search
Back to results

Genetics of Response to Canagliflozin

Primary Purpose

Diabetes Mellitus, Type 2

Status
Enrolling by invitation
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Canagliflozin
Sponsored by
University of Maryland, Baltimore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Diabetes Mellitus, Type 2 focused on measuring Glucosuria, SGLT2 inhibitors, Canagliflozin, FGF23, Parathyroid hormone, 1,25-Dihydroxyvitamin D, Glucagon, Ketone bodies, Uric acid, Pharmacogenomics

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Of Amish descent
  • Age 18 or older
  • BMI: 18-40 kg/m2

Exclusion Criteria:

  • Known allergy to canagliflozin
  • History of diabetes, random glucose greater than 200 mg/dL, or HbA1c greater than or equal to 6.5%
  • Currently taking diuretics, antihypertensive medication uric acid lowering medications, or other medication that the investigator judges will make interpretation of the results difficult
  • Significant debilitating chronic cardiac, hepatic, pulmonary, or renal disease or other diseases that the investigator judges will make interpretation of the results difficult or increase the risk of participation
  • Seizure disorder
  • Unwilling to go off of vitamin supplements and over the counter medication (except for acetaminophen) for at least two weeks prior to the first home visit and agree to avoid these medications for the duration of the study.
  • Positive urine human chorionic gonadotropin test or known pregnancy within 3 months of the start of the study
  • Estimated glomerular filtration rate less than 60 mL/min
  • Currently breast feeding or breast feeding within 3 month of the start of the study
  • Liver function tests greater than 2 times the upper limit of normal
  • Hematocrit less than 35%
  • Abnormal thyroid hormone stimulating hormone

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Single arm

    Arm Description

    Healthy volunteers will receive canagliflozin to assess pharmacodynamic responses to drug.

    Outcomes

    Primary Outcome Measures

    Urinary glucose excretion (during the time interval 24-48 hours after first administration of canagliflozin)
    Urine collection will be initiated 24 hours after initiation of canagliflozin treatment, and continued for an additional 24 hours.

    Secondary Outcome Measures

    Bone-related biomarkers
    Serum phosphorus, FGF23, 1,25-dihydroxyvitamin D, PTH, P1NP, and beta-CTX
    Bone-related biomarkers
    Serum phosphorus, FGF23, 1,25-dihydroxyvitamin D, PTH, P1NP, and beta-CTX
    Ketosis-related biomarkers
    glucagon, acetoacetate, beta-hydroxybutyrate
    Ketosis-related biomarkers
    glucagon, acetoacetate, beta-hydroxybutyrate
    Serum uric acid
    Change in serum uric acid at 48 hours
    Serum uric acid
    Change in serum uric acid at 120 hours

    Full Information

    First Posted
    August 30, 2016
    Last Updated
    September 25, 2023
    Sponsor
    University of Maryland, Baltimore
    Collaborators
    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
    search

    1. Study Identification

    Unique Protocol Identification Number
    NCT02891954
    Brief Title
    Genetics of Response to Canagliflozin
    Official Title
    Pharmacogenomics to Predict Responses to SGLT2 Inhibitors
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2023
    Overall Recruitment Status
    Enrolling by invitation
    Study Start Date
    September 2016 (Actual)
    Primary Completion Date
    September 25, 2023 (Actual)
    Study Completion Date
    September 25, 2024 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    University of Maryland, Baltimore
    Collaborators
    National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    Five daily doses of canagliflozin (300 mg) will be administered to healthy volunteers. Pharmacodynamic responses to canagliflozin will be assessed both at 2 days and 6 days after administration of the first dose of canagliflozin. A genome-wide association study (GWAS) will be conducted to search for genetic variants that are associated with each of the pharmacodynamic responses to canagliflozin.
    Detailed Description
    After obtaining informed consent, healthy Amish research subjects will be screened for eligibility. Immediately after obtaining blood samples for baseline clinical chemistry tests wills, patients will initiate 5 days of canagliflozin (300 mg) treatment. Fasting blood samples will be obtained to assess pharmacodynamic responses at both 48 hours and 120 hours after initiating canagliflozin. The principal pharmacodynamic responses will include 24 hour urinary excretion of glucose, serum chemistries (phosphorus, FGF23, 1,25-dihydroxyvitamin D, parathyroid hormone (PTH), glucagon, beta-hydroxybutyrate, acetoacetate, procollagen type I N-terminal peptide (P1NP), and beta-CTX). Research subjects will undergo genotyping, and a genome-wide association study will be conducted to search for genetic variants that are associated with pharmacodynamic responses to canagliflozin.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Diabetes Mellitus, Type 2
    Keywords
    Glucosuria, SGLT2 inhibitors, Canagliflozin, FGF23, Parathyroid hormone, 1,25-Dihydroxyvitamin D, Glucagon, Ketone bodies, Uric acid, Pharmacogenomics

