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
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
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
NCT ID
NCT02891954
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)
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
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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
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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
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Genetics of Response to Canagliflozin
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