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
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
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).
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.
Main Inclusion: Part 1

 -  Independent Ethics Committee (IEC)-approved written Informed Consent and privacy
 language as per national regulations must be obtained from the subject or legally
 authorized representative prior to any study-related procedures (including withdrawal
 of prohibited medication, if applicable).

 -  Male subject and his female spouse/partner who is of childbearing potential must be
 using highly effective contraception consisting of 2 forms of birth control (1 of
 which must be a barrier method) starting at screening and continue throughout the
 study period and for 28 days (or 5 half-lives of the study drug whichever is longer)
 after final study drug administration.

 -  Male subject must not donate sperm starting at screening and throughout the study
 period and for at least 90 days after final study drug administration.

 -  Female subject must be either:

 -  post-menopausal (defined as at least one year without any menses) prior to
 screening, or

 -  premenarchal prior to screening, or

 -  documented surgically sterile or status post hysterectomy (at least 1 month
 before screening), or

 -  if of childbearing potential, must have a negative urine pregnancy test at
 screening and must be using highly effective contraception. All females of
 childbearing potential will be required to use highly effective contraception
 consisting of 2 forms of birth control (1 of which must be a barrier method)
 starting at screening and throughout the study period and for 28 days (or 5
 half-lives of the study drug whichever is longer) after final study drug
 administration.

 -  Female subject must not be lactating, and must not be breast feeding at screening or
 during the study period and for 28 days [or 5 half-lives of the study drug whichever
 is longer] after final study drug administration.

 -  Female subject must not donate ova starting at screening and throughout the study
 period and for 28 days [or 5 half-lives of the study drug whichever is longer] after
 final study drug administration.

 -  Subject agrees not to participate in another interventional study while on treatment.

 Healthy Subjects:

 -  Subject must have pre dose eGFR values (based on the MDRD method) at screening and day
 -1 higher or equal to 80 mL/min/1.73 m2.

 Renal Impaired Subjects:

 -  Subject must have pre dose eGFR values (based on the MDRD method) at screening and day
 -1 of 15 to < 30 mL/min/1.73 m2, 30 to

 < 60 mL/min/1.73 m2 or 60 to < 80 mL/min/1.73 m2 for severe, moderate or mild renal
 impaired subjects, respectively.

 Part 2 Inclusion:

 -  Independent Ethics Committee (IEC)-approved written Informed Consent and privacy
 language as per national regulations must be obtained from the subject or legally
 authorized representative prior to any study-related procedures (including withdrawal
 of prohibited medication, if applicable).

 -  Subject has either known or confirmed T2DM with CKD for at least 1 year [screening].

 -  Subject is ≥ 35 and ≤ 80 years of age.

 -  Male subject and his female spouse/partner who is of childbearing potential must be
 using highly effective contraception consisting of 2 forms of birth control (1 of
 which must be a barrier method) starting at screening and continue throughout the
 study period and for 28 days (or 5 half-lives of the study drug whichever is longer)
 after final study drug administration.

 -  Male subject must not donate sperm starting at screening and throughout the study
 period and for at least 90 days after final study drug administration.

 -  Female subject must be either

 -  post-menopausal (defined as at least one year without any menses) prior to
 Screening, or

 -  premenarchal prior to screening, or

 -  documented surgically sterile or status post hysterectomy (at least 1 month
 before screening), or

 -  if of childbearing potential, must have a negative urine pregnancy test at
 screening and must be using highly effective contraception1. All females of
 childbearing potential will be required to use highly effective contraception
 consisting of 2 forms of birth control (1 of which must be a barrier method)
 starting at screening and throughout the study period and for 28 days (or 5
 half-lives of the study drug whichever is longer) after final study drug
 administration.

 -  Female subject must not be lactating, and must not be breast feeding at screening or
 during the study period and for 28 days (or 5 half-lives of the study drug whichever
 is longer) after final study drug administration.

 -  Female subject must not donate ova starting at screening and throughout the study
 period and for 28 days (or 5 half-lives of the study drug whichever is longer] after
 final study drug administration.

 -  Subject is on a stable therapy with ACE inhibitors or ARB for at least 3 months
 [screening].

 -  Subject is on a stable anti-hyperglycaemia therapy, e.g. with Metformin, SUD, TZD or
 DPP-4 inhibitor.

