<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/NCT03306732</url>
  </required_header>
  <id_info>
    <org_study_id>10</org_study_id>
    <nct_id>NCT03306732</nct_id>
  </id_info>
  <brief_title>Thiamine Supplementation in High Risk Cardiac Surgery Patients</brief_title>
  <acronym>APPLY</acronym>
  <official_title>Thiamine Supplementation in High Risk Cardiac Surgery Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Meshalkin Research Institute of Pathology of Circulation</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Meshalkin Research Institute of Pathology of Circulation</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This pilot trial will evaluate the ability of thiamine to affect on postoperative vasoplegia&#xD;
      in high risk cardiac surgery patients&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Thiamine has a pivotal role and is an essential cofactor for pyruvate dehydrogenase activity.&#xD;
      Widely known wet beri-beri is developed due to thiamine deficiency and characterized by&#xD;
      vasodilatory shock and despaired oxygen extraction leading to kidney, heart and central&#xD;
      nervous system dysfunction. Thiamine deficiency is often underestimated and even in primary&#xD;
      absence of vitamin B1 deficiency, high-consumptive state of many critical illness and cardiac&#xD;
      surgery itself can lead to its lack. Reported that in patients on chronic dialysis and&#xD;
      patients with AKI requiring RRT thiamine deficiency is a usual finding. In cross-sectional&#xD;
      observational study it has been shown that up to 33% of patients with a diagnosis of&#xD;
      congestive heart failure (CHF) had thiamine deficiency due to chronic loop diuretic use. Also&#xD;
      reported that 96% of patients (21 of 23) with heart failure receiving loop diuretic therapy&#xD;
      (daily dose: 80-240 mg furosemide) developed thiamine deficiency. In prospective&#xD;
      observational trial it has been shown that plasma thiamine levels were decreased after CABG&#xD;
      surgery.&#xD;
&#xD;
      In a secondary analysis of a randomized, double-blind, placebo-controlled trial conducted in&#xD;
      septic patients, thiamine supplementation showed highly-promising renal protective effect.&#xD;
      Need for RRT was 8 patients (21%) in placebo group and 1 patient (3%) in thiamine group&#xD;
      (p=0.04).&#xD;
&#xD;
      On the other hand it was unable to show any benefit of thiamine supplementation in patients&#xD;
      undergoing CABG surgery. Although, postoperative oxygen consumption was significantly&#xD;
      increased among patients receiving thiamine.&#xD;
&#xD;
      Nevertheless, existing evidence suggests that thiamine supplementation might be an attractive&#xD;
      strategy in counteracting organ dysfunction and thus morbidity and mortality in high-risk&#xD;
      cardiac surgical patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 19, 2017</start_date>
  <completion_date type="Actual">June 18, 2018</completion_date>
  <primary_completion_date type="Actual">May 18, 2018</primary_completion_date>
  <phase>Phase 4</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>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Recruitment rate</measure>
    <time_frame>8 month</time_frame>
    <description>Recruitment of trial patients: successful recruitment is defined as 2 patients per week on average</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Compliance with the protocol</measure>
    <time_frame>8 month</time_frame>
    <description>Successful compliance with protocol is defined as ≥ 90% of prescribed intervention being administered across all patients</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Vasoinotropic score</measure>
    <time_frame>3 days</time_frame>
    <description>dosage of vasoinotropic agents and total vasopressor/norepinephrine equivalent dose</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peak lactate level after CPB weaning to 48 hours</measure>
    <time_frame>48 hours</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The value of postoperative peak serum creatinine concentration during 3 postoperative days</measure>
    <time_frame>3 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The incidence of acute kidney injury (AKI) according to &quot;Kidney Disease: Improving Global Outcomes (KDIGO) criteria&quot; during ICU stay</measure>
    <time_frame>30 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The daily incidence of cardiovascular and renal dysfunction according to Sequential Organ Failure Assessment (SOFA) score during 48 hours postoperatively</measure>
    <time_frame>48 hours</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rates of postoperative complications</measure>
    <time_frame>30 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events</measure>
    <time_frame>30 days</time_frame>
    <description>The safety of high dose IV thiamine supplementation will be evaluated by comparison of adverse, serious adverse events and routinely assessed biochemical parameters (i.e. complete blood count, coagulation parameters, standard biochemistry, etc.)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Availability of data needed</measure>
    <time_frame>8 month</time_frame>
    <description>We expect that loss of follow up will not exceed 5% and data loss less than 10%</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>7-day all-cause mortality (or mortality at any time during the first hospitalization)</measure>
    <time_frame>7 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>30-day all-cause mortality</measure>
    <time_frame>30 days</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Cardiac Surgery</condition>
  <arm_group>