    7. Study Design

    Primary Purpose
    Basic Science
    Study Phase
    Phase 1
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    700 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Single arm
    Arm Type
    Experimental
    Arm Description
    Healthy volunteers will receive canagliflozin to assess pharmacodynamic responses to drug.
    Intervention Type
    Drug
    Intervention Name(s)
    Canagliflozin
    Other Intervention Name(s)
    Invokana (brand name for canagliflozin)
    Intervention Description
    Healthy volunteers will receive canagliflozin (300 mg per day) in the morning for five days.
    Primary Outcome Measure Information:
    Title
    Urinary glucose excretion (during the time interval 24-48 hours after first administration of canagliflozin)
    Description
    Urine collection will be initiated 24 hours after initiation of canagliflozin treatment, and continued for an additional 24 hours.
    Time Frame
    24-48 hours
    Secondary Outcome Measure Information:
    Title
    Bone-related biomarkers
    Description
    Serum phosphorus, FGF23, 1,25-dihydroxyvitamin D, PTH, P1NP, and beta-CTX
    Time Frame
    48 hrs
    Title
    Bone-related biomarkers
    Description
    Serum phosphorus, FGF23, 1,25-dihydroxyvitamin D, PTH, P1NP, and beta-CTX
    Time Frame
    120 hrs
    Title
    Ketosis-related biomarkers
    Description
    glucagon, acetoacetate, beta-hydroxybutyrate
    Time Frame
    48 hrs
    Title
    Ketosis-related biomarkers
    Description
    glucagon, acetoacetate, beta-hydroxybutyrate
    Time Frame
    120 hurs
    Title
    Serum uric acid
    Description
    Change in serum uric acid at 48 hours
    Time Frame
    48 hrs
    Title
    Serum uric acid
    Description
    Change in serum uric acid at 120 hours
    Time Frame
    120 hrs

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    Accepts Healthy Volunteers
    Eligibility Criteria
    Inclusion Criteria: Of Amish descent Age 18 or older BMI: 18-40 kg/m2 Exclusion Criteria: Known allergy to canagliflozin History of diabetes, random glucose greater than 200 mg/dL, or HbA1c greater than or equal to 6.5% Currently taking diuretics, antihypertensive medication uric acid lowering medications, or other medication that the investigator judges will make interpretation of the results difficult Significant debilitating chronic cardiac, hepatic, pulmonary, or renal disease or other diseases that the investigator judges will make interpretation of the results difficult or increase the risk of participation Seizure disorder Unwilling to go off of vitamin supplements and over the counter medication (except for acetaminophen) for at least two weeks prior to the first home visit and agree to avoid these medications for the duration of the study. Positive urine human chorionic gonadotropin test or known pregnancy within 3 months of the start of the study Estimated glomerular filtration rate less than 60 mL/min Currently breast feeding or breast feeding within 3 month of the start of the study Liver function tests greater than 2 times the upper limit of normal Hematocrit less than 35% Abnormal thyroid hormone stimulating hormone
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Simeon I Taylor, MD, PhD
    Organizational Affiliation
    Unversity of Maryland School of Medicine
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    No
    Citations:
    PubMed Identifier
    25523498
    Citation
    Taylor SI, Blau JE, Rother KI. Possible adverse effects of SGLT2 inhibitors on bone. Lancet Diabetes Endocrinol. 2015 Jan;3(1):8-10. doi: 10.1016/S2213-8587(14)70227-X. Epub 2014 Dec 16. No abstract available.
    Results Reference
    background
    PubMed Identifier
    26086329
    Citation
    Taylor SI, Blau JE, Rother KI. SGLT2 Inhibitors May Predispose to Ketoacidosis. J Clin Endocrinol Metab. 2015 Aug;100(8):2849-52. doi: 10.1210/jc.2015-1884. Epub 2015 Jun 18.
    Results Reference
    background
    PubMed Identifier
    29669938
    Citation
    Blau JE, Bauman V, Conway EM, Piaggi P, Walter MF, Wright EC, Bernstein S, Courville AB, Collins MT, Rother KI, Taylor SI. Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study. JCI Insight. 2018 Apr 19;3(8):e99123. doi: 10.1172/jci.insight.99123. eCollection 2018 Apr 19.
    Results Reference
    background
    PubMed Identifier
    29875481
    Citation
    Blau JE, Taylor SI. Adverse effects of SGLT2 inhibitors on bone health. Nat Rev Nephrol. 2018 Aug;14(8):473-474. doi: 10.1038/s41581-018-0028-0.
    Results Reference
    background
    PubMed Identifier
    31109940
    Citation
    Beitelshees AL, Leslie BR, Taylor SI. Sodium-Glucose Cotransporter 2 Inhibitors: A Case Study in Translational Research. Diabetes. 2019 Jun;68(6):1109-1120. doi: 10.2337/dbi18-0006.
    Results Reference
    background

    Learn more about this trial

    Genetics of Response to Canagliflozin

    We'll reach out to this number within 24 hrs