 -  Subject's eGFR is between 15-60 mL/min/1.73 m2 (based on the MDRD method).

 -  Subject's HbA1c level is lower than 7.5% at clinic admission on day -2.

 -  Subject has a stable blood pressure for at least 3 to 6 months prior to enrolment.

 -  Subject's UACR is higher than 30 mg/g at clinic admission on day -2.

 Part 1 Exclusion:

 All Subjects:

 -  Female subject who has been pregnant within 6 months before screening or breast
 feeding within 3 months before screening.

 -  Subject has a known or suspected hypersensitivity to ASP8232, or any components of the
 formulation used.

 -  Subject has any clinically significant history of allergic conditions (including drug
 allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated,
 asymptomatic, seasonal allergies at time of dosing).

 -  Subject has Gilbert's syndrome.

 -  Subject has/had febrile illness or symptomatic, viral, bacterial (including upper
 respiratory infection), or fungal (non-cutaneous) infection within 1 week prior to
 clinic check in.

 -  Subject has a history of smoking more than 10 cigarettes (or equivalent amount of
 tobacco) per day within 3 months prior to admission to the Clinical Unit.

 -  Subject has a history of drinking more than 21 units of alcohol per week (1 unit = 10
 g pure alcohol = 250 mL of beer [5%] or 35 mL of spirits [35%] or 100 mL of wine
 [12%]) (> 14 units of alcohol for female subjects) within 3 months prior to admission
 to the Clinical Unit.

 -  Subject uses drugs of abuse within 3 months prior to admission to the Clinical Unit.

 -  Subject regularly uses any inducer of metabolism (e.g. barbiturates, rifampin ) in the
 3 months prior to admission to the Clinical Unit.

 -  Subject had any significant blood loss, donated one unit (450 mL) of blood or more, or
 received a transfusion of any blood or blood products within 60 days or donated plasma
 within 7 days prior to clinic admission on day -1.

 -  Subject has positive serology test for Hepatitis B Surface Antigen (HBsAg),
 anti-Hepatitis A virus (anti-HAV [IgM]), anti-Hepatitis C virus (anti-HCV) or anti-
 Human immunodeficiency virus 1 + 2 (anti-HIV 1+2).

 -  Subject participated in any interventional clinical study or has been treated with any
 investigational drugs within 30 days or 5 half-lives whichever is longer, prior to the
 initiation of screening.

 -  Subject is an employee of the Astellas Group or Clinical Research Organization (CRO)
 involved in the study.

 Healthy Subjects:

 -  Subject has any of the liver function tests (Alanine Aminotransferase [ALT], Aspartate
 Aminotransferase [AST], total bilirubin [TBL]) above the upper limit of normal. In
 such a case the assessment may be repeated once [day -1].

 -  Subject has a mean QTc(F) interval of > 430 ms (for males) and > 450 ms (for females)
 at screening and day -1. If the mean QTc(F) exceeds the limits above, one additional
 triplicate electrocardiogram (ECG) can be taken. If this triplicate also gives
 abnormal result the subject should be excluded.

 -  Subject uses any prescribed or non-prescribed drugs (including vitamins, hormone
 replacement therapy, natural and herbal remedies, e.g. St. John's Wort) in the 2 weeks
 prior to study drug administration, except for occasional use of paracetamol (up to 2
 g/day).

 Renal Impaired Subjects:

 -  Subject is on or requires hemodialysis or has received a kidney transplantation.

 -  Subject has a supine mean systolic blood pressure < 90 or > 160 mmHg and a mean
 diastolic blood pressure < 50 or > 100 mmHg, or pulse rate < 40 or > 90 beats p/m, on
 screening and day -1. In such a case the assessment may be repeated once (day -1).

 -  Subject has a mean QTc(F) interval of > 450 ms (for males) and > 470 ms (for females)
 at screening and day -1. If the mean QTc(F) exceeds the limits above, one additional
 triplicate ECG can be taken. If this triplicate also gives abnormal result the subject
 should be excluded.

 -  Subject has not been on a stable dose of allowed concomitant medications for at least
 2 weeks prior to day 1 and/or for whom dose changes are likely to occur during the
 study.

