open label therapy

Drug: iNO
iNO30 mcg/kg IBW/hr, iNO45 mcg/kg IBW/hr, iNO75 mcg/kg IBW/hr
Other Name: inhaled nitric oxide

Drug: Placebo
Placebo




Primary Outcome Measures :
  1. Change in 6-Minute Walking Distance [ Time Frame: 8 or 16 Weeks ]
    Change in 6-minute walking distance from baseline

  2. Clinically meaningful reduction in 6MWD [ Time Frame: 8 or 16 Weeks ]
    Percentage of patients with a clinically meaningful reduction in 6MWD (≥15% decrease) from baseline

  3. Change in right ventricular function [ Time Frame: 8 or 16 Weeks ]
    Assessed as the change from baseline in parameters such as RV Tei index and RV free wall longitudinal strain by echocardiography

  4. Change in left ventricular function [ Time Frame: 8 or 16 Weeks ]
    Assessed as the change from baseline in parameters such as LV Tei index and LV ejection fraction by echocardiography

  5. Change in Nadir SpO2 during 6MWT [ Time Frame: 8 or 16 Weeks ]
    Difference in the Nadir SpO2 during 6MWT from baseline

  6. Change in Oxygen desaturation during 6MWT [ Time Frame: 8 or 16 Weeks ]
    Difference in oxygen desaturation during 6MWT from baseline

  7. Patients who remain above 88% SPO2 during 6MWT [ Time Frame: 8 or 16 Weeks ]
    Percentage of patients who remain above 88% oxygen saturation (SpO2) during 6MWT

  8. Change in Oxygen during the 6MWT [ Time Frame: 8 or 16 Weeks ]
    Change in supplemental oxygen during 6MWT as compared to baseline

  9. Increase in supplemental oxygen [ Time Frame: 8 or 16 Weeks ]
    Increase in supplemental oxygen during 6MWT

  10. Change in Distance Saturation Product (DSP) [ Time Frame: 8 or 16 Weeks ]
    Difference in Distance Saturation Product (DSP) from baseline

  11. Decrease in Distance Saturation Product (DSP) [ Time Frame: 8 or 16 Weeks ]
    Percentage of patients with ≥15% decrease in DSP from baseline

  12. Change in Integral Distance Saturation Product (IDSP) [ Time Frame: 8 or 16 Weeks ]
    Difference in Integral Distance Saturation Product (IDSP) from baseline

  13. Decrease in Integral Distance Saturation Product (IDSP) [ Time Frame: 8 or 16 Weeks ]
    Percentage of patients with ≥15% decrease in IDSP from baseline

  14. Change in Activity Monitoring Measurement [ Time Frame: 8 or 16 Weeks ]
    Difference in activity as measured by activity monitoring from baseline

  15. Decrease in Activity Monitoring Measurment [ Time Frame: 8 or 16 Weeks ]
    Percentage of patients with ≥15% decrease in activity monitoring from baseline

  16. Difference in Dyspnea [ Time Frame: 8 or 16 Weeks ]
    Difference in dyspnea as measured by University of California, San Diego (UCSD) Shortness of Breath Questionnaire (SOBQ) from baseline

  17. Change in St. George Respiratory Questionnaire (SGRQ) [ Time Frame: 8 or 16 Weeks ]
    Difference in St. George Respiratory Questionnaire (SGRQ) and sub-groups from baseline

  18. Change in Disease-specific quality of life [ Time Frame: 8 or 16 Weeks ]
    Percentage of patients with a clinically meaningful difference (reduction of at least 4 points) in the disease-specific quality of life measured using the disease specific St. George Respiratory Questionnaire (SGRQ) from baseline

  19. Change in Borg Dyspnea Score [ Time Frame: 8 or 16 Weeks ]
    Change in Borg Dyspnea score from baseline

  20. Change in Composite of Borg Dyspnea and 6MWD [ Time Frame: 8 or 16 Weeks ]
    Change in composite of Borg Dyspnea and 6MWD from baseline

