Pharmacogenomic Evaluation of Antihypertensive Responses

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Dr. Julie A Johnson, National Institute of General Medical Sciences (NIGMS)
ClinicalTrials.gov Identifier:
NCT00246519
First received: October 27, 2005
Last updated: July 8, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Hypertension
Drug: HCTZ + atenolol
Drug: Atenolol + HCTZ
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR)

Resource links provided by NLM:


Further study details as provided by National Institute of General Medical Sciences (NIGMS):

Primary Outcome Measures:
  • Blood Pressure Response (Delta BP (After 18 Weeks of Medication - Baseline)). [ Time Frame: baseline to 18 weeks of treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Adverse Metabolic Responses [ Time Frame: 9-18 weeks of treatment ] [ Designated as safety issue: Yes ]

Enrollment: 1701
Study Start Date: October 2005
Study Completion Date: December 2010
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Atenolol +HCTZ arm
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 + HCTZ
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: HCTZ + atenolol
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: HCTZ + atenolol
atenolol 50 or 100 mg hydrochlorothiazide 12.5 or 25 mg
Other Names:
  • Aquazide H or HydroDIURIL or Microzide
  • Lopressor

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 (HCTZ) 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 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.

  Eligibility

Ages Eligible for Study:   17 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

An average seated home DBP > 85 mmHg and home 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, COX2-inhibitors, oral contraceptives or estrogen.

  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00246519

Locations
United States, Florida
University of Florida Department of Community Health and Family Medicine
Gainesville, Florida, United States, 32610
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Investigators
Principal Investigator: Julie A Johnson, PharmD University of Florida
  More Information

Additional Information:
Publications:

Responsible Party: Dr. Julie A Johnson, Distinguished Professor, National Institute of General Medical Sciences (NIGMS)
ClinicalTrials.gov Identifier: NCT00246519     History of Changes
Other Study ID Numbers: U01 GM074492
Study First Received: October 27, 2005
Results First Received: May 20, 2013
Last Updated: July 8, 2013
Health Authority: United States: Federal Government

Keywords provided by National Institute of General Medical Sciences (NIGMS):
hypertension
pharmacogenetics
pharmacogenomics
beta-blocker
atenolol
diuretic
hydrochlorothiazide
blood pressure
metabolic adverse effects

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Antihypertensive Agents
Atenolol
Metoprolol
Hydrochlorothiazide
Trichlormethiazide
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Anti-Arrhythmia Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Diuretics
Natriuretic Agents
Sodium Chloride Symporter Inhibitors
Membrane Transport Modulators

ClinicalTrials.gov processed this record on April 23, 2014