<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03260569</url>
  </required_header>
  <id_info>
    <org_study_id>2017 Goodman</org_study_id>
    <nct_id>NCT03260569</nct_id>
  </id_info>
  <brief_title>Inhaled Nitric Oxide in Brain Injury</brief_title>
  <official_title>Respiratory Mechanics Following Brain Injury: The Role of Inhaled Nitric Oxide</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Cincinnati</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Cincinnati</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will evaluate the changes in respiratory mechanics following traumatic brain&#xD;
      injury and determine the effect of inhaled nitric oxide on gas exchange.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Intubation and mechanical ventilation are common treatments in the care of patients with&#xD;
      traumatic brain injury (TBI). Intubation allows for airway control and facilitates removal of&#xD;
      respiratory secretions. Mechanical ventilation allows control of arterial carbon dioxide to&#xD;
      aid in control of intracranial pressure. Recent evidence suggests that lung protective&#xD;
      ventilation (tidal volumes of 6 ml/kg of predicted body weight and moderate positive end&#xD;
      expiratory pressure) improves outcomes following brain injury and reduces brain-lung cross&#xD;
      talk.&#xD;
&#xD;
      The treatment of respiratory failure in TBI must balance the need to improve lung function&#xD;
      with the negative consequences of increased intrathoracic pressure on mean arterial pressure,&#xD;
      intracranial pressure and venous return. Traditional treatment of increasing positive end&#xD;
      expiratory (PEEP) and mean airway pressure then, represent competing interests. Methods for&#xD;
      improving arterial oxygenation while avoiding negative hemodynamic effects are needed.&#xD;
&#xD;
      The impact of head injury on respiratory mechanics has been studied in just a few clinical&#xD;
      investigations. (1-3) Of note, the earliest of these noted that the ventilation perfusion&#xD;
      (V/Q) matching following TBI was not the result of lung collapse or parenchymal lung disease&#xD;
      but secondary to alterations in perfusion. There are three possibilities for this finding:&#xD;
&#xD;
        1. redistribution in regional perfusion, which is partially mediated by the hypothalamus&#xD;
&#xD;
        2. pulmonary microembolism, leading to increased dead space&#xD;
&#xD;
        3. lung surfactant depletion due to excessive sympathetic stimulation and hyperventilation.&#xD;
&#xD;
      The introduction of inhaled pulmonary vasodilators such as inhaled nitric oxide or&#xD;
      aerosolized epoprostenol offer an opportunity to improve oxygenation in patients with TBI&#xD;
      without increasing airway pressures in the face of V/Q inequalities.&#xD;
&#xD;
      This study will evaluate the changes in respiratory mechanics following TBI and determine the&#xD;
      effect of inhaled nitric oxide on gas exchange.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 12, 2018</start_date>
  <completion_date type="Anticipated">December 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2024</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Following initial non-invasive measurements, patients will be randomized to either an active treatment (inhaled nitric oxide at 30 parts per million) or placebo (nitrogen only). After two hours, measurements will be reassessed. If the patient remains on the mechanical ventilator at 72 hours post-admission, a third set of non-invasive measurements will be taken.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Both nitric oxide and placebo nitrogen will be made available in unmarked cylinders.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in PaO2</measure>
    <time_frame>Randomization through Day 3 of the study</time_frame>
    <description>The primary endpoint is a change in PaO2 of 20 percent or greater (yes/no)</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">38</enrollment>
  <condition>Traumatic Brain Injury</condition>
  <arm_group>
    <arm_group_label>Inhaled Nitric Oxide</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Inhaled nitric oxide at 20 parts per million, administered once during first 36 hours following admission</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Nitrogen only, administered once during first 36 hours following admission</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Inhaled Nitric Oxide</intervention_name>
    <description>Patients randomized to this arm will receive inhaled nitric oxide 20 parts per million.</description>
    <arm_group_label>Inhaled Nitric Oxide</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Nitrogen plus oxygen</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Hospital admission with traumatic brain injury (penetrating or blunt)&#xD;
&#xD;
          -  Requirement for mechanical ventilation&#xD;
&#xD;
          -  Glasgow Coma Score &gt; 3&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Brain death&#xD;
&#xD;
          -  Expected survival &lt; 48 hours&#xD;
&#xD;
          -  Air leak (bronchopleural fistula, tracheal injury)&#xD;
&#xD;
          -  Current inspired oxygen concentration (FiO2) &gt; 0.65&#xD;
&#xD;
          -  Hemodynamic instability (systolic blood pressure &lt; 100 mm Hg, cardiac arrhythmia)&#xD;
&#xD;
          -  Uncontrolled intracranial pressure (&gt; 20 mm Hg)&#xD;
&#xD;
          -  Spinal cord injury with hypotension&#xD;
&#xD;
          -  Severe acute respiratory distress syndrome (ARDS) (PaO2/FiO2 &lt; 100)&#xD;
&#xD;
          -  Chest abbreviated injury score (AIS) &gt; 3&#xD;
&#xD;
          -  First rib fracture&#xD;
&#xD;
          -  Flail chest&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Michael D Goodman, MD</last_name>
    <phone>513-558-5661</phone>
