<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/NCT03797534</url>
  </required_header>
  <id_info>
    <org_study_id>CLW2018WA</org_study_id>
    <nct_id>NCT03797534</nct_id>
  </id_info>
  <brief_title>Individualized Administration of Warfarin by Polymorphisms of VKORC1 and CYP2C9 Genes</brief_title>
  <official_title>Individualized Administration of Warfarin by Polymorphisms of VKORC1 and CYP2C9 Genes:A Randomized Controlled Trial, Multi-center Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fujian Medical University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fujian Medical University</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to explore the individualized administration model of warfarin&#xD;
      suitable for Chinese people, and provide a scientific reference for the use of warfarin to&#xD;
      Chinese people.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      About 600 patients with VKORC1 and CYP2C9 gene mutations were included in the treatment of&#xD;
      warfarin anticoagulant therapy. The main indications include valve replacement, atrial&#xD;
      fibrillation, pulmonary embolism, etc., randomly divided into 2 groups, respectively, the&#xD;
      control group (that is, the use of fixed-dose group), Bayesian-model group, the use of&#xD;
      single-blind treatment method, to evaluate the number of major adverse events, TTR and INR&#xD;
      adjustments in patients between different groups after three months of taking warfarin, and&#xD;
      then to explore the individualized drug use model of warfarin suitable for Chinese&#xD;
      population.&#xD;
&#xD;
      In the Bayesian group, according to the genotype of VKORC1 and CYP2C9, the stable dose was&#xD;
      calculated by the dose prediction model of Bayesian, and the first three drugs were taken at&#xD;
      this dose, and then adjusted to the actual stable dose according to the change of INR.&#xD;
      Meanwhile, the control group was administered according to the traditional way, that is, the&#xD;
      initial dose is 2.5 or 3mg/d and is gradually adjusted to a stable dose according to changes&#xD;
      of INR. The monitoring frequency of INR is: once a day from the beginning of the drug to the&#xD;
      time of discharge, once a week after discharge, and once a month after the stable dose is&#xD;
      obtained. Detailed records of the number of days to reach a stable dose, the INR value and&#xD;
      the occurrence of side effects and time are documented. The concrete steps are as follows:&#xD;
&#xD;
        1. clinicians to judge the standard of the selection criteria;&#xD;
&#xD;
        2. to obtain the consent of the patient and sign an informed consent certificate;&#xD;
&#xD;
        3. to collect 2ml anticoagulant blood before the drug, fill in the application form for&#xD;
           individualized drug use in warfarin, and indicate the experimental group and control&#xD;
           group;&#xD;
&#xD;
        4. the specimen assigned to the laboratory for Genotyping;&#xD;
&#xD;
        5. lab to calculate the predicted stable warfarin dose and the results fed back to the&#xD;
           clinician within one working day after receiving the specimen;&#xD;
&#xD;
        6. in the control group, the drug retained at the regular dose, and the first 3 days of the&#xD;
           experimental group administered at the predicted dose;&#xD;
&#xD;
        7. the dosage of warfarin in the two groups of cases adjusted to the stable dose according&#xD;
           to the value, and the adjustment amplitude of the experimental group also referred to&#xD;
           the predicted stable dose.&#xD;
&#xD;
        8. to monitor INR once a day during hospitalization, and to those who do not receive a&#xD;
           stable dose of discharge, follow up and monitor INR once a week until a stable dose or&#xD;
           medication is obtained for 90 days;&#xD;
&#xD;
        9. to document clinical trial records, including the daily use of warfarin, each detection&#xD;
           of the appearance of the situation like INR value, bleeding, venous embolism and other&#xD;
           side effects.&#xD;
&#xD;
      Finally，according to the outcome parameters,statistical analysis were performed with SPSS&#xD;
      11.5 software. A value of P &lt; 0.05 was considered statistically significant.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Anticipated">February 1, 2019</start_date>
  <completion_date type="Anticipated">January 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">January 1, 2022</primary_completion_date>
  <phase>N/A</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>Supportive Care</primary_purpose>
