Hepatic Impairment, Healthy Volunteers
Conditions
Keywords
Drug Therapy
Brief summary
The main aim is to check the effect of a single dose of soticlestat in adults with moderate or mild liver failure compared to healthy adults with normal liver function. Participants will check into the study clinic for 8 days. During the stay, one oral dose of soticlestat will be given and the participant will be monitored. The clinic staff will follow up with the participant about a week after discharge from the clinic.
Detailed description
The drug being tested in this study is called soticlestat (TAK-935). The study will assess the safety and tolerability of single oral dose of soticlestat in participants with moderate or mild Hepatic Impairment (HI) compared to healthy participants matched by age (mean ±10 years), sex (±2 per sex), and body mass index (BMI, mean ±10 percent \[%\]) with normal hepatic function. The study will enroll approximately 40 participants. Participants will be assigned to following study arms: * Arm 1, Moderate HI: Soticlestat 300 milligram (mg) (Child-Pugh Class B) * Arm 2, Mild HI: Soticlestat 300 mg (Child-Pugh Class A) * Arm 3, Normal hepatic function: Soticlestat 300 mg All participants will receive single oral dose of study drug. The data will be collected and stored in electronic case report form (eCRF). This multi-center trial will be conducted in the United States and Hungary. The overall duration of the study is approximately 42 days. Participants will be followed up for 14 days after the last dose of study drug for a follow-up assessment.
Interventions
DRUGSoticlestat
Soticlestat tablets.
Sponsors
Takeda
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
A. For Participants with Hepatic Impairment 1. Has a BMI greater than or equal to (\>=) 18.0 and less than or equal to (\<=) 40.0 kilogram per square meter (kg/m\^2), at screening. At least 50% of the participants will be required to be of BMI \>=18.0 and \<=35.0 kg/m\^2, at screening. * Supine blood pressure (BP) is \>=80/40 millimeter of mercury (mmHg) (asymptomatic) and \<=150/95 mmHg at screening; * Supine pulse rate (PR) is \>=40 beats per minute (bpm) and \<=99 bpm, at screening; * QT interval corrected for heart rate using Fridericia's formula (QTcF) is \<=500 millisecond (msec) and ECG findings considered normal or not clinically significant by the Investigator or designee, at screening. 2. Must have had chronic HI for at least 3 months before screening, and the HI must be stable, that is, no significant changes in hepatic function in the 30 days preceding screening (or since the last visit if within 6 months before screening) and treatment with stable doses of medication. Has a score on the Child-Pugh Class at screening as follows: * (Arm 1) Moderate HI, Child-Pugh Class B: \>=7 and \<=9 * (Arm 2) Mild HI, Child-Pugh Class A: \>=5 and \<=6 3. Should not have renal dysfunction as demonstrated by a relatively adequate renal function (creatinine clearance \>=50 milliliter per minute \[mL/min\]), at screening. B. For Healthy Participants 1. Has a BMI \>=18.0 and \<=40.0 kg/m\^2, at screening. At least 50% of the participants will be required to be of BMI \>=18.0 and \<=35.0 kg/m\^2, at screening. Healthy participants will be matched to hepatic impaired participants in this study by age (mean ±10 years), sex (±2 per sex), and BMI, mean ±10%. * Supine BP is \>=90/40 mmHg and \<=150/95 mmHg, at screening; * Supine PR is \>=40 bpm and \<=99 bpm, at screening; * QTcF is \<=450 msec (males) or \<=470 msec (females) and ECG findings considered normal or not clinically significant by the Investigator or designee, at screening; * Liver function tests including alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin \<= the upper limit of normal (ULN) at screening and check-in. 2. Should not have renal dysfunction as demonstrated by a relatively adequate renal function (creatinine clearance \>=60 mL/min), at screening. C. For Participants with Hepatic Impairment and Healthy Participants 1\. Continuous non-smoker or moderate smoker (\<=10 cigarettes/day or the equivalent) before screening. Participant must agree to consume no more than 5 cigarettes or equivalent/day from the 7 days prior check-in and until discharge from the Clinical Research Unit (CRU).
