Phase I Open-label Study to Evaluate Pharmacokinetics of TAK-272 in Participants With Renal or Hepatic Impairment

Hepatic Impairment Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02367872
• Other study ID #: TAK-272/CPH-012
• Secondary ID: U1111-1166-3774J
• Status: Completed
• Phase: Phase 1
• First received: February 13, 2015
• Last updated: October 2, 2017
• Start date: March 2015
• Est. completion date: June 2016

Study information

• Verified date: October 2017
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 48
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Hepatic Impairment
• Liver Diseases
• Renal Impairment
• Renal Insufficiency

Intervention

Drug:
• TAK-272
TAK-272 tablet

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Takeda

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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		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
Primary	Cmax: Maximum Observed Plasma Concentration for TAK-272F and Its Metabolite M-I		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
Primary	AUC8: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-272F and Its Metabolite M-I		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
Primary	AUClast,u: Area Under the Unbound Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration for TAK-272F	AUClast,u is the area under the concentration-time curve of the unbound drug in plasma over the time interval from 0 to time of last quantifiable post-dose of TAK-272.	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
Primary	Cmax,u: Maximum Unbound Plasma Concentration for TAK-272F	Cmax,u is the peak unbound plasma concentration of a drug after administration, obtained directly from the unbound plasma concentration-time curve.	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
Primary	AUC8,u: Area Under the Unbound Plasma Concentration-time Curve From Time 0 to Infinity for TAK-272F	AUC8,u is the area under the concentration-time curve of the unbound drug in plasma over the time interval from 0 to infinity of TAK-272.	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
Primary	Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-272F and Its Metabolite M-I		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
Primary	Apparent Clearance (CL/F) for TAK-272F		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
Primary	CLu/F: Apparent Clearance for Unbound Drug After Extravascular Administration for TAK-272F	CLu/F is the apparent clearance for unbound drug after extravascular administration of TAK-272.	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
Primary	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	Urinary excretion ratio (percentage [%] of dose) of TAK-272 and its metabolite M-I in urine was calculated for each participant.	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
Primary	Plasma Protein Binding Rate of TAK-272F in Cohorts 1R, 2R, 3R, 4R, 5R, 1H, 2H and 3H	Plasma protein binding rate was the percentage of unbound fraction of TAK-272F in plasma protein.	Baseline
Primary	Excretion Ratio of TAK-272F in Dialysate in Cohort 5R	Excretion ratio (% of dose) of TAK-272F in dialysis fluid was calculated for each participant.	Day 1: Pre-dose, up to 6 hours post-dose
Secondary	Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE)		Baseline up to Day 8 of each Cohort
Secondary	Number of Participants With TEAE Related to Vital Signs	Number of participants with TEAE related to vital signs was reported in this outcome measure. The related event to report was only "Blood Pressure Decreased" throughout this study.	Baseline up to Day 8 of each Cohort
Secondary	Number of Participants With TEAE Related to Body Weight	Number of participants with TEAE related to body weight was reported in this outcome measure. There were no events to report as TEAE related to body weight throughout this study.	Baseline up to Day 8 of each Cohort
Secondary	Number of Participants With TEAE Related to 12-lead Electrocardiograms (ECG)	Number of participants with TEAE related to ECG was reported in this outcome measure. There were no events to report as TEAE related to ECG throughout this study.	Baseline up to Day 8 of each Cohort
Secondary	Number of Participants With TEAE Related to Laboratory Tests	Number of participants with TEAE related to laboratory tests was reported in this outcome measure. The related event to report was only "Alanine Aminotransferase Increased" throughout this study.	Baseline up to Day 8 of each Cohort