Digoxin Dosing in Heart Failure: A Simplified Nomogram Versus Standard Care

May 19, 2014 updated by: Robert J. DiDomenico, University of Illinois at Chicago

Use of a Simplified Nomogram and Pharmacogenetics to Individualize Digoxin Dosing in Heart Failure Patients vs. Standard Care

Dosing methods for digoxin, a drug used to treat heart failure, have not been updated in decades despite evidence in recent years suggesting that blood levels of digoxin achieved with traditional dosing practices may increase the risk of adverse events. We developed a simple dosing tool that targets lower blood levels of digoxin that have been associated with improved outcomes compared to higher blood levels. The aim of this study is to determine if this simplified dosing tool is more effective than standard digoxin dosing practices at achieving lower blood levels and also to determine if digoxin dosing may be further optimized by incorporating patients' genetic information believed to influence the drug's properties.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Digoxin is recommended as adjunctive therapy in patients with left ventricular dysfunction and symptoms of heart failure despite treatment with standard therapy. Recently, the therapeutic range for digoxin in patients with heart failure has been redefined to a narrower therapeutic window (0.5 - 0.9 ng/ml) because lower serum levels in this range have been associated with improved survival whereas higher serum levels have been associated with increased mortality. However, dosing methods have not been updated to reflect the newly defined therapeutic range for digoxin. We developed a simplified dosing nomogram for digoxin in patients with heart failure designed to achieve serum digoxin concentrations (SDC) within the new therapeutic range using retrospective data. The long-term goal of this study is to prospectively validate the ability of our digoxin dosing nomogram to achieve desired SDC and provide clinicians a simplified tool to optimize digoxin dosing in patients with heart failure. Because digoxin is a substrate of the efflux pump p-glycoprotein (pGP) and genetic polymorphisms of the MDR1 gene (known to regulate pGP expression) have demonstrated conflicting results on the pharmacokinetic profile of digoxin, we will also characterize the influence MDR1 functional gene variants may have on digoxin dosing. This study will include a total of 170 subjects with symptomatic heart failure treated with digoxin, comparing steady-state SDC in a prospective group of patients dosed according to our nomogram to a historical control group in whom the dose of digoxin was derived from standard dosing practices. We will also conduct an analysis of genetic polymorphisms of the MDR1 gene known to affect digoxin pharmacokinetics. The primary objectives of the study are to compare the percentage of patients in each group achieving steady-state SDC within the desired range of 0.5 - 0.9 ng/ml, characterize the relationship between genetic variability in the MDR1 gene and digoxin dosing, and to update our digoxin dosing nomogram to account for the clinical and genetic variability shown to have the greatest influence on digoxin dosing. The rationale for this study is that lower doses of digoxin are recommended because lower SDC are associated with improved survival. Therefore, digoxin dosing methods must be updated to reflect these recommendations and account for genetic variability of the MDR1 gene in an effort to improve clinical outcomes and minimize the potential for adverse events. To address these issues, the specific aims of this research are:

Aim 1: Compare steady-state SDC observed using our dosing nomogram to those obtained using standard dosing practices.

Aim 2: Characterize the relationship of the genetic variability of the MDR1 gene and SDC observed using our digoxin dosing nomogram.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
131

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Illinois
      • Chicago, Illinois, United States, 60612
        • University of Illinois at Chicago

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age > 21 years
  • Diagnosis of heart failure secondary to left ventricular dysfunction
  • Receiving chronic digoxin therapy or digoxin therapy is being initiated

Exclusion Criteria:

  • Pregnant
  • Unstable renal function, defined as either a rise in serum creatinine by > 0.5mg/dl from baseline or a decrease in creatinine clearance by 25% or more within two to four weeks of study entry.
  • End-stage renal disease requiring hemodialysis
  • Concomitant therapy with drugs known to interact with digoxin (e.g., amiodarone, quinidine, verapamil, macrolide antibiotics)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Digoxin Dosing per Nomogram
Subjects will have their digoxin maintenance dose determined according to the nomogram we have developed.
Other: Digoxin Dosing per Nomogram
Simplified dosing nomogram for digoxin. The dose is determined by plotting a subject's creatinine clearance (x-axis) and ideal body weight (y-axis) on the nomogram. Alternatively, the dose may be determined by plotting creatinine clearance (x-axis) and gender/height (z-axis).
Drug: Digoxin
All patients included in the trial were treated with digoxin as clinically indicated. The intervention for this study required determining the digoxin dose via a proposed nomogram.
Other Names:
  • Lanoxin
Other: Standard Digoxin Dosing
This arm represents historical control subjects in whom the dose of digoxin was determined at the physician's discretion using traditional dosing methods.
Drug: Digoxin
All patients included in the trial were treated with digoxin as clinically indicated. The intervention for this study required determining the digoxin dose via a proposed nomogram.
Other Names:
  • Lanoxin

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Percent of Patients Achieving a Desired Steady-state Serum Digoxin Concentration Between 0.5 - 0.9ng/ml
Time Frame: Steady-state (2 - 4 weeks after initiation)
Steady-state (2 - 4 weeks after initiation)

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Mean Serum Digoxin Concentration
Time Frame: Steady-state (2 - 4 weeks after initiation)
Steady-state (2 - 4 weeks after initiation)
Serum Digoxin Concentration < 1.0 ng/ml
Time Frame: Steady-state (2 - 4 weeks after initiation)
Steady-state (2 - 4 weeks after initiation)
Serum Digoxin Concentration by ABCB1 Single Nucleotide Polymorphism (SNP) C1236T
Time Frame: Steady-state (2 - 4 weeks after initiation)
55 patients in the Digoxin Dosing per Nomogram group consented to the Pharmacogenetic substudy and provided blood samples to perform pharmacogenetic analyses. We compared serum digoxin concentrations by ABCB1 genotype.
Steady-state (2 - 4 weeks after initiation)
Serum Digoxin Concentration by ABCB1 SNP C3435T
Time Frame: Steady-state (2 - 4 weeks after initiation)
Serum digoxin concentration by genotypes for the ABCB1 SNP C3435T
Steady-state (2 - 4 weeks after initiation)
Serum Digoxin Concentration by ABCB1 SNP G2677T/A
Time Frame: Steady-state (2 - 4 weeks after initiation)
Serum digoxin concentration by ABCB1 SNP genotypes
Steady-state (2 - 4 weeks after initiation)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Illinois at Chicago

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
American College of Clinical Pharmacy

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Robert J DiDomenico, PharmD, University of Illinois at Chicago

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 1, 2006

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 1, 2009

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2009

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
October 30, 2009

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
October 30, 2009

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
November 1, 2009

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 22, 2014

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 19, 2014

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • ACCP 2006-07
  • 2008-05762

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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