Genetics of Response to Canagliflozin

Sponsor

University of Maryland, Baltimore (Other)

Overall Status

Enrolling by invitation

CT.gov ID

NCT02891954

Collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)

700

Enrollment

Arm

93.9

Anticipated Duration (Months)

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2	Drug: Canagliflozin	Phase 1

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

700 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

Pharmacogenomics to Predict Responses to SGLT2 Inhibitors

Actual Study Start Date :

Sep 1, 2016

Anticipated Primary Completion Date :

Jun 30, 2023

Anticipated Study Completion Date :

Jun 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single arm Healthy volunteers will receive canagliflozin to assess pharmacodynamic responses to drug.	Drug: Canagliflozin Healthy volunteers will receive canagliflozin (300 mg per day) in the morning for five days. Other Names: Invokana (brand name for canagliflozin)

Arm

Intervention/Treatment

Experimental: Single arm

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

Drug: Canagliflozin

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

Other Names:

Invokana (brand name for canagliflozin)

Outcome Measures

Primary Outcome Measures

Urinary glucose excretion (during the time interval 24-48 hours after first administration of canagliflozin) [24-48 hours]
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 [48 hrs]
Serum phosphorus, FGF23, 1,25-dihydroxyvitamin D, PTH, P1NP, and beta-CTX
Bone-related biomarkers [120 hrs]
Serum phosphorus, FGF23, 1,25-dihydroxyvitamin D, PTH, P1NP, and beta-CTX
Ketosis-related biomarkers [48 hrs]
glucagon, acetoacetate, beta-hydroxybutyrate
Ketosis-related biomarkers [120 hurs]
glucagon, acetoacetate, beta-hydroxybutyrate
Serum uric acid [48 hrs]
Change in serum uric acid at 48 hours
Serum uric acid [120 hrs]
Change in serum uric acid at 120 hours

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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