Clinical trial NCT02367872: Phase I Open-label Study to Evaluate Pharmacokinetics of TAK-272 in Participants With Renal or Hepatic Impairment
Official title: Phase I Open-label, Parallel-group, Comparative Study to Evaluate the Effects of Renal or Hepatic Impairment on TAK-272 Pharmacokinetics With a Single Oral Administration of TAK-272 in Patients With Renal or Hepatic Impairment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Renal Impairment
Hepatic Impairment
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2015-02-20
Enrollment: 48
Sex: ALL
Minimum age (years): 20
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to examine the effects of renal and hepatic impairment on TAK-272 pharmacokinetics with a single oral administration of TAK-272 in participants with renal or hepatic impairment.

Detailed description: This study is a phase I, open-label, parallel-group, comparative study to evaluate the effects of renal or hepatic impairment on pharmacokinetics of TAK-272 with a single oral administration of TAK-272 in participants with renal or hepatic impairment as compared with participants with normal renal and hepatic function.

Eligibility criteria: Inclusion Criteria:

All participants

1. In the opinion of the investigator or subinvestigator, the participant is capable of understanding and complying with protocol requirements.
2. Signs and dates a written, informed consent form prior to the initiation of any study procedures.
3. Is either male or female and aged 20 to 85 years, inclusive, at the time of informed consent.
4. Weighs at least 45 kilogram (kg) for males and 40 kg for females and have a body mass index (BMI) of less than (\<) 35.0 kilogram per square meter (kg/m\^2) at screening and Day 1.
5. A male participant who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent until 12 weeks after study drug administration.
6. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to routinely use adequate contraception from signing of informed consent until 1 month after the completion of the study.

   Participants with normal renal or hepatic function (Cohorts 1R and 1H)
7. Estimated glomerular filtration rate (eGFR) is greater than or equal to (\>=) 90 milliliter per minute per 1.73 square meter (mL/min/1.73 m\^2) at screening.
8. Based on the participant's medical history, clinical laboratory values, and physical examination findings, the investigator or subinvestigator judges the participant to be in good health (hypertension, type 2 diabetes, and hypercholesteremia or dyslipidemia are controlled, if present).
9. Is within +/-10 years of the mean age and +/-20 percent (%) of the mean weight for the 24 participants with renal impairment and 12 participants with hepatic impairment administered the study drug.

   Participants with renal impairment (Cohorts 2R, 3R, 4R, 5R)
10. Falls into any of the following categories:

    * With mild renal impairment (Cohort 2R): eGFR \>=60 mL/min/1.73 m\^2 and \<90 mL/min/1.73 m\^2 at screening.
    * With moderate renal impairment (Cohort 3R): eGFR \>=30 mL/min/1.73 m\^2 and \<60 mL/min/1.73 m\^2 at screening.
    * With severe renal impairment or end-stage renal failure (non-hemodialysis participants) (Cohort 4R): eGFR \<30 mL/min/1.73 m\^2 at screening.
    * Hemodialysis participants (Cohort 5R): with end-stage renal failure and little or no urine output who are undergoing hemodialysis 3 times weekly.
11. For non-hemodialysis participants, difference in eGFR obtained between 3 months and 7 days before screening from eGFR at screening is less than or equal to (\<=) 30%.

    Participants with hepatic impairment (Cohorts 2H, 3H)
12. In observations during the screening period, those diagnosed with hepatic impairment corresponding to any of the following Child-Pugh classes:

    * With mild hepatic impairment (Cohort 2H): Child-Pugh class A.
    * With moderate hepatic impairment (Cohort 3H): Child-Pugh class B.
13. Is diagnosed by the investigator or subinvestigator with hepatic impairment that has remained stable during the 3 months before screening.