    <masking>Double (Participant, Care Provider)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>excessive anticoagulant time ratio</measure>
    <time_frame>3 months postoperatively</time_frame>
    <description>INR&gt;3，INR&gt;4</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The occurrence of primary bleeding events</measure>
    <time_frame>3 months postoperatively</time_frame>
    <description>gastrointestinal hemorrhage, intracerebral hemorrhage,etc</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The occurance of secondary bleeding events</measure>
    <time_frame>3 months postoperatively</time_frame>
    <description>nasal bleeding, skin stasis,etc</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The occurrence of thrombosis events</measure>
    <time_frame>3 months postoperatively</time_frame>
    <description>ischemic stroke, deep vein thrombosis,etc</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percentage of time in therapeutic range</measure>
    <time_frame>3 months, 6 months, 12 months postoperatively</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The time required to reach the treatment target INR for the first time;</measure>
    <time_frame>3 months postoperatively</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The time required from the beginning of treatment to the stable dose;</measure>
    <time_frame>3 months postoperatively</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The percentage of time below the target INR range;</measure>
    <time_frame>3 months postoperatively</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The percentage of time above the target INR range;</measure>
    <time_frame>3 months postoperatively</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The number of dose adjustments and the number of INR measured during the first month of treatment;</measure>
    <time_frame>3 months postoperatively</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The proportion of patients in each group receiving a stable dose after follow-up;</measure>
    <time_frame>3 months postoperatively</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The proportion of patients in each group having side effects after follow-up</measure>
    <time_frame>3 months postoperatively</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">600</enrollment>
  <condition>Heart Valve Prosthesis</condition>
  <arm_group>
    <arm_group_label>Standard anticoagulant group</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Bayesian model group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>dose regime</intervention_name>
    <description>The initial dose of the experimental group will be calculated by the Bayesian model.</description>
    <arm_group_label>Bayesian model group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age &gt; 14 years old；&#xD;
&#xD;
          2. Warfarin anticoagulant therapy is required for at least 3 months；&#xD;
&#xD;
          3. The genotype of patient VKORC1 is non-AA, CYP2C9 genotype is non*1/*1； the patients&#xD;
             who are followed up, regularly monitored for INR and willing to provide peripheral&#xD;
             blood for DNA extraction and genetic testing；&#xD;
&#xD;
          4. The patient or family members can understand the research plan and will participate in&#xD;
             this study and provide a written informed consent；&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Severe liver dysfunction (ChildPugh ≥ 10);&#xD;
&#xD;
          2. Severe infection, respiratory failure;&#xD;
&#xD;
          3. Severe heart failure ( NYHA ≥ IV);&#xD;
&#xD;
          4. Severe renal insufficiency (Ccr ≤ 20ml / min);&#xD;
&#xD;
          5. Cancer;&#xD;
&#xD;
          6. Diseases of the blood system;&#xD;
&#xD;
          7. Severe pulmonary hypertension (PAPm ≥ 45mmHg);&#xD;
&#xD;
          8. Abnormal thyroid function;&#xD;
&#xD;
          9. Patients with a history of venous thromboembolism, or serious events such as severe&#xD;
             bleeding or embolism;&#xD;
&#xD;
         10. Women who are pregnant or breastfeeding;&#xD;
&#xD;
         11. Taking or planning to take other oral anticoagulants;&#xD;
&#xD;
         12. The base INR value is &gt;1.4;&#xD;
&#xD;
         13. VKORC1, CYP2C9 genotypes are AA, *1/*1;&#xD;
&#xD;
         14. Secondary valve replacement surgery;&#xD;
&#xD;
         15. Emergency hospital admission for valve surgery;&#xD;
&#xD;
         16. Diagnosis of coronary atherosclerotic heart disease;&#xD;
&#xD;
         17. Severe mental illness, mental disorder ; -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>14 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>the Department of Cardiovascular Surgery</name>
