Hepatic Impairment
Conditions
Keywords
Pharmacokinetics
Brief summary
Phase 1, multicenter, open-label, 2-part, single- and multiple-dose study designed to assess the effect of hepatic insufficiency on the PK of aramchol
Detailed description
Each of the 2 parts of the study consisted of a screening period, a check in day, a treatment period, and an end of study (EOS) visit. In Part 1 (single-dose): 39 subjects were enrolled: 8 subjects each in the mild (Cohort A), moderate (Cohort B), and severe (Cohort C) hepatic impairment cohorts and 15 healthy control subjects with normal hepatic function (Cohort D). Enrollment of 8 subjects with mild hepatic impairment (Cohort A) proceeded only if there is evidence of reduced clearance of aramchol in Cohort B. Assignment to cohorts A to C, was according to Child Pugh classification system. Serial blood samples for PK analysis of aramchol concentrations in plasma were collected before dosing (0 hour) and up to 168 hours for healthy subjects and 240 hours for hepatically impaired subjects after administration of aramchol. In Part 2 (multiple-dose), a cohort of 4 subjects comprising of mild, 7 moderate , as well as a cohort of 7 healthy volunteers was administered with aramchol as multiple doses to obtain the PK profile of aramchol at steady state. Aramchol was given twice daily for 12 days. Trough blood samples for analysis of aramchol plasma concentrations was collected before the AM dose on several days and at intervals to 12 hours after the AM dose on Day 12.
Interventions
DRUGAramchol free acid tablet 600mg, single dose
Aramchol free acid tablet 600mg, single dose
DRUGAramchol free acid tablet 300mg, bid
Aramchol acid tablet 300mg, bid for 12 days
Sponsors
Galmed Research and Development, Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
Yes
Inclusion criteria
1. The subject is male or female 18 to 79 years of age, inclusive. 2. The subject has a body mass index of 19 to 40 kg/m2, inclusive, at screening. 3. Females of childbearing potential must practice a highly effective method of contraception throughout the study period and for 1 month after treatment discontinuation. 4. Male subjects with female partners of childbearing potential must be vasectomized, be willing to use an acceptable method of birth control, or practice abstinence during the study. 5. The subject has a resting pulse rate of ≥40 and \<100 beats per minute with no clinically significant deviation as judged by the investigator. 6. The subject has a QT interval corrected for heart rate using Fridericia's formula of \<500 msec. 7. The subject agrees to comply with all protocol requirements. 8. The subject is able to provide written informed consent. Additional Inclusion Criteria for Healthy Subjects Only (Cohort D): 9. The subject has normal hepatic function. 10. The subject has a resting blood pressure of 90 to 150 mm Hg (systolic) and 50 to 100 mm Hg (diastolic). 11. The subject is judged by the investigator to be in good general health, as determined by medical history, clinical laboratory assessments, vital sign measurements, 12 lead electrocardiogram (ECG) results, and physical examination findings. Additional Inclusion Criteria for Subjects With Hepatic Impairment Only (Cohorts A, B, and C): 12. The subject has cirrhosis with evidence of impaired liver function. The etiology of the cirrhosis may be alcoholic, autoimmune, nonalcoholic steatohepatitis, or chronic viral hepatitis type B or C. 13. The subject has chronic (more than 6 months) and stable hepatic impairment (ie, no acute episodes of illness within 30 days before screening due to deterioration of hepatic function) as assessed by a Child-Pugh classification score of mild (5 to 6 points), moderate (7 to 9 points), or severe (10 to 15 points). 14. The subject has a resting blood pressure of 90 to 155 mm Hg (systolic) and 50 to 100 mm Hg (diastolic). 15. The subject is judged by the investigator to be in good general health, as determined by medical history, clinical laboratory assessments, vital sign measurements, 12 lead ECG results, and physical examination findings, except for findings that, as judged by the investigator, are consistent with the subject's hepatic impairment or other stable concomitant medical conditions.
