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Genetic Determinants of ACEI Prodrug Activation

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ClinicalTrials.gov Identifier: NCT03051282
Recruitment Status : Suspended (Enrollment and interactions/interventions are paused due to COVID-19 and are expected to resume in the future. This is not a suspension of IRB approval.)
First Posted : February 13, 2017
Last Update Posted : June 19, 2020
Sponsor:
Information provided by (Responsible Party):
Haojie Zhu, University of Michigan

Tracking Information
First Submitted Date  ICMJE February 9, 2017
First Posted Date  ICMJE February 13, 2017
Last Update Posted Date June 19, 2020
Actual Study Start Date  ICMJE April 1, 2017
Estimated Primary Completion Date January 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 9, 2017)
The measurements of the mean area under the curve (AUC) of enalaprilat plasma concentrations [ Time Frame: 72 hours ]
To compare the mean AUC of enalaprilat plasma concentrations between the non-carrier control and the G143E carriers groups
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 9, 2017)
  • The measurements of the maximum enalaprilat plasma concentrations [ Time Frame: 72 hours ]
    To compare the maximum enalaprilat plasma concentrations between the non-carrier control and the G143E carriers groupsG143E carriers groups
  • The measurements of angiotensin converting enzyme (ACE) activity in plasma [ Time Frame: 72 hours ]
    To compare the plasma ACE activity between the non-carrier control and the G143E carriers groupsG143E carriers groups following enalapril treatment
  • The measurements of blood pressures (BPs) following enalapril treatment [ Time Frame: 72 hours ]
    To compare the changes of BPs between the non-carrier control and the G143E carriers groupsG143E carriers groups following enalapril treatment
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Genetic Determinants of ACEI Prodrug Activation
Official Title  ICMJE Genetic Determinants of ACEI Prodrug Activation
Brief Summary Angiotensin-converting enzyme inhibitors (ACEIs) are among the most frequently prescribed medications worldwide for the treatment of essential hypertension, left ventricular systolic dysfunction, acute myocardial infarction, and prevention of the progression of diabetic nephropathy. However, the outcome of ACEI treatment varies significantly between individuals and selected populations. Suboptimal response, therapeutic failure, and significant side effects are commonly documented in patients receiving ACEI therapy. Approximately 80% of the ACEIs available for use in the US are synthesized as esterified prodrugs in order to improve otherwise poor oral bioavailability of the active molecule. The activation of ACEI prodrugs primarily occurs in the liver via metabolic de-esterification of the parent drug. The critical activation step is essential in delivering a successful therapeutic outcome since the active metabolites are approximately 10-1000 times more potent relative to their respective parent compounds. Carboxylesterase 1 (CES1), the most abundant hydrolase in the liver, is responsible for the activation of ACEI prodrugs in humans. Marked interindividual variability in CES1 expression and activity has been documented, which results in varied therapeutic efficacy and tolerability of many drugs serving as substrates of CES1. Genetic variation of CES1 is considered to be a major factor contributing to variability in CES1 function. The study team proposes to conduct a multiple-dose healthy volunteer study to evaluate the impact of CES1 genetic variation on the activation, pharmacokinetics, and pharmacodynamics of enalapril, a model ACEI prodrug activated by CES1. The completion of this study will represent a major step towards the establishment of an evidence base from which a more individualized use of ACEI prodrugs can emerge.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Screening
Condition  ICMJE Healthy Volunteers
Intervention  ICMJE Drug: Enalapril
Study participants in both arms will be treated with 10 mg enalapril orally once daily for seven consecutive days
Other Name: Vasotec®
Study Arms  ICMJE
  • Active Comparator: non-carrier control group
    Subjects who do not carry the CES1 variant G143E (rs71647871) will receive 10 mg Enalapril orally once daily for 7 consecutive days.
    Intervention: Drug: Enalapril
  • Active Comparator: G143E carriers group
    Subjects who carry the CES1 variant G143E (rs71647871) will receive 10 mg Enalapril orally once daily for 7 consecutive days.
    Intervention: Drug: Enalapril
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Suspended
Estimated Enrollment  ICMJE
 (submitted: February 9, 2017)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2021
Estimated Primary Completion Date January 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Subjects must be male and female (50:50) between the ages of 18-55 years
  • Females must have a negative urine pregnancy test prior to the study
  • All subjects must have no clinically significant diseases or clinically significant abnormal laboratory values as assessed during the screening medical history, nursing assessment, and laboratory evaluations
  • Informed consent must be signed by the eligible subject prior to the initiation of any study procedures

Exclusion Criteria:

  • The presence of a known medical condition that would preclude the use of enalapril
  • The presence of any surgical or medical condition (active or chronic) that may interfere with drug absorption, distribution, metabolism, or excretion.
  • A positive urine pregnancy test in the MCRU prior to the study
  • No subjects weighing under 50 kg will be selected
  • The lack of use of acceptable methods of birth control unless abstinent
  • Subjects who regularly take medications, vitamins, herbal supplements
  • The use of any illicit drugs or habitual consumption of large quantities of ethanol (>3 drinks/day)
  • The consumption of grapefruit or grapefruit juice a week prior to, and during the study
  • Asians will not be included in the study as the CES1 SNP G143E is absent in this population
  • Subjects hypersensitive to enalapril
  • Subject with a history of angioedema
  • Smokers
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03051282
Other Study ID Numbers  ICMJE HUM00114879
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Haojie Zhu, University of Michigan
Study Sponsor  ICMJE University of Michigan
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account University of Michigan
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP