<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/NCT03756220</url>
  </required_header>
  <id_info>
    <org_study_id>2018R1C1B6006821</org_study_id>
    <nct_id>NCT03756220</nct_id>
  </id_info>
  <brief_title>Ascorbic Acid and Thiamine Effect in Septic Shock</brief_title>
  <acronym>ATESS</acronym>
  <official_title>Combination Therapy of Vitamin C and Thiamine for Septic Shock: Multi-center, Double-blinded, Randomized, Controlled Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tae Gun Shin</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Research Foundation of Korea</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Samsung Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of this study is to evaluate the efficacy of early metabolic resuscitation with&#xD;
      combination therapy using vitamin C and thiamine in improving organ function and survival in&#xD;
      patients with septic shock.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Sepsis is a complex disease involving life-threatening organ dysfunction caused by a&#xD;
      dysregulated host response to infection and is still associated with unacceptably high&#xD;
      mortality. Sepsis management should be undertaken as a medical emergency and focused on&#xD;
      timely intervention, including early identification and treatment of infection through&#xD;
      appropriate antimicrobial therapy and source control when applicable as well as reversing&#xD;
      hemodynamic instability through fluid resuscitation and vasopressor use if necessary. Despite&#xD;
      these supportive therapies, morbidity and mortality have remained high, suggesting the need&#xD;
      for adjuvant therapies for inflammatory and oxidative stress in patients with sepsis;&#xD;
      however, no agents have been proven to definitely improve survival.&#xD;
&#xD;
      Vitamin C plays a role in mediating inflammation through antioxidant activities and is also&#xD;
      important as a cofactor/co-substrate for the synthesis of endogenous adrenaline, cortisol,&#xD;
      and vasopressin. Recently, several clinical trials have reported the positive effects of&#xD;
      vitamin C on outcomes in sepsis or septic shock. During sepsis, vitamin C prevents&#xD;
      neutrophil-induced lipid oxidation and protects against the loss of the endothelial barrier.&#xD;
      Early intravenous supplementation is therefore needed to limit loss of microcirculation and&#xD;
      oxidation of lipids. Thiamine is also a key cofactor for glucose metabolism, the generation&#xD;
      of ATP (adenosine triphosphate), and the production of NADPH. Considering acute consumption&#xD;
      in the hypermetabolic state, thiamine supplementation might be a reasonable therapeutic&#xD;
      adjunct for patients with sepsis and was added to reduce the risk of renal oxalate&#xD;
      crystallization. These findings led to a recent before-and-after study showing that treatment&#xD;
      of sepsis with a combination of vitamin C, hydrocortisone, and thiamine prevented organ&#xD;
      dysfunction and reduced the mortality rate.&#xD;
&#xD;
      The aim of this study is to evaluate the efficacy of early metabolic resuscitation with&#xD;
      combination therapy using vitamin C and thiamine in improving organ function and survival in&#xD;
      patients with septic shock.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 1, 2018</start_date>
  <completion_date type="Actual">April 14, 2020</completion_date>
  <primary_completion_date type="Actual">January 13, 2020</primary_completion_date>
  <phase>Phase 2</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>Multi-center, Double-blinded, Randomized, Controlled Study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Delta Sequential Organ Failure Assessment (SOFA) score</measure>
    <time_frame>Enrollment to 72 hours</time_frame>
    <description>72-hour change in SOFA score, which reflected recovery from organ failure (delta SOFA = SOFA at enrollment - SOFA after 72 hours)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>28-day mortality</measure>
    <time_frame>Day 28</time_frame>
    <description>The number of participants who did not survive until Day 28 will be compared between the treatment and the control group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>7-day mortality (early death)</measure>
    <time_frame>Day 7</time_frame>
    <description>The number of participants who did not survive until Day 7 will be compared between the treatment and the control group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>90-day mortality</measure>
    <time_frame>Day 90</time_frame>
    <description>The number of participants who did not survive until Day 90 will be compared between the treatment and the control group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to death</measure>
