<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/NCT04453761</url>
  </required_header>
  <id_info>
    <org_study_id>LB.02.01/VII/225/KEP.066/2017</org_study_id>
    <nct_id>NCT04453761</nct_id>
  </id_info>
  <brief_title>Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass</brief_title>
  <official_title>Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Congenital Heart Disease Surgery With Cardiopulmonary Bypass Procedure and Oral Thyroid Supplementation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cardiovascular Center Harapan Kita Hospital Indonesia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cardiovascular Center Harapan Kita Hospital Indonesia</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a randomized, double-blind, controlled trial design. It was conducted with a main&#xD;
      purpose of evaluating the effect of thiamine supplementation on serum lactate and&#xD;
      lactate-pyruvate ratio after surgery as direct indicators of tissue perfusion and indirect&#xD;
      markers of energy substrate availability for effective mitochondrial function and intubation&#xD;
      time as clinical outcome.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      All patients who undergo open cardiac surgery for their congenital heart disease on the&#xD;
      research period will be recruited consecutively and evaluated according to the study&#xD;
      criteria. Parents or guardians were explained about the procedure. Agreement will be&#xD;
      concluded by signing the informed consent. Baseline data including age, nutritional status,&#xD;
      diagnosis, types of heart disease (cyanotic or acyanotic), restrictive or non restrictive&#xD;
      pulmonary blood flow heart disease, pre-surgical peripheral saturation, pulmonary&#xD;
      hypertension and any syndromes associated with heart disease will be recorded on the study&#xD;
      sheets.&#xD;
&#xD;
      Patients will be randomised using block randomisation procedure with a block size of 4 on&#xD;
      treatment and control group. Included participants will be marked by specific randomisation&#xD;
      number by a research assistant physician who is not involved in patients' management. A&#xD;
      pharmacist will acquire and open a prepared envelope containing the randomisation number. The&#xD;
      patients, parents/guardians, research physicians, other physicians or paramedics involved in&#xD;
      patients' treatment will be blinded.&#xD;
&#xD;
      Placebo (Intravenous Normal Saline) and intravenous thiamine (2 mg/kg) will be administered&#xD;
      at induction time, 1 hours after surgery and once everyday for three days by pharmacist&#xD;
      according to randomization result. All subject are given oral T3 supplementation (1 mcg/kg)&#xD;
      every 6 hours by pharmacist as research protocol. Oral T3 supplementations are given every 6&#xD;
      hours, started from induction time until 11 doses (60 hours until the first dose). Drugs is&#xD;
      diluted with 2.5 cc aqua and administerednisterd using nasogastric tube.&#xD;
&#xD;
      Blood will be withdrawn from arterial line access for 2.5 cc in order to test thiamine,&#xD;
      lactate, and pyruvate concentration, as well as, measuring LDH and PDH activity. Thiamine&#xD;
      will be examined from blood plasma using liquid chromatography tandem mass spectometry.&#xD;
      Thiamine concentration below ≤ 7 nmol/L is considered low. PDH will be examined from&#xD;
      Peripheral Blood Mononuclear Cells (PBMCs) which will be isolated from fresh blood. PDH&#xD;
      activity will be tested after breaking cell membrane to initiate mitochondria lysis, this&#xD;
      process will be done by immunocapture and micro-plate based assay. Lactate and pyruvate&#xD;
      measurement will be tested using an enzymatic kit specific for lactate and pyruvate called&#xD;
      Sigma Aldrich reagent. Thiamine concentration, lactate concentration, pyruvate concentration,&#xD;
      LDH and PDH activity is going to be measured at 4 time; induction time, one hour, 24 hours,&#xD;
      72 hours after aortic clamp removal.&#xD;
&#xD;
      Measurement of blood gas analysis, blood glucose, central vein saturation and oxygen&#xD;
      extraction ratio will be performed at induction time, 1 hours, and 12 hours post-surgery.&#xD;
&#xD;
      Organ functions evaluation was performed by serially measuring SGOT and SGPT (liver function)&#xD;
      as well as ureum and creatinine (renal function) on ICU admission.&#xD;
&#xD;
      Echocardiography evaluation will be done on the first, second and third day after surgery to&#xD;
      assess the patient's ejection fraction, stroke volume, cardiac volume and index, tricuspid&#xD;
      annular plane systolic excursion (TAPSE), left heart diastolic functions and SVRI&#xD;
      calculation. It will be done by 2 research cardiologists.&#xD;
&#xD;
      Post-surgical managements will be decided according to the paediatric ICU National&#xD;
      Cardiovascular Center Harapan Kita treatment protocols. Inotropic concentration will be&#xD;
      evaluated by inotropic and vasoactive-inotropic scoring every 6 hours in the first 24 hours&#xD;
      and every 12 hours after the second and third 24 hours. The amount of diuretics used will be&#xD;
      calculated 72 hours after ICU admission. Peritoneal dialysis and continuous veno-venous&#xD;
      hemofiltration (CVVH) is going to be assessed by means of the length of therapy, renal&#xD;
      function and fluid balance. Decision to extubate will be carried out by a physician&#xD;
      responsible according to the treatment protocols. Every reintubation is going to be recorded&#xD;
      as number and length of intubation. The length of ICU and hospital stay and mortality will be&#xD;
      evaluated in both study groups.&#xD;
&#xD;
      Operative data such as Aristotle score, residual lesions presence, open thorax on ICU&#xD;
      admission, CPB duration, Aox duration and a number of procedures during CPB including&#xD;
      ultrafiltration, hypothermia and hemodilution is going to be recorded in the research sheets.&#xD;
      History of medication used which may interfere with the function of thyroid such as steroids,&#xD;
      dopamine and amiodarone will also be recorded.&#xD;
&#xD;
      There will be one physician who know the subject's allocation. This physician is not involve&#xD;
      in any kind of patients' treatment and act as the study supervisor to evaluate if any&#xD;
      suspicion on drug adverse reactions occurred. Drug adverse reaction is going to be monitored&#xD;
      by evaluating heart rhythm, heart rate, blood pressure and peripheral temperature for every 6&#xD;
      hours in the first 24 hours and every 12 hours in the second and third 24 hours of ICU&#xD;