Exclusion criteria
A. For Participants with Hepatic Impairment 1. Has history or presence of clinically significant medical or psychiatric condition or disease (aside from HI) or presence of psychotic disorders such as psychosis, delusions, or schizophrenia in the opinion of the Investigator or designee. 2. Has a history of liver or other solid organ transplant. 3. Positive result at screening for human immunodeficiency virus (HIV). Hepatitis B surface antigen (HBsAg) positive participants are allowed to be enrolled if Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is below 1000 copies per milliliter (/mL) in the plasma. Participants with moderate or mild HI who are positive for Hepatitis C virus antibodies (HCVAb) can be enrolled but must not have detectable Hepatitis C virus (HCV) ribonucleic acid (RNA) in the plasma. B. For Healthy Participants 1. Has history or presence of clinically significant medical or psychiatric condition or disease or presence of psychotic disorders such as psychosis, delusions, or schizophrenia in the opinion of the Investigator or designee. 2. Positive results at screening for HIV, HBsAg, or HCV. C. For Participants with Hepatic Impairment and Healthy Participants 1. Has been on a diet incompatible with the on-study diet, in the opinion of the Investigator or designee, within the 30 days prior to dosing. 2. Any positive responses on the Columbia-Suicide Severity Rating Scale (C-SSRS) or has a risk of suicide according to the Investigator's judgment based on the assessment of the C-SSRS at screening or check-in or has made a suicide attempt in the previous 12 months prior to dosing.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Cmax: Maximum Observed Plasma Concentration for Soticlestat | Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose |
| AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Time of Infinity for Soticlestat | Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose |
| AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Soticlestat | Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | From Day 1 up to 16 days after the last dose of study drug (up to Day 17) | An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE was defined as an AE that started or worsened at the time of or after dosing of study drug. |
Countries
Hungary, United States
Participant flow
Recruitment details
Participants took part in the study at 4 investigative sites in the United States from 29 October 2021 to 07 June 2022.
Pre-assignment details
Participants diagnosed with moderate/mild hepatic impairment (HI) compared to matched healthy participants with normal hepatic function received single dose of soticlestat. 1 with severe HI, 8 with moderate HI, 8 with mild HI and overall 19 participants with normal hepatic function (12 matched to moderate HI and 12 matched to mild HI participants) were enrolled. Five of same participants with normal hepatic function served as matched to moderate and mild HI.
Participants by arm
| Arm | Count |
|---|---|
| Severe HI: Soticlestat 300 mg Soticlestat 300 mg, tablets, orally, once on Day 1 to participants with severe HI. | 1 |
| Moderate HI: Soticlestat 300 mg Soticlestat 300 mg, tablets, orally, once on Day 1 to participant with moderate HI. | 8 |
| Mild HI: Soticlestat 300 mg Soticlestat 300 mg, tablets, orally, once on Day 1 to participant with mild HI. | 8 |
| Normal Hepatic Function: Soticlestat 300 mg Soticlestat 300 mg, tablets, orally, once on Day 1 to healthy participants. | 19 |
| Total | 36 |
Baseline characteristics
| Characteristic | Severe HI: Soticlestat 300 mg | Moderate HI: Soticlestat 300 mg | Mild HI: Soticlestat 300 mg | Normal Hepatic Function: Soticlestat 300 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 66.0 years | 59.4 years STANDARD_DEVIATION 8.52 | 56.4 years STANDARD_DEVIATION 10.03 | 58.2 years STANDARD_DEVIATION 6.6 | 58.3 years STANDARD_DEVIATION 7.74 |
| Body Mass Index (BMI) | 26.460 kilogram per square meter (kg/m^2) | 30.344 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.0131 | 30.595 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 4.9193 | 29.849 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 1.7734 | 30.031 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.1868 |
| Child-Pugh Score | 10.00 score on scale | 8.00 score on scale STANDARD_DEVIATION 0.926 | 5.50 score on scale STANDARD_DEVIATION 0.535 | — | 6.94 score on scale STANDARD_DEVIATION 1.64 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 6 Participants | 5 Participants | 11 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 2 Participants | 3 Participants | 8 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 159.0 centimeter (cm) | 166.1 centimeter (cm) STANDARD_DEVIATION 11.72 | 169.4 centimeter (cm) STANDARD_DEVIATION 13.39 | 167.5 centimeter (cm) STANDARD_DEVIATION 9.02 | 167.4 centimeter (cm) STANDARD_DEVIATION 10.41 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 5 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 7 Participants | 7 Participants | 14 Participants | 29 Participants |
| Region of Enrollment United States | 1 Participants | 8 Participants | 8 Participants | 19 Participants | 36 Participants |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 2 Participants | 11 Participants | 16 Participants |
| Sex: Female, Male Male | 1 Participants | 5 Participants | 6 Participants | 8 Participants | 20 Participants |
| Weight | 66.90 kilogram (kg) | 83.80 kilogram (kg) STANDARD_DEVIATION 14.289 | 88.51 kilogram (kg) STANDARD_DEVIATION 22.709 | 84.07 kilogram (kg) STANDARD_DEVIATION 11.124 | 84.52 kilogram (kg) STANDARD_DEVIATION 14.844 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 8 | 0 / 8 | 0 / 19 |