    <time_frame>Enrollment to Day 28</time_frame>
    <description>Days until death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>In-hospital death</measure>
    <time_frame>Up to 12 weeks</time_frame>
    <description>The number of participants who did not survive at hospital discharge will be compared between the treatment and the control group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intensive care unit death (ICU) death</measure>
    <time_frame>Up to 12 weeks</time_frame>
    <description>The number of participants who did not survive at ICU discharge from the first index ICU admission will be compared between the treatment and the control group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Shock reversal</measure>
    <time_frame>Enrollment to Day 14</time_frame>
    <description>Days from enrollment to shock reversal until Day 14. Shock reversal is defined as discontinuation of all vasopressors and mean arterial pressure is maintained at 60 mmHg or more for more than 24 hours.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Vasopressor free days</measure>
    <time_frame>Enrollment to Day 14</time_frame>
    <description>Days not receiving any vasopressor</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ventilator free days</measure>
    <time_frame>Enrollment to Day 14</time_frame>
    <description>Days not receiving mechanical ventilation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Ventilator duration</measure>
    <time_frame>Up to 12 weeks</time_frame>
    <description>Days receiving mechanical ventilation during hospital stay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Renal replacement therapy (RRT) free days</measure>
    <time_frame>Enrollment to Day 14</time_frame>
    <description>Days not receiving Renal replacement therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New use of renal replacement therapy (RRT)</measure>
    <time_frame>Up to 12 weeks</time_frame>
    <description>The number of participants who receive RRT during hospital stay will be compared between the treatment and the control group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>New onset or aggravation of acute kidney injury (AKI)</measure>
    <time_frame>Enrollment to Day 14</time_frame>
    <description>The number of participants who suffer from new onset or aggravation of AKI will be compared between the treatment and the control group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of ICU stay</measure>
    <time_frame>Up to 12 weeks</time_frame>
    <description>Number of days in the ICU during hospital admission</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ICU free day</measure>
    <time_frame>Enrollment to Day 14</time_frame>
    <description>Days not being in the ICU</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Length of hospital stay</measure>
    <time_frame>Up to 12 weeks</time_frame>
    <description>Number of days in the hospital during hospital admission</description>
  </secondary_outcome>
  <other_outcome>
    <measure>CRP (C-reactive protein) change during initial 72 hours</measure>
    <time_frame>Enrollment to 72 hours</time_frame>
    <description>72-hour change in CRP (%)</description>
  </other_outcome>
  <other_outcome>
    <measure>Procalcitonin change during initial 72 hours</measure>
    <time_frame>Enrollment to 72 hours</time_frame>
    <description>72-hour change in procalcitonin (%)</description>
  </other_outcome>
  <other_outcome>
    <measure>Dose of vasopressor at 24-hour</measure>
    <time_frame>Enrollment to 24 hours</time_frame>
    <description>Norepinephrine equivalent dose at 24 hours from enrollment</description>
  </other_outcome>
  <other_outcome>
    <measure>Dose of vasopressor at 48-hour</measure>
    <time_frame>Enrollment to 48 hours</time_frame>
    <description>Norepinephrine equivalent dose at 48 hours from enrollment</description>
  </other_outcome>
  <other_outcome>
    <measure>Dose of vasopressor at 72-hour</measure>
    <time_frame>Enrollment to 72 hours</time_frame>
    <description>Norepinephrine equivalent dose at 72 hours from enrollment</description>
  </other_outcome>
  <other_outcome>
    <measure>Maximum dose of vasopressor during initial 72 hours</measure>
    <time_frame>Enrollment to 72 hours</time_frame>
    <description>Maximum norepinephrine equivalent dose during initial 72 hours</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">116</enrollment>
  <condition>Septic Shock</condition>
  <condition>Sepsis</condition>
  <arm_group>
    <arm_group_label>Treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Combination therapy of vitamin C and thiamine for 2 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Normal Saline Solution</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Combination therapy of vitamin C and thiamine</intervention_name>