      treatment. The criteria of drug adverse reaction are stated in the adverse effects form; they&#xD;
      are tachycardia, arrhythmia, hypertension and refractory hyperthermia. Any suspicion of the&#xD;
      presence of drug adverse effect is going to be recorded in the form and reported to the&#xD;
      supervising doctor for further analysis. Management on this reaction will be done by the ICU&#xD;
      treating doctor&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date type="Actual">July 1, 2018</start_date>
  <completion_date type="Anticipated">December 1, 2022</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2021</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>Evaluate the effect of thiamine supplementation to pyruvate levels</measure>
    <time_frame>at 6 hours post cross clamp removal</time_frame>
    <description>Comparing the lab parameter indicate pyruvate levels</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evaluate the effect of thiamine supplementation to cardiac output.</measure>
    <time_frame>Within 1 days of surgery</time_frame>
    <description>Measuring Cardiac output</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Thiamine Deficiency</condition>
  <condition>Congenital Heart Disease</condition>
  <condition>Cardiopulmonary Bypass</condition>
  <arm_group>
    <arm_group_label>Drugs Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Thiamine IV</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>NaCl IV</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Neurobion</intervention_name>
    <description>Intravenous Thiamine 2 mg/kg in Neurobion injection</description>
    <arm_group_label>Drugs Group</arm_group_label>
    <other_name>Vitamin B1 IV</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Intravenous NaCl0.9%</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>NaCl 0.9%</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        All patients with congenital heart disease, 2 years old or less, with moderate to severe&#xD;
        malnutrition are included. Types of congenital heart disease suffered required subject to&#xD;
        undergo surgery using cardiopulmonary bypass machine with Aristotle score of 6-9.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Body weight of less than 2 kg at the study period&#xD;
&#xD;
          2. Suffering from pre-surgical tachyarrhythmia or other types of arrhythmias&#xD;
&#xD;
          3. Pre-surgical sepsis&#xD;
&#xD;
          4. Serum creatinine of more than 2 mg/dL&#xD;
&#xD;
          5. Diagnosed with thyroid abnormalities prior to the surgery&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Month</minimum_age>
    <maximum_age>2 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Eva M Marwali, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cardiovascular Centre Harapan Kita Jakarta Indonesia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Cardiovascular Center Harapan Kita</name>
      <address>
        <city>Jakarta</city>
        <state>DKI Jakarta</state>
        <zip>11420</zip>
        <country>Indonesia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Indonesia</country>
  </location_countries>
  <results_reference>
    <citation>Marwali EM, Boom CE, Budiwardhana N, Fakhri D, Roebiono PS, Santoso A, Sastroasmoro S, Slee A, Portman MA. Oral Triiodothyronine for Infants and Children Undergoing Cardiopulmonary Bypass. Ann Thorac Surg. 2017 Aug;104(2):688-695. doi: 10.1016/j.athoracsur.2017.01.001. Epub 2017 Feb 6.</citation>
    <PMID>28185643</PMID>
  </results_reference>
  <results_reference>
    <citation>Marwali EM, Boom CE, Sakidjan I, Santoso A, Fakhri D, Kartini A, Kekalih A, Schwartz SM, Haas NA. Oral triiodothyronine normalizes triiodothyronine levels after surgery for pediatric congenital heart disease*. Pediatr Crit Care Med. 2013 Sep;14(7):701-8. doi: 10.1097/PCC.0b013e3182917f87.</citation>
    <PMID>23842591</PMID>
  </results_reference>
  <results_reference>
    <citation>Luger M, Hiesmayr M, Koppel P, Sima B, Ranz I, Weiss C, Konig J, Luger E, Kruschitz R, Ludvik B, Schindler K. Influence of intravenous thiamine supplementation on blood lactate concentration prior to cardiac surgery: A double-blinded, randomised controlled pilot study. Eur J Anaesthesiol. 2015 Aug;32(8):543-8. doi: 10.1097/EJA.0000000000000205.</citation>
    <PMID>26066773</PMID>
  </results_reference>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>April 10, 2018</study_first_submitted>
  <study_first_submitted_qc>June 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 1, 2020</study_first_posted>
  <last_update_submitted>June 28, 2020</last_update_submitted>
  <last_update_submitted_qc>June 28, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 1, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>National Cardiovascular Center Harapan Kita Hospital Indonesia</investigator_affiliation>
    <investigator_full_name>Eva M Marwali,MD</investigator_full_name>
    <investigator_title>Eva M Marwali, MD, Phd</investigator_title>
  </responsible_party>
  <keyword>thiamine supplementation</keyword>
  <keyword>congenital heart disease</keyword>
  <keyword>paediatric cardiac surgery</keyword>
  <keyword>cardiopulmonary bypass</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Diseases</mesh_term>
    <mesh_term>Heart Defects, Congenital</mesh_term>
    <mesh_term>Thiamine Deficiency</mesh_term>
    <mesh_term>Beriberi</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin B Complex</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/NCT04453761
org study id: LB.02.01/VII/225/KEP.066/2017
nct id: NCT04453761
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is a randomized, double-blind, controlled trial design. It was conducted with a main
      purpose of evaluating the effect of thiamine supplementation on serum lactate and
      lactate-pyruvate ratio after surgery as direct indicators of tissue perfusion and indirect
      markers of energy substrate availability for effective mitochondrial function and intubation
      time as clinical outcome.
All patients who undergo open cardiac surgery for their congenital heart disease on the
      research period will be recruited consecutively and evaluated according to the study
      criteria. Parents or guardians were explained about the procedure. Agreement will be
      concluded by signing the informed consent. Baseline data including age, nutritional status,
      diagnosis, types of heart disease (cyanotic or acyanotic), restrictive or non restrictive
      pulmonary blood flow heart disease, pre-surgical peripheral saturation, pulmonary
      hypertension and any syndromes associated with heart disease will be recorded on the study
      sheets.