Exclusion Criteria:

All participants

1. Has received any investigational product within 16 weeks (112 days) prior to the start of study drug administration.
2. Has received TAK-272 in a previous clinical study.
3. Is an immediate family member, study site employee, or in a dependent relationship with a study site employee who is involved in the conduct of this study (example, spouse, parent, child, sibling) or may consent under duress.
4. Has a history of cancer. This does not include individuals who have been in remission for at least 1 year prior to the start of screening and who are judged by the investigator or subinvestigator to have had no recurrence during the study.
5. Has a known hypersensitivity or allergy to any component of the TAK-272 formulation or renin inhibitors.
6. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 1 year prior to the screening visit or is unwilling to agree to abstain from alcohol and drugs throughout the study.
7. Has any positive urine drug test result at screening (including test for alcohol) if a non-hemodialysis participant.
8. Has taken any excluded medication or food product listed in the Excluded Medications and Dietary Products section during the period in which excluded medication use is prohibited, or needs to take any excluded medication or food product during the study.
9. Previously has undergone kidney or liver transplantation.
10. Has poor peripheral venous access.
11. Has undergone whole blood collection of 800 milliliter (mL) or more within 52 weeks (364 days) prior to the start of study drug administration.
12. Has undergone whole blood collection of 200 mL or more within 4 weeks (28 days) or 400 mL or more within 12 weeks (84 days) for males and 16 weeks (112 days) for females prior to the start of study drug administration.
13. Has undergone blood component collection within 2 weeks (14 days) prior to the start of study drug administration.
14. Has onset of myocardial infarction or coronary revascularization within 6 months before screening.
15. Has a history of abdominal surgery (excluding laparoscopic cholecystectomy or appendectomy without complications) or chest or non-peripheral vascular surgery within 6 months before screening.
16. Has onset of acute disease (example, renal and urinary tract disease) within 30 days before screening.
17. Has clinically significant abnormal electrocardiogram (ECG) in the screening period or the pretreatment examination.
18. Has clinically significant hyperkalemia.
19. If female, the participant is pregnant or lactating or intending to become pregnant before, during or within 1 month after participating in this study, or intending to donate ova during such time period.
20. If male, the participant intends to donate sperm during the course of this study or for 12 weeks thereafter.
21. In the opinion of the investigator or subinvestigator, is unlikely to comply with protocol or is unsuitable for any other reason.

    Participants with normal renal and hepatic function (Cohorts 1R and 1H)
22. Has uncontrolled, clinically significant hepatic, renal, neurologic, cardiovascular, blood, pulmonary, metabolic, gastrointestinal, urologic or endocrine disease, immune disease, infection or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results.
23. Has clinical laboratory results at screening suggestive of a clinically significant underlying disease other than controlled hypertension, type 2 diabetes, hypercholesteremia, or dyslipidemia.
24. Systolic blood pressure is \<80 millimeter of mercury (mmHg) at screening, in the pretreatment examination, or in the examination prior to the start of study drug administration and has repeated instances of the findings listed below, suggesting the presence of hypotension:

    - Dizziness postural, facial pallor, cold sweats.
25. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is \>2.0 times higher than the upper limit of normal at screening.
26. Has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antigen/antibody, or serological reactions for syphilis at screening.

    Participants with renal impairment (Cohorts 2R, 3R, 4R, 5R)
27. Has uncontrolled, clinically significant hepatic, neurologic, cardiovascular, blood, pulmonary, metabolic, gastrointestinal, urologic or endocrine disease, immune disease, infection or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results.
28. Sitting systolic blood pressure is \<110 mmHg at screening, in the pretreatment examination, or in the examination before administration on Day 1.
29. ALT or AST is \>2.0 times higher than the upper limit of normal at screening.
30. Has a positive test result for HBsAg, HCV antibody, HIV antigen/antibody, or serological reactions for syphilis at screening.

    Participants with hepatic impairment (Cohorts 2H, 3H)
31. Has uncontrolled, clinically significant renal, neurologic, cardiovascular, blood, pulmonary, metabolic, gastrointestinal, urologic or endocrine disease, immune disease, infection or other abnormality, which may impact the ability of the participant to participate or potentially confound the study results.
32. Has ascites requiring invasive treatment.
33. Systolic blood pressure is \<80 mmHg at screening, in the pretreatment examination, or in the examination prior to the start of study drug administration and has repeated instances of the findings listed below, suggesting the presence of hypotension:

    - Dizziness postural, facial pallor, cold sweats.
34. eGFR is \<60 mL/min/1.73 m\^2 at screening.
35. Has a positive test result for HIV antigen/antibody or the participant has a positive test result for serological reactions for syphilis and syphilis is judged not to have been cured at screening.

