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 is an interventional basic science trial for Healthy Subjects focused on measuring ASP8232, Multiple doses, Phase 1, Single dose Read More

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.