      Patients will be randomised using block randomisation procedure with a block size of 4 on
      treatment and control group. Included participants will be marked by specific randomisation
      number by a research assistant physician who is not involved in patients' management. A
      pharmacist will acquire and open a prepared envelope containing the randomisation number. The
      patients, parents/guardians, research physicians, other physicians or paramedics involved in
      patients' treatment will be blinded.

      Placebo (Intravenous Normal Saline) and intravenous thiamine (2 mg/kg) will be administered
      at induction time, 1 hours after surgery and once everyday for three days by pharmacist
      according to randomization result. All subject are given oral T3 supplementation (1 mcg/kg)
      every 6 hours by pharmacist as research protocol. Oral T3 supplementations are given every 6
      hours, started from induction time until 11 doses (60 hours until the first dose). Drugs is
      diluted with 2.5 cc aqua and administerednisterd using nasogastric tube.

      Blood will be withdrawn from arterial line access for 2.5 cc in order to test thiamine,
      lactate, and pyruvate concentration, as well as, measuring LDH and PDH activity. Thiamine
      will be examined from blood plasma using liquid chromatography tandem mass spectometry.
      Thiamine concentration below ≤ 7 nmol/L is considered low. PDH will be examined from
      Peripheral Blood Mononuclear Cells (PBMCs) which will be isolated from fresh blood. PDH
      activity will be tested after breaking cell membrane to initiate mitochondria lysis, this
      process will be done by immunocapture and micro-plate based assay. Lactate and pyruvate
      measurement will be tested using an enzymatic kit specific for lactate and pyruvate called
      Sigma Aldrich reagent. Thiamine concentration, lactate concentration, pyruvate concentration,
      LDH and PDH activity is going to be measured at 4 time; induction time, one hour, 24 hours,
      72 hours after aortic clamp removal.

      Measurement of blood gas analysis, blood glucose, central vein saturation and oxygen
      extraction ratio will be performed at induction time, 1 hours, and 12 hours post-surgery.

      Organ functions evaluation was performed by serially measuring SGOT and SGPT (liver function)
      as well as ureum and creatinine (renal function) on ICU admission.

      Echocardiography evaluation will be done on the first, second and third day after surgery to
      assess the patient's ejection fraction, stroke volume, cardiac volume and index, tricuspid
      annular plane systolic excursion (TAPSE), left heart diastolic functions and SVRI
      calculation. It will be done by 2 research cardiologists.

