<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/NCT03828929</url>
  </required_header>
  <id_info>
    <org_study_id>1220432</org_study_id>
    <nct_id>NCT03828929</nct_id>
  </id_info>
  <brief_title>Effect of IV Vitamin C, Thiamine, and Steroids on Mortality of Septic Shock</brief_title>
  <official_title>Effect of IV Vitamin C, Thiamine, and Steroids on Mortality of Septic Shock</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>New York Presbyterian Brooklyn Methodist Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>New York Presbyterian Brooklyn Methodist Hospital</source>
  <oversight_info>
    <has_dmc>Yes</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>
      Preliminary studies show that giving a &quot;cocktail&quot; of intravenous vitamin C, vitamin B1, and&#xD;
      steroids to critically ill patients with septic shock may dramatically improve mortality in&#xD;
      those patients. These studies suffer from inadequate design due to lack of controls and&#xD;
      blinding to prove the causal effect. Our goal is to conduct a prospective blinded randomized&#xD;
      control trial to investigate whether this intervention truly effect outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a double-blind randomized placebo controlled study. Only the dispensing pharmacist,&#xD;
      who has no clinical interaction with the patient and is not part of the bedside treatment&#xD;
      team, will be aware of the treatment allocation. Patients will be randomized into one of 2&#xD;
      groups: the intervention group and the control group. Intervention group will receive&#xD;
      intravenous vitamin C and thiamine according to the dosing regimen described below. The&#xD;
      control group will receive placebo that is prepared to look identical to the medications&#xD;
      within the intervention group.&#xD;
&#xD;
      Randomization will be performed using a random number table generated by the dispensing&#xD;
      pharmacist using randomization software. The software will generate subject Identification&#xD;
      numbers (IDs) from 1 to 130 and randomize half of the IDs to the control and half to the&#xD;
      treatment group. The table will be generated prior to enrollment of the first participant.&#xD;
      Once enrollment begins, each participant's medical record number (MRN) will be assigned to&#xD;
      the subject IDs in sequential order from 1 to 130. This process will be triggered by the&#xD;
      fellow ordering the vitamin C protocol. Only the pharmacist will have access to the&#xD;
      table(which will be stored securely) until completion of the study.&#xD;
&#xD;
      The hydrocortisone, vitamin C, thiamine, and their corresponding placebos will be formulated&#xD;
      as follows:&#xD;
&#xD;
      Vitamin C: Vitamin C is provided by the manufacturer as a 50ml vial at a concentration of&#xD;
      500mg/ml. Three (3) ml of vitamin C will be placed in a 50 ml bag of Normal Saline (1500mg&#xD;
      vitamin C in 50ml bag) which will then be infused over 1 hour. The bag will be labeled by the&#xD;
      pharmacy as Vitamin C. The dosing schedule is 1500mg every 6 hours for 4 days or until&#xD;
      discharge from the ICU.&#xD;
&#xD;
      Vitamin C placebo will consist of an identical bag of 50cc normal saline (but with no vitamin&#xD;
      C) and will be labelled vitamin C. Placebo will be infused over 30-60 minutes as per the&#xD;
      infusion instructions of the active vitamin.&#xD;
&#xD;
      Thiamine: As a high percentage of septic patients have been shown to be thiamine deficient,&#xD;
      patients will receive intravenous thiamine 200mg q 12 hourly for 4 days or until ICU&#xD;
      discharge. Thiamine is also a cofactor for the metabolism of oxalate (a byproduct of vitamin&#xD;
      C metabolism), with thiamine deficiency increasing oxalate levels. Thiamine placebo will&#xD;
      consist of 50mL of 5% dextrose.&#xD;
&#xD;
      Steroids: Hydrocortisone 50 mg IV q 6 hourly will be continued for at least 4 days or until&#xD;
      ICU discharge. All patients(both in the treatment and the control groups) included in the&#xD;
      study will receive this steroid regimen. If participants were already started on steroids for&#xD;
      another indication (i.e Asthma) prior to inclusion, they may continue their regimen as long&#xD;
      as the dosing is equivalent to the steroid regimen described above. Alternatively, dosing may&#xD;
      need to be increased or regimen switched entirely to the one described in this protocol. This&#xD;
      decision will be made by the treating physician.&#xD;
&#xD;
      Procalcitonin will be drawn at time of admission and again at 96 hours after admission.&#xD;
&#xD;
      Patients who are enrolled in the study will have their capillary blood glucose levels&#xD;
      measured using the StatStrip Glucometer and Test Strips. This glucometer is currently being&#xD;
      used for all patients at NYPBMH.&#xD;
&#xD;
      Data collection: data collection will be performed by the research associate and other study&#xD;
      personnel in real time and as the schedule allows. The data collection sheet (see Appendix)&#xD;
      will include all needed data associated with the patient's MRN. Once the data sheet is&#xD;
      completed, the patient's treatment group can be unmasked - this will occur after the 60 day&#xD;
      mark, as that is the last data point (60-day mortality).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Recent similar studies have been completed and published showing no benefit to the&#xD;
    intervention.&#xD;
  </why_stopped>
  <start_date type="Actual">October 15, 2019</start_date>
  <completion_date type="Actual">February 4, 2020</completion_date>
  <primary_completion_date type="Actual">January 28, 2020</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>Study is performed with 2 arms, interventional arm with thiamine and vitamin C, and the control arm with placebo in a 1:1 ratio.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Pharmacist who prepares the medication is in charge of blinding randomization.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Hospital Mortality</measure>
