Mechanistic Clinical Trial Comparing the Pharmacokinetics/Pharmacodynamics of Metoprolol in Heart Failure With Reduced Ejection Fraction Patients With Low vs. High Polygenic Score

NCT07490067 | Recruiting Phase 4 FDA Drug FDA Device

• 2 other identifiers: HUM002660211R01HL178410-01
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this trial is to better understand how the beta-blocker metoprolol works in people with Heart Failure with Reduced Ejection Fraction (HFrEF) according to participants genetics. Participants will have the beta-blocker (BB) polygenic score calculated from genotype data. The score will be used to stratify the patients in the low and high polygenic score groups in the study. The hypotheses for this trial are:

• HFrEF patients with high polygenic score will have weaker cardiovascular responses to metoprolol succinate than HFrEF patients with low polygenic score.
• HFrEF patients with high polygenic score have lower steady-state plasma concentrations of metoprolol succinate than HFrEF patients with low polygenic score.
• HFrEF patients with high polygenic score require higher metoprolol succinate plasma concentrations to achieve similar cardiovascular effects as those with low polygenic score.

Conditions

Heart Failure With Reduced Ejection Fraction

Keywords

Beta-blocker; Polygenic Risk Score; Pharmacokinetic; Pharmacogenomics; Pharmacodynamics; Pharmacogenetic; Cardiac testing

Outcome Measures

Primary Outcomes (1)

• Half Maximal Effective Concentration of Change in Exercise-Induced Heart Rate (EC50 of ΔEIHR)

  The plasma concentration of s-metoprolol succinate that causes 50% of the change in exercise-induced heart rate.

  Baseline to approximately 6 months

Secondary Outcomes (3)

• Change in left ventricular ejection fraction (LVEF)

  Baseline to approximately 6 months

• Area Under the Curve from 0 to 24 hours s-metoprolol plasma concentration-time curve "at steady state"

  Approximately 6 months

• Maximum tolerated dose of metoprolol succinate (total daily dose in milligram)

  Approximately 6 months

Study Arms (1)

Metoprolol succinate

EXPERIMENTAL

Treatment will be given for approximately 6 months

Drug: Metoprolol Succinate; Device: Beta-Blocker Polygenic Score; Device: Illumina Infinium Global Diversity Array with Enhanced Pharmacogenomics (PGx)

Interventions

Metoprolol Succinate DRUG

Participants will be given daily metoprolol and the dose will be titrated up to 200 milligrams daily (over 6-12 weeks) or the maximum tolerated dose. Once this dose is reached treatment will continue for approximately 5-8 months. In addition, participants, will have various visits that include laboratory and cardiac testing at certain time points.

Also known as: Lopressor, Toprol-Extended Release (XL)

Metoprolol succinate

Beta-Blocker Polygenic Score DEVICE

The purpose of the beta-blocker polygenic score is to predict which HFrEF patients will respond better to beta-blocker therapy. It will be used to stratify the patients in the low and high polygenic score groups in the study. There are no post-manufacturing modifications to the score.

Metoprolol succinate

Illumina Infinium Global Diversity Array with Enhanced Pharmacogenomics (PGx) DEVICE

If the participant does not already have genotype data available through Michigan Genomics Initiative (MGI), then this device will be used to genotype DNA sample, which will be used to calculate the polygenic score. There are no post-manufacturing modifications to the device.

Metoprolol succinate

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Heart Failure with Reduced Ejection Fraction (HFrEF)
• Has not taken a beta-blocker within the past 6 months (preferred), or if needed to meet enrollment target, patients that have not taken a beta-blocker in the past 3 months, or only taken a low dose of beta-blocker within the past 6 months (i.e., \< 50% of the guideline-recommended HFrEF target dose, or for beta-blockers that are not approved for HFrEF, \<50% of the maximum dose)
• Genetic data already available to calculate the polygenic score (e.g., through participation in the Michigan Genomics Initiative (MGI) or other genetic tests) or willingness to provide a deoxyribonucleic acid (DNA) sample for genetic analysis
• White race
• Has been prescribed a stable dose (including no dose) of angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), ARB-neprilysin inhibitor (ARNI), sodium-glucose cotransporter 2 (SGLT-2) inhibitor, or mineralocorticoid receptor antagonist (MRA) for at least the past 4 weeks
• Has been prescribed a stable dose (including no dose) of diuretic(s) for at least the past 2 weeks
• For women of child-bearing potential: the participant is willing to perform a pregnancy test and use a highly effective contraceptive method for at least 4 weeks prior to the start of metoprolol treatment, during the entire metoprolol treatment period, and for at least 5 days after the discontinuation of metoprolol treatment
• Ability to understand and willing to sign a written informed consent

You may not qualify if:

• Prior heart transplant or left ventricular assist device (LVAD) or planned within treatment period
• Planned implantation of a pacemaker or Cardiac Resynchronization Therapy (CRT) during treatment period
• Patients with a pacemaker that does not allow their heart rate to change in response to exercise per protocol
• Pregnant
• Systolic blood pressure \< 95 millimeters of mercury (mmHg)
• Heart rate \< 60 beats per minute
• Second (Mobitz II)- or third-degree heart block
• Cardiogenic shock
• Patients with acute decompensated heart failure requiring current hospitalization or immediate medical intervention.
• Sick sinus syndrome
• Pheochromocytoma
• Known hypersensitivity to the metoprolol succinate oral tablet used in the trial
• Hypertrophic obstructive cardiomyopathy
• Active myocarditis
• Acute coronary syndrome within the past month

Sponsors & Collaborators

• University of Michigan: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

University of Michigan

Ann Arbor, Michigan, 48109, United States

RECRUITING

MeSH Terms

Conditions

Genetic Risk Score

Interventions

Metoprolol

Condition Hierarchy (Ancestors)

Genetic Predisposition to Disease; Disease Susceptibility; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines

Study Officials

• Jasmine Luzum, PharmD, PhD

  University of Michigan

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Diamond Thomas

CONTACT

734-615-4532; diamthom@med.umich.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinical Pharmacist and Assistant Professor of Pharmacy

Model Details: Single site; open-label to treatment (metoprolol), but double-blinded to the participants' polygenic score (low vs. high)

Study Record Dates

• First Submitted: March 18, 2026
• First Posted: March 24, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): July 1, 2029
• Study Completion (Estimated): July 1, 2029
• Last Updated: April 14, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)