    <description>Vitamin C (50 mg/kg up to 3 g, every 12 hours) and thiamine (200 mg every 12 hours) intravenously administered mixed in 50 mL solution bags of normal saline for 2 days</description>
    <arm_group_label>Treatment</arm_group_label>
    <other_name>Ascorbic Acid Injection</other_name>
    <other_name>Thiamine Injection</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Normal saline solution</intervention_name>
    <description>Normal saline solution in a volume to match the treatment components administered mixed in 50 mL solution bags of normal saline for 2 days</description>
    <arm_group_label>Control</arm_group_label>
    <other_name>0.9% NaCl</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult patients (&gt; 18 years)&#xD;
&#xD;
          2. Septic shock: sepsis with persisting hypotension requiring vasopressors to maintain a&#xD;
             mean arterial pressure ≥65 mm Hg and a serum lactate level &gt;2 mmol/L despite adequate&#xD;
             volume resuscitation. Sepsis is defined as clinically suspected or confirmed infection&#xD;
             with acute organ failure identified as an acute change in total SOFA score with 2&#xD;
             points or more.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Transferred patients from other hospitals after application of vasopressors or&#xD;
             mechanical ventilation&#xD;
&#xD;
          2. Patients who signed a &quot;Do not attempt resuscitation&quot; order or who had set limitations&#xD;
             on invasive care&#xD;
&#xD;
          3. Patients who have a terminal, unresponsive illness and survival discharge is not&#xD;
             expected (metastatic terminal cancer, etc.)&#xD;
&#xD;
          4. Patients who experienced cardiac arrest before enrollment or when death is anticipated&#xD;
             within 24 hours despite maximal treatment&#xD;
&#xD;
          5. Patients who take more than 1g of Vitamin C per day before enrollment or who take&#xD;
             supplemental thiamine&#xD;
&#xD;
          6. Pregnant woman&#xD;
&#xD;
          7. Known Glucose-6-phosphate dehydrogenase deficiency&#xD;
&#xD;
          8. Patients with a history of hypersensitivity to vitamin C or thiamine&#xD;
&#xD;
          9. Known Mediterranean anemia&#xD;
&#xD;
         10. Known hyperoxaluria&#xD;
&#xD;
         11. Known cystinuria&#xD;
&#xD;
         12. Acute gout attack&#xD;
&#xD;
         13. Known oxalate renal stone&#xD;
&#xD;
         14. Patients who meet the inclusion criteria 24 hours after emergency department arrival&#xD;
             or when enrollment is delayed more than 24 hours after diagnosis of septic shock&#xD;
&#xD;
         15. Inability or refusal of a subject or legal surrogate to give informed consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>19 Years</minimum_age>
    <maximum_age>89 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Tae Gun Shin, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Samsung Medical Center, Sungkyunkwan University School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Department of Emergency Medicine, Seoul National University Bundang Hospital,</name>
      <address>
        <city>Seongnam</city>
        <state>Gyeonggi-do</state>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Emergency Medicine, Borame Medical Center, Seoul National University, College of Medicine</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Emergency Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine,</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Emergency Medicine, Seoul National University College of Medicine,</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Emergency Medicine, University of Ulsan College of Medicine, Asan Medical Center,</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Department of Emergency Medicine, Yonsei University College of Medicine</name>
      <address>
        <city>Seoul</city>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</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>Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017 Mar;45(3):486-552. doi: 10.1097/CCM.0000000000002255.</citation>
    <PMID>28098591</PMID>
  </reference>
  <reference>
    <citation>Teng J, Pourmand A, Mazer-Amirshahi M. Vitamin C: The next step in sepsis management? J Crit Care. 2018 Feb;43:230-234. doi: 10.1016/j.jcrc.2017.09.031. Epub 2017 Sep 18.</citation>
    <PMID>28934705</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>
  <reference>
    <citation>Oudemans-van Straaten HM, Spoelstra-de Man AM, de Waard MC. Vitamin C revisited. Crit Care. 2014 Aug 6;18(4):460. doi: 10.1186/s13054-014-0460-x.</citation>
    <PMID>25185110</PMID>
  </reference>
  <reference>
    <citation>Donnino MW, Andersen LW, Chase M, Berg KM, Tidswell M, Giberson T, Wolfe R, Moskowitz A, Smithline H, Ngo L, Cocchi MN; Center for Resuscitation Science Research Group. Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study. Crit Care Med. 2016 Feb;44(2):360-7. doi: 10.1097/CCM.0000000000001572.</citation>