Exclusion criteria
1. The subject has a history or clinical manifestations of a significant neurological, renal, cardiovascular, gastrointestinal, pulmonary, hematologic, immunologic, or psychiatric disease that would preclude study participation, as judged by the investigator. 2. The subject has a positive test result for human immunodeficiency virus type 1 or 2 antibodies at screening. 3. The subject has a history of drug abuse within 3 months before screening. 4. The subject has a history of alcoholism within 3 months before screening, or excessive alcohol consumption (regular alcohol intake \>15 units per week) (1 unit is equal to approximately ½ pint \[200 mL\] of beer, 1 small glass \[100 mL\] of wine, or 1 measure \[25 mL\] of spirits). 5. The subject smokes \>10 cigarettes daily and is unwilling to reduce to \<5 daily from the time of screening through the last PK sample. 6. The subject is unable or unwilling to abstain from alcohol, caffeine, xanthine containing beverages or food (eg, coffee, tea, chocolate, and caffeinated sodas, colas), grapefruit, grapefruit juice, Seville oranges, or products containing any of these, from 48 hours prior to study drug dosing until discharge. 7. The subject is involved in strenuous activity or contact sports within 24 hours of the first dose of study drug or during the study. 8. The subject has donated blood or blood products \>450 mL within 3 months before the first dose of study drug. 9. The subject has a presence or history of relevant drug and/or food allergies (ie, allergy to aramchol, cholic acid, or any excipients, or any significant food allergy. 10. The subject has received study drug in another investigational study within 30 days of dosing. 11. In the opinion of the investigator, the subject is not suitable for entry into the study. For additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-tau, Steady State | Day 12 | AUC from time 0 to the dosing interval tau measured at steady state. Blood was collected at the following time points: before dosing (0 hour) and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 18, 24, 48, 72, 96, 120, 144, 168, 192, and 240 hours |
| Cmax,ss | Day 12 | Maximum plasma concentrations (Cmax,ss) Blood was collected at the following time points: before dosing (0 hour) and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 18, 24, 48, 72, 96, 120, 144, 168, 192, and 240 hours |
| Apparent Total Oral Clearance, Single Dose | Day 11 | CL/F measured after single dose in Part 1 Blood was collected at the following time points: before dosing (0 hour) and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 18, 24, 48, 72, 96, 120, 144, 168, 192, and 240 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Significant TEAEs | Part 1: up to 22 days; Part 2: up to 27 days | The number of significant treatment-related adverse events |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Mild Hepatic Impairment (Cohort A) 8 mild hepatic impaired subjects
Aramchol 600mg single dose: aramchol acid tablet 600mg, single dose | 8 |
| Part 1: Moderate Hepatic Impairment (Cohort B) 8 moderate hepatic impaired subjects
Aramchol 600mg single dose: aramchol acid tablet 600mg, single dose | 8 |
| Part 1: Severe Hepatic Impairment (Cohort C) 8 severe hepatic impaired subjects
Aramchol 600mg single dose: aramchol acid tablet 600mg, single dose | 8 |
| Part 1: Healthy Volunteers (Cohort D) 15 matched healthy volunteers
Aramchol 600mg single dose: aramchol acid tablet 600mg, single dose | 15 |
| Part 2: Mild Hepatic Impairment Cohort 4 mild hepatic impaired subjects (mild, moderate or severe)
Aramchol 300mg, bid: aramchol acid tablet 300mg, bid for 12 days | 4 |
| Part 2: Moderate Hepatic Impairment Cohort 7 moderate hepatic impaired subjects (mild, moderate or severe)
Aramchol 300mg, bid: aramchol acid tablet 300mg, bid for 12 days | 7 |
| Part 2: Healthy Volunteers Cohort 7 matched healthy volunteers
Aramchol 300mg, bid: aramchol acid tablet 300mg, bid for 12 days | 7 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Part 1: Moderate Hepatic Impairment (Cohort B) | Part 1: Severe Hepatic Impairment (Cohort C) | Part 1: Healthy Volunteers (Cohort D) | Part 1: Mild Hepatic Impairment (Cohort A) | Part 2: Mild Hepatic Impairment Cohort | Part 2: Moderate Hepatic Impairment Cohort | Part 2: Healthy Volunteers Cohort | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 3 Participants | 5 Participants | 1 Participants | 2 Participants | 3 Participants | 1 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 10 Participants | 7 Participants | 2 Participants | 4 Participants | 6 Participants | 39 Participants |
| Age, Continuous | 63.3 Years STANDARD_DEVIATION 9.02 | 62.0 Years STANDARD_DEVIATION 6.35 | 59.7 Years STANDARD_DEVIATION 8.5 | 59.1 Years STANDARD_DEVIATION 8.1 | 64.0 Years STANDARD_DEVIATION 4.16 | 60.1 Years STANDARD_DEVIATION 8.47 | 60.1 Years STANDARD_DEVIATION 6.82 | 60.86 Years STANDARD_DEVIATION 7.63 |
| Child-Pugh total scores | 8.25 points STANDARD_DEVIATION 0.886 | 11.50 points STANDARD_DEVIATION 1.512 | — | 5.38 points STANDARD_DEVIATION 0.518 | 5.75 points STANDARD_DEVIATION 0.5 | 7.71 points STANDARD_DEVIATION 0.756 | — | 7.94 points STANDARD_DEVIATION 2.25 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants | 3 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 7 Participants | 14 Participants | 8 Participants | 3 Participants | 4 Participants | 4 Participants | 44 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 3 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 8 Participants | 10 Participants | 5 Participants | 2 Participants | 7 Participants | 6 Participants | 46 Participants |
