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Personalized Medicine Interface Tool (PerMIT): Warfarin: A Trial Comparing Usual Care Warfarin Initiation to PerMIT Pharmacogenetic Guided Warfarin Therapy (PerMIT)

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ClinicalTrials.gov Identifier: NCT00993200
Recruitment Status : Completed
First Posted : October 12, 2009
Results First Posted : May 16, 2013
Last Update Posted : June 24, 2015
Sponsor:
Collaborator:
University of Louisville
Information provided by (Responsible Party):
Robert Pendleton, University of Utah

Tracking Information
First Submitted Date  ICMJE October 8, 2009
First Posted Date  ICMJE October 12, 2009
Results First Submitted Date  ICMJE August 13, 2012
Results First Posted Date  ICMJE May 16, 2013
Last Update Posted Date June 24, 2015
Study Start Date  ICMJE August 2009
Actual Primary Completion Date December 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 8, 2013)
The Number of Days to First International Normalized Ratio (INR) Within Therapeutic Range [ Time Frame: variable as defined ]
The number of days to first International Normalized Ratio (INR) is being measured from initiation of warfarin to the time when a subject first has an INR lab test result within +/- 0.5 of mean target INR range. The period during which this time interval could be measured is any time during the subject's warfarin therapy.
Original Primary Outcome Measures  ICMJE
 (submitted: October 9, 2009)
  • The time to first INR within therapeutic [ Time Frame: variable as defined ]
  • Time to stable warfarin therapy [ Time Frame: variable as defined ]
Change History Complete list of historical versions of study NCT00993200 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 8, 2013)
  • Adverse Major and Minor Bleeding Events [ Time Frame: 12 week ]
    Number of major and minor bleeding events
  • Thrombotic Complication [ Time Frame: 12 week ]
    Number of thrombotic events
Original Secondary Outcome Measures  ICMJE
 (submitted: October 9, 2009)
  • Adverse Major and Minor Bleeding Events [ Time Frame: 12 week ]
  • Thrombotic Complication [ Time Frame: 12 week ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Personalized Medicine Interface Tool (PerMIT): Warfarin: A Trial Comparing Usual Care Warfarin Initiation to PerMIT Pharmacogenetic Guided Warfarin Therapy
Official Title  ICMJE PerMIT: Warfarin : A Prospective Randomized Controlled Trial Comparing Usual Care Warfarin Initiation to PerMIT Pharmacogenetic Guided Warfarin Therapy
Brief Summary Warfarin is the most commonly used oral anticoagulant medicine (blood thinner). Although this medicine works well, it is difficult to know how much medicine a patient needs. Many things affect how much medicine a patient needs and doses can be very different from patient to patient. It is important for patients to get the right dose to prevent clotting or bleeding problems that can happen with this medicine if the dose is too low or too high. These problems can be life-threatening. To help find the right dose, patients on warfarin must have frequent blood tests to measure how well the medicine is working. The investigators know differences in people's genes can affect how much warfarin medicine someone needs, but they don't yet know with certainty how to use this information in making patient care decisions. The hypothesis of this study is that using a patients warfarin related genetic information incorporated into a computer algorithm to be used by a warfarin provider will lead to better warfarin management compared to usual care.
Detailed Description

Warfarin is the most commonly used oral anticoagulant medication. Due to the difficulty in determining an individual's proper warfarin dose, therapy is typically initiated with a standard dose followed by INR monitoring with frequent dose adjustment to ensure the medicine is working properly. Unfortunately, therapeutic warfarin doses vary significantly from patient to patient, so that even a standard dose can lead to excessive anticoagulation with its associated risk of causing life-threatening hemorrhaging. Genetic and non-genetic factors both influence an individual's warfarin dose requirement and response characteristics. There has been substantial evidence demonstrating a clear gene-dose relationship. Although this importance of pharmacogenetics to warfarin therapy is understood, clear guidance for how such information should be applied to patient therapy is woefully absent. The Personalized Medicine Interface Tool (PerMIT) is a software utility that supplies this critical guidance by modeling the dose requirements and response characteristics of individual patients based on their genotypic and physical characteristics. Using state-of-the-art multivariate computations, PerMIT calculates a warfarin maintenance dose estimate and also models the influence of repeated dosing on plasma drug concentration.