    <PMID>26771781</PMID>
  </reference>
  <reference>
    <citation>Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose Ascorbic acid on vasopressor's requirement in septic shock. J Res Pharm Pract. 2016 Apr-Jun;5(2):94-100. doi: 10.4103/2279-042X.179569.</citation>
    <PMID>27162802</PMID>
  </reference>
  <reference>
    <citation>Fowler AA 3rd, Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, Farthing CA, Larus TL, Martin E, Brophy DF, Gupta S; Medical Respiratory Intensive Care Unit Nursing; Fisher BJ, Natarajan R. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014 Jan 31;12:32. doi: 10.1186/1479-5876-12-32.</citation>
    <PMID>24484547</PMID>
  </reference>
  <reference>
    <citation>May JM, Harrison FE. Role of vitamin C in the function of the vascular endothelium. Antioxid Redox Signal. 2013 Dec 10;19(17):2068-83. doi: 10.1089/ars.2013.5205. Epub 2013 May 29.</citation>
    <PMID>23581713</PMID>
  </reference>
  <reference>
    <citation>Leite HP, de Lima LF. Metabolic resuscitation in sepsis: a necessary step beyond the hemodynamic? J Thorac Dis. 2016 Jul;8(7):E552-7. doi: 10.21037/jtd.2016.05.37.</citation>
    <PMID>27501325</PMID>
  </reference>
  <reference>
    <citation>de Grooth HJ, Geenen IL, Girbes AR, Vincent JL, Parienti JJ, Oudemans-van Straaten HM. SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis. Crit Care. 2017 Feb 24;21(1):38. doi: 10.1186/s13054-017-1609-1.</citation>
    <PMID>28231816</PMID>
  </reference>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>October 30, 2018</study_first_submitted>
  <study_first_submitted_qc>November 26, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 28, 2018</study_first_posted>
  <last_update_submitted>October 27, 2020</last_update_submitted>
  <last_update_submitted_qc>October 27, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 28, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Samsung Medical Center</investigator_affiliation>
    <investigator_full_name>Tae Gun Shin</investigator_full_name>
    <investigator_title>Associate professor</investigator_title>
  </responsible_party>
  <keyword>Septic shock</keyword>
  <keyword>Sepsis</keyword>
  <keyword>Vitamin C</keyword>
  <keyword>Thiamine</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>Ascorbic Acid</mesh_term>
    <mesh_term>Thiamine</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/NCT03756220
org study id: 2018R1C1B6006821
nct id: NCT03756220
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The aim of this study is to evaluate the efficacy of early metabolic resuscitation with
      combination therapy using vitamin C and thiamine in improving organ function and survival in
      patients with septic shock.
Sepsis is a complex disease involving life-threatening organ dysfunction caused by a
      dysregulated host response to infection and is still associated with unacceptably high
      mortality. Sepsis management should be undertaken as a medical emergency and focused on
      timely intervention, including early identification and treatment of infection through
      appropriate antimicrobial therapy and source control when applicable as well as reversing
      hemodynamic instability through fluid resuscitation and vasopressor use if necessary. Despite
      these supportive therapies, morbidity and mortality have remained high, suggesting the need
      for adjuvant therapies for inflammatory and oxidative stress in patients with sepsis;
      however, no agents have been proven to definitely improve survival.

      Vitamin C plays a role in mediating inflammation through antioxidant activities and is also
      important as a cofactor/co-substrate for the synthesis of endogenous adrenaline, cortisol,
      and vasopressin. Recently, several clinical trials have reported the positive effects of
      vitamin C on outcomes in sepsis or septic shock. During sepsis, vitamin C prevents
      neutrophil-induced lipid oxidation and protects against the loss of the endothelial barrier.
      Early intravenous supplementation is therefore needed to limit loss of microcirculation and
      oxidation of lipids. Thiamine is also a key cofactor for glucose metabolism, the generation
      of ATP (adenosine triphosphate), and the production of NADPH. Considering acute consumption
      in the hypermetabolic state, thiamine supplementation might be a reasonable therapeutic
      adjunct for patients with sepsis and was added to reduce the risk of renal oxalate
      crystallization. These findings led to a recent before-and-after study showing that treatment
      of sepsis with a combination of vitamin C, hydrocortisone, and thiamine prevented organ
      dysfunction and reduced the mortality rate.