      <address>
        <city>FuZhou</city>
        <state>Fujian</state>
        <zip>350001</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Liang-Wan Chen, M.D Ph.D</last_name>
      <phone>86 13358255333</phone>
      <email>343983217@qq.com</email>
    </contact>
    <contact_backup>
      <last_name>Jin-Hua Zhang, Ph.D</last_name>
      <phone>86 13609532263</phone>
      <email>pollyzhang2006@126.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>Gage BF, Eby C, Johnson JA, Deych E, Rieder MJ, Ridker PM, Milligan PE, Grice G, Lenzini P, Rettie AE, Aquilante CL, Grosso L, Marsh S, Langaee T, Farnett LE, Voora D, Veenstra DL, Glynn RJ, Barrett A, McLeod HL. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther. 2008 Sep;84(3):326-31. doi: 10.1038/clpt.2008.10. Epub 2008 Feb 27. Erratum In: Clin Pharmacol Ther. 2008 Sep;84(3):430.</citation>
    <PMID>18305455</PMID>
  </reference>
  <reference>
    <citation>International Warfarin Pharmacogenetics Consortium; Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009 Feb 19;360(8):753-64. doi: 10.1056/NEJMoa0809329. Erratum In: N Engl J Med. 2009 Oct 15;361(16):1613. Dosage error in article text.</citation>
    <PMID>19228618</PMID>
  </reference>
  <reference>
    <citation>Hamberg AK, Hellman J, Dahlberg J, Jonsson EN, Wadelius M. A Bayesian decision support tool for efficient dose individualization of warfarin in adults and children. BMC Med Inform Decis Mak. 2015 Feb 7;15:7. doi: 10.1186/s12911-014-0128-0.</citation>
    <PMID>25889768</PMID>
  </reference>
  <reference>
    <citation>Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, Kesteven P, Christersson C, Wahlstrom B, Stafberg C, Zhang JE, Leathart JB, Kohnke H, Maitland-van der Zee AH, Williamson PR, Daly AK, Avery P, Kamali F, Wadelius M; EU-PACT Group. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013 Dec 12;369(24):2294-303. doi: 10.1056/NEJMoa1311386. Epub 2013 Nov 19.</citation>
    <PMID>24251363</PMID>
  </reference>
  <reference>
    <citation>Kimmel SE, French B, Kasner SE, Johnson JA, Anderson JL, Gage BF, Rosenberg YD, Eby CS, Madigan RA, McBane RB, Abdel-Rahman SZ, Stevens SM, Yale S, Mohler ER 3rd, Fang MC, Shah V, Horenstein RB, Limdi NA, Muldowney JA 3rd, Gujral J, Delafontaine P, Desnick RJ, Ortel TL, Billett HH, Pendleton RC, Geller NL, Halperin JL, Goldhaber SZ, Caldwell MD, Califf RM, Ellenberg JH; COAG Investigators. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med. 2013 Dec 12;369(24):2283-93. doi: 10.1056/NEJMoa1310669. Epub 2013 Nov 19.</citation>
    <PMID>24251361</PMID>
  </reference>
  <reference>
    <citation>Li X, Yang J, Wang X, Xu Q, Zhang Y, Yin T. Clinical benefits of pharmacogenetic algorithm-based warfarin dosing: meta-analysis of randomized controlled trials. Thromb Res. 2015 Apr;135(4):621-9. doi: 10.1016/j.thromres.2015.01.018. Epub 2015 Jan 17.</citation>
    <PMID>25628141</PMID>
  </reference>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 6, 2019</study_first_submitted>
  <study_first_submitted_qc>January 6, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 9, 2019</study_first_posted>
  <last_update_submitted>January 13, 2019</last_update_submitted>
  <last_update_submitted_qc>January 13, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 15, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Fujian Medical University</investigator_affiliation>
    <investigator_full_name>Liang-Wan Chen MD</investigator_full_name>
    <investigator_title>The director of the department of cardiovascular surgery</investigator_title>
  </responsible_party>
  <keyword>warfarin</keyword>
  <keyword>gene</keyword>
  <!-- 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/NCT03797534
org study id: CLW2018WA
nct id: NCT03797534
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to explore the individualized administration model of warfarin
      suitable for Chinese people, and provide a scientific reference for the use of warfarin to
      Chinese people.
About 600 patients with VKORC1 and CYP2C9 gene mutations were included in the treatment of
      warfarin anticoagulant therapy. The main indications include valve replacement, atrial
      fibrillation, pulmonary embolism, etc., randomly divided into 2 groups, respectively, the
      control group (that is, the use of fixed-dose group), Bayesian-model group, the use of
      single-blind treatment method, to evaluate the number of major adverse events, TTR and INR
      adjustments in patients between different groups after three months of taking warfarin, and
      then to explore the individualized drug use model of warfarin suitable for Chinese
      population.