| Region of Enrollment United States | 8 Participants | 8 Participants | 15 Participants | 8 Participants | 4 Participants | 7 Participants | 7 Participants | 57 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 4 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 16 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 11 Participants | 7 Participants | 3 Participants | 6 Participants | 5 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 15 | 0 / 4 | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 15 | 0 / 4 | 1 / 7 | 0 / 7 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 15 | 0 / 4 | 0 / 7 | 0 / 7 |
Outcome results
Primary
Apparent Total Oral Clearance, Single Dose
CL/F measured after single dose in Part 1 Blood was collected at the following time points: before dosing (0 hour) and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 18, 24, 48, 72, 96, 120, 144, 168, 192, and 240 hours
Time frame: Day 11
Population: Note that apparent total oral clearance data was analyzed for Part 1 only, where comparison was made between Healthy volunteers and Hepatic impairment patients. Such data was not collected and analyzed for Part 2
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Mild Hepatic Impairment (Cohort A) | Apparent Total Oral Clearance, Single Dose | 5.96 L/h | Geometric Coefficient of Variation 43.8 |
| Part 1: Moderate Hepatic Impairment (Cohort B) | Apparent Total Oral Clearance, Single Dose | 5.23 L/h | Geometric Coefficient of Variation 29.2 |
| Part 1: Severe Hepatic Impairment (Cohort C) | Apparent Total Oral Clearance, Single Dose | 5.86 L/h | Geometric Coefficient of Variation 52.5 |
| Part 1: Healthy Volunteers (Cohort D) | Apparent Total Oral Clearance, Single Dose | 8.01 L/h | Geometric Coefficient of Variation 50.1 |
Primary
AUC0-tau, Steady State
AUC from time 0 to the dosing interval tau measured at steady state. Blood was collected at the following time points: before dosing (0 hour) and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 18, 24, 48, 72, 96, 120, 144, 168, 192, and 240 hours
Time frame: Day 12
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Mild Hepatic Impairment (Cohort A) | AUC0-tau, Steady State | 96100 h•ng/mL | Geometric Coefficient of Variation 138.29 |
| Part 1: Moderate Hepatic Impairment (Cohort B) | AUC0-tau, Steady State | 107000 h•ng/mL | Geometric Coefficient of Variation 154.13 |
| Part 1: Severe Hepatic Impairment (Cohort C) | AUC0-tau, Steady State | 103000 h•ng/mL | Geometric Coefficient of Variation 148.09 |
| Part 1: Healthy Volunteers (Cohort D) | AUC0-tau, Steady State | 69500 h•ng/mL | Geometric Coefficient of Variation 0 |
| Part 2: Mild Hepatic Impairment Cohort | AUC0-tau, Steady State | 63300 h•ng/mL | Geometric Coefficient of Variation 4.3 |
| Part 2: Moderate Impairment Cohort | AUC0-tau, Steady State | 55900 h•ng/mL | Geometric Coefficient of Variation 31.4 |
| Part 2: Healthy Volunteers Cohort | AUC0-tau, Steady State | 61400 h•ng/mL | Geometric Coefficient of Variation 26 |
Primary
Cmax,ss
Maximum plasma concentrations (Cmax,ss) Blood was collected at the following time points: before dosing (0 hour) and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 18, 24, 48, 72, 96, 120, 144, 168, 192, and 240 hours
Time frame: Day 12
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Mild Hepatic Impairment (Cohort A) | Cmax,ss | 1950 ng/mL | Geometric Coefficient of Variation 138.17 |
| Part 1: Moderate Hepatic Impairment (Cohort B) | Cmax,ss | 1890 ng/mL | Geometric Coefficient of Variation 134.26 |
| Part 1: Severe Hepatic Impairment (Cohort C) | Cmax,ss | 1480 ng/mL | Geometric Coefficient of Variation 105.22 |
| Part 1: Healthy Volunteers (Cohort D) | Cmax,ss | 1410 ng/mL | Geometric Coefficient of Variation 0 |
| Part 2: Mild Hepatic Impairment Cohort | Cmax,ss | 5750 ng/mL | Geometric Coefficient of Variation 5.2 |
| Part 2: Moderate Impairment Cohort | Cmax,ss | 5380 ng/mL | Geometric Coefficient of Variation 26.1 |
| Part 2: Healthy Volunteers Cohort | Cmax,ss | 6040 ng/mL | Geometric Coefficient of Variation 21.3 |
Secondary
Number of Subjects With Significant TEAEs
The number of significant treatment-related adverse events
Time frame: Part 1: up to 22 days; Part 2: up to 27 days
Population: All subjects
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Mild Hepatic Impairment (Cohort A) | Number of Subjects With Significant TEAEs | 0 Participants |
| Part 1: Moderate Hepatic Impairment (Cohort B) | Number of Subjects With Significant TEAEs | 0 Participants |
| Part 1: Severe Hepatic Impairment (Cohort C) | Number of Subjects With Significant TEAEs | 0 Participants |
| Part 1: Healthy Volunteers (Cohort D) | Number of Subjects With Significant TEAEs | 0 Participants |
| Part 2: Mild Hepatic Impairment Cohort | Number of Subjects With Significant TEAEs | 0 Participants |
| Part 2: Moderate Impairment Cohort | Number of Subjects With Significant TEAEs | 0 Participants |
| Part 2: Healthy Volunteers Cohort | Number of Subjects With Significant TEAEs | 0 Participants |