      The aim of this study is to evaluate the efficacy of early metabolic resuscitation with
      combination therapy using vitamin C and thiamine in improving organ function and survival in
      patients with septic shock.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Multi-center, Double-blinded, Randomized, Controlled Study
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Delta Sequential Organ Failure Assessment (SOFA) score
time frame: Enrollment to 72 hours
description: 72-hour change in SOFA score, which reflected recovery from organ failure (delta SOFA = SOFA at enrollment - SOFA after 72 hours)
measure: 28-day mortality
time frame: Day 28
description: The number of participants who did not survive until Day 28 will be compared between the treatment and the control group
measure: 7-day mortality (early death)
time frame: Day 7
description: The number of participants who did not survive until Day 7 will be compared between the treatment and the control group
measure: 90-day mortality
time frame: Day 90
description: The number of participants who did not survive until Day 90 will be compared between the treatment and the control group
measure: Time to death
time frame: Enrollment to Day 28
description: Days until death
measure: In-hospital death
time frame: Up to 12 weeks
description: The number of participants who did not survive at hospital discharge will be compared between the treatment and the control group
measure: Intensive care unit death (ICU) death
time frame: Up to 12 weeks
description: The number of participants who did not survive at ICU discharge from the first index ICU admission will be compared between the treatment and the control group
measure: Time to Shock reversal
time frame: Enrollment to Day 14
description: Days from enrollment to shock reversal until Day 14. Shock reversal is defined as discontinuation of all vasopressors and mean arterial pressure is maintained at 60 mmHg or more for more than 24 hours.
measure: Vasopressor free days
time frame: Enrollment to Day 14
description: Days not receiving any vasopressor
measure: Ventilator free days
time frame: Enrollment to Day 14
description: Days not receiving mechanical ventilation
measure: Ventilator duration
time frame: Up to 12 weeks
description: Days receiving mechanical ventilation during hospital stay
measure: Renal replacement therapy (RRT) free days
time frame: Enrollment to Day 14
description: Days not receiving Renal replacement therapy
measure: New use of renal replacement therapy (RRT)
time frame: Up to 12 weeks
description: The number of participants who receive RRT during hospital stay will be compared between the treatment and the control group
measure: New onset or aggravation of acute kidney injury (AKI)
time frame: Enrollment to Day 14
description: The number of participants who suffer from new onset or aggravation of AKI will be compared between the treatment and the control group
measure: Length of ICU stay
time frame: Up to 12 weeks
description: Number of days in the ICU during hospital admission
measure: ICU free day
time frame: Enrollment to Day 14
description: Days not being in the ICU
measure: Length of hospital stay
time frame: Up to 12 weeks
description: Number of days in the hospital during hospital admission
measure: CRP (C-reactive protein) change during initial 72 hours
time frame: Enrollment to 72 hours
description: 72-hour change in CRP (%)
measure: Procalcitonin change during initial 72 hours
time frame: Enrollment to 72 hours
description: 72-hour change in procalcitonin (%)
measure: Dose of vasopressor at 24-hour
time frame: Enrollment to 24 hours
description: Norepinephrine equivalent dose at 24 hours from enrollment
measure: Dose of vasopressor at 48-hour
time frame: Enrollment to 48 hours
description: Norepinephrine equivalent dose at 48 hours from enrollment
measure: Dose of vasopressor at 72-hour
time frame: Enrollment to 72 hours
description: Norepinephrine equivalent dose at 72 hours from enrollment
measure: Maximum dose of vasopressor during initial 72 hours
time frame: Enrollment to 72 hours
description: Maximum norepinephrine equivalent dose during initial 72 hours
arm group label: Treatment
arm group type: Experimental
description: Combination therapy of vitamin C and thiamine for 2 days.