      In the Bayesian group, according to the genotype of VKORC1 and CYP2C9, the stable dose was
      calculated by the dose prediction model of Bayesian, and the first three drugs were taken at
      this dose, and then adjusted to the actual stable dose according to the change of INR.
      Meanwhile, the control group was administered according to the traditional way, that is, the
      initial dose is 2.5 or 3mg/d and is gradually adjusted to a stable dose according to changes
      of INR. The monitoring frequency of INR is: once a day from the beginning of the drug to the
      time of discharge, once a week after discharge, and once a month after the stable dose is
      obtained. Detailed records of the number of days to reach a stable dose, the INR value and
      the occurrence of side effects and time are documented. The concrete steps are as follows:

        1. clinicians to judge the standard of the selection criteria;

        2. to obtain the consent of the patient and sign an informed consent certificate;

        3. to collect 2ml anticoagulant blood before the drug, fill in the application form for
           individualized drug use in warfarin, and indicate the experimental group and control
           group;

        4. the specimen assigned to the laboratory for Genotyping;

        5. lab to calculate the predicted stable warfarin dose and the results fed back to the
           clinician within one working day after receiving the specimen;

        6. in the control group, the drug retained at the regular dose, and the first 3 days of the
           experimental group administered at the predicted dose;

        7. the dosage of warfarin in the two groups of cases adjusted to the stable dose according
           to the value, and the adjustment amplitude of the experimental group also referred to
           the predicted stable dose.

        8. to monitor INR once a day during hospitalization, and to those who do not receive a
           stable dose of discharge, follow up and monitor INR once a week until a stable dose or
           medication is obtained for 90 days;

        9. to document clinical trial records, including the daily use of warfarin, each detection
           of the appearance of the situation like INR value, bleeding, venous embolism and other
           side effects.

