Healthy Volunteers, Hepatic Impairment
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to evaluate the effect of varying degrees of hepatic function on the single dose PK of IV TAK-954.
Detailed description
The drug being tested in this study is called TAK-954. This study will evaluate the safety and tolerability of single intravenous doses of TAK-954 in participants with varying degrees of hepatic function. The study will enroll approximately up to 32 participants. Participants will be enrolled in one of the 4 treatment groups based on their degree of hepatic impairment which will be determined based on Child-Pugh Score as follow: * Group 1 TAK-954 0.2 mg: Mild Hepatic Impairment (Child Pugh Class A) * Group 2 TAK-954 0.2 mg: Moderate Hepatic Impairment (Child Pugh Class B) * Group 3 TAK-954 0.2 mg: Severe Hepatic Impairment (Child Pugh Class C) * Group 4 TAK-954 0.2 mg: Healthy Participants The Child-Pugh classification will assess the severity of 5 hepatic parameters (total serum bilirubin, serum albumin, prothrombin time, ascites and encephalopathy grade) on a scale of 1 (none) to 3 (moderate). Total hepatic impairment score ranges from 5 (mild) to 15 (severe) where higher score indicates more severity. All participants will receive a single dose of TAK-954 0.2 mg on Day 1. This study may have a full study design, where Group 1 to Group 4 will enroll approximately 8 participants in each group or a reduced study design, where no participants will be enrolled in Group 1 and approximately 8 participants will be enrolled in Group 2 to Group 4. This multi-center trial will be conducted in Czech Republic and Slovakia. The overall time to participate in this study is approximately 7 weeks. Participants will remain confined to the clinic for 4 days, with 2 further out-patient visits, and will make a final visit to the clinic 10-14 days after receiving their last dose of TAK-954 for a follow-up assessment.
Interventions
DRUGTAK-954
TAK-954 intravenous infusion.
Sponsors
Takeda
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
1. Male and female participants (non-childbearing potential), with a body mass index (BMI) between 18 to 35 kilogram per square meter (kg/m\^2) (All participants). 2. Participants with hepatic impairment who are medically stable as determined by the investigator, based on medical history and clinical evaluations including physical examinations, clinical laboratory tests, vital sign measurements, and 12-lead ECGs performed at the Screening Visit and at check-in on Day -1 (Group 1 to 3). 3. Healthy participants (Group 4).
Exclusion criteria
Participants who have: 1. A history of hepatic carcinoma, hepatorenal syndrome, or presence of a liver mass by ultrasound, CT or MRI, or acute liver disease caused by an infection or drug toxicity (Group 1 to 3). 2. Have severe hepatic encephalopathy (\[greater than\] \> Grade II Portal Systemic Encephalopathy Score) (Group 1 to 3). 3. Surgical porto-systemic shunts, including transjugular intrahepatic portosystemic shunt (Group 1 to 3). 4. A history of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less than 1 month prior to trial entry (Group 1 to 3). 5. Bilirubin levels above 5 times the upper limit of normal (ULN) at screening or Day -1 for Groups 1 and 2, there is no limit for Group 3. 6. Severe/advanced ascites and/or pleural effusion which requires emptying and albumin supplementation, as judged by the investigator (Group 1 to 3). 7. Renal creatinine clearance (CLcr) less than or equal to (\<=) 50 milliliter per minute (mL/min), calculated using the Cockcroft-Gault equation from the serum creatinine measurement taken at screening (Group 1 to 3). 8. Who have a history of clinically significant endocrine, gastrointestinal (GI) (including motility disorder and intestinal obstruction), cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases will be excluded from the trial (Group 4).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Cmax: Maximum Observed Plasma Concentration for TAK-954 (Total and Free) | Day 1 pre-infusion and at multiple time points (up to 96 hours) post-infusion |
| AUClast: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-954 (Total and Free) | Day 1 pre-infusion and at multiple time points (up to 96 hours) post-infusion |
| AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for TAK-954 (Total and Free) | Day 1 pre-infusion and at multiple time points (up to 96 hours) post-infusion |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values | Up to 14 days after the last dose of study drug (Day 15) |
| Number of Participants With Clinically Significant Physical Examination Findings | Up to 14 days after the last dose of study drug (Day 15) |
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | Baseline up to 30 days after last dose of study drug (Day 31) |
| Number of Participants With Markedly Abnormal Electrocardiograms (ECGs) | Up to 14 days after the last dose of study drug (Day 15) |
| Number of Participants With Markedly Abnormal Values of Vital Signs | Up to 14 days after the last dose of study drug (Day 15) |
Countries
Czechia, Slovakia
Participant flow
Recruitment details
Participants took part in the study at 2 investigative sites in Czech Republic and Slovakia from 09 November 2017 to 10 September 2018.
Pre-assignment details
Participants with normal hepatic function and hepatic impairment were enrolled in 1 of the groups:B(moderate), C(severe) or D(healthy) to receive TAK-954 0.2mg. Based on available safety and PK data from Group B, participants were enrolled in reduced study design and were not enrolled in GroupA(mild). Groups A-D are equal to Groups 1-4 in protocol.
