Pharmacogenetic Prediction of Metoprolol Effectiveness

Not Applicable

Terminated

• Conditions: Hypertension
• Interventions: Drug: metoprolol succinate; Genetic: Genotyping; Procedure: CYP2D6 Phenotyping

• Registration Number: NCT02293096
• Lead Sponsor: University of Colorado, Denver

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2014-09
• Study First Submitted: 2014-11-13
• Study First Submitted QC: 2014-11-17
• Study First Posted: 2014-11-18
• Primary Completion: 2017-08-23
• Study Completion: 2017-08-23
• Status Verified: 2021-08
• Results First Submitted: 2021-08-18
• Results First Submitted QC: 2021-08-18
• Last Update Submitted: 2021-08-18
• Results First Posted: 2021-09-16
• Last Update Posted: 2021-09-16

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 462

Inclusion Criteria

1. Subjects between age >30 years and < 80 years
2. Subjects have diagnosis of uncontrolled essential hypertension.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Metoprolol succinate, CYP2D6 Genotyping, CYP2D6 Phenotyping	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.
Metoprolol succinate, CYP2D6 Genotyping, CYP2D6 Phenotyping	metoprolol succinate	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.
Metoprolol succinate, CYP2D6 Genotyping, CYP2D6 Phenotyping	Genotyping	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.

Primary Outcome Measures

Name	Time	Method
Blood Pressure Decline	4-6 weeks status post initiation	Participants with at least a 10% decrease in SBP

Secondary Outcome Measures

Name	Time	Method
Adverse Drug Events: CYP2D6 Metabolizer Status	6 weeks	Occurrence of adverse drug events will be captured and stratified by CYP2D6 metabolizer status (Poor Metabolizer (PM), Extensive Metabolizer (EM), Intermediate Metabolizer (IM), and Ultra rapid Metabolizer).
Heart Rate Decline	4-6 weeks	10 % decline from pre-initiation heart rate will considered a HR decline success. Number of of participants with at least 10% decline is reported.
Adverse Drug Events: ADRB1 Genotype	6 weeks	Occurrence of adverse drug events will be captured and stratified by ADRB1 genotype (strong responder, good responder, non-responder).

Trial Locations

Locations (1)

University of Colorado Denver; Emergency Department; 🇺🇸 Aurora, Colorado, United States