How metoprolol works in HFrEF patients with low versus high beta‑blocker genetic scores
Personalizing Heart Failure Treatment With Genomics: A Clinical Trial to Understand the Mechanisms and Validate a Polygenic Risk Score for Beta-Blocker Response
This trial will test if people with HFrEF who have a high beta‑blocker polygenic score respond differently to metoprolol than those with a low score.
Quick facts
| Phase | Phase 4 |
|---|---|
| Study type | Interventional |
| Enrollment | 100 (estimated) |
| Ages | 18 Years and up |
| Sex | All |
| Sponsor | University of Michigan Academic / other |
| Locations | 1 site (Ann Arbor, Michigan) |
| Trial ID | NCT07490067 on ClinicalTrials.gov |
What this trial studies
This phase 4 interventional study enrolls people with heart failure with reduced ejection fraction and stratifies them into low- and high-score groups based on a calculated beta‑blocker polygenic score. Participants receive metoprolol succinate and undergo pharmacokinetic blood sampling to measure steady‑state plasma concentrations and pharmacodynamic monitoring of cardiovascular responses. The primary comparisons are between the two genetic groups for drug levels, cardiovascular effect size, and the dose–response relationship. Genetic data come from existing genotyping or an on-site DNA sample, and all visits and sampling occur in person at the University of Michigan.
Who should consider this trial
Good fit: Ideal candidates are adults with HFrEF who are White, not recently on beta‑blockers (or only on low doses), have or can provide genetic data for a polygenic score, and are on stable background heart‑failure therapy.
Not a fit: Patients who are non‑White (and therefore not eligible for this protocol), already on full-dose beta‑blockers, or unable to attend frequent in-person PK and monitoring visits are unlikely to benefit from this specific study.
Why it matters
Potential benefit: If successful, the results could help personalize metoprolol dosing by using genetic scores to identify who may need higher or lower doses for better effect and fewer side effects.
How similar studies have performed: Single-gene pharmacogenetic evidence (for example CYP2D6 effects on metoprolol metabolism) indicates genetics can affect metoprolol levels, but using a multi-variant polygenic score to predict clinical response in HFrEF is relatively novel and not yet proven.
Eligibility criteria
Show full inclusion / exclusion criteria
Inclusion Criteria: * 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 Exclusion Criteria: * 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 * Active or uncorrected severe mitral or aortic valvular dysfunction * Patients with known severe congenital heart disease per protocol * Child-Pugh Class C liver disease * Patients with end-stage renal disease (ESRD) requiring hemodialysis * Concomitant disease that prohibits participating in Cardiopulmonary Exercise Test (CPET) per protocol * Concomitant disease with expected survival less than the duration of the study (e.g., metastatic cancer) * Current or planned treatment with cardiotoxic medications, including interferons and the cancer therapies per protocol * Concurrent participation in another clinical trial that may affect participant safety or validity of data collected in this clinical trial * Inability to take oral medication * Unwilling or unlikely to adhere to the study procedures, as determined at the discretion of the study team, including but not limited to the following reasons: 1. Psychiatric illness or other comorbidities 2. Substance abuse 3. Social or logistical circumstances
Where this trial is running
Ann Arbor, Michigan
- University of Michigan — Ann Arbor, Michigan, United States (Recruiting)
Study contacts
- Principal investigator: Jasmine Luzum, PharmD, PhD — University of Michigan
- Study coordinator: Diamond Thomas
- Email: diamthom@med.umich.edu
- Phone: 734-615-4532
How to participate
- Review the eligibility criteria above with your treating physician.
- Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
- Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.