| other Total, other adverse events | 1 / 1 | 1 / 8 | 1 / 8 | 2 / 19 |
| serious Total, serious adverse events | 0 / 1 | 0 / 8 | 0 / 8 | 0 / 19 |
Outcome results
Primary
AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Time of Infinity for Soticlestat
Time frame: Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose
Population: PK Analysis Set included all participants who complied sufficiently with the protocol and displayed an evaluable PK profile (example, exposure to treatment, availability of measurements and absence of major protocol violations) and were included in the statistical analyses. Five of the same participants with normal hepatic function served as matched to moderate and mild HI arms. Here, overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe HI: Soticlestat 300 mg | AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Time of Infinity for Soticlestat | 2980 nanogram*hour per milliliter (ng•hr/mL) | — |
| Moderate HI: Soticlestat 300 mg | AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Time of Infinity for Soticlestat | 5760 nanogram*hour per milliliter (ng•hr/mL) | Geometric Coefficient of Variation 263 |
| Mild HI: Soticlestat 300 mg | AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Time of Infinity for Soticlestat | 1539 nanogram*hour per milliliter (ng•hr/mL) | Geometric Coefficient of Variation 67.1 |
| Normal Hepatic Function (Matched to Moderate HI): Soticlestat 300 mg | AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Time of Infinity for Soticlestat | 1925 nanogram*hour per milliliter (ng•hr/mL) | Geometric Coefficient of Variation 53.3 |
| Normal Hepatic Function (Matched to Mild HI): Soticlestat 300 mg | AUCinf: Area Under the Plasma Concentration-time Curve From Time 0 to Time of Infinity for Soticlestat | 1182 nanogram*hour per milliliter (ng•hr/mL) | Geometric Coefficient of Variation 46.3 |
90% CI: [111.75, 801.17]
90% CI: [77.02, 220.26]
Primary
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Soticlestat
Time frame: Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose
Population: PK Analysis Set included all participants who complied sufficiently with the protocol and displayed an evaluable PK profile (example, exposure to treatment, availability of measurements and absence of major protocol violations) and were included in the statistical analyses. Five of the same participants with normal hepatic function served as matched to moderate and mild HI arms.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe HI: Soticlestat 300 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Soticlestat | 2960 ng*hr/mL | — |
| Moderate HI: Soticlestat 300 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Soticlestat | 5732 ng*hr/mL | Geometric Coefficient of Variation 266.1 |
| Mild HI: Soticlestat 300 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Soticlestat | 1522 ng*hr/mL | Geometric Coefficient of Variation 55.5 |
| Normal Hepatic Function (Matched to Moderate HI): Soticlestat 300 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Soticlestat | 1812 ng*hr/mL | Geometric Coefficient of Variation 58.1 |
| Normal Hepatic Function (Matched to Mild HI): Soticlestat 300 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration for Soticlestat | 1126 ng*hr/mL | Geometric Coefficient of Variation 46.2 |
90% CI: [117.68, 849.97]
90% CI: [91.22, 200.57]
Primary
Cmax: Maximum Observed Plasma Concentration for Soticlestat
Time frame: Day 1 pre-dose and at multiple time points (up to 144 hours) post-dose
Population: Pharmacokinetic (PK) Analysis Set included all participants who complied sufficiently with the protocol and displayed an evaluable PK profile (example, exposure to treatment, availability of measurements and absence of major protocol violations) and were included in the statistical analyses. Five of the same participants with normal hepatic function served as matched to moderate and mild HI arms.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Severe HI: Soticlestat 300 mg | Cmax: Maximum Observed Plasma Concentration for Soticlestat | 3230 nanogram per milliliter (ng/mL) | — |
| Moderate HI: Soticlestat 300 mg | Cmax: Maximum Observed Plasma Concentration for Soticlestat | 3666 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 130.9 |
| Mild HI: Soticlestat 300 mg | Cmax: Maximum Observed Plasma Concentration for Soticlestat | 1435 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 109.9 |
| Normal Hepatic Function (Matched to Moderate HI): Soticlestat 300 mg | Cmax: Maximum Observed Plasma Concentration for Soticlestat | 1705 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 81.9 |
| Normal Hepatic Function (Matched to Mild HI): Soticlestat 300 mg | Cmax: Maximum Observed Plasma Concentration for Soticlestat | 986.9 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 58 |
90% CI: [103.47, 446.45]
90% CI: [77.18, 273.98]
Secondary
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
An Adverse Event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE was defined as an AE that started or worsened at the time of or after dosing of study drug.
Time frame: From Day 1 up to 16 days after the last dose of study drug (up to Day 17)
Population: Safety analysis set included all participants who received the dose of soticlestat.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Severe HI: Soticlestat 300 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 1 Participants |
| Moderate HI: Soticlestat 300 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 1 Participants |
| Mild HI: Soticlestat 300 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 1 Participants |
| Normal Hepatic Function (Matched to Moderate HI): Soticlestat 300 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) | 2 Participants |