Pharmacogenomic Evaluation of Antihypertensive Responses

April 4, 2018 updated by: University of Florida

Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR)

There are many medications available for the treatment of high blood pressure (hypertension), but finding the right one for a specific patient can be challenging. In fact, it is estimated that only 34% of people with hypertension have their blood pressure under control. The hypothesis is that genetic differences between individuals influence their response to antihypertensive medications. This study is aimed at determining the genetic factors that may influence a person's response to either a beta-blocker or a thiazide diuretic. The hope is that through this research, we may someday be able to use an individual's genetic information to guide the selection of their blood pressure medicine, leading to better control of blood pressure, and less need for the current trial and error process.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The proposed work should help move toward the long-term goal of selection of antihypertensive drug therapy based on a patient's genetic make-up. Hypertension (HTN) is the most common chronic disease for which drugs are prescribed, and the most prevalent risk factor for heart attack, stroke, renal failure and heart failure. Responses to antihypertensive drug therapy exhibit considerable interpatient variability, contributing to poor rates of HTN control (currently 34% in the US), and frequent nonadherence and dropout from therapy. We propose to identify genetic predictors of the antihypertensive and adverse metabolic responses to two preferred and pharmacodynamically contrasting drugs, a beta-blocker (atenolol) and a thiazide diuretic (hydrochlorothiazide) given initially as monotherapy, and subsequently in combination, to 800 individuals with uncomplicated hypertension. High quality phenotype data, including both home and ambulatory measures of blood pressure (BP) response, and lipid and insulin sensitivity measures of adverse metabolic responses will be related to genetic variation through two approaches. First, testing 7 single nucleotide polymorphisms (SNPs) in each of 70 candidate genes, we will examine the influence of these genes' variation on responses to beta-blockers and diuretics (Specific Aim 1). This will include assessment of genetic associations with: antihypertensive responses to monotherapy (Aim 1a), addition of a second drug to monotherapy (Aim 1b), and combination therapy (Aim 1c); and adverse metabolic responses to mono and combination therapy (Aim 1d). This candidate gene approach will be supplemented by discovery of novel genes involved in variable BP and metabolic responses to beta-blockers and diuretics through testing of 20,000 putative functional SNPs that span the human genome (Specific Aim 2). As in Aim 1, Aim 2 will include testing for associations with antihypertensive and adverse metabolic responses to monotherapy and combination therapy. The proposed research will substantially increase our understanding of the pharmacogenetics of mono- and combination antihypertensive drug therapy. It will also lead to creation of data sets and samples that can be used by others in the field, through deposit of data to PharmGKB, and creation of immortalized cell lines from all study participants to share data and biological samples with other researchers. The proposed research is significant because genetically-targeted antihypertensive therapy could lead to dramatically higher response rates and fewer adverse effects than the usual trial-and-error approach. This would likely lead to higher rates of HTN control, less need for polypharmacy, reduced health care costs, and improved outcomes.

Study Type

Interventional

Enrollment (Actual)

1701

Phase

  • 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
    • Florida
      • Gainesville, Florida, United States, 32610
        • University of Florida Department of Community Health and Family Medicine
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory University
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic

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

Ages Eligible for Study

17 years to 65 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

An average seated home diastolic blood pressure (DBP) > 85 mmHg and home systolic blood pressure (SBP) < 180 mmHg. Subjects must also have an average seated (> 5 minutes) clinic DBP between 90 mmHg and 110 mmHg and SBP < 180 mmHg

Exclusion Criteria:

secondary forms of HTN, patients currently treated with three or more antihypertensive drugs, isolated systolic HTN, other diseases requiring treatment with BP lowering medications, heart rate < 55 beats/min, known cardiovascular disease (including history of angina pectoris, heart failure, presence of a cardiac pacemaker, history of myocardial infarction or revascularization procedure, or cerebrovascular disease, including stroke and TIA), diabetes mellitus (Type 1 or 2), renal insufficiency (serum creatinine > 1.5 in men or 1.4 in women), primary renal disease, pregnancy or lactation, liver enzymes > 2.5 upper limits of normal, current treatment with NSAIDS, cyclooxygenase-2 (COX2) inhibitors, oral contraceptives or estrogen.

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: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Atenolol
atenolol 50 mg, then 100 mg if BP < 120/70, then add HCTZ 12.5 mg if BP < 120/70, then HCTZ 25 mg if BP < 120/70
Drug: Atenolol
atenolol 50 mg, then 100 mg if BP < 120/70, then add HCTZ 12.5 mg if BP < 120/70, then HCTZ 25 mg if BP < 120/70
Other Names:
  • Lopressor
  • Aquazide H or HydroDIURIL or Microzide
Experimental: Hydrochlorothiazide (HCTZ)
HCTZ 12.5 mg then HCTZ 25 mg if BP < 120/70, then add atenolol 50 mg if BP < 120/70, then atenolol 100 mg if BP < 120/70.
Drug: Hydrochlorothiazide
atenolol 50 or 100 mg hydrochlorothiazide 12.5 or 25 mg
Other Names:
  • Lopressor
  • Aquazide H or HydroDIURIL or Microzide

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Blood Pressure Response (Delta BP (After 18 Weeks of Medication - Baseline)).
Time Frame: baseline to 18 weeks of treatment
baseline to 18 weeks of treatment

Secondary Outcome Measures

Outcome Measure
Time Frame
Adverse Metabolic Responses
Time Frame: 9-18 weeks of treatment
9-18 weeks of treatment

Collaborators and Investigators

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

Sponsor

University of Florida

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

Helpful Links

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

October 1, 2005

Primary Completion (Actual)

December 1, 2010

Study Completion (Actual)

December 1, 2010

Study Registration Dates

First Submitted

October 27, 2005

First Submitted That Met QC Criteria

October 27, 2005

First Posted (Estimate)

October 30, 2005

Study Record Updates

Last Update Posted (Actual)

May 7, 2018

Last Update Submitted That Met QC Criteria

April 4, 2018

Last Verified

April 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • U01GM074492 (U.S. NIH Grant/Contract)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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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