 -  Subject requires or is likely to require any new concomitant medications during the
 course of the study.

 -  Subject has obstructive uropathy or other causes of renal impairment not related to
 parenchymal renal disorder and/or disease of the kidney.

 -  Subject has renal disease secondary to malignancy.

 -  Subject has a fluctuating or rapidly deteriorating renal function within 4 weeks prior
 to screening, as indicated by strongly varying or worsening of clinical and/or
 laboratory signs of renal impairment within the screening period.

 -  Subject has any of the liver function tests (ALT, AST, TBL) out of range. In such a
 case the assessment may be repeated once [day -1].

 -  ALT or AST > 2 x upper limit of normal (ULN)

 -  TBL > 1.5 x ULN

 Part 2 Exclusion

 -  Female subject who has been pregnant within 6 months prior to screening assessment or
 breast feeding within 3 months prior to screening.

 -  Subject has known or suspected hypersensitivity to ASP8232 or sinistrin, or any
 components of the formulation used.

 -  Subject has participated in part 1 of the 8232-CL-0002 study.

 -  Subject has a mean QTc(F) interval of > 450 ms (for males) and > 470 ms (for females)
 at screening and day -2. If the mean QTc(F) exceeds the limits above, one additional
 triplicate ECG can be taken. If this triplicate also gives abnormal result the subject
 should be excluded.

 -  Subject has a pulse < 40 or > 90 bpm; mean systolic blood pressure >140 mmHg; mean
 diastolic blood pressure > 90 mmHg (measurements taken in triplicate after subject has
 been resting in supine position for 5 min; pulse will be measured automatically) at
 screening and day -2. In such a case the assessment may be repeated once [day -2].

 -  Subject is on or requires hemodialysis or has received a kidney transplantation.

 -  Subject has not been on a stable dose of allowed concomitant medications for at least
 2 weeks prior to day 1 and/or for whom dose changes are likely to occur during the
 study.

 -  Subject who requires or is likely to require any new concomitant medications during
 the course of the study.

 -  Subject who has obstructive uropathy or other causes of renal impairment not related
 to parenchymal renal disorder and/or disease of the kidney.

 -  Subject who has renal disease secondary to malignancy.

 -  Subject who has a fluctuating or rapidly deteriorating renal function within 4 weeks
 prior to the study, as indicated by strongly varying or worsening of clinical and/or
 laboratory signs of renal impairment within the screening period.

 -  Subject has type 1 diabetes mellitus.

 -  Subject with any of the liver function tests (ALT, AST, TBL) out of range as indicated
 below. In such a case the assessment may be repeated once [day -2].

 -  ALT or AST > 2 x ULN

 -  Total bilirubin > 1.5 x ULN

 -  Subject has had myocardial infarct or stroke within 6 months prior to screening.

 -  The subject has Gilbert's Syndrome.

 -  Subject has any clinically significant history of allergic conditions (including drug
 allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated,
 asymptomatic, seasonal allergies at time of dosing).

 -  The subject has/had febrile illness or symptomatic, viral, bacterial (including upper
 respiratory infection), or fungal (non-cutaneous) infection within one week prior to
 clinic admission on day -2.

 -  Subject has a history of drinking more than 21 units of alcohol per week (1 unit = 10
 g pure alcohol = 250 mL of beer [5%] or 35 mL of spirits [35%] or 100 mL of wine
 [12%]) (> 14 units of alcohol for female subjects) within 3 months prior to admission
 to the Clinical Unit.

 -  Subject uses of drugs of abuse within 3 months prior to admission to the Clinical
 Unit.

 -  Subject regularly uses any inducer of metabolism (e.g. barbiturates, rifampin) in the
 3 months prior to admission to the Clinical Unit.

 -  Subject had any significant blood loss, donated one unit (450 mL) of blood or more, or
 received a transfusion of any blood or blood products within 60 days or donated plasma
 within 7 days prior to clinic admission on day -2.

 -  Subject has positive serology test for HBsAg, anti HAV (IgM), anti-HCV or anti-HIV
 1+2.

 -  Subject participated in any interventional clinical study or has been treated with any
 investigational drugs within 30 days or 5 half-lives whichever is longer, prior to the
 initiation of screening.

 -  Subject is employee of the Astellas Group or CRO involved in the study.