Trial record 1 of 1 for:    NCT00927862
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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
  Purpose

The purpose of this study is to determine whether DNA analysis improves the efficiency of dosing and safety in patients who are being started on warfarin therapy.Warfarin, a blood thinner (anticoagulant) prescribed to 1-2 million patients in the United States, is a leading cause of drug-related adverse events (e.g., severe bleeding), in large part due to dramatic (20-fold) differences between individuals in dose requirements. At least half of this variability now can be explained by 3 common genetic variants, age, body size, and sex; however, warfarin therapy continues to begin with the same dose in every patient with the correct individual dose determined by trial and error. This study proposes to determine genetic variations the same day from DNA simply obtained by swabbing the inside of the cheek and use this information to determine the proper dose regimen individually in each patient. The aim is to show that the investigators can achieve more rapid, efficient, and safe dosing in up to 500-1000 individuals who are initiating warfarin therapy for various clotting disorders across a large healthcare system in order to demonstrate improved dosing effectiveness, efficiency, and safety with genetic-based dosing, which could lead to a nationwide application resulting in as much as a $1 billion dollar annual benefit in healthcare outcomes.


Condition Intervention Phase
Thromboembolism
Genetic: IWPC adapted genotype-guided dosing algorithm for warfarin
Genetic: Modified IWPC genetic-guided warfarin dosing algorithm
Other: Standard of care treatment
Phase 2
Phase 3

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
Official Title: The Clinical Impact of Applying Pharmacogenetic Algorithms to Individualize Dosing of Warfarin in Patients Being Initiated on Oral Anticoagulation

Resource links provided by NLM:


Further study details as provided by Intermountain Health Care, Inc.:

Primary Outcome Measures:
  • 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) ] [ Designated as safety issue: Yes ]
    The percent of out of range (OOR) international normalized prothrombin time ratio (INRs) in the standard and modified pharmacogentic algorithms at 1 month. To account for laboratory INR-measurement error, a 10% margin outside of the target range was allowed in determination of OOR values, ie, INRs <1.8, >3.3 for INR 2.5 target; <2.25, >3.85 for INR 3.0 target. What is reported is the percent of patients with an OOR INR at 1 month.

  • 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) ] [ Designated as safety issue: No ]
    The percent of out of range (OOR) INRs in the pharmacogenetic (PG)-dosing (standard + modified IWPC warfarin algorithms) and parallel controls. A 10% margin outside of the target INR range was allowed in determination of OOR values, ie, INRs <1.8, >3.3 for INR 2.5 target; <2.25, >3.85 for INR 3.0 target. What is reported is the percent of patients with OOR INRs at 1 month.

  • The Percent of Time in Therapeutic Range (TTR) for the Standard and Modified Pharmacogenetic Algorithms. [ Time Frame: 1 month (from baseline to day 30) ] [ Designated as safety issue: No ]
    The percent of time in therapeutic INR range for the standard and modified pharmacogenetic algorithms at 1 month. To account for laboratory INR-measurement error, a 10% margin inside of the target range was allowed in determine TTR values, ie, INRs 1.8-3.3 for INR 2.5 target; 2.25-3.85 for INR 3.0 target. What is reported is the percent of TTR for each patient during 1 month.

  • The Time in Therapeutic Range (TTR) for the Pharmacogenetic-guided Patients and Parallel Controls [ Time Frame: 1 month (from baseline to day 30) ] [ Designated as safety issue: No ]
    The percent of time in therapeutic INR range for the pharmacogenetic (PG)-dosing (standard + modified IWPC warfarin algorithms) guided patients and parallel controls. To account for laboratory INR-measurement error, a 10% margin inside of the target range was allowed in determine TTR values, ie, INRs 1.8-3.3 for INR 2.5 target; 2.25-3.85 for INR 3.0 target. What is reported is the percent of TTR for each patient during 1 month.


Secondary Outcome Measures:
  • 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) ] [ Designated as safety issue: Yes ]
    The percent of INRs ≥4 or ≤1.5 for the pharmacogenetic (modified IWPC warfarin algorithm and the standard IWPC warfarin) algorithms. What is reported is the percent of patients with INRs ≥4 or ≤1.5 at the end of follow-up.

  • 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) ] [ Designated as safety issue: Yes ]
    What is reported is the percent of patients with INRs ≥4 or ≤1.5 or having experienced a serious adverse event (SAE) at the end of follow-up.

  • 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) ] [ Designated as safety issue: Yes ]
    What is reported is the mean number of INRs measured/drawn among the patients in each arm.

  • 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) ] [ Designated as safety issue: No ]
    Prediction of a stable maintenance dose (within 1 mg/day) among the pharmacogenetic (PG)-guided dosing and the parallel control group. For the parallel control group, an empiric starting dose of 5 mg/day was assumed. What is reported is the percent of patients who had their maintenance dose predicted as described above.

  • 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) ] [ Designated as safety issue: Yes ]
    What is reported is the percent of patients with an INR ≥4 or ≤1.5 at the end of follow-up.


Enrollment: 2415
Study Start Date: August 2008
Study Completion Date: June 2011
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Standard IWPC warfarin dosing algorithm
Standard International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm.
Genetic: IWPC adapted genotype-guided dosing algorithm for warfarin

Within the first or second dose, apply an International Warfarin Pharmacogenetics Consortium (IWPC) adapted genotype-guided dosing algorithm to determine the daily maintenance dose of warfarin, based on clinical factors (age, sex, weight, height, etc.), and VKORC1 and CYP2C9 genotypes, to individualize the initial dosing of warfarin. (IWPC algorithm submitted for publication, 5-08)

Note that a second comparison will be made between the combined genotype-guided dosing groups (standard and modified IWPC warfarin dosing algorithms) and a historical comparator group.

