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Applying Pharmacogenetic Algorithms to Individualize Dosing of Warfarin (Coumagen-II)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Intermountain Health Care, Inc.
ClinicalTrials.gov Identifier:
NCT00927862
First received: June 23, 2009
Last updated: August 24, 2012
Last verified: August 2012
Results First Received: April 9, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator);   Primary Purpose: Treatment
Condition: Thromboembolism
Interventions: Genetic: IWPC adapted genotype-guided dosing algorithm for warfarin
Genetic: Modified IWPC genetic-guided warfarin dosing algorithm
Other: Standard of care treatment

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Those >= 18 years and being initiated on warfarin therapy with a target international normalized prothrombin time ratio (INR) of 2-3 or 2.5 –3.5 among participating hospitals and outpatient clinics were invited to participate and sign informed consent.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
If after enrollment, pt was found to be not appropriate for warfarin or pharmacogenetic (PG)-guided dosing or physician preference not to have pt participate they were not randomized. Description below and baseline characteristics report combined PG arms because of similarities but outcome measures report combined and individual PG results.

Reporting Groups
  Description
PG Dosing Patients Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the PG-dosing algorithms were randomized to receive either standard or modified International Warfarin Pharmacogenetics Consortium [IWPC] warfarin dosing. The IWPC derived and published a common algorithm to predict stable maintenance dose based on ~5000 patients across broad geographic and ethnic/racial groups (N Engl J Med 2009;360:753-764). Hence, we based our standard algorithm on the IWPC algorithm with minor modifications to accommodate different INR targets and smoking status, based on supplemental data from Gage et al (Clini Pharmacol Ther 2008;84:326 -331). The modified IWPC algorithm included 2 further modifications: (1) It ignored the CYP2C9 variant status for the first 2 days; and (2) It used a special dose-revision algorithm based on a day 4 (or day 5) INR after 3 (or 4) warfarin doses.
Parellel/Historical Controls A parallel, standard-dosing patient control cohort was identified by a query of the electronic medical records databases of the 3 participating hospitals for the time interval spanning enrollment of the randomized pharmacogenetic-guided cohorts (July 2008 through December 2010). Patients >=18 years of age initiating warfarin therapy with a baseline and at least 1 follow-up INR level between days 3 and 14 were selected. Initial dose selection and therapy modification was at individual Intermountain-credentialed physician/healthcare provider discretion. Standard management is non-PG-based. A standard (fixed) initial maintenance dose of 5 mg/d is generally assumed, with loading doses and clinical-factor modifications not specified.

Participant Flow:   Overall Study
    PG Dosing Patients   Parellel/Historical Controls
STARTED   504   1911 
COMPLETED   477 [1]   1866 
NOT COMPLETED   27   45 
Missing data needed for endpt analyses                27                45 
[1] 477 patients evaluated in primary analyses and 488 evaluated in secondary analyses.



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
PG Dosing Patients Patients who were enrolled in CoumaGen-II and thus, received their warfarin dosing by the pharmacogenetic (PG)-dosing algorithms (standard or modified IWPC warfarin algorithms)
Historical Controls A parallel, clinical effectiveness comparison group that used an algorithm with standard dosing
Total Total of all reporting groups

Baseline Measures
   PG Dosing Patients   Historical Controls   Total 
Overall Participants Analyzed 
[Units: Participants]
 504   1911   2415 
Age 
[Units: Participants]
     
<=18 years   0   0   0 
Between 18 and 65 years   288   1214   1502 
>=65 years   216   697   913 
Age 
[Units: Years]
Mean (Standard Deviation)
 61.3  (14.6)   57.3  (17.5)   58.0  (16.8) 
Gender 
[Units: Participants]
     
Female   268   984   1252 
Male   236   927   1163 
Region of Enrollment 
[Units: Participants]
     
United States   504   1911   2415 


  Outcome Measures
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1.  Primary:   The Percent of Out of Range (OOR) International Normalized Prothrombin Time Ratio (INRs) in the Standard and Modified Pharmacogenetic Arms.   [ Time Frame: 1 month (from day 3 to day 30) ]

2.  Primary:   The Percent of Out of Range (OOR) INRs in Pharmacogenetic-guided Patients and Parallel Controls   [ Time Frame: 1 month (from day 3 to day 30) ]

3.  Primary:   The Percent of Time in Therapeutic Range (TTR) for the Standard and Modified Pharmacogenetic Algorithms.   [ Time Frame: 1 month (from baseline to day 30) ]

4.  Primary:   The Time in Therapeutic Range (TTR) for the Pharmacogenetic-guided Patients and Parallel Controls   [ Time Frame: 1 month (from baseline to day 30) ]

5.  Secondary:   The Percent of INRs ≥4 or ≤1.5 for the Modified IWPC Warfarin Algorithm and the Standard IWPC Warfarin Algorithm   [ Time Frame: 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first) ]

6.  Secondary:   The Percent of INRs ≥4 or ≤1.5 or SAEs Among the Modified IWPC Warfarin Algorithm and Standard IWPC Warfarin Algorithm.   [ Time Frame: 3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first) ]

7.  Secondary:   The Number of INRs Measured up to 3 Months in the Pharmacogenetic (PG) (Modified and Standard) Algorithms and Parallel Controls.   [ Time Frame: 1-3 months (from baseline to 3 months or end of warfarin therapy, whichever occurs first) ]

8.  Secondary:   Prediction of a Stable Maintenance Dose Among the Pharmacogenetic (PG)-Guided Dosing Algorithms and the Parallel Controls   [ Time Frame: 3 months (from baseline to 3 months or until stable dosing is achieved, whichever occurs first) ]

9.  Secondary:   The Percent of INRs ≥4 or ≤1.5 in the Pharmacogenetic (PG)-Guided Dosing Arms and the Parallel Control Arm   [ Time Frame: 3 months (baseline to 3 months or to end of warfarin therapy, whichever occurs first) ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
All Principal Investigators ARE employed by the organization sponsoring the study.


Results Point of Contact:  
Name/Title: Dr. Jeffrey L. Anderson, Director of CV Research and Professor of Medicine
Organization: Intermountain Healthcare
phone: 801-507-4704
e-mail: jeffrey.anderson@imail.org


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Intermountain Health Care, Inc.
ClinicalTrials.gov Identifier: NCT00927862     History of Changes
Other Study ID Numbers: 154-001
Study First Received: June 23, 2009
Results First Received: April 9, 2012
Last Updated: August 24, 2012
Health Authority: United States: Institutional Review Board