      Post-surgical managements will be decided according to the paediatric ICU National
      Cardiovascular Center Harapan Kita treatment protocols. Inotropic concentration will be
      evaluated by inotropic and vasoactive-inotropic scoring every 6 hours in the first 24 hours
      and every 12 hours after the second and third 24 hours. The amount of diuretics used will be
      calculated 72 hours after ICU admission. Peritoneal dialysis and continuous veno-venous
      hemofiltration (CVVH) is going to be assessed by means of the length of therapy, renal
      function and fluid balance. Decision to extubate will be carried out by a physician
      responsible according to the treatment protocols. Every reintubation is going to be recorded
      as number and length of intubation. The length of ICU and hospital stay and mortality will be
      evaluated in both study groups.

      Operative data such as Aristotle score, residual lesions presence, open thorax on ICU
      admission, CPB duration, Aox duration and a number of procedures during CPB including
      ultrafiltration, hypothermia and hemodilution is going to be recorded in the research sheets.
      History of medication used which may interfere with the function of thyroid such as steroids,
      dopamine and amiodarone will also be recorded.

      There will be one physician who know the subject's allocation. This physician is not involve
      in any kind of patients' treatment and act as the study supervisor to evaluate if any
      suspicion on drug adverse reactions occurred. Drug adverse reaction is going to be monitored
      by evaluating heart rhythm, heart rate, blood pressure and peripheral temperature for every 6
      hours in the first 24 hours and every 12 hours in the second and third 24 hours of ICU
      treatment. The criteria of drug adverse reaction are stated in the adverse effects form; they
      are tachycardia, arrhythmia, hypertension and refractory hyperthermia. Any suspicion of the
      presence of drug adverse effect is going to be recorded in the form and reported to the
      supervising doctor for further analysis. Management on this reaction will be done by the ICU
      treating doctor
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Evaluate the effect of thiamine supplementation to pyruvate levels
time frame: at 6 hours post cross clamp removal
description: Comparing the lab parameter indicate pyruvate levels
measure: Evaluate the effect of thiamine supplementation to cardiac output.
time frame: Within 1 days of surgery
description: Measuring Cardiac output
arm group label: Drugs Group
arm group type: Experimental
description: Thiamine IV
arm group label: Placebo
arm group type: Placebo Comparator
description: NaCl IV
intervention type: Drug
intervention name: Neurobion
description: Intravenous Thiamine 2 mg/kg in Neurobion injection
arm group label: Drugs Group
other name: Vitamin B1 IV
intervention type: Drug
intervention name: Placebo
description: Intravenous NaCl0.9%
arm group label: Placebo
other name: NaCl 0.9%
criteria: 
gender: All
minimum age: 1 Month
maximum age: 2 Years
healthy volunteers: No
last name: Eva M Marwali, MD, PhD
role: Principal Investigator
affiliation: National Cardiovascular Centre Harapan Kita Jakarta Indonesia
facility: 
country: Indonesia
citation: Marwali EM, Boom CE, Budiwardhana N, Fakhri D, Roebiono PS, Santoso A, Sastroasmoro S, Slee A, Portman MA. Oral Triiodothyronine for Infants and Children Undergoing Cardiopulmonary Bypass. Ann Thorac Surg. 2017 Aug;104(2):688-695. doi: 10.1016/j.athoracsur.2017.01.001. Epub 2017 Feb 6.
PMID: 28185643
citation: Marwali EM, Boom CE, Sakidjan I, Santoso A, Fakhri D, Kartini A, Kekalih A, Schwartz SM, Haas NA. Oral triiodothyronine normalizes triiodothyronine levels after surgery for pediatric congenital heart disease*. Pediatr Crit Care Med. 2013 Sep;14(7):701-8. doi: 10.1097/PCC.0b013e3182917f87.
PMID: 23842591
citation: Luger M, Hiesmayr M, Koppel P, Sima B, Ranz I, Weiss C, Konig J, Luger E, Kruschitz R, Ludvik B, Schindler K. Influence of intravenous thiamine supplementation on blood lactate concentration prior to cardiac surgery: A double-blinded, randomised controlled pilot study. Eur J Anaesthesiol. 2015 Aug;32(8):543-8. doi: 10.1097/EJA.0000000000000205.
PMID: 26066773
responsible party type: Principal Investigator
investigator affiliation: National Cardiovascular Center Harapan Kita Hospital Indonesia
investigator full name: Eva M Marwali,MD
investigator title: Eva M Marwali, MD, Phd
mesh term: Heart Diseases
mesh term: Heart Defects, Congenital
mesh term: Thiamine Deficiency
mesh term: Beriberi
mesh term: Vitamin B Complex
sharing ipd: No