Clinical trial NCT02218099: 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
Official title: A Phase 1 Study to Evaluate the Effect of Renal Impairment on the Pharmacokinetics, Pharmacodynamics and Safety of ASP8232 (Part 1) and a Multiple Dose, Placebo-controlled Exploratory Safety, Pharmacokinetic and Pharmacodynamic Study in Type 2 Diabetes Mellitus Subjects With Chronic Kidney Disease (Part 2)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Healthy Subjects
Pharmacokinetics of ASP8232
Pharmacodynamics of ASP8232
Chronic Kidney Disease (CKD)
Type 2 Diabetes Mellitus (T2DM)
Keywords: ASP8232
Multiple doses
Phase 1
Single dose
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2014-08-15
Enrollment: 55
Sex: ALL
Minimum age (years): 35
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: Day 1 to Day 56
measure: Part 1: PK of ASP8232 in plasma measured by AUC from zero up to last time point of observation (AUClast)
timeFrame: Day 1 to Day 56
measure: Part 1: PK of ASP8232 in plasma measured by AUC from zero up to last time point of observation, unbound fraction (AUClast,u)
timeFrame: Day 1 to Day 56
measure: Part 1: PK of ASP8232 in plasma measured by AUC from 0 to infinity with extrapolation of the terminal phase, unbound fraction (AUCinf,u)
timeFrame: Day 1 to Day 56
measure: Part 1: PK of ASP8232 in plasma measured by maximum concentration (Cmax)
timeFrame: Day 1 to Day 56
measure: Part 1: PK of ASP8232 in plasma measured by maximum concentration, unbound fraction (Cmax,u)
timeFrame: Day 1 to Day 56
measure: Part 2: Safety and tolerability of ASP8232 measured by nature, frequency and severity of AEs, vital signs, safety laboratory tests, routine ECG
timeFrame: Screening to End of Study Visit (ESV)
Secondary outcomes:
measure: Part 1: PK profile of ASP8232 in plasma
timeFrame: Day 1 to Day 56
measure: Part 1: PK profile of ASP8232 in urine
timeFrame: Day -1 to Day 8
measure: Part 1: PD of Vascular adhesion protein-1 (VAP-1) activity in plasma
timeFrame: Day -1 to Day 56
measure: Part 1: PD of Total antioxidant status (TAS) in serum
timeFrame: Day -1 to Day 56
measure: Part 1: Safety and tolerability of ASP8232
timeFrame: Screening to Day 56
measure: Part 2: PK profile of ASP8232 in plasma
timeFrame: Day 1 to Day 29
measure: Part 2: PK profile of ASP8232 in urine
timeFrame: Day 1 to Day 8 and Day 28 to Day 29
measure: Part 2: PD of VAP-1 activity in plasma
timeFrame: Day -2 to Day 21 and Day 28 to ESV
measure: Part 2: PD of TAS in serum
timeFrame: Day -2 to Day 21 and Day 28 to ESV
measure: Part 2: 24-hour urinary albumin excretion rate (UAER)
timeFrame: Day -1, Day 7 and Day 28
Other outcomes:
Locations:
city: Sofia
country: Bulgaria
facility: Site: 35901
city: Chisinau
country: Moldova, Republic of
facility: Site: 37301
city: Bucharest
country: Romania
facility: Site: 40001
Study officials:
affiliation: Astellas Pharma Europe B.V.
name: Central contact
role: STUDY_DIRECTOR
References: