A Study to Evaluate the Pharmacokinetics, Pharmacodynamics and Safety of ASP8232 in Subjects With Renal Impairment and in Type 2 Diabetes Mellitus Subjects With Chronic Kidney Disease

Phase 1

Completed

• Conditions: Chronic Kidney Disease (CKD); Pharmacokinetics of ASP8232; Type 2 Diabetes Mellitus (T2DM); Healthy Subjects; Pharmacodynamics of ASP8232
• Interventions: Drug: ASP8232; Drug: Placebo

• Registration Number: NCT02218099
• Lead Sponsor: Astellas Pharma Europe B.V.

Brief Summary

This study consists of two parts.

Part 1 evaluates the effect of renal impairment on the PK and PD of a single dose of ASP8232. In addition, the safety and tolerability will be assessed.

Part 2 evaluates the PK, PD, and safety and tolerability of multiple doses of ASP8232 compared with placebo in Type 2 Diabetes Mellitus (T2DM) subjects with Chronic Kidney Disease (CKD).

Detailed Description

This is a two-part study. Part 1 compares the pharmacokinetics (PK), pharmacodynamics (PD) and safety and tolerability of ASP8232 in healthy subjects with subjects with different degrees of renal impairment; Part 2 is a multiple-dose, placebo-controlled study to evaluate the PK, PD and safety and tolerability of multiple doses of ASP8232 in T2DM subjects with CKD.

Part 1:

Subjects reside in the clinic for 9 days, receiving a single oral dose of ASP8232 on Day 1 under fasted conditions followed by a 168-hours blood and urine PK/PD sampling period. Subjects are discharged on Day 8 and return to the clinic on Days 10, 12, 14, 21, 28, and 42 for the collection of blood PK/PD samples. An End of Study Visit (ESV) takes place after the last PK sample is collected on Day 56.

Part 2:

Subjects are admitted to the clinic on Day -2 in order to collect PD urine samples before dosing begins on Day 1. Subjects receive multiple oral doses of ASP8232 or placebo for 28 days. They are discharged on Day 8 and return to the clinic on Days 14 and 21, and Days 27 to 29 for blood PK/PD and urine PD samples. An ESV takes place 14 to 28 days after the last PK/PD sample is collected.

Study Timeline

• Study Start: 2013-09-16
• Study First Submitted: 2014-08-14
• Study First Submitted QC: 2014-08-14
• Study First Posted: 2014-08-15
• Primary Completion: 2014-09-09
• Study Completion: 2014-09-09
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-29
• Last Update Posted: 2024-10-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 55

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1: Single dose of ASP8232	ASP8232	Subjects receive a single oral dose of ASP8232
2: Multiple doses of ASP8232 or placebo	ASP8232	Subjects receive multiple oral doses of ASP8232 or placebo
2: Multiple doses of ASP8232 or placebo	Placebo	Subjects receive multiple oral doses of ASP8232 or placebo

Primary Outcome Measures

Name	Time	Method
Part 1: PK of ASP8232 in plasma measured by Area Under the concentration-time Curve (AUC) from zero to infinity with extrapolation of the terminal phase (AUCinf)	Day 1 to Day 56
Part 1: PK of ASP8232 in plasma measured by AUC from zero up to last time point of observation (AUClast)	Day 1 to Day 56
Part 1: PK of ASP8232 in plasma measured by AUC from 0 to infinity with extrapolation of the terminal phase, unbound fraction (AUCinf,u)	Day 1 to Day 56
Part 1: PK of ASP8232 in plasma measured by maximum concentration (Cmax)	Day 1 to Day 56
Part 1: PK of ASP8232 in plasma measured by AUC from zero up to last time point of observation, unbound fraction (AUClast,u)	Day 1 to Day 56
Part 1: PK of ASP8232 in plasma measured by maximum concentration, unbound fraction (Cmax,u)	Day 1 to Day 56
Part 2: Safety and tolerability of ASP8232 measured by nature, frequency and severity of AEs, vital signs, safety laboratory tests, routine ECG	Screening to End of Study Visit (ESV)

Secondary Outcome Measures

Name	Time	Method
Part 1: PD of Vascular adhesion protein-1 (VAP-1) activity in plasma	Day -1 to Day 56	maximum activity (Rmax), maximum activity in percent (Rmax%), time to attain maximal Response (tmax, R), average response over the first 24 h after dosing (Ravg, 0-24h)
Part 1: PD of Total antioxidant status (TAS) in serum	Day -1 to Day 56	Rmax, Rmax%, tmax, R, Ravg, 0-24h
Part 2: PD of VAP-1 activity in plasma	Day -2 to Day 21 and Day 28 to ESV	Rmax and Rmax%
Part 2: PD of TAS in serum	Day -2 to Day 21 and Day 28 to ESV	Rmax, Rmax%, tmax, R, Ravg, 0-24h
Part 1: PK profile of ASP8232 in plasma	Day 1 to Day 56	apparent total plasma clearance of drug after oral administration (CL/F), renal clearance based on unbound plasma concentrations (CLu/F), fraction unbound (fu), lag-time (time delay between drug administration and first observed concentration above LOQ in plasma) (tlag), time to reach Cmax (tmax), terminal elimination half-life (t1/2), apparent volume of distribution during terminal phase after oral administration (Vz/F), apparent volume of distribution during terminal phase after oral administration, unbound fraction (Vz,u/F)
Part 1: PK profile of ASP8232 in urine	Day -1 to Day 8	renal clearance (CLR), CLR unbound fraction (CLR,u), amount of drug excreted in urine from time point 0 to time point 24 h (Ae0-24h), percent of drug excreted in urine from time point 0 to time point 24 h (Ae0-24h%), cumulative amount of drug excreted in urine from time of dosing up to the collection time of the last measurable concentration (Aelast), percent of drug dose excreted in urine (Aelast) from time of dosing up to the collection time of the last measurable concentration (Aelast%), cumulative amount of drug excreted in urine from time of dosing extrapolated to time infinity (Aeinf), percent of drug dose excreted in urine (Aeinf) from time of dosing extrapolated to time infinity (Aeinf%)
Part 2: 24-hour urinary albumin excretion rate (UAER)	Day -1, Day 7 and Day 28
Part 1: Safety and tolerability of ASP8232	Screening to Day 56	nature, frequency and severity of Adverse Events (AEs), vital signs, safety laboratory tests, routine Electrocardiogram (ECG)
Part 2: PK profile of ASP8232 in urine	Day 1 to Day 8 and Day 28 to Day 29	amount of unchanged drug excreted in urine over a dosing interval in steady state (Aetau), amount of unchanged drug excreted in urine over a dosing interval in steady state in % (Aetau%), CLR, CLR,u
Part 2: PK profile of ASP8232 in plasma	Day 1 to Day 29	free drug fraction (fu), area under the concentration-time curve from the time of dosing to the start of the next dosing interval (AUCtau), area under the concentration-time curve during a dosing interval at steady state, unbound fraction (AUCtau,u), tmax, Cmax, Cmax,u, CL/F, CLu/F, Peak Trough Ratio (PTR), concentration immediately prior to dosing at multiple dosing (Ctrough), Ctrough, unbound (Ctrough, u)

Trial Locations

Locations (3)

Site: 35901; 🇧🇬 Sofia, Bulgaria

Site: 37301; 🇲🇩 Chisinau, Moldova, Republic of

Site: 40001; 🇷🇴 Bucharest, Romania