    <arm_group_label>Thiamine group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo group</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Thiamine hydrochloride (200mg) dissolved in 100 ml of normal saline</intervention_name>
    <description>After anesthesia induction&#xD;
After separation from CPB&#xD;
On the evening of the day of surgery (22:00)&#xD;
On POD 1 twice a day at 8:00 and 22:00&#xD;
On POD 2 twice a day at 8:00 and 22:00 (if patient is still in ICU)&#xD;
On POD 3 twice a day at 8:00 and 22:00 (if patient is still in ICU)</description>
    <arm_group_label>Thiamine group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Normal saline (100ml)</intervention_name>
    <description>After anesthesia induction&#xD;
After separation from CPB&#xD;
On the evening of the day of surgery (22:00)&#xD;
On POD 1 twice a day at 8:00 and 22:00&#xD;
On POD 2 twice a day at 8:00 and 22:00 (if patient is still in ICU)&#xD;
On POD 3 twice a day at 8:00 and 22:00 (if patient is still in ICU)</description>
    <arm_group_label>Placebo group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Valve surgery + CABG that required cardiac surgery with CPB&#xD;
&#xD;
          -  Aged 18 years or older&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Emergency surgery&#xD;
&#xD;
          -  Chronic kidney disease of G4-G5 categories according to KDIGO criteria (at least one&#xD;
             of the following present for &gt; 3 months: glomerular filtration rate ≤ 29 ml/min/1.73&#xD;
             m2, history of kidney transplantation)&#xD;
&#xD;
          -  Known allergy to thiamine&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Current enrollment into another RCT (in the last 30 days)&#xD;
&#xD;
          -  Previous enrollment and randomisation into the APPLY trial&#xD;
&#xD;
          -  Administration of thiamine in the previous 30 day&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Meshalkin Research Institute of Pathology of Circulation</name>
      <address>
        <city>Novosibirsk</city>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Russian Federation</country>
  </location_countries>
  <reference>
    <citation>Wiesen P, Van Overmeire L, Delanaye P, Dubois B, Preiser JC. Nutrition disorders during acute renal failure and renal replacement therapy. JPEN J Parenter Enteral Nutr. 2011 Mar;35(2):217-22. doi: 10.1177/0148607110377205.</citation>
    <PMID>21378251</PMID>
  </reference>
  <reference>
    <citation>Seligmann H, Halkin H, Rauchfleisch S, Kaufmann N, Motro M, Vered Z, Ezra D. Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study. Am J Med. 1991 Aug;91(2):151-5. doi: 10.1016/0002-9343(91)90007-k.</citation>
    <PMID>1867241</PMID>
  </reference>
  <reference>
    <citation>Donnino MW, Cocchi MN, Smithline H, Carney E, Chou PP, Salciccioli J. Coronary artery bypass graft surgery depletes plasma thiamine levels. Nutrition. 2010 Jan;26(1):133-6. doi: 10.1016/j.nut.2009.06.004. Erratum In: Nutrition. 2011 Sep;27(9):982. Salciccoli, Justin [corrected to Salciccioli, Justin].</citation>
    <PMID>20005469</PMID>
  </reference>
  <reference>
    <citation>Andersen LW, Holmberg MJ, Doherty M, Khabbaz K, Lerner A, Berg KM, Donnino MW. Postoperative Lactate Levels and Hospital Length of Stay After Cardiac Surgery. J Cardiothorac Vasc Anesth. 2015 Dec;29(6):1454-60. doi: 10.1053/j.jvca.2015.06.007. Epub 2015 Jun 6.</citation>
    <PMID>26456273</PMID>
  </reference>
  <verification_date>June 2018</verification_date>
  <study_first_submitted>September 19, 2017</study_first_submitted>
  <study_first_submitted_qc>October 5, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 11, 2017</study_first_posted>
  <last_update_submitted>June 26, 2018</last_update_submitted>
  <last_update_submitted_qc>June 26, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">June 27, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Meshalkin Research Institute of Pathology of Circulation</investigator_affiliation>
    <investigator_full_name>Efremov Sergey</investigator_full_name>
    <investigator_title>MD PHD Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Thiamine</keyword>
  <keyword>Thiamine Supplementation</keyword>
  <keyword>Vasoplegia Syndrome</keyword>
  <keyword>Inotropic support</keyword>
  <keyword>Cardiac surgery</keyword>
  <keyword>Renal Failure</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thiamine</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 18, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/32/NCT03306732/Prot_SAP_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/NCT03306732
org study id: 10
nct id: NCT03306732
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This pilot trial will evaluate the ability of thiamine to affect on postoperative vasoplegia
      in high risk cardiac surgery patients
Thiamine has a pivotal role and is an essential cofactor for pyruvate dehydrogenase activity.
      Widely known wet beri-beri is developed due to thiamine deficiency and characterized by
      vasodilatory shock and despaired oxygen extraction leading to kidney, heart and central
      nervous system dysfunction. Thiamine deficiency is often underestimated and even in primary
      absence of vitamin B1 deficiency, high-consumptive state of many critical illness and cardiac
      surgery itself can lead to its lack. Reported that in patients on chronic dialysis and
      patients with AKI requiring RRT thiamine deficiency is a usual finding. In cross-sectional
      observational study it has been shown that up to 33% of patients with a diagnosis of
      congestive heart failure (CHF) had thiamine deficiency due to chronic loop diuretic use. Also
      reported that 96% of patients (21 of 23) with heart failure receiving loop diuretic therapy
      (daily dose: 80-240 mg furosemide) developed thiamine deficiency. In prospective
      observational trial it has been shown that plasma thiamine levels were decreased after CABG
      surgery.

