<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/NCT02211326</url>
  </required_header>
  <id_info>
    <org_study_id>XY3-WARF1405A01</org_study_id>
    <secondary_id>ChiCTR-TRC-14004757</secondary_id>
    <nct_id>NCT02211326</nct_id>
  </id_info>
  <brief_title>Genotype-guided Warfarin Individualized Treatment</brief_title>
  <official_title>Pharmacogenetic Algorithm of Response to Warfarin During Initial Anticoagulation in Chinese Elderly Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Third Xiangya Hospital of Central South University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The Third Xiangya Hospital of Central South University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine whether the international pharmacogenetic algorithm&#xD;
      is better than the standard initiation dosing and whether the two algorithms are suitable for&#xD;
      Chinese elderly patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study protocol is a multicenter, randomized, patient-blinded and controlled trial,&#xD;
      comparing two approaches among 864 enrolled AF(atrial fibrillation) or DVT(deep venous&#xD;
      thrombosis) patients for guiding warfarin initial anticoagulation in Chinese elderly&#xD;
      patients: the intervention group using the algorithm of International Warfarin&#xD;
      Pharmacogenetic Consortium and its dose revision, and the control group using a standard&#xD;
      initiation dose (2.25 mg).The study hypothesis is that the intervention group relative to the&#xD;
      control group will increase the percentage of time in therapeutic INR (international&#xD;
      normalized ratio) range during the first 3 months.This trial is the first prospective&#xD;
      large-scale randomized controlled trial for elders in China. It is of great significance for&#xD;
      promoting special crowd individualization of anticoagulants at home and abroad.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 1, 2014</start_date>
  <completion_date type="Actual">May 1, 2017</completion_date>
  <primary_completion_date type="Actual">January 16, 2017</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>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>%TTR</measure>
    <time_frame>12 weeks</time_frame>
    <description>percentage of time in the therapeutic INR (%TTR) of INR 2-3 (&lt;60 years old) or 1.5-2.5 (≥ 60 years old) within 12 weeks</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>the time to reach therapeutic INR</measure>
    <time_frame>12 weeks</time_frame>
    <description>the time to reach therapeutic INR</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the time to reach stable warfarin dose which defined as the dose to achieve INR within ±0.1 of therapeutic range at Day 8 post-dose</measure>
    <time_frame>12 weeks</time_frame>
    <description>the time to reach stable warfarin dose which defined as the dose to achieve INR within ±0.1 of therapeutic range at Day 8 post-dose</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The number of adjustment units in the dose of warfarin (with 0.375 mg (1/8 tablet) as a unit); Incidence of INR ≥ 4</measure>
    <time_frame>12 weeks</time_frame>
    <description>The number of adjustment units in the dose of warfarin (with 0.375 mg (1/8 tablet) as a unit); Incidence of INR ≥ 4</description>
  </secondary_outcome>
  <other_outcome>
    <measure>the number of additional clinic visits</measure>
    <time_frame>12 weeks</time_frame>
    <description>the number of additional clinic visits</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">660</enrollment>
  <condition>Atrial Fibrillation</condition>
  <condition>Deep Venous Thrombosis</condition>
  <arm_group>
    <arm_group_label>genotype-guided group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Interventions：on day1~day3, patients received dose according to IWPC formula (PGx-1) included clinical variables and genotype data for VKORC1, CYP2C9*1, CYP2C9*2, and CYP2C9*3; on day4~day7, patients received dose according to Lenzini formula consisted of clinical variables, VKORC1, CYP2C9*2, CYP2C9*3 and previous INR and dosing information (PGx-2); and on day8, the clinicians adjusted the dose according to observed INR.The overall follow-up period is 12 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>control group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Interventions：on day1~day3, patients were given initial dose (2.25mg); and starting from day4, the clinicians began to adjust the dose for patients according to observed INR.The overall follow-up period is 12 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Genotype-guided dosing algorithm for warfarin</intervention_name>
    <description>Intervention：initial dosing of warfarin for the first 3 days of treatment will be determined by IWPC( International Warfarin Pharmacogenetics Consortium) algorithm (PG-1),a second dose adjustment will be made after 3 doses of warfarin using a dose revision algorithm (PG-2) that combined INR values,the dose will be adjusted depending on the measurements of INR values after 7 days.The overall follow-up period is 12 weeks.</description>
    <arm_group_label>genotype-guided group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Standard initiation dose for warfarin</intervention_name>
