<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/NCT04446871</url>
  </required_header>
  <id_info>
    <org_study_id>HCG/CEI-0252/17</org_study_id>
    <nct_id>NCT04446871</nct_id>
  </id_info>
  <brief_title>Methylene Blue in Early Septic Shock</brief_title>
  <acronym>SHOCKEM-Blue</acronym>
  <official_title>Early Use of Methylene Blue in Patients With Septic Shock: a Pilot Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital Civil de Guadalajara</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hospital Civil de Guadalajara</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Septic shock is a subset of sepsis characterized by a decrease in vascular tone, which&#xD;
      contributes to impaired regional blood flow distribution, and leads to organic failure.&#xD;
      Besides intravenous fluids and adequate antimicrobial therapy, patients with septic shock&#xD;
      require vasopressor support, which can lead to many adverse effects, therefore,&#xD;
      non-vasopressor agents that can improve hemodynamic status are needed. In this randomized&#xD;
      controlled-study, the investigators will address the efficacy and safety of infusion with&#xD;
      methylene blue in patients with septic shock.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Unlike sepsis, septic shock mortality is not declining for the last decade, and is still&#xD;
      around 40%. After restoring intravascular volume, many patients need vasopressor agents to&#xD;
      maintain arterial blood pressure, which leads to improvement of perfusion at some vascular&#xD;
      beds, however some organs may suffer from maldistribution of blood flow. These changes of&#xD;
      regional blood flow may compromise oxygen delivery and perpetuate the inflammation and tissue&#xD;
      damage associated with the state of shock.&#xD;
&#xD;
      One of the main mechanisms of vasodilation after inflammatory insults, is the activation of&#xD;
      the inducible isoform of Nitric Oxide Synthase (iNOS), and the subsequent increase in the&#xD;
      levels of nitric oxide, which even reduces the response to vasoconstrictor agents. Methylene&#xD;
      blue (MB) is a selective inhibitor of iNOS, which has been used successfully in patients with&#xD;
      post-cardiopulmonary bypass associated vasoplegia, however, the evidence of the use of MB in&#xD;
      septic shock patients is limited to case reports, observational and small studies. In this&#xD;
      randomized controlled trial, the investigators will compare the efficacy and safety outcomes&#xD;
      of repeated doses of MB in patients with septic shock.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 17, 2017</start_date>
  <completion_date type="Actual">January 25, 2021</completion_date>
  <primary_completion_date type="Actual">December 10, 2020</primary_completion_date>
  <phase>Phase 2/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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Vasopressor requirement</measure>
    <time_frame>28 days</time_frame>
    <description>Total time to shock resolution (hours)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to lactate normalization</measure>
    <time_frame>7 days</time_frame>
    <description>Time in hours until lactate is &lt;2 mmol/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of stay in intensive care unit</measure>
    <time_frame>28 days</time_frame>
    <description>Time in days until ICU discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intensive care unit mortality</measure>
    <time_frame>28 days</time_frame>
    <description>Mortality in intensive care unit</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in pulmonary function after treatment</measure>
    <time_frame>7 days</time_frame>
    <description>Change in P/F index after three doses of methylene blue</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">91</enrollment>
  <condition>Septic Shock</condition>
  <arm_group>
    <arm_group_label>Standard care</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Methylene blue</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Methylene blue</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>0.9% sodium chloride</intervention_name>
    <description>Intravenous infusion of 500 cc of 0.9% sodium chloride solution for 6 h, once a day for a total of 3 doses.</description>
    <arm_group_label>Standard care</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methylene Blue</intervention_name>
    <description>Intravenous infusion of 100 mg methylene blue in 500 cc of 0.9% sodium chloride solution for 6 h, once a day for a total of 3 doses.</description>
    <arm_group_label>Methylene blue</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Septic shock diagnosis, according to the Sepsis-3 consensus.&#xD;
&#xD;
          -  Prior adequate fluid resuscitation according to dynamic predictors of volume&#xD;
             responsiveness.&#xD;
&#xD;
          -  More than 6 h and less than 24 h of norepinephrine requirement to maintain a mean&#xD;
             arterial pressure ≥65 mmHg.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age &lt; 18 years.&#xD;
&#xD;
          -  Pregnancy.&#xD;
&#xD;
          -  Not expected to survive 48 hours.&#xD;
&#xD;
          -  Presence or high suspicion of concurrent hemorrhagic, obstructive or hypovolemic&#xD;
