Genetics of Response to Canagliflozin

Phase 1Active Not RecruitingNCT02891954

University of Maryland, Baltimore700 enrolled

Overview

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.

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 Type

INTERVENTIONAL

Allocation

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

700

Conditions

Diabetes Mellitus, Type 2

Interventions

CanagliflozinDRUG

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

Eligibility

Sex: ALLMin age: 18 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: 24-48 hours

Secondary Outcomes

Bone-related biomarkers

Serum phosphorus, FGF23, 1,25-dihydroxyvitamin D, PTH, P1NP, and beta-CTX

Time frame: 48 hrs

Bone-related biomarkers

Serum phosphorus, FGF23, 1,25-dihydroxyvitamin D, PTH, P1NP, and beta-CTX

Time frame: 120 hrs

Ketosis-related biomarkers

glucagon, acetoacetate, beta-hydroxybutyrate

Time frame: 48 hrs

Ketosis-related biomarkers

glucagon, acetoacetate, beta-hydroxybutyrate

Time frame: 120 hurs

Serum uric acid

Change in serum uric acid at 48 hours

Time frame: 48 hrs

Serum uric acid

Change in serum uric acid at 120 hours

Time frame: 120 hrs

Data from ClinicalTrials.gov

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