Pharmacogenomic Evaluation of Antihypertensive Responses 2 (PEAR2)

Study Description

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Brief Summary:

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 less than 50% 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, the investigators 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 or disease	Intervention/treatment	Phase
Hypertension	Drug: Metoprolol; Drug: Chlorthalidone	Phase 4

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 about 40-50% 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 (metoprolol) and a thiazide diuretic (chlorthalidone) in a sequential monotherapy design in 400 hypertensive individuals. Data collected will include home and clinic blood pressure, blood samples for testing for adverse metabolic effects and other biomarkers, RNA, and DNA and urine sample. We will conduct genome-wide association single nucleotide polymorphism (SNP) genotyping and data from the study will be used for replication of findings from the previous PEAR trial, along with new discoveries. The primary aims are to define the genetic determinants of the antihypertensive response and adverse metabolic responses (e.g. changes in glucose, triglycerides and uric acid). 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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	839 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Pharmacogenomic Evaluation of Antihypertensive Responses 2
Study Start Date :	August 2010
Actual Primary Completion Date :	April 2014
Actual Study Completion Date :	April 2014

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Metoprolol + Chlorthalidone; Study participants in this group had their current hypertension treatment withdrawn, baseline labs drawn and hypertension documented. Participants were initiated on metoprolol tartrate 50 mg twice daily for two weeks, followed by dose titration to 100 mg twice daily for six additional weeks if blood pressure (BP) > 120/70 mmHg. BP measures were again recorded. Participants entered a washout where metoprolol was titrated, then discontinued, and the patient's hypertension was re-established. After another set of identical baseline labs, study participants were initiated on chlorthalidone 25 mg four days per week (Monday, Wednesday, Thursday, Saturday) 15 mg daily for two weeks, followed by 25 mg daily for an additional six weeks.

Drug: Metoprolol; Metoprolol 50 mg twice daily titrated to 100 mg twice daily Note: due to discontinuation of the manufacture of chlorthalidone 15 mg, effective Jan 1, 2013; the starting dose of chlorthalidone will be 25 mg 4 times per week (Mon, Wed, Thur, Sat) with subsequent titration to 25 mg daily.; Other Names: Lopressor; Toprol XL Drug: Chlorthalidone; Chlorthalidone 25 mg 4 times per week titrated to 25 mg daily; Other Name: Thalitone

Outcome Measures

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Primary Outcome Measures :

1. Change in Blood Pressure From Baseline to Treatment [ Time Frame: after 6-8 weeks of treatment ]
   Response to blood pressure medication will be assessed by measuring blood pressure before and after treatment

Secondary Outcome Measures :

1. Adverse Metabolic Effects [ Time Frame: after 6-8 weeks treatment ]
   Change in glucose after treatment with study medication

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 65 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• An average seated home diastolic blood pressure (DBP) > 85 mmHg and < 110 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 hypertension (HTN) (including sleep apnea)
• Isolated systolic HTN
• Other diseases requiring treatment with BP lowering medications
• Heart rate < 55 beats/min (for metoprolol only)
• 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.

Contacts and Locations

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Locations

United States, Florida
University of Florida
Gainesville, Florida, United States, 32610
United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30322
United States, Minnesota
Mayo Clinic, Division of Hypertension
Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

University of Florida

National Institute of General Medical Sciences (NIGMS)

Investigators

Principal Investigator:	Julie A Johnson, PharmD	University of Florida

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

PEAR study website 

Publications:

Hamadeh IS, Langaee TY, Dwivedi R, Garcia S, Burkley BM, Skaar TC, Chapman AB, Gums JG, Turner ST, Gong Y, Cooper-DeHoff RM, Johnson JA. Impact of CYP2D6 polymorphisms on clinical efficacy and tolerability of metoprolol tartrate. Clin Pharmacol Ther. 2014 Aug;96(2):175-81. doi: 10.1038/clpt.2014.62. Epub 2014 Mar 17.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Singh S, McDonough CW, Gong Y, Alghamdi WA, Arwood MJ, Bargal SA, Dumeny L, Li WY, Mehanna M, Stockard B, Yang G, de Oliveira FA, Fredette NC, Shahin MH, Bailey KR, Beitelshees AL, Boerwinkle E, Chapman AB, Gums JG, Turner ST, Cooper-DeHoff RM, Johnson JA. Genome Wide Association Study Identifies the HMGCS2 Locus to be Associated With Chlorthalidone Induced Glucose Increase in Hypertensive Patients. J Am Heart Assoc. 2018 Mar 9;7(6). pii: e007339. doi: 10.1161/JAHA.117.007339.

Shahin MH, Sá AC, Webb A, Gong Y, Langaee T, McDonough CW, Riva A, Beitleshees AL, Chapman AB, Gums JG, Turner ST, Boerwinkle E, Scherer SE, Sadee W, Cooper-DeHoff RM, Johnson JA. Genome-Wide Prioritization and Transcriptomics Reveal Novel Signatures Associated With Thiazide Diuretics Blood Pressure Response. Circ Cardiovasc Genet. 2017 Jan;10(1). pii: e001404. doi: 10.1161/CIRCGENETICS.116.001404.

Responsible Party:	University of Florida
ClinicalTrials.gov Identifier:	NCT01203852 History of Changes
Other Study ID Numbers:	IRB201700661-N; U01GM074492-06 ( U.S. NIH Grant/Contract )
First Posted:	September 16, 2010
Results First Posted:	May 19, 2015
Last Update Posted:	April 6, 2018
Last Verified:	April 2018

Studies a U.S. FDA-regulated Drug Product:		No
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by University of Florida:

hypertension; antihypertensive drug; pharmacogenetics	genetics; blood pressure; glucose

Additional relevant MeSH terms:

Hypertension; Vascular Diseases; Cardiovascular Diseases; Metoprolol; Antihypertensive Agents; Chlorthalidone; 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