Other Name: IWPC=international warfarin pharmacogenetic collaboration
Experimental: Modified IWPC warfarin dosing algorithm
Modified International Warfarin Pharmacogenetics Consortium (IWPC) warfarin dosing algorithm
Genetic: Modified IWPC genetic-guided warfarin dosing algorithm

Within the first or second warfarin dose, apply a modified International Warfarin Pharmacogenetics Consortium (IWPC)-adapted genotype-guided dosing algorithm to determine the daily maintenance dose of warfarin. The active comparator algorithm (see above) will be further modified to account for the temporal pharmacodynamics of warfarin metabolism, e.g., by ignoring the CYP2C9 variants for the first 2 days.

Note that a second comparison will be made between the combined genotype-guided dosing groups (standard and modified IWPC warfarin dosing algorithms) and a historical comparator group.

Other Name: IWPC=international warfarin pharmacogenetic collaboration
Historical controls
The parallel, standard-dosing patient control cohort was identified by a query of the electronic medical records database of the 3 participating hospitals for the time interval spanning enrollment of the randomized pharmacogenetic (PG)-guided cohorts (July 2008 through December 2010). Patients ≥18 years old initiating warfarin therapy with a baseline and at least 1 follow-up international normalized prothrombin time ratio (INR) level between days 3-14 were selected. Initial dose selection and therapy modification was at individual Intermountain-credentialed physician/healthcare provider discretion. Standard management is non-PG based.
Other: Standard of care treatment
The 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 cohorts (July 2008-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.

Detailed Description:

Study Objectives:

The specific objectives of CoumaGen-II to be tested are:

  1. To apply routine pharmacogenetic (PG)-guided dosing of warfarin in clinical practice at Intermountain Healthcare facilities in the Urban Central Region (i.e., Intermountain Medical Center [IMC], LDS Hospital, Alta View Hospital [AVH]), and selected physician offices that are frequent initiators of warfarin) in a major new quality improvement and clinical research initiative.
  2. To compare the percentage out-of-range (%OOR) international normalized prothrombin time ratios (INRs) during the first month (and secondarily, 3 months) of warfarin therapy using PG-guided dosing with parallel or historical standard (STD), empiric dosed controls.
  3. To compare a modified PG-guided dosing algorithm (modified-International Warfarin Pharmacogenetics Consortium [IWPC]) with a previously generated and validated, multicenter PG-guided algorithm (IWPC).

Study Design:

Qualifying patients being initiated on warfarin therapy with a target INR of 1.5-2.5, 2-3, or 2.5-3.5 will be invited to participate and sign informed consent. Enrolled patients will receive DNA sampling by buccal swab, and samples will be processed and a PG-guided initial dose calculated with a goal of <6 hours (maximum, 24 hours). Dosing and dose adjustments will be managed through the Urban Central Region (IMC/LDSH) anticoagulation management service (AMS). Dose adjustments through day 8 will use a PG-modified algorithm, after which modification will revert to the standard IHC algorithm. AMS pharmacists and study coordinators will ascertain warfarin doses, INRs, dose changes, and adverse events, and record information on case report forms.

Study Duration:

Each patient will participate for approximately 3 months (90 days ± 10 days). The anticipated enrollment period is 24 months or until 1000 patients are enrolled. The length of the enrollment period is subject to revision as it is dependent on the availability of a robust patient pool.

Further study details on dosing algorithm and genotyping methodology may be provided by Intermountain Healthcare Inc.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • New participants will be those >=18 years old who are appropriate candidates for and being initiated on warfarin therapy with target international normalized prothrombin time ratio (INR) range of either 2-3 or 2.5-3.5 and with intent to be treated for at least 1 month and willing to sign informed consent.
  • Those with target INR 2.5-3.5 may be enrolled with dose adjustment for this higher target per Gage et-al. (i.e., 11% increase in dose).
  • Dose modification also will be made for amiodarone based on prior, published experience (i.e., 22% decrease in dose).

Exclusion Criteria:

  • Those not appropriate for warfarin (e.g., pregnancy) or for pharmacogenetic (PG)-guided dosing for any reason,
  • Those having received rifampin within 3 weeks,
  • Those with severe co-morbidities (e.g., creatinine > 2.5,hepatic insufficiency, active malignancy, advanced physiological age, noncompliance risk, expected survival <6 months), and
  • Physician or patient preference.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00927862

Locations
United States, Utah
Intermountain Healthcare Hospitals and Clinics
Salt Lake City, Utah, United States, 84107
Sponsors and Collaborators
Intermountain Health Care, Inc.
Investigators
Principal Investigator: Jeffrey L Anderson, MD Intermountain Health Care, Inc.
  More Information

No publications provided by Intermountain Health Care, Inc.

Additional 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

Keywords provided by Intermountain Health Care, Inc.:
warfarin metabolism
CYP2C9
genotyping
VKORC1
anticoagulation
atrial fibrillation
deep vein thrombosis
pulmonary embolism
Patients initiating warfarin for thromboembolic conditions

Additional relevant MeSH terms:
Thromboembolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Thrombosis
Warfarin
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 20, 2014