    <description>Intervention：initial dosing of warfarin for the first 3 days of treatment will be determined by standard initiation dose. Following this initiation dose of warfarin,the dose will be adjusted depending on the measurements of INR values after 3 days.The overall follow-up period is 12 weeks.</description>
    <arm_group_label>control group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria：1) Chinese male or female aged ≥18 years; 2) Requiring at least 12-week&#xD;
        warfarin therapy as judged by clinicians; 3) Subjects with DVT/AF and a post-therapy target&#xD;
        INR of 1.5-2.5; 4) Capable of providing written informed consent; 5) Capable of maintaining&#xD;
        excellent communications with investigators and completing trial in accordance with trial&#xD;
        stipulations.&#xD;
&#xD;
        Exclusion criteria：1) Subjects previously taking warfarin; 2) Known genotypes of CYP2C9&#xD;
        or/and VKORC1; 3) Subjects receiving or expecting to receive other therapies or other&#xD;
        anticoagulants; 4) Subjects with contraindications for warfarin; 5) Subjects with severe&#xD;
        cognitive dysfunctions; 6) Baseline INR ≥1.5; 7) Subjects with drug or alcohol dependence&#xD;
        within the last 12 months; 8) Subjects receiving blood transfusion or bone marrow&#xD;
        transplantation within the last 2 weeks; 9) Planning to receive invasive examinations&#xD;
        (except for standard endoscopy) with a hemorrhagic tendency or undergoing surgery during&#xD;
        trial.10) Prior to randomization, subjects receiving any trial drug or device within the&#xD;
        last 3 months or planning to receive such an investigational therapy during trial; 11)&#xD;
        Subjects with the following diagnoses or conditions: active malignant carcinomas (diagnosed&#xD;
        within the last 5 years), but excluding adequately-treated non-melanoma skin cancer or&#xD;
        other non-invasive or in situ cancer (e.g. cervical cancer in situ); anti-neoplastic&#xD;
        therapy within the last 5 years (medication, radiotherapy or/and surgery); overt active&#xD;
        disease or infection; life expectancy &lt;6 months; 12）Other clinical reasons for unsuitable&#xD;
        recruitment as judged by clinicians.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>GuoPing Yang, professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Third Xiangya Hospital of Central South University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The People's Hospital of Hunan Province</name>
      <address>
        <city>Changsha</city>
        <state>Hunan</state>
        <zip>410002</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Central Hospital of Changsha</name>
      <address>
        <city>Changsha</city>
        <state>Hunan</state>
        <zip>410004</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Fourth Hospital of Changsha</name>
      <address>
        <city>Changsha</city>
        <state>Hunan</state>
        <zip>410006</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Third Xiangya Hospital of Central South University</name>
      <address>
        <city>Changsha</city>
        <state>Hunan</state>
        <zip>410013</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Third Hospital of Changsha</name>
      <address>
        <city>Changsha</city>
        <state>Hunan</state>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Xiangya Hospital of Central South University</name>
      <address>
        <city>Changsha</city>
        <state>Hunan</state>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The First People's Hospital of Chenzhou</name>
      <address>
        <city>Chenzhou</city>
        <state>Hunan</state>
        <zip>423000</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The First Affiliated Hospital of Nanhua university</name>
      <address>
        <city>Hengyang</city>
        <state>Hunan</state>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Second Affiliated Hospital of Nanhua university</name>
      <address>
        <city>Hengyang</city>
        <state>Hunan</state>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Central Hospital of Loudi</name>
      <address>
        <city>Loudi</city>
        <state>Hunan</state>
        <zip>417000</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Central Hospital of Shaoyang</name>
      <address>
        <city>Shaoyang</city>
        <state>Hunan</state>
        <zip>422000</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The First People's Hospital of Shaoyang</name>
      <address>
        <city>Shaoyang</city>
        <state>Hunan</state>
        <zip>422001</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Central Hospital of Xiangtan</name>
      <address>
        <city>Xiangtan</city>
        <state>Hunan</state>
        <zip>411100</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The First People's Hospital of Xiangtan</name>
      <address>
        <city>Xiangtan</city>
        <state>Hunan</state>
        <zip>411101</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Central Hospital of Yiyang</name>
      <address>
        <city>Yiyang</city>
        <state>Hunan</state>