    <email>goodmanmd@uc.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of Cincinnati</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45267</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Carolina Rodriguez</last_name>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Schumacker PT, Rhodes GR, Newell JC, Dutton RE, Shah DM, Scovill WA, Powers SR. Ventilation-perfusion imbalance after head trauma. Am Rev Respir Dis. 1979 Jan;119(1):33-43. doi: 10.1164/arrd.1979.119.1.33.</citation>
    <PMID>420436</PMID>
  </reference>
  <reference>
    <citation>Cooper KR, Boswell PA. Accurate measurement of functional residual capacity and oxygen consumption of patients on mechanical ventilation. Anaesth Intensive Care. 1983 May;11(2):151-7. doi: 10.1177/0310057X8301100212.</citation>
    <PMID>6346942</PMID>
  </reference>
  <reference>
    <citation>Koutsoukou A, Perraki H, Raftopoulou A, Koulouris N, Sotiropoulou C, Kotanidou A, Orfanos S, Roussos C. Respiratory mechanics in brain-damaged patients. Intensive Care Med. 2006 Dec;32(12):1947-54. doi: 10.1007/s00134-006-0406-0. Epub 2006 Oct 20.</citation>
    <PMID>17053881</PMID>
  </reference>
  <reference>
    <citation>Gruber A, Reinprecht A, Illievich UM, Fitzgerald R, Dietrich W, Czech T, Richling B. Extracerebral organ dysfunction and neurologic outcome after aneurysmal subarachnoid hemorrhage. Crit Care Med. 1999 Mar;27(3):505-14. doi: 10.1097/00003246-199903000-00026.</citation>
    <PMID>10199529</PMID>
  </reference>
  <reference>
    <citation>Holland MC, Mackersie RC, Morabito D, Campbell AR, Kivett VA, Patel R, Erickson VR, Pittet JF. The development of acute lung injury is associated with worse neurologic outcome in patients with severe traumatic brain injury. J Trauma. 2003 Jul;55(1):106-11. doi: 10.1097/01.TA.0000071620.27375.BE.</citation>
    <PMID>12855888</PMID>
  </reference>
  <reference>
    <citation>Pelosi P, Severgnini P, Chiaranda M. An integrated approach to prevent and treat respiratory failure in brain-injured patients. Curr Opin Crit Care. 2005 Feb;11(1):37-42. doi: 10.1097/00075198-200502000-00006.</citation>
    <PMID>15659943</PMID>
  </reference>
  <reference>
    <citation>Garry PS, Ezra M, Rowland MJ, Westbrook J, Pattinson KT. The role of the nitric oxide pathway in brain injury and its treatment--from bench to bedside. Exp Neurol. 2015 Jan;263:235-43. doi: 10.1016/j.expneurol.2014.10.017. Epub 2014 Oct 29.</citation>
    <PMID>25447937</PMID>
  </reference>
  <reference>
    <citation>Terpolilli NA, Kim SW, Thal SC, Kuebler WM, Plesnila N. Inhaled nitric oxide reduces secondary brain damage after traumatic brain injury in mice. J Cereb Blood Flow Metab. 2013 Feb;33(2):311-8. doi: 10.1038/jcbfm.2012.176. Epub 2012 Nov 28.</citation>
    <PMID>23188422</PMID>
  </reference>
  <reference>
    <citation>Papadimos TJ, Medhkour A, Yermal S. Successful use of inhaled nitric oxide to decrease intracranial pressure in a patient with severe traumatic brain injury complicated by acute respiratory distress syndrome: a role for an anti-inflammatory mechanism? Scand J Trauma Resusc Emerg Med. 2009 Feb 17;17:5. doi: 10.1186/1757-7241-17-5.</citation>
    <PMID>19222848</PMID>
  </reference>
  <reference>
    <citation>Papadimos TJ. The beneficial effects of inhaled nitric oxide in patients with severe traumatic brain injury complicated by acute respiratory distress syndrome: a hypothesis. J Trauma Manag Outcomes. 2008 Jan 14;2(1):1. doi: 10.1186/1752-2897-2-1.</citation>
    <PMID>18272001</PMID>
  </reference>
  <reference>
    <citation>Vavilala MS, Roberts JS, Moore AE, Newell DW, Lam AM. The influence of inhaled nitric oxide on cerebral blood flow and metabolism in a child with traumatic brain injury. Anesth Analg. 2001 Aug;93(2):351-3 , 3rd contents page. doi: 10.1097/00000539-200108000-00023.</citation>
    <PMID>11473859</PMID>
  </reference>
  <reference>
    <citation>Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis K Jr, Hyers TM, Papadakos P. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med. 1998 Jan;26(1):15-23. doi: 10.1097/00003246-199801000-00011.</citation>
    <PMID>9428538</PMID>
  </reference>
  <reference>
    <citation>Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. The European Study Group of Inhaled Nitric Oxide. Intensive Care Med. 1999 Sep;25(9):911-9. doi: 10.1007/s001340050982.</citation>
    <PMID>10501745</PMID>
  </reference>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>August 22, 2017</study_first_submitted>
  <study_first_submitted_qc>August 22, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 24, 2017</study_first_posted>
  <last_update_submitted>May 11, 2023</last_update_submitted>
  <last_update_submitted_qc>May 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Cincinnati</investigator_affiliation>
    <investigator_full_name>Michael Goodman</investigator_full_name>
    <investigator_title>Instructor</investigator_title>
  </responsible_party>
  <keyword>Mechanical ventilation</keyword>
  <keyword>Inhaled nitric oxide</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
    <mesh_term>Wounds and Injuries</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nitric Oxide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03260569
org study id: 2017 Goodman
nct id: NCT03260569
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This study will evaluate the changes in respiratory mechanics following traumatic brain
      injury and determine the effect of inhaled nitric oxide on gas exchange.
Intubation and mechanical ventilation are common treatments in the care of patients with
      traumatic brain injury (TBI). Intubation allows for airway control and facilitates removal of
      respiratory secretions. Mechanical ventilation allows control of arterial carbon dioxide to
      aid in control of intracranial pressure. Recent evidence suggests that lung protective
      ventilation (tidal volumes of 6 ml/kg of predicted body weight and moderate positive end
      expiratory pressure) improves outcomes following brain injury and reduces brain-lung cross
      talk.