             shock.&#xD;
&#xD;
          -  Personal or familiar history of glucose-6-phosphate dehydrogenase deficiency.&#xD;
&#xD;
          -  Allergic to methylene blue, phenothiazines, or food dyes.&#xD;
&#xD;
          -  Recent intake (4-weeks) of selective serotonin re-uptake inhibitors.&#xD;
&#xD;
          -  Refusal of the patient or decision maker to enroll in the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Miguel Ibarra-Estrada, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Investigator</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Civil Fray Antonio Alcalde</name>
      <address>
        <city>Guadalajara</city>
        <zip>44280</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Mexico</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>June 22, 2020</study_first_submitted>
  <study_first_submitted_qc>June 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 25, 2020</study_first_posted>
  <last_update_submitted>November 2, 2022</last_update_submitted>
  <last_update_submitted_qc>November 2, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hospital Civil de Guadalajara</investigator_affiliation>
    <investigator_full_name>Miguel Á Ibarra-Estrada</investigator_full_name>
    <investigator_title>Principal investigator</investigator_title>
  </responsible_party>
  <keyword>Septic shock</keyword>
  <keyword>Methylene blue</keyword>
  <keyword>Norepinephrine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Shock, Septic</mesh_term>
    <mesh_term>Shock</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methylene Blue</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT04446871
org study id: HCG/CEI-0252/17
nct id: NCT04446871
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Septic shock is a subset of sepsis characterized by a decrease in vascular tone, which
      contributes to impaired regional blood flow distribution, and leads to organic failure.
      Besides intravenous fluids and adequate antimicrobial therapy, patients with septic shock
      require vasopressor support, which can lead to many adverse effects, therefore,
      non-vasopressor agents that can improve hemodynamic status are needed. In this randomized
      controlled-study, the investigators will address the efficacy and safety of infusion with
      methylene blue in patients with septic shock.
Unlike sepsis, septic shock mortality is not declining for the last decade, and is still
      around 40%. After restoring intravascular volume, many patients need vasopressor agents to
      maintain arterial blood pressure, which leads to improvement of perfusion at some vascular
      beds, however some organs may suffer from maldistribution of blood flow. These changes of
      regional blood flow may compromise oxygen delivery and perpetuate the inflammation and tissue
      damage associated with the state of shock.

      One of the main mechanisms of vasodilation after inflammatory insults, is the activation of
      the inducible isoform of Nitric Oxide Synthase (iNOS), and the subsequent increase in the
      levels of nitric oxide, which even reduces the response to vasoconstrictor agents. Methylene
      blue (MB) is a selective inhibitor of iNOS, which has been used successfully in patients with
      post-cardiopulmonary bypass associated vasoplegia, however, the evidence of the use of MB in
      septic shock patients is limited to case reports, observational and small studies. In this
      randomized controlled trial, the investigators will compare the efficacy and safety outcomes
      of repeated doses of MB in patients with septic shock.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Vasopressor requirement
time frame: 28 days
description: Total time to shock resolution (hours)
measure: Time to lactate normalization
time frame: 7 days
description: Time in hours until lactate is <2 mmol/L
measure: Length of stay in intensive care unit
time frame: 28 days
description: Time in days until ICU discharge
measure: Intensive care unit mortality
time frame: 28 days
description: Mortality in intensive care unit
measure: Change in pulmonary function after treatment
time frame: 7 days
description: Change in P/F index after three doses of methylene blue
arm group label: Standard care
arm group type: Placebo Comparator
description: Placebo
arm group label: Methylene blue
arm group type: Experimental
description: Methylene blue
intervention type: Drug
intervention name: 0.9% sodium chloride
description: Intravenous infusion of 500 cc of 0.9% sodium chloride solution for 6 h, once a day for a total of 3 doses.
arm group label: Standard care
intervention type: Drug
intervention name: Methylene Blue
description: Intravenous infusion of 100 mg methylene blue in 500 cc of 0.9% sodium chloride solution for 6 h, once a day for a total of 3 doses.
arm group label: Methylene blue
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Miguel Ibarra-Estrada, MD
role: Principal Investigator
affiliation: Investigator
facility: 
country: Mexico
responsible party type: Principal Investigator
investigator affiliation: Hospital Civil de Guadalajara
investigator full name: Miguel Á Ibarra-Estrada
investigator title: Principal investigator
mesh term: Shock, Septic
mesh term: Shock
mesh term: Methylene Blue
sharing ipd: No