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HypertensionPhase 4PEAR2NCT01203852

Pharmacogenomic Evaluation of Antihypertensive Responses 2

A Phase 4 study testing Metoprolol and Chlorthalidone in people with Hypertension, run by University of Florida at 3 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 65 years
Conditions the study is for
Hypertension
What is being tested?
Metoprolol and Chlorthalidone
Could I receive a placebo?
No, everyone receives an active treatment
How many people
839 participants
Where
3 sitesUnited States
Study dates
Aug 2010to Apr 2014
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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)
Show all 11Show fewer
  • 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.

Trial locations and contacts

3 sites in 1 country.

United States3 sites

  • Emory University School of Medicine

    Atlanta, Georgia, 30322

  • University of Florida

    Gainesville, Florida, 32610

  • Mayo Clinic, Division of Hypertension

    Rochester, Minnesota, 55905

Other trials in United States

About this study

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.

Read the 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.

Conditions
Hypertension
Being tested
Metoprolol, Chlorthalidone
Keywords
hypertension, antihypertensive drug, pharmacogenetics, genetics, blood pressure, glucose
Medical subject headings
Hypertension

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MetoprololDrug

    Also called Lopressor, Toprol XL

    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.

  • ChlorthalidoneDrug

    Also called Thalitone

    Chlorthalidone 25 mg 4 times per week titrated to 25 mg daily

Study groups in NCT01203852
Study groupRoleWhat they receive
Metoprolol + ChlorthalidoneExperimentalStudy 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.
Receives: Drug: Metoprolol; Drug: Chlorthalidone

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Blood Pressure From Baseline to Treatment

    Response to blood pressure medication will be assessed by measuring blood pressure before and after treatment

    Measured: after 6-8 weeks of treatment

Secondary outcomes (1)

  1. Adverse Metabolic Effects

    Change in glucose after treatment with study medication

    Measured: after 6-8 weeks treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Sep 2010 (estimated)
  2. Study startAug 2010
  3. Primary completionApr 2014
  4. Study completionApr 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
839 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01203852
Sponsor's protocol ID
IRB201700661-N
Other IDs
U01GM074492-06
Acronym
PEAR2
Status last verified
Apr 2018
First submitted
15 Sep 2010
Last updated
6 Apr 2018
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

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.

    PubMed 24637943

  • Mehanna M, McDonough CW, Smith SM, Gong Y, Gums JG, Chapman AB, Johnson JA, Cooper-DeHoff RM. Integrated metabolomics analysis reveals mechanistic insights into variability in blood pressure response to thiazide diuretics and beta blockers. Clin Transl Sci. 2024 May;17(5):e13816. doi: 10.1111/cts.13816.

    PubMed 38747311

  • Chekka LMS, Tantawy M, Langaee T, Wang D, Renne R, Chapman AB, Gums JG, Boerwinkle E, Cooper-DeHoff RM, Johnson JA. Circulating microRNA Biomarkers of Thiazide Response in Hypertension. J Am Heart Assoc. 2024 Feb 20;13(4):e032433. doi: 10.1161/JAHA.123.032433. Epub 2024 Feb 14.

    PubMed 38353215

  • Mehanna M, Wang Z, Gong Y, McDonough CW, Beitelshees AL, Gums JG, Chapman AB, Schwartz GL, Bailey KR, Johnson JA, Turner ST, Cooper-DeHoff RM. Plasma Renin Activity Is a Predictive Biomarker of Blood Pressure Response in European but not in African Americans With Uncomplicated Hypertension. Am J Hypertens. 2019 Jun 11;32(7):668-675. doi: 10.1093/ajh/hpz022.

    PubMed 30753254

  • Sa ACC, Webb A, Gong Y, McDonough CW, Shahin MH, Datta S, Langaee TY, Turner ST, Beitelshees AL, Chapman AB, Boerwinkle E, Gums JG, Scherer SE, Cooper-DeHoff RM, Sadee W, Johnson JA. Blood pressure signature genes and blood pressure response to thiazide diuretics: results from the PEAR and PEAR-2 studies. BMC Med Genomics. 2018 Jun 20;11(1):55. doi: 10.1186/s12920-018-0370-x.

    PubMed 29925376

  • 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):e007339. doi: 10.1161/JAHA.117.007339.

    PubMed 29523524

  • Shahin MH, Sa 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):e001404. doi: 10.1161/CIRCGENETICS.116.001404.

    PubMed 28115488

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Metoprolol and Chlorthalidone in people with Hypertension, run by University of Florida at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Apr 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 May 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Blood Pressure From Baseline to Treatment (time frame: after 6-8 weeks of treatment). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01203852, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Apr 2018.

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