Primary outcomes:
measure: AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Free Form of TAK-272 (TAK-272F) and Its Metabolite M-I
timeFrame: Day 1: Pre-dose and at multiple time points (0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 hours post dose; up to 120 hours) post-dose
measure: Cmax: Maximum Observed Plasma Concentration for TAK-272F and Its Metabolite M-I
timeFrame: Day 1: Pre-dose and at multiple time points (0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 hours post dose; up to 120 hours) post-dose
measure: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-272F and Its Metabolite M-I
timeFrame: Day 1: Pre-dose and at multiple time points (0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 hours post dose; up to 120 hours) post-dose
measure: AUClast,u: Area Under the Unbound Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration for TAK-272F
timeFrame: Day 1: Pre-dose and at multiple time points (0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 hours post dose; up to 120 hours) post-dose
measure: Cmax,u: Maximum Unbound Plasma Concentration for TAK-272F
timeFrame: Day 1: Pre-dose and at multiple time points (0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 hours post dose; up to 120 hours) post-dose
measure: AUC∞,u: Area Under the Unbound Plasma Concentration-time Curve From Time 0 to Infinity for TAK-272F
timeFrame: Day 1: Pre-dose and at multiple time points (0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 hours post dose; up to 120 hours) post-dose
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-272F and Its Metabolite M-I
timeFrame: Day 1: Pre-dose and at multiple time points (0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 hours post dose; up to 120 hours) post-dose
measure: Apparent Clearance (CL/F) for TAK-272F
timeFrame: Day 1: Pre-dose and at multiple time points (0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 hours post dose; up to 120 hours) post-dose
measure: CLu/F: Apparent Clearance for Unbound Drug After Extravascular Administration for TAK-272F
timeFrame: Day 1: Pre-dose and at multiple time points (0.5, 1, 1.5, 2, 3, 4, 5, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 hours post dose; up to 120 hours) post-dose
measure: Cumulative Urinary Excretion Ratio of TAK-272F and Its Metabolite M-I From 0 to 72 Hours Post-dose in Cohorts 1R, 2R, 3R, 4R, 1H, 2H and 3H
timeFrame: Day 1: Pre-dose and at multiple time points (4, 8, 12, 24, 36, 48, 72 hours post dose; up to 72 hours) post-dose
measure: Plasma Protein Binding Rate of TAK-272F in Cohorts 1R, 2R, 3R, 4R, 5R, 1H, 2H and 3H
timeFrame: Baseline
measure: Excretion Ratio of TAK-272F in Dialysate in Cohort 5R
timeFrame: Day 1: Pre-dose, up to 6 hours post-dose
Secondary outcomes:
measure: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE)
timeFrame: Baseline up to Day 8 of each Cohort
measure: Number of Participants With TEAE Related to Vital Signs
timeFrame: Baseline up to Day 8 of each Cohort
measure: Number of Participants With TEAE Related to Body Weight
timeFrame: Baseline up to Day 8 of each Cohort
measure: Number of Participants With TEAE Related to 12-lead Electrocardiograms (ECG)
timeFrame: Baseline up to Day 8 of each Cohort
measure: Number of Participants With TEAE Related to Laboratory Tests
timeFrame: Baseline up to Day 8 of each Cohort
Other outcomes:
Locations:
city: Kurume
country: Japan
state: Fukuoka
city: Moriya
country: Japan
state: Ibaragi
city: Sagamihara
country: Japan
state: Kanagawa
city: Shinagawa
country: Japan
state: Tokyo
Study officials:
affiliation: Takeda
name: General Manager
role: STUDY_DIRECTOR
References:
citation: Shimasaki Y, Sakaki M, Itou M, Kobayashi T, Aso M, Kagawa T, Saiki T, Matsuno K, Sano Y, Shimizu K, Kuroda S, Koumura E. Pharmacokinetics and Safety After a Single Dose of Imarikiren in Subjects with Renal or Hepatic Impairment. Clin Drug Investig. 2018 Nov;38(11):1041-1051. doi: 10.1007/s40261-018-0695-4.