    <time_frame>All Cause in Hospital Mortality average 30 days</time_frame>
    <description>In Hospital Mortality</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">3</enrollment>
  <condition>Septic Shock</condition>
  <arm_group>
    <arm_group_label>Vitamin C and Thiamine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>IV vitamin C, 1500mg in 50ml of normal saline every six hours, infused over one hour and IV Thiamine 200mg in 50ml of 5% dextrose every 12 hours, for 4 days or until discharge from the intensive care unit, whichever comes first.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>50ml of IV normal saline every six hours and 50ml of IV 5% dextrose every 12 hours, for 4 days or until discharge from the intensive care unit, whichever comes first.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vitamin C</intervention_name>
    <description>IV vitamin C, 1500mg in 50ml of normal saline every six hours, infused over one hour and IV Thiamine 200mg in 50ml of 5% dextrose every 12 hours, for 4 days or until discharge from the intensive care unit, whichever comes first.</description>
    <arm_group_label>Vitamin C and Thiamine</arm_group_label>
    <other_name>Thiamine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Normal saline</intervention_name>
    <description>50ml of IV normal saline every six hours and 50ml of IV 5% dextrose every 12 hours, for 4 days or until discharge from the intensive care unit, whichever comes first.</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>5% dextrose</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients admitted to medical intensive care unit (MICU) for less than 24 hours, who&#xD;
             are hypotensive despite a fluid bolus of 30 mL/kg and who are requiring pressors to&#xD;
             keep MAP &gt; 65 of at least 5 mcg/min of levophed or equivalent and whose shock is&#xD;
             clinically suspected to be secondary to sepsis.&#xD;
&#xD;
          -  In addition, stress dose corticosteroids, hydrocortisone 50mg IV Q6hrs, will have to&#xD;
             have been started or intended to be started.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Contraindication to corticosteroids, thiamine, or vitamin C&#xD;
&#xD;
          -  Treating physician opposed to administering corticosteroids to the patient&#xD;
&#xD;
          -  Age &lt; 18 years&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  DNR/DNI/limitations of care&#xD;
&#xD;
          -  Patients with a fatal underlying disease who are unlikely to survive to hospital&#xD;
             discharge&#xD;
&#xD;
          -  Patients with a primary admitting diagnosis of an acute cerebral vascular event, acute&#xD;
             coronary syndrome, active gastrointestinal bleeding, burn or trauma&#xD;
&#xD;
          -  Requirement for immediate surgery&#xD;
&#xD;
          -  Patients with HIV and a CD4 &lt; 50 mm2&#xD;
&#xD;
          -  Patients with known glucose-6 phosphate dehydrogenase (G-6PD) deficiency.8&#xD;
&#xD;
          -  Involvement in another clinical trial&#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_official>
    <last_name>Liam Gross, DO</last_name>
    <role>Principal Investigator</role>
    <affiliation>New York Presbyterian Brooklyn Methodist Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>New York Methodist Hospital</name>
      <address>
        <city>Brooklyn</city>
        <state>New York</state>
        <zip>11215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.</citation>
    <PMID>26903338</PMID>
  </reference>
  <reference>
    <citation>Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017 Jun;151(6):1229-1238. doi: 10.1016/j.chest.2016.11.036. Epub 2016 Dec 6.</citation>
    <PMID>27940189</PMID>
  </reference>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>January 29, 2019</study_first_submitted>
  <study_first_submitted_qc>January 31, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 4, 2019</study_first_posted>
  <last_update_submitted>February 6, 2020</last_update_submitted>
  <last_update_submitted_qc>February 6, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 10, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>New York Presbyterian Brooklyn Methodist Hospital</investigator_affiliation>
    <investigator_full_name>Liam Gross</investigator_full_name>
    <investigator_title>Instructor of Clinical Medicine, Principle Investigator</investigator_title>
  </responsible_party>
  <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>Thiamine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>January 15, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/29/NCT03828929/Prot_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT03828929
org study id: 1220432
nct id: NCT03828929
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Preliminary studies show that giving a "cocktail" of intravenous vitamin C, vitamin B1, and
      steroids to critically ill patients with septic shock may dramatically improve mortality in
      those patients. These studies suffer from inadequate design due to lack of controls and
      blinding to prove the causal effect. Our goal is to conduct a prospective blinded randomized
      control trial to investigate whether this intervention truly effect outcomes.
This is a double-blind randomized placebo controlled study. Only the dispensing pharmacist,
      who has no clinical interaction with the patient and is not part of the bedside treatment
      team, will be aware of the treatment allocation. Patients will be randomized into one of 2
      groups: the intervention group and the control group. Intervention group will receive
      intravenous vitamin C and thiamine according to the dosing regimen described below. The
      control group will receive placebo that is prepared to look identical to the medications
      within the intervention group.