      In a secondary analysis of a randomized, double-blind, placebo-controlled trial conducted in
      septic patients, thiamine supplementation showed highly-promising renal protective effect.
      Need for RRT was 8 patients (21%) in placebo group and 1 patient (3%) in thiamine group
      (p=0.04).

      On the other hand it was unable to show any benefit of thiamine supplementation in patients
      undergoing CABG surgery. Although, postoperative oxygen consumption was significantly
      increased among patients receiving thiamine.

      Nevertheless, existing evidence suggests that thiamine supplementation might be an attractive
      strategy in counteracting organ dysfunction and thus morbidity and mortality in high-risk
      cardiac surgical patients.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Recruitment rate
time frame: 8 month
description: Recruitment of trial patients: successful recruitment is defined as 2 patients per week on average
measure: Compliance with the protocol
time frame: 8 month
description: Successful compliance with protocol is defined as ≥ 90% of prescribed intervention being administered across all patients
measure: Vasoinotropic score
time frame: 3 days
description: dosage of vasoinotropic agents and total vasopressor/norepinephrine equivalent dose
measure: Peak lactate level after CPB weaning to 48 hours
time frame: 48 hours
measure: The value of postoperative peak serum creatinine concentration during 3 postoperative days
time frame: 3 days
measure: The incidence of acute kidney injury (AKI) according to "Kidney Disease: Improving Global Outcomes (KDIGO) criteria" during ICU stay
time frame: 30 days
measure: The daily incidence of cardiovascular and renal dysfunction according to Sequential Organ Failure Assessment (SOFA) score during 48 hours postoperatively
time frame: 48 hours
measure: Rates of postoperative complications
time frame: 30 days
measure: Incidence of Treatment-Emergent Adverse Events
time frame: 30 days
description: The safety of high dose IV thiamine supplementation will be evaluated by comparison of adverse, serious adverse events and routinely assessed biochemical parameters (i.e. complete blood count, coagulation parameters, standard biochemistry, etc.)
measure: Availability of data needed
time frame: 8 month
description: We expect that loss of follow up will not exceed 5% and data loss less than 10%
measure: 7-day all-cause mortality (or mortality at any time during the first hospitalization)
time frame: 7 days
measure: 30-day all-cause mortality
time frame: 30 days
arm group label: Thiamine group
arm group type: Active Comparator
arm group label: Placebo group
arm group type: Placebo Comparator
intervention type: Drug
intervention name: Thiamine hydrochloride (200mg) dissolved in 100 ml of normal saline
description: After anesthesia induction
After separation from CPB
On the evening of the day of surgery (22:00)
On POD 1 twice a day at 8:00 and 22:00
On POD 2 twice a day at 8:00 and 22:00 (if patient is still in ICU)
On POD 3 twice a day at 8:00 and 22:00 (if patient is still in ICU)
arm group label: Thiamine group
intervention type: Drug
intervention name: Normal saline (100ml)
description: After anesthesia induction
After separation from CPB
On the evening of the day of surgery (22:00)
On POD 1 twice a day at 8:00 and 22:00
On POD 2 twice a day at 8:00 and 22:00 (if patient is still in ICU)
On POD 3 twice a day at 8:00 and 22:00 (if patient is still in ICU)
arm group label: Placebo group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Russian Federation
citation: Wiesen P, Van Overmeire L, Delanaye P, Dubois B, Preiser JC. Nutrition disorders during acute renal failure and renal replacement therapy. JPEN J Parenter Enteral Nutr. 2011 Mar;35(2):217-22. doi: 10.1177/0148607110377205.
PMID: 21378251
citation: Seligmann H, Halkin H, Rauchfleisch S, Kaufmann N, Motro M, Vered Z, Ezra D. Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study. Am J Med. 1991 Aug;91(2):151-5. doi: 10.1016/0002-9343(91)90007-k.
PMID: 1867241
citation: Donnino MW, Cocchi MN, Smithline H, Carney E, Chou PP, Salciccioli J. Coronary artery bypass graft surgery depletes plasma thiamine levels. Nutrition. 2010 Jan;26(1):133-6. doi: 10.1016/j.nut.2009.06.004. Erratum In: Nutrition. 2011 Sep;27(9):982. Salciccoli, Justin [corrected to Salciccioli, Justin].
PMID: 20005469
citation: Andersen LW, Holmberg MJ, Doherty M, Khabbaz K, Lerner A, Berg KM, Donnino MW. Postoperative Lactate Levels and Hospital Length of Stay After Cardiac Surgery. J Cardiothorac Vasc Anesth. 2015 Dec;29(6):1454-60. doi: 10.1053/j.jvca.2015.06.007. Epub 2015 Jun 6.
PMID: 26456273
responsible party type: Principal Investigator
investigator affiliation: Meshalkin Research Institute of Pathology of Circulation
investigator full name: Efremov Sergey
investigator title: MD PHD Principal Investigator
mesh term: Thiamine
provided document: 