  21. Change in Pulmonary Hemodynamics [ Time Frame: 8 or 16 Weeks ]
    Change in pulmonary hemodynamics (i.e., cardiac output [CO], cardiac index [CI], mean pulmonary artery pressure [mPAP], mean pulmonary capillary wedge pressure [mPCWP],systolic pulmonary artery pressure [sPAP], diastolic pulmonary artery pressure [dPAP],pulmonary vascular resistance [PVR], and oxygen saturation by pulse oximeter [SpO2], mixed venous O2, and right atrial pressure [RAP]), measured by right heart catheterization (RHC),with iNO as compared to placebo, from Baseline

  22. Pulmonary Hemodynamics Change ≥20% [ Time Frame: 8 or 16 Weeks ]
    Percentage of patients with a ≥20% change in pulmonary hemodynamic parameters (see #20) from baseline

  23. Change in NT-ProBNP [ Time Frame: 8 or 16 Weeks ]
    Change in NT-ProBNP (absolute and percentage) from baseline

  24. Time to Clinical Improvement [ Time Frame: 8 or 16 Weeks ]
    Time to Clinical Improvement

  25. Time to Clinical Worsening [ Time Frame: 8 or 16 Weeks ]
    Time to clinical worsening

  26. Percent of Responders [ Time Frame: 8 or 16 Weeks ]
    Percent of Responders

  27. Change in REVEAL RISK [ Time Frame: 8 or 16 Weeks ]
    Change in REVEAL RISK



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed Informed Consent
  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. At least 50% of the subjects will have confirmed intermediate or high probability of pulmonary hypertension as determined by echocardiography according to the 2015 ESC/ERS Guidelines for Diagnosis and Treatment of Pulmonary Hypertension.
  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 ≤ 450 meters prior to randomization
  6. WHO Functional Class II-IV
  7. Forced Vital Capacity ≥ 40% predicted within last 6 months prior to screening the screening run-in period.
  8. For at least 1 week prior to Baseline/Randomization, subjects must demonstrate the ability to consistently use the device greater than 12 hrs/day in the opinion of the Investigator.
  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 prior to the Baseline/Randomization visit.
  11. Age between 18 and 85 years (inclusive)
  12. Subject should be clinically stable for at least 4 weeks prior to Baseline/Randomization in the opinion of the Principal Investigator.

Exclusion Criteria:

  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 any PAH-specific medications regardless of reason for use
  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 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. In the last 6 months prior to screening, evidence of any connective tissue disease with FVC > 60% unless there is evidence of moderate to severe fibrosis on CT scan in the opinion of the Investigator
  12. Evidence of clinically significant Combined Pulmonary Fibrosis and Emphysema (CPFE) if > 15% of lung fields by CT scan show evidence of emphysema in the opinion of the Investigator

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03267108


Contacts
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Contact: Deena Peace 908-574-4847 deena.peace@bellerophon.com
Contact: Amy Edmonds 908-574-4765 amy.edmonds@bellerophon.com

  Show 20 Study Locations
Sponsors and Collaborators
Bellerophon Pulse Technologies
Bellerophon
Investigators
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Study Director: Hunter Gillies, MD Bellerophon Therapeutics

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Responsible Party: Bellerophon Pulse Technologies
ClinicalTrials.gov Identifier: NCT03267108     History of Changes
Other Study ID Numbers: PULSE-PHPF-001
First Posted: August 30, 2017    Key Record Dates
Last Update Posted: January 10, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Bellerophon ( Bellerophon Pulse Technologies ):
Pulmonary Fibrosis
PF
Pulmonary Hypertension
Inhaled Nitric Oxide
iNO
Long Term Oxygen Therapy
Oxygen

Additional relevant MeSH terms:
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Hypertension
Fibrosis
Hypertension, Pulmonary
Pulmonary Fibrosis
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Nitric Oxide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Endothelium-Dependent Relaxing Factors
Vasodilator Agents
Gasotransmitters
Protective Agents