Participants by arm
| Arm | Count |
|---|---|
| Healthy Participants: TAK-954 0.2 mg TAK-954 0.2 milligram (mg), infusion, intravenously, once on Day 1. | 8 |
| Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg TAK-954 0.2 mg, infusion, intravenously, once on Day 1. | 10 |
| Group C, Severe Hepatic Impairment: TAK-954 0.2 mg TAK-954 0.2 mg, infusion, intravenously, once on Day 1. | 7 |
| Total | 25 |
Baseline characteristics
| Characteristic | Total | Healthy Participants: TAK-954 0.2 mg | Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg | Group C, Severe Hepatic Impairment: TAK-954 0.2 mg |
|---|---|---|---|---|
| Age, Continuous | 57.2 years STANDARD_DEVIATION 11.21 | 58.5 years STANDARD_DEVIATION 9.46 | 55.6 years STANDARD_DEVIATION 12.25 | 57.9 years STANDARD_DEVIATION 12.88 |
| Body Mass Index (BMI) | 29.9 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.87 | 31.1 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.18 | 30.4 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.02 | 27.9 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 6.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 25 Participants | 8 Participants | 10 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 170.8 centimeter (cm) STANDARD_DEVIATION 10.01 | 169.8 centimeter (cm) STANDARD_DEVIATION 11.3 | 168.0 centimeter (cm) STANDARD_DEVIATION 10.47 | 176.1 centimeter (cm) STANDARD_DEVIATION 6.28 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 25 Participants | 8 Participants | 10 Participants | 7 Participants |
| Region of Enrollment Czech Republic | 8 Participants | 3 Participants | 3 Participants | 2 Participants |
| Region of Enrollment Slovakia | 17 Participants | 5 Participants | 7 Participants | 5 Participants |
| Sex: Female, Male Female | 8 Participants | 3 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Male | 17 Participants | 5 Participants | 6 Participants | 6 Participants |
| Weight | 87.90 kilogram (kg) STANDARD_DEVIATION 18.667 | 89.95 kilogram (kg) STANDARD_DEVIATION 17.098 | 86.77 kilogram (kg) STANDARD_DEVIATION 19.823 | 87.19 kilogram (kg) STANDARD_DEVIATION 21.331 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 10 | 0 / 7 |
| other Total, other adverse events | 2 / 8 | 3 / 10 | 1 / 7 |
| serious Total, serious adverse events | 0 / 8 | 0 / 10 | 0 / 7 |
Outcome results
Primary
AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for TAK-954 (Total and Free)
Time frame: Day 1 pre-infusion and at multiple time points (up to 96 hours) post-infusion
Population: The PK set consisted of all participants who were enrolled and received the correct dose of study drug and had at least 1 measurable plasma concentration or amount of drug in the urine for TAK-954.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Participants: TAK-954 0.2 mg | AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for TAK-954 (Total and Free) | TAK-954 (Total) | 31.30 h*ng/mL | Geometric Coefficient of Variation 20.1 |
| Healthy Participants: TAK-954 0.2 mg | AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for TAK-954 (Total and Free) | TAK-954 (Free) | 1.643 h*ng/mL | Geometric Coefficient of Variation 13.8 |
| Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg | AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for TAK-954 (Total and Free) | TAK-954 (Total) | 25.44 h*ng/mL | Geometric Coefficient of Variation 27.1 |
| Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg | AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for TAK-954 (Total and Free) | TAK-954 (Free) | 1.875 h*ng/mL | Geometric Coefficient of Variation 24 |
| Group C, Severe Hepatic Impairment: TAK-954 0.2 mg | AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for TAK-954 (Total and Free) | TAK-954 (Total) | 22.60 h*ng/mL | Geometric Coefficient of Variation 34.3 |
| Group C, Severe Hepatic Impairment: TAK-954 0.2 mg | AUC∞: Area Under the Concentration-time Curve From Time 0 to Infinity for TAK-954 (Total and Free) | TAK-954 (Free) | 2.122 h*ng/mL | Geometric Coefficient of Variation 21.8 |
p-value: 0.138ANOVA
p-value: 0.029ANOVA
p-value: 0.201ANOVA
p-value: 0.023ANOVA
Primary
AUClast: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-954 (Total and Free)
Time frame: Day 1 pre-infusion and at multiple time points (up to 96 hours) post-infusion
Population: The PK set consisted of all participants who were enrolled and received the correct dose of study drug and had at least 1 measurable plasma concentration or amount of drug in the urine for TAK-954.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Participants: TAK-954 0.2 mg | AUClast: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-954 (Total and Free) | TAK-954 (Total) | 28.57 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 19.2 |
| Healthy Participants: TAK-954 0.2 mg | AUClast: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-954 (Total and Free) | TAK-954 (Free) | 1.501 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 12 |
| Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg | AUClast: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-954 (Total and Free) | TAK-954 (Free) | 1.737 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 23 |
| Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg | AUClast: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-954 (Total and Free) | TAK-954 (Total) | 23.57 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 26.2 |
| Group C, Severe Hepatic Impairment: TAK-954 0.2 mg | AUClast: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-954 (Total and Free) | TAK-954 (Free) | 1.898 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 19.3 |
| Group C, Severe Hepatic Impairment: TAK-954 0.2 mg | AUClast: Area Under the Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-954 (Total and Free) | TAK-954 (Total) | 20.19 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 32.7 |
p-value: 0.151ANOVA
p-value: 0.017ANOVA
p-value: 0.129ANOVA
p-value: 0.023ANOVA
Primary
Cmax: Maximum Observed Plasma Concentration for TAK-954 (Total and Free)
Time frame: Day 1 pre-infusion and at multiple time points (up to 96 hours) post-infusion
Population: The pharmacokinetic (PK) set consisted of all participants who were enrolled and received the correct dose of study drug and had at least 1 measurable plasma concentration or amount of drug in the urine for TAK-954.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Participants: TAK-954 0.2 mg | Cmax: Maximum Observed Plasma Concentration for TAK-954 (Total and Free) | TAK-954 (Total) | 2.629 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 19.1 |
| Healthy Participants: TAK-954 0.2 mg | Cmax: Maximum Observed Plasma Concentration for TAK-954 (Total and Free) | TAK-954 (Free) | 0.1381 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 15.6 |
| Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg | Cmax: Maximum Observed Plasma Concentration for TAK-954 (Total and Free) | TAK-954 (Total) | 2.440 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 25.3 |
| Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg | Cmax: Maximum Observed Plasma Concentration for TAK-954 (Total and Free) | TAK-954 (Free) | 0.1799 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 24.4 |
| Group C, Severe Hepatic Impairment: TAK-954 0.2 mg | Cmax: Maximum Observed Plasma Concentration for TAK-954 (Total and Free) | TAK-954 (Total) | 1.893 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 35.4 |
| Group C, Severe Hepatic Impairment: TAK-954 0.2 mg | Cmax: Maximum Observed Plasma Concentration for TAK-954 (Total and Free) | TAK-954 (Free) | 0.1778 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 23.1 |
p-value: 0.579ANOVA
p-value: 0.026ANOVA
p-value: 0.02ANOVA
p-value: 0.031ANOVA
Secondary
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
Time frame: Baseline up to 30 days after last dose of study drug (Day 31)
Population: The safety set consisted of all participants who were enrolled and received the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Healthy Participants: TAK-954 0.2 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 2 Participants |
| Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| Group C, Severe Hepatic Impairment: TAK-954 0.2 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 1 Participants |
Secondary
Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values
Time frame: Up to 14 days after the last dose of study drug (Day 15)
Population: The safety set consisted of all participants who were enrolled and received the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Healthy Participants: TAK-954 0.2 mg | Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values | 0 Participants |
| Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg | Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values | 0 Participants |
| Group C, Severe Hepatic Impairment: TAK-954 0.2 mg | Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Values | 0 Participants |
Secondary
Number of Participants With Clinically Significant Physical Examination Findings
Time frame: Up to 14 days after the last dose of study drug (Day 15)
Population: The safety set consisted of all participants who were enrolled and received the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Healthy Participants: TAK-954 0.2 mg | Number of Participants With Clinically Significant Physical Examination Findings | 0 Participants |
| Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg | Number of Participants With Clinically Significant Physical Examination Findings | 0 Participants |
| Group C, Severe Hepatic Impairment: TAK-954 0.2 mg | Number of Participants With Clinically Significant Physical Examination Findings | 0 Participants |
Secondary
Number of Participants With Markedly Abnormal Electrocardiograms (ECGs)
Time frame: Up to 14 days after the last dose of study drug (Day 15)
Population: The safety set consisted of all participants who were enrolled and received the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Healthy Participants: TAK-954 0.2 mg | Number of Participants With Markedly Abnormal Electrocardiograms (ECGs) | 0 Participants |
| Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg | Number of Participants With Markedly Abnormal Electrocardiograms (ECGs) | 0 Participants |
| Group C, Severe Hepatic Impairment: TAK-954 0.2 mg | Number of Participants With Markedly Abnormal Electrocardiograms (ECGs) | 2 Participants |
Secondary
Number of Participants With Markedly Abnormal Values of Vital Signs
Time frame: Up to 14 days after the last dose of study drug (Day 15)
Population: The safety set consisted of all participants who were enrolled and received the study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Healthy Participants: TAK-954 0.2 mg | Number of Participants With Markedly Abnormal Values of Vital Signs | 0 Participants |
| Group B, Moderate Hepatic Impairment: TAK-954 0.2 mg | Number of Participants With Markedly Abnormal Values of Vital Signs | 1 Participants |
| Group C, Severe Hepatic Impairment: TAK-954 0.2 mg | Number of Participants With Markedly Abnormal Values of Vital Signs | 1 Participants |