A Study to Compare the Pharmacodynamics of Canagliflozin and Dapagliflozin in Healthy Volunteers

Study Overview
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Brief Summary
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The purpose of this study is to compare the pharmacodynamics (ie, how the drug affects the body) of canagliflozin with the pharmacodynamics of dapagliflozin.

Detailed Description
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The study will be conducted as a 2-part study. Part 1 is an open-label pilot study (the investigator and the participants know the identity of the assigned treatment) in which 6 healthy volunteers will be given 300 mg of canagliflozin once daily for 4 consecutive days. The total study duration for each volunteer in Part 1 will be approximately 35 days (including a screening phase, an open-label treatment phase, and a follow-up phase). Part 2 will be a double-blind (neither the investigator nor volunteers know the identity of the assigned treatment), randomized (the treatment is assigned by chance), 2-period crossover study (all volunteers will receive each of the 2 treatments but in a different order) with a two-stage sequential group design. Approximately 34 healthy volunteers will be participating in the first stage. After all the participants of the first stage will complete Part 2, and the results are analyzed, based on the first stage outcomes the study will be either terminated or will proceed to the second stage, which will be conducted using the same study method as in the first stage. Potentially, up to 30 volunteers will participate in the second stage. A total number of participants in Part 2 will be up to 64. Volunteers assigned to Treatment Sequence 1 will receive 10 mg of dapagliflozin once daily for 4 consecutive days (Period 1), and after a 12- to 14-day washout period (with no medication), 300 mg of canagliflozin once daily for 4 days (Period 2). Volunteers assigned to Treatment Sequence 2 will receive 300 mg of canagliflozin once daily for 4 days (Period 1), and after a 12- to 14-day washout period, 10 mg of dapagliflozin once daily for 4 consecutive days (Period 2). The total study duration for each volunteer in Part 2 will be up to approximately 65 days (including a screening phase, a baseline phase, a double-blind treatment phase, a washout period, and a follow-up phase). Volunteers can participate in Part 1 or Part 2 of the study, but not in both parts. Canagliflozin and dapagliflozin are used for the treatment of type 2 diabetes mellitus.

Official Title
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A Double-Blind, Randomized, 2-Way Crossover Study to Compare the Pharmacodynamics of Canagliflozin 300 mg Versus Dapagliflozin 10 mg in Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: Canagliflozin
* Drug: Dapagliflozin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Volunteers must have a body mass index (BMI = weight in kg/height in m2) between 20 and 27 kg/m2 (inclusive), and body weight >= 50 kg at Screening Volunteers must have a systolic blood pressure between 90 and 140 mmHg, inclusive, and a diastolic blood pressure no higher than 90 mmHg (based upon an average of 3 blood pressure readings at Screening) Volunteers must be non-smokers Exclusion Criteria: Major surgery (eg, requiring general anesthesia) within 12 weeks before Screening, or planned during participation in the study, or within 2 weeks after the last dose of study drug administration, or volunteer will not have fully recovered from surgery during participation in the study; volunteers with planned surgical procedures to be conducted under local anesthesia may participate History of hepatitis B surface antigen (HBsAg) or hepatitis C antibody (anti-HCV) positive, or other clinically active liver disease, or tests positive for HBsAg or anti-HCV at Screening History of human immunodeficiency virus (HIV) antibody positive, or tests positive for HIV at Screening History of, or currently active illness, considered to be clinically significant by the Investigator or any other illness that the Investigator considers should exclude the volunteer from the study or that could interfere with the interpretation of the study results

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Cana<br>Each volunteer will receive 300 mg of canagliflozin once daily for 4 days. | Drug: Canagliflozin<br>* One 300 mg over-encapsulated tablet taken orally (by mouth) once daily for 4 days during Part 1 and Part 2 (Sequence 1 [treatment period 2] or Sequence 2 [treatment period 1]).<br>* Other names: Invokana;|
| Experimental: Part 2: Sequence 1 (Dapa/Cana)<br>Each volunteer will receive 10 mg of dapagliflozin once daily for 4 days (treatment period 1) followed by 300 mg of canagliflozin once daily for 4 days (treatment period 2). Each treatment period will be separated by a 12- to 14-day washout period (with no medication). | Drug: Canagliflozin<br>* One 300 mg over-encapsulated tablet taken orally (by mouth) once daily for 4 days during Part 1 and Part 2 (Sequence 1 [treatment period 2] or Sequence 2 [treatment period 1]).<br>* Other names: Invokana;Drug: Dapagliflozin<br>* One 10 mg over-encapsulated tablet taken orally once daily for 4 days during Part 2 (Sequence 1 [treatment period 1] or Sequence 2 [treatment period 2]).<br>* Other names: Forxiga;|
| Experimental: Part 2: Sequence 2 (Cana/Dapa)<br>Each volunteer will receive 300 mg of canagliflozin once daily for 4 days (treatment period 1) followed by 10 mg of dapagliflozin once daily for 4 days (treatment period 2). Each treatment period will be separated by a 12- to 14-day washout period. | Drug: Canagliflozin<br>* One 300 mg over-encapsulated tablet taken orally (by mouth) once daily for 4 days during Part 1 and Part 2 (Sequence 1 [treatment period 2] or Sequence 2 [treatment period 1]).<br>* Other names: Invokana;Drug: Dapagliflozin<br>* One 10 mg over-encapsulated tablet taken orally once daily for 4 days during Part 2 (Sequence 1 [treatment period 1] or Sequence 2 [treatment period 2]).<br>* Other names: Forxiga;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Between treatment difference in 24-hour mean renal threshold for glucose for canagliflozin (300 mg once daily for 4 days) compared to dapagliflozin (10 mg once daily for 4 days) | Renal threshold is defined as the plasma glucose concentration above which glucose is excreted in the urine. | Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change from baseline in postprandial glucose area under the curve at 0-2 hours post-dose on Day 4 following 300 mg of canagliflozin once daily for 4 days or 10 mg of dapagliflozin once daily for 4 days | Area under the concentration time curve (or area under the curve) is a measure of the body's exposure to glucose over a specific time period. | Day -10 (Baseline) and Day 4 | 
| Number of volunteers with adverse events | Adverse events will be used as a measure of safety and tolerability | Up to Day 65 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy, Canagliflozin, INVOKANA, Dapagliflozin, FORXIGA, Pharmacodynamics