Randomized, Placebo-controlled Study to Evaluate Effects of E5555 on Renal Function Parameters and OCT2 Activity

Study Overview
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Brief Summary
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This is a drug-drug interaction study to evaluate the effects of steady-state exposure of E5555 and its main metabolites on the pharmacokinetics (PK) of metformin, an organic cation transporter-2 (OCT2) substrate. In addition, the study will also investigate the effects of E5555 on several renal function parameters.

Official Title
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A Single-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effects of Multiple Doses of E5555 on the Pharmacokinetics of Metformin (a Substrate for OCT2 Transporter) and on Renal Function in Healthy Subjects

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: E5555
* Drug: E5555


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Healthy male or female subjects aged greater than or equal to 18 years to 55 years Exclusion Criteria: History of any medical condition which will result in an increased risk of bleeding including but not limited to active or recurrent gastric ulcers, recent head trauma or surgery, severe hypertension, bacterial endocarditis, etc. Creatinine clearance < 90 mL/min as estimated using Cockcroft-Gault formula at screening or baseline History of any renal disorders, proteinuria, hepato-biliary disease.

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: Arm 1<br> | Drug: E5555<br>* Drug: Oral E5555 400 mg/matching placebo, oral metformin 500 mg, iohexal 20 mL intravenous (IV), and para-aminohippuric acid (PAH) 7 mg/kg IV.<br>|
| Experimental: Arm 2<br> | Drug: E5555<br>* Drug: Oral E5555 100 mg/matching placebo, oral metformin 500 mg, iohexal 20 mL intravenous (IV), and para-aminohippuric acid (PAH) 7 mg/kg IV bolus.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the effects of multiple doses of E5555 on single dose pharmacokinetics of metformin. |  | 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the effects of multiple doses of E5555 on the glomerular filtration rate estimated using iohexol. |  | Days 7 and 14 | 
| To assess the effects of multiple doses of E5555 on the effective renal plasma flow estimated using para-aminohippuric acid (PAH). |  | Days 7 and 14 | 
| To assess the multiple dose pharmacokinetics of E5555 and its main 6 metabolites. |  | Days 12-18 | 
| To assess the safety and tolerability of multiple doses of E5555 and a single dose of metformin either given alone or concomitantly |  | Day 1 - Day 18 |