      The treatment of respiratory failure in TBI must balance the need to improve lung function
      with the negative consequences of increased intrathoracic pressure on mean arterial pressure,
      intracranial pressure and venous return. Traditional treatment of increasing positive end
      expiratory (PEEP) and mean airway pressure then, represent competing interests. Methods for
      improving arterial oxygenation while avoiding negative hemodynamic effects are needed.

      The impact of head injury on respiratory mechanics has been studied in just a few clinical
      investigations. (1-3) Of note, the earliest of these noted that the ventilation perfusion
      (V/Q) matching following TBI was not the result of lung collapse or parenchymal lung disease
      but secondary to alterations in perfusion. There are three possibilities for this finding:

        1. redistribution in regional perfusion, which is partially mediated by the hypothalamus

        2. pulmonary microembolism, leading to increased dead space

        3. lung surfactant depletion due to excessive sympathetic stimulation and hyperventilation.

      The introduction of inhaled pulmonary vasodilators such as inhaled nitric oxide or
      aerosolized epoprostenol offer an opportunity to improve oxygenation in patients with TBI
      without increasing airway pressures in the face of V/Q inequalities.

      This study will evaluate the changes in respiratory mechanics following TBI and determine the
      effect of inhaled nitric oxide on gas exchange.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Following initial non-invasive measurements, patients will be randomized to either an active treatment (inhaled nitric oxide at 30 parts per million) or placebo (nitrogen only). After two hours, measurements will be reassessed. If the patient remains on the mechanical ventilator at 72 hours post-admission, a third set of non-invasive measurements will be taken.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: Both nitric oxide and placebo nitrogen will be made available in unmarked cylinders.
measure: Change in PaO2
time frame: Randomization through Day 3 of the study
description: The primary endpoint is a change in PaO2 of 20 percent or greater (yes/no)
arm group label: Inhaled Nitric Oxide
arm group type: Active Comparator
description: Inhaled nitric oxide at 20 parts per million, administered once during first 36 hours following admission
arm group label: Placebo
arm group type: Placebo Comparator
description: Nitrogen only, administered once during first 36 hours following admission
intervention type: Drug
intervention name: Inhaled Nitric Oxide
description: Patients randomized to this arm will receive inhaled nitric oxide 20 parts per million.
arm group label: Inhaled Nitric Oxide
intervention type: Drug
intervention name: Placebo
description: Nitrogen plus oxygen
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michael D Goodman, MD
phone: 513-558-5661
email: goodmanmd@uc.edu
facility: 
status: Recruiting
contact: 
country: United States
citation: Schumacker PT, Rhodes GR, Newell JC, Dutton RE, Shah DM, Scovill WA, Powers SR. Ventilation-perfusion imbalance after head trauma. Am Rev Respir Dis. 1979 Jan;119(1):33-43. doi: 10.1164/arrd.1979.119.1.33.
PMID: 420436
citation: Cooper KR, Boswell PA. Accurate measurement of functional residual capacity and oxygen consumption of patients on mechanical ventilation. Anaesth Intensive Care. 1983 May;11(2):151-7. doi: 10.1177/0310057X8301100212.