Both genetic and non-genetic factors (such as age, weight and gender) influence warfarin dose requirement and response characteristics of the individual. Recently, multi-variate mathematical equations, which take into account these genetic and non-genetic factors, such as age, weight and gender, have been developed to calculate an estimate of the warfarin maintenance dose requirement (Linder 2002, Zhu 2007, Sconce 2005, Millican 2007). The temporal response to routine administration of medications is dictated by the clearance rate of the medication and its effective concentration, the blood concentration over the dosing interval that is required to elicit the desired pharmacologic effect. The clearance of S-warfarin is primarily dictated by the patient's Cytochrome P4502C9 (CYP2C9) genotype, whereas the effective S-warfarin concentration is primarily dictated by the patient's vitamin K epoxide reductase complex protein 1 (VKORC1) genotype (Linder 2002, Herman 2005, Zhu 2007).

It is now well-known that genetic variants of CYP2C9 lead to decreased S-warfarin metabolism (clearance) and an increased elimination half-life. The elimination half-life of medications dictates the time required for repeated dosing to result in reproducible drug concentrations over the dosing interval for a given dosage. This situation is referred to as steady-state and is the most reliable time to interpret the dose-response relationship (INR measurements). S-warfarin half-life can be estimated based on the individual's CYP2C9 genotype (Linder 2002, Herman 2005, Loebstein 2001) and the steady-state concentration of S-warfarin under optimal anti-coagulation conditions is closely related to the patient's VKORC1 genotype (Zhu 2007).

PerMIT: Warfarin has clear theoretical benefits and has been demonstrated to be accurate; however, prospective randomized control clinical trials are required to demonstrate the efficacy of the PerMIT: Warfarin software in comparison to standard of care. We have designed this two-arm, prospective randomized control trial to directly assess the efficacy of PerMIT: Warfarin in (a) identifying patients' optimal dose requirements; (b) reducing patients' time to achieve stable therapy; (c) reducing the frequency of out-of-range INR measurements; and (d) reducing the number of dose adjustments. This study will evaluate whether, and to what degree, PerMIT: Warfarin improves these patient care outcomes and, by extension, reduces their risk of adverse drug reactions when compared to patients who receive therapy based on the standard of care.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Blood Clotting
Intervention  ICMJE
  • Genetic: warfarin pharmacogenetic dosing
    Warfarin pharmacogenetic dosing incorporated into a validated clinical algorithm displayed in a computer (PERMIT) management interface
  • Drug: Warfarin
    Usual care warfarin dosing
Study Arms  ICMJE
  • Active Comparator: Warfarin, control
    Subjects naive to warfarin therapy with anticipated warfarin duration of at least 12 weeks managed by usual care dosing.
    Intervention: Drug: Warfarin
  • Experimental: Warfarin: PERMIT
    Subjects naive to warfarin therapy with anticipated warfarin duration of at least 12 weeks managed by warfarin pharmacogenetic dosing (warfarin dosing using genetic information incorporated into the PERMIT algorithm).
    Intervention: Genetic: warfarin pharmacogenetic dosing
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 8, 2013)
26
Original Estimated Enrollment  ICMJE
 (submitted: October 9, 2009)
180
Actual Study Completion Date  ICMJE December 2010
Actual Primary Completion Date December 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Prescribed warfarin for any indication, so long as they are naïve to the drug at enrollment and are expected to receive therapy for at least 12 weeks

Exclusion Criteria:

  • Recent cardiothoracic surgery as indication for warfarin.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00993200
Other Study ID Numbers  ICMJE 35279
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Robert Pendleton, University of Utah
Study Sponsor  ICMJE Robert Pendleton
Collaborators  ICMJE University of Louisville
Investigators  ICMJE
Principal Investigator: Robert C Pendleton, MD University of Utah Health Care
PRS Account University of Utah
Verification Date May 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP