Pharmacogenomic Evaluation of Antihypertensive Responses 2 (PEAR2)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University of Florida
ClinicalTrials.gov Identifier:
NCT01203852
First received: September 15, 2010
Last updated: July 30, 2015
Last verified: July 2015

September 15, 2010
July 30, 2015
August 2010
April 2014   (final data collection date for primary outcome measure)
Change in Blood Pressure From Baseline to Treatment [ Time Frame: after 6-8 weeks of treatment ] [ Designated as safety issue: No ]
Response to blood pressure medication will be assessed by measuring blood pressure before and after treatment
Antihypertensive Response [ Time Frame: after 6-8 weeks of treatment ] [ Designated as safety issue: No ]
antihypertensive response will be assessed by measuring blood pressure before and after treatment
Complete list of historical versions of study NCT01203852 on ClinicalTrials.gov Archive Site
Adverse Metabolic Effects [ Time Frame: after 6-8 weeks treatment ] [ Designated as safety issue: Yes ]
Change in glucose after treatment with study medication
adverse metabolic effects [ Time Frame: after 6-8 weeks treatment ] [ Designated as safety issue: Yes ]
Not Provided
Not Provided
 
Pharmacogenomic Evaluation of Antihypertensive Responses 2
Pharmacogenomic Evaluation of Antihypertensive Responses 2

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.

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.

Interventional
Phase 4
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Hypertension
  • 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
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.
Interventions:
  • Drug: Metoprolol
  • Drug: Chlorthalidone
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
839
April 2014
April 2014   (final data collection date for primary outcome measure)

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.
Both
18 Years to 65 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01203852
U01 GM074492-06
Yes
University of Florida
University of Florida
Not Provided
Principal Investigator: Julie A Johnson, PharmD University of Florida
University of Florida
July 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP