Pharmacogenetic Prediction of Metoprolol Effectiveness

NCT ID: NCT02293096

Last Updated: 2021-09-16

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: NA
• Total Enrollment: 462 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-09-30
• Study Completion Date: 2017-08-23

Brief Summary

The investigators will prospectively follow a population of patients with uncontrolled high blood pressure beginning metoprolol succinate therapy to determine the drug effect in an observational clinical trial. The investigators will determine each individual's genotype for both CYP2D6 and Adrenoceptor Beta 1 (ADRB1). Metabolomic markers will be identified to determine if specific metabolites are associated with drug response. The investigators' overall objective is to determine if genetics predicts metoprolol succinate response better than clinical factors such as age, race, body mass index, dose, and medication co-ingestion.

Conditions

Hypertension

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Metoprolol succinate, CYP2D6 Genotyping, CYP2D6 Phenotyping

The parent study will integrate covariates to predict metoprolol effectiveness for SBP decline of 10%. All patients will receive metoprolol. The following covariates will be used to predict metoprolol effectiveness: clinical variables (Age, sex, race/ethnicity, co-medications, and BMI) CYP2D6 genotype, CYP2D6 phenotype, and metabolomic factors.

metoprolol succinate

Genotyping: CYP2D6 only clinically pertinent pathway of metoprolol metabolism and polymorphisms have been associated with altered levels of metoprolol. ADRB1 is the drug target and polymorphism in this receptor has been associated with variable drug response. Genotyping will occur after the treatment phase is complete.

CYP2D6 Phenotyping: Phenotype can be discordant from what is predicted by genotype. CYP2D6 henotyping using dextromethorphan will be used. Investigators will be blind to the patient blood pressure outcome for this intervention.

Group Type: EXPERIMENTAL

metoprolol succinate

Intervention Type: DRUG

Genotyping

Intervention Type: GENETIC

CYP2D6 only clinically pertinent pathway of metoprolol metabolism and polymorphisms have been associated with altered levels of metoprolol. ADRB1 is the drug target and polymorphism in this receptor has been associated with variable drug response. Genotyping will occur after the treatment phase is complete. Thus the investigator, the subject, and the outcomes investigator will be blind to the intervention.

CYP2D6 Phenotyping

Intervention Type: PROCEDURE

Phenotype can be discordant from what is predicted by genotype due to variability in absorption, hepatic blood flow, drug interaction and drug elimination. These factors can be accounted for by utilizing a phenotyping assay that determines area under the curve of the probe since the probe is affected by the same variables dictating metabolism phenotype of the therapeutic drug. Investigators will be blind to the patient blood pressure outcome for this intervention.

Interventions

metoprolol succinate

Intervention Type: DRUG

Genotyping

CYP2D6 only clinically pertinent pathway of metoprolol metabolism and polymorphisms have been associated with altered levels of metoprolol. ADRB1 is the drug target and polymorphism in this receptor has been associated with variable drug response. Genotyping will occur after the treatment phase is complete. Thus the investigator, the subject, and the outcomes investigator will be blind to the intervention.

Intervention Type: GENETIC

CYP2D6 Phenotyping

Phenotype can be discordant from what is predicted by genotype due to variability in absorption, hepatic blood flow, drug interaction and drug elimination. These factors can be accounted for by utilizing a phenotyping assay that determines area under the curve of the probe since the probe is affected by the same variables dictating metabolism phenotype of the therapeutic drug. Investigators will be blind to the patient blood pressure outcome for this intervention.

Intervention Type: PROCEDURE

Other Intervention Names

Lopressor; CYP2D6 genotyping and ADRB1 genotyping; Dextromethorphan probe of CYP2D6

Eligibility Criteria

Inclusion Criteria

1. Subjects between age >30 years and < 80 years

2. Subjects have diagnosis of uncontrolled essential hypertension.

Exclusion Criteria

1. end stage liver disease,

2. end stage renal disease,

3. pregnant females,

4. American Society of Anesthesiologists (ASA) classification of >3,

5. wards of the state, prisoners,

6. decisionally challenged,

7. HR<60 bpm,

8. AV block>240 msec,

9. active reactive airway disease,

10. illicit drug abuse in the preceding 30 days,

11. hypersensitivity to metoprolol or its derivatives

12. severe peripheral arterial circulatory disorders.

Subjects will have a screening physical exam performed by Dr. Monte prior to enrollment in the study.

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of General Medical Sciences (NIGMS)

NIH

Sponsor Role: collaborator

University of Colorado, Denver

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Andrew Monte, MD

Role: PRINCIPAL_INVESTIGATOR

University of Colorado, Denver

Locations

University of Colorado Denver; Emergency Department

Aurora, Colorado, United States

Countries

United States

References

Brocker CN, Velenosi T, Flaten HK, McWilliams G, McDaniel K, Shelton SK, Saben J, Krausz KW, Gonzalez FJ, Monte AA. Metabolomic profiling of metoprolol hypertension treatment reveals altered gut microbiota-derived urinary metabolites. Hum Genomics. 2020 Mar 11;14(1):10. doi: 10.1186/s40246-020-00260-w.

Reference Type: DERIVED

PMID: 32160915 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

1K23GM110516-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

13-3174

Identifier Type: -

Identifier Source: org_study_id