Genetics of Response to Canagliflozin

Diabetes Mellitus, Type 2 Clinical Trial

Official title:

Pharmacogenomics to Predict Responses to SGLT2 Inhibitors

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT02891954
• Other study ID #: HP-00069977
• Secondary ID: R01DK118942
• Status: Enrolling by invitation
• Phase: Phase 1
• Start date: September 2016
• Est. completion date: September 25, 2024

Study information

• Verified date: September 2023
• Source: University of Maryland, Baltimore
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 700
• Est. completion date: September 25, 2024
• Est. primary completion date: September 25, 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2

Intervention

Drug:
• Canagliflozin
Healthy volunteers will receive canagliflozin (300 mg per day) in the morning for five days.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
University of Maryland, Baltimore	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

References & Publications (5)

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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	24-48 hours
Secondary	Bone-related biomarkers	Serum phosphorus, FGF23, 1,25-dihydroxyvitamin D, PTH, P1NP, and beta-CTX	48 hrs
Secondary	Bone-related biomarkers	Serum phosphorus, FGF23, 1,25-dihydroxyvitamin D, PTH, P1NP, and beta-CTX	120 hrs
Secondary	Ketosis-related biomarkers	glucagon, acetoacetate, beta-hydroxybutyrate	48 hrs
Secondary	Ketosis-related biomarkers	glucagon, acetoacetate, beta-hydroxybutyrate	120 hurs
Secondary	Serum uric acid	Change in serum uric acid at 48 hours	48 hrs
Secondary	Serum uric acid	Change in serum uric acid at 120 hours	120 hrs