Back to resultsPharmacogenetic Prediction of Metoprolol Effectiveness
Primary Purpose
Hypertension
Status
Terminated
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
metoprolol succinate
Genotyping
CYP2D6 Phenotyping
Sponsored by
About this trial
This is an interventional treatment trial for Hypertension focused on measuring Genotype, CYP2D6, ADRB1
Eligibility Criteria
Inclusion Criteria:
- Subjects between age >30 years and < 80 years
- Subjects have diagnosis of uncontrolled essential hypertension.
Exclusion Criteria:
- end stage liver disease,
- end stage renal disease,
- pregnant females,
- American Society of Anesthesiologists (ASA) classification of >3,
- wards of the state, prisoners,
- decisionally challenged,
- HR<60 bpm,
- AV block>240 msec,
- active reactive airway disease,
- illicit drug abuse in the preceding 30 days,
- hypersensitivity to metoprolol or its derivatives
- severe peripheral arterial circulatory disorders.
Subjects will have a screening physical exam performed by Dr. Monte prior to enrollment in the study.
Sites / Locations
- University of Colorado Denver; Emergency Department
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Metoprolol succinate, CYP2D6 Genotyping, CYP2D6 Phenotyping
Arm Description
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.
Outcomes
Primary Outcome Measures
Blood Pressure Decline
Participants with at least a 10% decrease in SBP
Secondary Outcome Measures
Heart Rate Decline
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: CYP2D6 Metabolizer Status
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).
Adverse Drug Events: ADRB1 Genotype
Occurrence of adverse drug events will be captured and stratified by ADRB1 genotype (strong responder, good responder, non-responder).
Full Information
NCT ID
NCT02293096
First Posted
November 13, 2014
Last Updated
August 18, 2021
Sponsor
University of Colorado, Denver
Collaborators
National Institute of General Medical Sciences (NIGMS)
1. Study Identification
Unique Protocol Identification Number
NCT02293096
Brief Title
Pharmacogenetic Prediction of Metoprolol Effectiveness
Official Title
Pharmacogenetic Prediction of Metoprolol Effectiveness
Study Type
Interventional
2. Study Status
Record Verification Date
August 2021
Overall Recruitment Status
Terminated
Why Stopped
Study was terminated due to the change in funding.
Study Start Date
September 2014 (undefined)
Primary Completion Date
August 23, 2017 (Actual)
Study Completion Date
August 23, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Colorado, Denver
Collaborators
National Institute of General Medical Sciences (NIGMS)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hypertension
Keywords
Genotype, CYP2D6, ADRB1
7. Study Design
Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
N/A
Enrollment
462 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Metoprolol succinate, CYP2D6 Genotyping, CYP2D6 Phenotyping
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
metoprolol succinate
Other Intervention Name(s)
Lopressor
Intervention Type
Genetic
Intervention Name(s)
Genotyping
Other Intervention Name(s)
CYP2D6 genotyping and ADRB1 genotyping
Intervention Description
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
Procedure
Intervention Name(s)
CYP2D6 Phenotyping
Other Intervention Name(s)
Dextromethorphan probe of CYP2D6
Intervention Description
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.
Primary Outcome Measure Information:
Title
Blood Pressure Decline
Description
Participants with at least a 10% decrease in SBP
Time Frame
4-6 weeks status post initiation
Secondary Outcome Measure Information:
Title
Heart Rate Decline
Description
10 % decline from pre-initiation heart rate will considered a HR decline success. Number of of participants with at least 10% decline is reported.
Time Frame
4-6 weeks
Title
Adverse Drug Events: CYP2D6 Metabolizer Status
Description
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).
Time Frame
6 weeks
Title
Adverse Drug Events: ADRB1 Genotype
Description
Occurrence of adverse drug events will be captured and stratified by ADRB1 genotype (strong responder, good responder, non-responder).
Time Frame
6 weeks
Other Pre-specified Outcome Measures:
Title
Metabolomic Factors
Description
The top 5 metabolomic factors associated with SBP decline will be captured and stratified by CYP2D6 genotype and phenotype groups.
Time Frame
0-6 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
30 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Subjects between age >30 years and < 80 years
Subjects have diagnosis of uncontrolled essential hypertension.
Exclusion Criteria:
end stage liver disease,
end stage renal disease,
pregnant females,
American Society of Anesthesiologists (ASA) classification of >3,
wards of the state, prisoners,
decisionally challenged,
HR<60 bpm,
AV block>240 msec,
active reactive airway disease,
illicit drug abuse in the preceding 30 days,
hypersensitivity to metoprolol or its derivatives
severe peripheral arterial circulatory disorders.
Subjects will have a screening physical exam performed by Dr. Monte prior to enrollment in the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew Monte, MD
Organizational Affiliation
University of Colorado, Denver
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Colorado Denver; Emergency Department
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
32160915
Citation
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.
Results Reference
derived
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Pharmacogenetic Prediction of Metoprolol Effectiveness
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