PEAR2: Pharmacogenomic Evaluation of Antihypertensive Responses 2

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT01203852
• Collaborator: National Institute of General Medical Sciences (NIGMS) (NIH)
• Enrollment: 839
• Locations: 3
• Arm: 1
• Duration (Months): 44
• Patients Per Site: 279.7
• Patients Per Site Per Month: 6.4

Study Details

Study Description

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

• Study Type: Interventional
• Actual Enrollment: 839 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pharmacogenomic Evaluation of Antihypertensive Responses 2
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Apr 1, 2014
• Actual Study Completion Date: Apr 1, 2014

Arms and Interventions

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 Names: Thalitone

Outcome Measures

Primary Outcome Measures

1. Change in Blood Pressure From Baseline to Treatment [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 [after 6-8 weeks treatment]

   Change in glucose after treatment with study medication

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	University of Florida	Gainesville	Florida	United States	32610
2	Emory University School of Medicine	Atlanta	Georgia	United States	30322
3	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

Study Documents (Full-Text)

None provided.

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.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT01203852
• Other Study ID Numbers: IRB201700661-N; U01GM074492-06
• First Posted: Sep 16, 2010
• Last Update Posted: Apr 6, 2018
• Last Verified: Apr 1, 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; Metoprolol; Chlorthalidone

Study Results

Participant Flow

Recruitment Details	The first subject was recruited on 8/10/10 and the final patient was recruited on 9/30/2013. Subjects were recruited from family medicine clinics and were identified through providers daily schedules, medical records, and encounter forms.
Pre-assignment Detail	Healthy volunteers with mild to moderate primary hypertension between the ages of 18-70 were eligible for the study. Subjects were washed-out from their hypertension medication prior to beginning study protocol. Participants with elevated systolic blood pressure greater than 180 mmHg after wash-out were excluded from the study.

Arm/Group Title	Metoprolol + Chlorthalidone
Arm/Group Description	This group was assigned the following: (Metoprolol 8 weeks): Metoprolol tartrate 50 mg twice daily for two weeks. After two weeks subjects will be seen in clinic and will have the dose doubled to 100 mg twice daily if either their home blood pressure (HBP) average or office blood pressure (OBP) is > 120/70 mmHg. They will continue on this dose for an additional 6 weeks. (Washout 2 weeks): Then will washout from all study medication. (Chlorthalidone 8 weeks): participants will initiate chlorthalidone 25 mg four times per week (Monday, Wednesday, Thursday, Saturday) for two weeks, then 25 mg daily of chlorthalidone for 6 weeks.
Period Title: Metoprolol 8 Weeks
STARTED	839
COMPLETED	369
NOT COMPLETED	470
Period Title: Metoprolol 8 Weeks
STARTED	328
COMPLETED	282
NOT COMPLETED	46
Period Title: Metoprolol 8 Weeks
STARTED	328
Continued From Metoprolol	282
COMPLETED	328
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Metoprolol + Chlorthalidone
Arm/Group Description	This group was assigned to the following: Metoprolol tartrate 50 mg twice daily for two weeks. After two weeks subjects will be seen in clinic and will have the dose doubled to 100 mg twice daily if either their HBP average or OBP is > 120/70 mmHg. They will continue on this dose for an additional 6 weeks. Then will washout from all study medication. After washout, participants will initiate chlorthalidone 25 mg four times per week (Monday, Wednesday, Thursday, Saturday) for two weeks, then 25 mg daily of chlorthalidone for 6 weeks. Metoprolol: Metoprolol 50 mg twice daily titrated to 100 mg twice daily Chlorthalidone: Chlorthalidone 25 mg 4 times per week titrated to 25 mg 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.
Overall Participants	839
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	839 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.3 (9.0)
Sex: Female, Male (Count of Participants)
Female	429 51.1%
Male	410 48.9%
Region of Enrollment (participants) [Number]
United States	839 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

All patients with antihypertensive response data. 282 patients completed all 3 study periods. 369 patients completed only period 1. 328 patients completed only period 3.

Arm/Group Title	Metoprolol + Chlorthalidone	Metorprolol Only	Chlorthalidone Only
Arm/Group Description	Study participants 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.	Study participants 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.	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.
Measure Participants	282	369	328
diastolic blood pressure response	-7.56 (6.39)	-7.97 (6.48)	-7.68 (5.84)
systolic blood pressure response	-11.70 (9.51)	-7.45 (9.85)	-13.65 (9.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metoprolol + Chlorthalidone
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for one sided t-test of mean change in blood pressure before and after treatment with metoprolol and chlorthalidone were <0.0001.
	Method	t-test, 1 sided
	Comments

2. Secondary Outcome

Title	Adverse Metabolic Effects
Description	Change in glucose after treatment with study medication
Time Frame	after 6-8 weeks treatment

Outcome Measure Data

Analysis Population Description

All patients with change in glucose data

Arm/Group Title	Adverse Metabolic Effects
Arm/Group Description	Change in glucose after treatment with study medications
Measure Participants	365
glucose response to metoprolol (n=365)	1.02 (9.83)
glucose response to chlorthalidone (n=318)	5.12 (10.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Metoprolol + Chlorthalidone
	Comments	Mean glucose change after treatment with chlorthalidone
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value for one sided t-test for mean glucose change before and after treatment with chlorthalidone was <0.0001.
	Method	t-test, 1 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Metoprolol + Chlorthalidone
	Comments	Mean glucose change after treatment with metoprolol
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.049
	Comments	P-value for one sided t-test for mean glucose change before and after treatment with metoprolol was 0.049.
	Method	t-test, 1 sided
	Comments

Adverse Events

Time Frame	Adverse events were recorded during subject participation in the study. Participation lasted between 3 and 4 months.
Adverse Event Reporting Description	Adverse events were not recorded according to intervention.
Arm/Group Title	All Study Participants
Arm/Group Description	Study participants 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. The subjects 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.
All Cause Mortality
	All Study Participants
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Study Participants
	Affected / at Risk (%)	# Events
Total	3/839 (0.4%)
Cardiac disorders
Heart Attack	1/839 (0.1%)	1
Vascular disorders
Headache	2/839 (0.2%)	2
Other (Not Including Serious) Adverse Events
	All Study Participants
	Affected / at Risk (%)	# Events
Total	114/839 (13.6%)
Cardiac disorders
Bradycardia	2/839 (0.2%)	2
Chest Pain	2/839 (0.2%)	2
Ear and labyrinth disorders
Dizziness	10/839 (1.2%)	11
Gastrointestinal disorders
Diarrhea	4/839 (0.5%)	4
Nausea	7/839 (0.8%)	8
General disorders
Fatigue	15/839 (1.8%)	16
Other	41/839 (4.9%)	55
Nervous system disorders
Dyspnea	1/839 (0.1%)	1
Skin and subcutaneous tissue disorders
Rash	3/839 (0.4%)	3
Vascular disorders
Headache	29/839 (3.5%)	32

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.