PMID: 6346942
citation: Koutsoukou A, Perraki H, Raftopoulou A, Koulouris N, Sotiropoulou C, Kotanidou A, Orfanos S, Roussos C. Respiratory mechanics in brain-damaged patients. Intensive Care Med. 2006 Dec;32(12):1947-54. doi: 10.1007/s00134-006-0406-0. Epub 2006 Oct 20.
PMID: 17053881
citation: Gruber A, Reinprecht A, Illievich UM, Fitzgerald R, Dietrich W, Czech T, Richling B. Extracerebral organ dysfunction and neurologic outcome after aneurysmal subarachnoid hemorrhage. Crit Care Med. 1999 Mar;27(3):505-14. doi: 10.1097/00003246-199903000-00026.
PMID: 10199529
citation: Holland MC, Mackersie RC, Morabito D, Campbell AR, Kivett VA, Patel R, Erickson VR, Pittet JF. The development of acute lung injury is associated with worse neurologic outcome in patients with severe traumatic brain injury. J Trauma. 2003 Jul;55(1):106-11. doi: 10.1097/01.TA.0000071620.27375.BE.
PMID: 12855888
citation: Pelosi P, Severgnini P, Chiaranda M. An integrated approach to prevent and treat respiratory failure in brain-injured patients. Curr Opin Crit Care. 2005 Feb;11(1):37-42. doi: 10.1097/00075198-200502000-00006.
PMID: 15659943
citation: Garry PS, Ezra M, Rowland MJ, Westbrook J, Pattinson KT. The role of the nitric oxide pathway in brain injury and its treatment--from bench to bedside. Exp Neurol. 2015 Jan;263:235-43. doi: 10.1016/j.expneurol.2014.10.017. Epub 2014 Oct 29.
PMID: 25447937
citation: Terpolilli NA, Kim SW, Thal SC, Kuebler WM, Plesnila N. Inhaled nitric oxide reduces secondary brain damage after traumatic brain injury in mice. J Cereb Blood Flow Metab. 2013 Feb;33(2):311-8. doi: 10.1038/jcbfm.2012.176. Epub 2012 Nov 28.
PMID: 23188422
citation: Papadimos TJ, Medhkour A, Yermal S. Successful use of inhaled nitric oxide to decrease intracranial pressure in a patient with severe traumatic brain injury complicated by acute respiratory distress syndrome: a role for an anti-inflammatory mechanism? Scand J Trauma Resusc Emerg Med. 2009 Feb 17;17:5. doi: 10.1186/1757-7241-17-5.
PMID: 19222848
citation: Papadimos TJ. The beneficial effects of inhaled nitric oxide in patients with severe traumatic brain injury complicated by acute respiratory distress syndrome: a hypothesis. J Trauma Manag Outcomes. 2008 Jan 14;2(1):1. doi: 10.1186/1752-2897-2-1.
PMID: 18272001
citation: Vavilala MS, Roberts JS, Moore AE, Newell DW, Lam AM. The influence of inhaled nitric oxide on cerebral blood flow and metabolism in a child with traumatic brain injury. Anesth Analg. 2001 Aug;93(2):351-3 , 3rd contents page. doi: 10.1097/00000539-200108000-00023.
PMID: 11473859
citation: Dellinger RP, Zimmerman JL, Taylor RW, Straube RC, Hauser DL, Criner GJ, Davis K Jr, Hyers TM, Papadakos P. Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med. 1998 Jan;26(1):15-23. doi: 10.1097/00003246-199801000-00011.
PMID: 9428538
citation: Lundin S, Mang H, Smithies M, Stenqvist O, Frostell C. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. The European Study Group of Inhaled Nitric Oxide. Intensive Care Med. 1999 Sep;25(9):911-9. doi: 10.1007/s001340050982.
PMID: 10501745
responsible party type: Principal Investigator
investigator affiliation: University of Cincinnati
investigator full name: Michael Goodman
investigator title: Instructor
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Wounds and Injuries
mesh term: Nitric Oxide
sharing ipd: Undecided