        <zip>413000</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, Blatchford J, Devenny K, Friedman J, Guiver K, Harper R, Khder Y, Lobmeyer MT, Maas H, Voigt JU, Simoons ML, Van de Werf F; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013 Sep 26;369(13):1206-14. doi: 10.1056/NEJMoa1300615. Epub 2013 Aug 31.</citation>
    <PMID>23991661</PMID>
  </reference>
  <reference>
    <citation>Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91. doi: 10.1056/NEJMoa1009638. Epub 2011 Aug 10.</citation>
    <PMID>21830957</PMID>
  </reference>
  <reference>
    <citation>Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104. doi: 10.1056/NEJMoa1310907. Epub 2013 Nov 19.</citation>
    <PMID>24251359</PMID>
  </reference>
  <reference>
    <citation>Arepally GM, Ortel TL. Changing practice of anticoagulation: will target-specific anticoagulants replace warfarin? Annu Rev Med. 2015;66:241-53. doi: 10.1146/annurev-med-051113-024633.</citation>
    <PMID>25587651</PMID>
  </reference>
  <reference>
    <citation>Healey JS, Oldgren J, Ezekowitz M, Zhu J, Pais P, Wang J, Commerford P, Jansky P, Avezum A, Sigamani A, Damasceno A, Reilly P, Grinvalds A, Nakamya J, Aje A, Almahmeed W, Moriarty A, Wallentin L, Yusuf S, Connolly SJ; RE-LY Atrial Fibrillation Registry and Cohort Study Investigators. Occurrence of death and stroke in patients in 47 countries 1 year after presenting with atrial fibrillation: a cohort study. Lancet. 2016 Sep 17;388(10050):1161-9. doi: 10.1016/S0140-6736(16)30968-0. Epub 2016 Aug 8. Erratum In: Lancet. 2017 Feb 11;389(10069):602.</citation>
    <PMID>27515684</PMID>
  </reference>
  <verification_date>November 2017</verification_date>
  <study_first_submitted>August 6, 2014</study_first_submitted>
  <study_first_submitted_qc>August 6, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 7, 2014</study_first_posted>
  <last_update_submitted>November 1, 2017</last_update_submitted>
  <last_update_submitted_qc>November 1, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">November 6, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>AF or DVT</keyword>
  <keyword>Age Over 18 Years, Acquired</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atrial Fibrillation</mesh_term>
    <mesh_term>Thrombosis</mesh_term>
    <mesh_term>Venous Thrombosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Warfarin</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02211326
org study id: XY3-WARF1405A01
secondary id: ChiCTR-TRC-14004757
nct id: NCT02211326
lead sponsor: 
has dmc: Yes
The purpose of this study is to determine whether the international pharmacogenetic algorithm
      is better than the standard initiation dosing and whether the two algorithms are suitable for
      Chinese elderly patients.
The study protocol is a multicenter, randomized, patient-blinded and controlled trial,
      comparing two approaches among 864 enrolled AF(atrial fibrillation) or DVT(deep venous
      thrombosis) patients for guiding warfarin initial anticoagulation in Chinese elderly
      patients: the intervention group using the algorithm of International Warfarin
      Pharmacogenetic Consortium and its dose revision, and the control group using a standard
      initiation dose (2.25 mg).The study hypothesis is that the intervention group relative to the
      control group will increase the percentage of time in therapeutic INR (international
      normalized ratio) range during the first 3 months.This trial is the first prospective
      large-scale randomized controlled trial for elders in China. It is of great significance for
      promoting special crowd individualization of anticoagulants at home and abroad.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: %TTR
time frame: 12 weeks
description: percentage of time in the therapeutic INR (%TTR) of INR 2-3 (<60 years old) or 1.5-2.5 (≥ 60 years old) within 12 weeks
measure: the time to reach therapeutic INR
time frame: 12 weeks
description: the time to reach therapeutic INR
measure: the time to reach stable warfarin dose which defined as the dose to achieve INR within ±0.1 of therapeutic range at Day 8 post-dose
time frame: 12 weeks
description: the time to reach stable warfarin dose which defined as the dose to achieve INR within ±0.1 of therapeutic range at Day 8 post-dose
measure: The number of adjustment units in the dose of warfarin (with 0.375 mg (1/8 tablet) as a unit); Incidence of INR ≥ 4
time frame: 12 weeks
description: The number of adjustment units in the dose of warfarin (with 0.375 mg (1/8 tablet) as a unit); Incidence of INR ≥ 4
measure: the number of additional clinic visits
time frame: 12 weeks
description: the number of additional clinic visits
arm group label: genotype-guided group
arm group type: Experimental
description: Interventions：on day1~day3, patients received dose according to IWPC formula (PGx-1) included clinical variables and genotype data for VKORC1, CYP2C9*1, CYP2C9*2, and CYP2C9*3; on day4~day7, patients received dose according to Lenzini formula consisted of clinical variables, VKORC1, CYP2C9*2, CYP2C9*3 and previous INR and dosing information (PGx-2); and on day8, the clinicians adjusted the dose according to observed INR.The overall follow-up period is 12 weeks.