arm group label: Control
arm group type: Placebo Comparator
description: Normal Saline Solution
intervention type: Drug
intervention name: Combination therapy of vitamin C and thiamine
description: Vitamin C (50 mg/kg up to 3 g, every 12 hours) and thiamine (200 mg every 12 hours) intravenously administered mixed in 50 mL solution bags of normal saline for 2 days
arm group label: Treatment
other name: Ascorbic Acid Injection
other name: Thiamine Injection
intervention type: Drug
intervention name: Normal saline solution
description: Normal saline solution in a volume to match the treatment components administered mixed in 50 mL solution bags of normal saline for 2 days
arm group label: Control
other name: 0.9% NaCl
criteria: 
gender: All
minimum age: 19 Years
maximum age: 89 Years
healthy volunteers: No
last name: Tae Gun Shin, MD, PhD
role: Principal Investigator
affiliation: Samsung Medical Center, Sungkyunkwan University School of Medicine
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Korea, Republic of
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: Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, Rochwerg B, Rubenfeld GD, Angus DC, Annane D, Beale RJ, Bellinghan GJ, Bernard GR, Chiche JD, Coopersmith C, De Backer DP, French CJ, Fujishima S, Gerlach H, Hidalgo JL, Hollenberg SM, Jones AE, Karnad DR, Kleinpell RM, Koh Y, Lisboa TC, Machado FR, Marini JJ, Marshall JC, Mazuski JE, McIntyre LA, McLean AS, Mehta S, Moreno RP, Myburgh J, Navalesi P, Nishida O, Osborn TM, Perner A, Plunkett CM, Ranieri M, Schorr CA, Seckel MA, Seymour CW, Shieh L, Shukri KA, Simpson SQ, Singer M, Thompson BT, Townsend SR, Van der Poll T, Vincent JL, Wiersinga WJ, Zimmerman JL, Dellinger RP. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017 Mar;45(3):486-552. doi: 10.1097/CCM.0000000000002255.
PMID: 28098591
citation: Teng J, Pourmand A, Mazer-Amirshahi M. Vitamin C: The next step in sepsis management? J Crit Care. 2018 Feb;43:230-234. doi: 10.1016/j.jcrc.2017.09.031. Epub 2017 Sep 18.
PMID: 28934705
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
citation: Oudemans-van Straaten HM, Spoelstra-de Man AM, de Waard MC. Vitamin C revisited. Crit Care. 2014 Aug 6;18(4):460. doi: 10.1186/s13054-014-0460-x.
PMID: 25185110
citation: Donnino MW, Andersen LW, Chase M, Berg KM, Tidswell M, Giberson T, Wolfe R, Moskowitz A, Smithline H, Ngo L, Cocchi MN; Center for Resuscitation Science Research Group. Randomized, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study. Crit Care Med. 2016 Feb;44(2):360-7. doi: 10.1097/CCM.0000000000001572.
PMID: 26771781
citation: Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose Ascorbic acid on vasopressor's requirement in septic shock. J Res Pharm Pract. 2016 Apr-Jun;5(2):94-100. doi: 10.4103/2279-042X.179569.
PMID: 27162802
citation: Fowler AA 3rd, Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, Farthing CA, Larus TL, Martin E, Brophy DF, Gupta S; Medical Respiratory Intensive Care Unit Nursing; Fisher BJ, Natarajan R. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014 Jan 31;12:32. doi: 10.1186/1479-5876-12-32.
PMID: 24484547
citation: May JM, Harrison FE. Role of vitamin C in the function of the vascular endothelium. Antioxid Redox Signal. 2013 Dec 10;19(17):2068-83. doi: 10.1089/ars.2013.5205. Epub 2013 May 29.
PMID: 23581713
citation: Leite HP, de Lima LF. Metabolic resuscitation in sepsis: a necessary step beyond the hemodynamic? J Thorac Dis. 2016 Jul;8(7):E552-7. doi: 10.21037/jtd.2016.05.37.
PMID: 27501325
citation: de Grooth HJ, Geenen IL, Girbes AR, Vincent JL, Parienti JJ, Oudemans-van Straaten HM. SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis. Crit Care. 2017 Feb 24;21(1):38. doi: 10.1186/s13054-017-1609-1.
PMID: 28231816
responsible party type: Sponsor-Investigator
investigator affiliation: Samsung Medical Center
investigator full name: Tae Gun Shin
investigator title: Associate professor
mesh term: Shock, Septic
mesh term: Shock
mesh term: Ascorbic Acid
mesh term: Thiamine
sharing ipd: No