      Randomization will be performed using a random number table generated by the dispensing
      pharmacist using randomization software. The software will generate subject Identification
      numbers (IDs) from 1 to 130 and randomize half of the IDs to the control and half to the
      treatment group. The table will be generated prior to enrollment of the first participant.
      Once enrollment begins, each participant's medical record number (MRN) will be assigned to
      the subject IDs in sequential order from 1 to 130. This process will be triggered by the
      fellow ordering the vitamin C protocol. Only the pharmacist will have access to the
      table(which will be stored securely) until completion of the study.

      The hydrocortisone, vitamin C, thiamine, and their corresponding placebos will be formulated
      as follows:

      Vitamin C: Vitamin C is provided by the manufacturer as a 50ml vial at a concentration of
      500mg/ml. Three (3) ml of vitamin C will be placed in a 50 ml bag of Normal Saline (1500mg
      vitamin C in 50ml bag) which will then be infused over 1 hour. The bag will be labeled by the
      pharmacy as Vitamin C. The dosing schedule is 1500mg every 6 hours for 4 days or until
      discharge from the ICU.

      Vitamin C placebo will consist of an identical bag of 50cc normal saline (but with no vitamin
      C) and will be labelled vitamin C. Placebo will be infused over 30-60 minutes as per the
      infusion instructions of the active vitamin.

      Thiamine: As a high percentage of septic patients have been shown to be thiamine deficient,
      patients will receive intravenous thiamine 200mg q 12 hourly for 4 days or until ICU
      discharge. Thiamine is also a cofactor for the metabolism of oxalate (a byproduct of vitamin
      C metabolism), with thiamine deficiency increasing oxalate levels. Thiamine placebo will
      consist of 50mL of 5% dextrose.

      Steroids: Hydrocortisone 50 mg IV q 6 hourly will be continued for at least 4 days or until
      ICU discharge. All patients(both in the treatment and the control groups) included in the
      study will receive this steroid regimen. If participants were already started on steroids for
      another indication (i.e Asthma) prior to inclusion, they may continue their regimen as long
      as the dosing is equivalent to the steroid regimen described above. Alternatively, dosing may
      need to be increased or regimen switched entirely to the one described in this protocol. This
      decision will be made by the treating physician.

      Procalcitonin will be drawn at time of admission and again at 96 hours after admission.

      Patients who are enrolled in the study will have their capillary blood glucose levels
      measured using the StatStrip Glucometer and Test Strips. This glucometer is currently being
      used for all patients at NYPBMH.

      Data collection: data collection will be performed by the research associate and other study
      personnel in real time and as the schedule allows. The data collection sheet (see Appendix)
      will include all needed data associated with the patient's MRN. Once the data sheet is
      completed, the patient's treatment group can be unmasked - this will occur after the 60 day
      mark, as that is the last data point (60-day mortality).
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Study is performed with 2 arms, interventional arm with thiamine and vitamin C, and the control arm with placebo in a 1:1 ratio.
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Pharmacist who prepares the medication is in charge of blinding randomization.
measure: Hospital Mortality
time frame: All Cause in Hospital Mortality average 30 days
description: In Hospital Mortality
arm group label: Vitamin C and Thiamine
arm group type: Experimental
description: IV vitamin C, 1500mg in 50ml of normal saline every six hours, infused over one hour and IV Thiamine 200mg in 50ml of 5% dextrose every 12 hours, for 4 days or until discharge from the intensive care unit, whichever comes first.
arm group label: Placebo
arm group type: Placebo Comparator
description: 50ml of IV normal saline every six hours and 50ml of IV 5% dextrose every 12 hours, for 4 days or until discharge from the intensive care unit, whichever comes first.
intervention type: Drug
intervention name: Vitamin C
description: IV vitamin C, 1500mg in 50ml of normal saline every six hours, infused over one hour and IV Thiamine 200mg in 50ml of 5% dextrose every 12 hours, for 4 days or until discharge from the intensive care unit, whichever comes first.
arm group label: Vitamin C and Thiamine
other name: Thiamine
intervention type: Drug
intervention name: Normal saline
description: 50ml of IV normal saline every six hours and 50ml of IV 5% dextrose every 12 hours, for 4 days or until discharge from the intensive care unit, whichever comes first.
arm group label: Placebo
other name: 5% dextrose
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Liam Gross, DO
role: Principal Investigator
affiliation: New York Presbyterian Brooklyn Methodist Hospital
facility: 
country: United States
citation: Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.
PMID: 26903338
citation: Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017 Jun;151(6):1229-1238. doi: 10.1016/j.chest.2016.11.036. Epub 2016 Dec 6.
PMID: 27940189
responsible party type: Principal Investigator
investigator affiliation: New York Presbyterian Brooklyn Methodist Hospital
investigator full name: Liam Gross
investigator title: Instructor of Clinical Medicine, Principle Investigator
mesh term: Shock, Septic
mesh term: Shock
mesh term: Thiamine
sharing ipd: No
provided document: 