arm group label: control group
arm group type: Active Comparator
description: Interventions：on day1~day3, patients were given initial dose (2.25mg); and starting from day4, the clinicians began to adjust the dose for patients according to observed INR.The overall follow-up period is 12 weeks.
intervention type: Behavioral
intervention name: Genotype-guided dosing algorithm for warfarin
description: Intervention：initial dosing of warfarin for the first 3 days of treatment will be determined by IWPC( International Warfarin Pharmacogenetics Consortium) algorithm (PG-1),a second dose adjustment will be made after 3 doses of warfarin using a dose revision algorithm (PG-2) that combined INR values,the dose will be adjusted depending on the measurements of INR values after 7 days.The overall follow-up period is 12 weeks.
arm group label: genotype-guided group
intervention type: Behavioral
intervention name: Standard initiation dose for warfarin
description: Intervention：initial dosing of warfarin for the first 3 days of treatment will be determined by standard initiation dose. Following this initiation dose of warfarin,the dose will be adjusted depending on the measurements of INR values after 3 days.The overall follow-up period is 12 weeks.
arm group label: control group
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: GuoPing Yang, professor
role: Principal Investigator
affiliation: The Third Xiangya Hospital of Central South University
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: China
citation: Eikelboom JW, Connolly SJ, Brueckmann M, Granger CB, Kappetein AP, Mack MJ, Blatchford J, Devenny K, Friedman J, Guiver K, Harper R, Khder Y, Lobmeyer MT, Maas H, Voigt JU, Simoons ML, Van de Werf F; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013 Sep 26;369(13):1206-14. doi: 10.1056/NEJMoa1300615. Epub 2013 Aug 31.
PMID: 23991661
citation: Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91. doi: 10.1056/NEJMoa1009638. Epub 2011 Aug 10.
PMID: 21830957
citation: Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Spinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104. doi: 10.1056/NEJMoa1310907. Epub 2013 Nov 19.
PMID: 24251359
citation: Arepally GM, Ortel TL. Changing practice of anticoagulation: will target-specific anticoagulants replace warfarin? Annu Rev Med. 2015;66:241-53. doi: 10.1146/annurev-med-051113-024633.
PMID: 25587651
citation: Healey JS, Oldgren J, Ezekowitz M, Zhu J, Pais P, Wang J, Commerford P, Jansky P, Avezum A, Sigamani A, Damasceno A, Reilly P, Grinvalds A, Nakamya J, Aje A, Almahmeed W, Moriarty A, Wallentin L, Yusuf S, Connolly SJ; RE-LY Atrial Fibrillation Registry and Cohort Study Investigators. Occurrence of death and stroke in patients in 47 countries 1 year after presenting with atrial fibrillation: a cohort study. Lancet. 2016 Sep 17;388(10050):1161-9. doi: 10.1016/S0140-6736(16)30968-0. Epub 2016 Aug 8. Erratum In: Lancet. 2017 Feb 11;389(10069):602.
PMID: 27515684
responsible party type: Sponsor
mesh term: Atrial Fibrillation
mesh term: Thrombosis
mesh term: Venous Thrombosis
mesh term: Warfarin