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Naproxen Pharmacogenetic Study (Project 1, Aim 2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04449471
Recruitment Status : Recruiting
First Posted : June 26, 2020
Last Update Posted : June 29, 2020
Oregon Health and Science University
National Institute of General Medical Sciences (NIGMS)
Information provided by (Responsible Party):
Kenneth Thummel, University of Washington

Brief Summary:
This is a mechanism-based study in healthy adults to determine the effect of the CYP2C9 M1L gene polymorphism on the functional activity of the encoded CYP2C9 enzyme towards the probe substrate naproxen. CYP2C9 activity will be evaluated by measurement of O-desmethyl naproxen and unchanged naproxen in 24-hour urine following administration of a single oral dose of naproxen (Aleve) in Yup'ik Alaska Native adult men and women who were previously determined in a separate observational study to be homozygous for the CYP2C9*1 allele or a carrier of the CYP2C9 M1L allele.

Condition or disease Intervention/treatment Phase
Pharmacogenetics Drug: Naproxen tablet Phase 4

Detailed Description:

This pharmacogenetics study will test the hypothesis that inheritance of a M1L variant in the CYP2C9 gene, which was first discovered in Yup'ik Alaska Native people, causes complete loss of function in CYP-2C9-dependent catalytic activity.

Study participants will be selected from a cross-sectional population of >750 Yup'ik men and women, ≥18 years, for whom CYP2C9 genotype has already been determined as part of a SNP discovery study, and who consented to be contacted for future research. There will be 15 participants in each of two genotyped groups ((1) Met1/Met1 and (2) Met1/Leu1 or Leu1/Leu1), for a total of 30 participants. The two groups will be matched for sex of the participants; the proportion determined by the composition of the least frequent Leu1 carrier group. The investigators will attempt to recruit a similar range of ages in each genotyped group and the widest range possible. Recruitment will occur in one of 10 communities in the Yukon-Kuskokwim delta that participated in our original SNP discovery study.

Participants will be asked to fast overnight prior to the study and will be allowed to eat ad libitum 2 hours after naproxen is taken. A fasting 13 ml venous blood sample will be collected from each participant for isolation of DNA and plasma. Spot urine will be collected from each participant as an analytic control the morning of the blood draw. At approximately 9 am, each participant will be given a single 220-mg dose of Naproxen, by mouth, with a glass of water. The total urine output over the next 24-hour will be collected by the participant and returned to the clinic the next day. The urine volume will be measured and recorded and two 5 mL aliquots will be frozen at -80°C and stored for unchanged drug and metabolite analysis analyses.

Total (conjugated and unconjugated) 6-O-Desmethyl naproxen and unchanged naproxen concentrations in urine will be measured by LC-MS/MS. A ratio of the total 6-O-desmethyl naproxen/naproxen (M/P) excreted in urine over 24-hours will be computed. 6-O-desmethyl naproxen is formed selectively by CYP2C9.

Pairwise comparison of the mean M/P ratios, assuming unequal variance, will be evaluated using a t-test to determine if there are significant differences in activity for carriers of the Leu 1 variant. The sample size provides 80% power to detect a difference, at a significance level of 0.05.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Healthy adults with predetermined CYP2C9 genotype will receive the probe drug, naproxen.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Project 1: Program on Genetic and Dietary Predictors of Drug Response in Rural and AI/AN Populations (Naproxen Study)
Actual Study Start Date : January 12, 2016
Estimated Primary Completion Date : July 31, 2021
Estimated Study Completion Date : July 31, 2022

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Naproxen Tablet
Subjects will received a single 220-mg dose of naproxen sodium (Aleve) by mouth.
Drug: Naproxen tablet
For this single intervention arm, each subject will receive a single 220-mg dose of naproxen sodium (Aleve), followed by urine collection for 24-hours.
Other Name: Aleve

Primary Outcome Measures :
  1. 6-O-desmethyl naproxen/naproxen ratio [ Time Frame: 24-hours ]
    A ratio of the total mount of 6-O-desmethyl naproxen/unchanged naproxen in 24-hour urine

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

Inclusion Criteria:

  1. No history of significant medical conditions including cardiac, pulmonary, gastrointestinal, or renal disease, HIV, or history of asthma, urticaria, or allergic-type reactions with aspirin (ASA) or other NSAID (nonsteroidal anti-inflammatory drug).
  2. Both males or females 18 years and older.
  3. Self-identified as Yup'ik or Cup'ik
  4. Able to read and understand English or Yup'ik.
  5. Able to provide informed consent.
  6. Women not currently pregnant or lactating.

Exclusion Criteria:

  1. Individuals with any significant chronic medical condition, including cardiac, pulmonary, hepatic, gastrointestinal, or renal disease, HIV, or history of asthma, urticaria, or allergic-type reactions with aspirin (ASA) or other NSAID
  2. Individuals less than 18 years of age.
  3. Individuals unable to read and understand English or Yup'ik.
  4. Individuals unable to provide informed consent.
  5. Individuals taking drugs or natural products known to affect the metabolic activity of CYP2C9 (e.g., rifampin, carbamazepine, barbiturates, phenytoin, valproic acid, fluconazole, ketoconazole, miconazole, amiodarone, fluvastatin and milk thistle.
  6. Women who are pregnant or lactating.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04449471

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Contact: Kenneth E. Thummel, PhD 205-543-0819

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United States, Oregon
Oregon Health & Science University Recruiting
Portland, Oregon, United States, 97239-3098
Contact: Bert B. Boyer, PhD    503-494-3368   
Contact: Scarlett Hopkins, RN, MA    503-494-3369   
Sponsors and Collaborators
University of Washington
Oregon Health and Science University
National Institute of General Medical Sciences (NIGMS)
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Principal Investigator: Kenneth E. Thummel, PhD University of Washington
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Responsible Party: Kenneth Thummel, Professor: Pharmaceutics, University of Washington Identifier: NCT04449471    
Other Study ID Numbers: SITE00000671
5P01GM116691 ( U.S. NIH Grant/Contract )
First Posted: June 26, 2020    Key Record Dates
Last Update Posted: June 29, 2020
Last Verified: June 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Kenneth Thummel, University of Washington:
Additional relevant MeSH terms:
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Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Gout Suppressants
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action