      Finally，according to the outcome parameters,statistical analysis were performed with SPSS
      11.5 software. A value of P < 0.05 was considered statistically significant.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Supportive Care
masking: Double (Participant, Care Provider)
measure: excessive anticoagulant time ratio
time frame: 3 months postoperatively
description: INR>3，INR>4
measure: The occurrence of primary bleeding events
time frame: 3 months postoperatively
description: gastrointestinal hemorrhage, intracerebral hemorrhage,etc
measure: The occurance of secondary bleeding events
time frame: 3 months postoperatively
description: nasal bleeding, skin stasis,etc
measure: The occurrence of thrombosis events
time frame: 3 months postoperatively
description: ischemic stroke, deep vein thrombosis,etc
measure: Percentage of time in therapeutic range
time frame: 3 months, 6 months, 12 months postoperatively
measure: The time required to reach the treatment target INR for the first time;
time frame: 3 months postoperatively
measure: The time required from the beginning of treatment to the stable dose;
time frame: 3 months postoperatively
measure: The percentage of time below the target INR range;
time frame: 3 months postoperatively
measure: The percentage of time above the target INR range;
time frame: 3 months postoperatively
measure: The number of dose adjustments and the number of INR measured during the first month of treatment;
time frame: 3 months postoperatively
measure: The proportion of patients in each group receiving a stable dose after follow-up;
time frame: 3 months postoperatively
measure: The proportion of patients in each group having side effects after follow-up
time frame: 3 months postoperatively
arm group label: Standard anticoagulant group
arm group type: No Intervention
arm group label: Bayesian model group
arm group type: Experimental
intervention type: Other
intervention name: dose regime
description: The initial dose of the experimental group will be calculated by the Bayesian model.
arm group label: Bayesian model group
criteria: 
gender: All
minimum age: 14 Years
maximum age: N/A
healthy volunteers: No
facility: 
status: Recruiting
contact: 
contact backup: 
country: China
citation: Gage BF, Eby C, Johnson JA, Deych E, Rieder MJ, Ridker PM, Milligan PE, Grice G, Lenzini P, Rettie AE, Aquilante CL, Grosso L, Marsh S, Langaee T, Farnett LE, Voora D, Veenstra DL, Glynn RJ, Barrett A, McLeod HL. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther. 2008 Sep;84(3):326-31. doi: 10.1038/clpt.2008.10. Epub 2008 Feb 27. Erratum In: Clin Pharmacol Ther. 2008 Sep;84(3):430.
PMID: 18305455
citation: International Warfarin Pharmacogenetics Consortium; Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009 Feb 19;360(8):753-64. doi: 10.1056/NEJMoa0809329. Erratum In: N Engl J Med. 2009 Oct 15;361(16):1613. Dosage error in article text.
PMID: 19228618
citation: Hamberg AK, Hellman J, Dahlberg J, Jonsson EN, Wadelius M. A Bayesian decision support tool for efficient dose individualization of warfarin in adults and children. BMC Med Inform Decis Mak. 2015 Feb 7;15:7. doi: 10.1186/s12911-014-0128-0.
PMID: 25889768
citation: Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, Kesteven P, Christersson C, Wahlstrom B, Stafberg C, Zhang JE, Leathart JB, Kohnke H, Maitland-van der Zee AH, Williamson PR, Daly AK, Avery P, Kamali F, Wadelius M; EU-PACT Group. A randomized trial of genotype-guided dosing of warfarin. N Engl J Med. 2013 Dec 12;369(24):2294-303. doi: 10.1056/NEJMoa1311386. Epub 2013 Nov 19.
PMID: 24251363
citation: Kimmel SE, French B, Kasner SE, Johnson JA, Anderson JL, Gage BF, Rosenberg YD, Eby CS, Madigan RA, McBane RB, Abdel-Rahman SZ, Stevens SM, Yale S, Mohler ER 3rd, Fang MC, Shah V, Horenstein RB, Limdi NA, Muldowney JA 3rd, Gujral J, Delafontaine P, Desnick RJ, Ortel TL, Billett HH, Pendleton RC, Geller NL, Halperin JL, Goldhaber SZ, Caldwell MD, Califf RM, Ellenberg JH; COAG Investigators. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N Engl J Med. 2013 Dec 12;369(24):2283-93. doi: 10.1056/NEJMoa1310669. Epub 2013 Nov 19.
PMID: 24251361
citation: Li X, Yang J, Wang X, Xu Q, Zhang Y, Yin T. Clinical benefits of pharmacogenetic algorithm-based warfarin dosing: meta-analysis of randomized controlled trials. Thromb Res. 2015 Apr;135(4):621-9. doi: 10.1016/j.thromres.2015.01.018. Epub 2015 Jan 17.
PMID: 25628141
responsible party type: Principal Investigator
investigator affiliation: Fujian Medical University
investigator full name: Liang-Wan Chen MD
investigator title: The director of the department of cardiovascular surgery