Compensated Cirrhosis, Hepatic Impairment, Primary Biliary Cholangitis
Conditions
Keywords
PBC, Primary Biliary Cholangitis (PBC)
Brief summary
The Effect of Hepatic Impairment on The Pharmacokinetics of Seladelpar: An Open-Label Study Following Oral Dosing of Seladelpar to Participants with Primary Biliary Cholangitis (PBC) and Hepatic Impairment (HI)
Interventions
DRUGSeladelpar
Tablets Administered Orally
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Males and females between 18 and 80 years of age (inclusive) who are able to comprehend instructions and follow the study procedures and are willing to sign an Informed Consent Form (ICF) 2. Females of childbearing potential who are sexually active with a non-sterile male partner (sterile male partners are defined as men vasectomized since at least 6 months) must be willing to use the contraceptive methods throughout the study and for 30 days after study drug administration. 3. For at least 90 days after study drug administration, non-vasectomized males must not donate sperm, be willing to use contraception with childbearing potential partners and any male participant with a pregnant partner must use a condom. 4. Willing to abstain from consuming grapefruit, pomelo, star fruit, or Seville orange containing products from 7 days prior to dose of study medication through day of discharge. 5. Confirmed diagnosis of PBC with evidence of cirrhosis and Child-Pugh classification of CP-A, CP-A + PHT, CP-B or CP-C 6. Screening laboratory parameters: * Alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 10 × upper Limit of normal (ULN) * Total bilirubin ≤ 5 × ULN 7. Ursodeoxycholic acid (UDCA) for a minimum of 12 weeks of treatment prior to Day 1 8. At screening confirmed diagnosis of PBC 9. Model for end-stage liver disease (MELD)-Na scores of 6 to 24
Exclusion criteria
1. Clinically significant or history of acute or chronic liver disease of an etiology other than PBC 2. Patients with a diagnosis of overlapping PBC and autoimmune hepatitis 3. History, evidence, or high suspicion of hepatobiliary malignancy based on imaging, screening laboratory values, and/or clinical symptoms. 4. Presumptive or diagnosed infection that requires systemic therapy within 12 weeks of Screening and through Day 1 5. Female participants who are pregnant or nursing 6. Screening electrocardiogram (ECG) that demonstrates a QT interval ≥ 500 msec, or any other significant ECG finding with clinically significant abnormalities as determined by the Investigator 7. Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus - ribonucleic acid (HCV RNA), or anti human immunodeficiency virus (HIV) antibody 8. Any non-hepatic acute or chronic condition that, in the opinion of the Investigator, would limit the patient's ability to complete and/or participate in the study or compromise the integrity of the data 9. Has experienced an illness that is considered by the Investigator to be clinically significant within 2 weeks before administration of investigational product 10. Clinically relevant drug or alcohol abuse within 6 months of Screening. A positive drug screen will exclude participants unless it can be explained by a prescribed medication 11. Use of obeticholic acid (OCA), any drug of the same class, or fibrates (e.g., bezafibrate, fenofibrate, elafibranor, lanifibranor, pemafibrate, saroglitizar) within 30 days of Baseline 12. Use of an experimental or unapproved treatment for PBC within 30 days of Baseline 13. Clinically evident complication(s) of cirrhosis and portal hypertension that required either emergency room visit, hospital admission or both during the 12 week period prior to investigational product administration Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Pharmacokinetic (PK) Parameter: Cmax of Seladelpar and Its Metabolites (M1, M2, and M3) | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | Cmax is defined as the maximum observed plasma concentration of the study drug. |
| Part A: PK Parameter: Tmax of Seladelpar and Its Metabolites (M1, M2, and M3) | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | Tmax is defined as the time to reach the maximum observed plasma concentration of the study drug. |
| Part A: PK Parameter: AUC0-t of Seladelpar and Its Metabolites (M1, M2, and M3) | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | AUC0-t is defined as area under the concentration--time curve from time zero to the last measurable concentration. |
| Part A: PK Parameter: AUC0-inf of Seladelpar and Its Metabolites (M1, M2, and M3) | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | AUC0-inf is defined as area under the concentration--time curve from time zero extrapolated to infinity, calculated as AUC0-t+Ct/Kel, where: Ct = the last measurable concentration and Kel = elimination rate constant. |
| Part B: PK Parameter: Cmax of Seladelpar and Its Metabolites (M1, M2, and M3) | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose | Cmax is defined as the maximum observed plasma concentration of the study drug. |
| Part B: PK Parameter: Cmax,ss of Seladelpar and Its Metabolites (M1, M2, and M3) | Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose | Cmax,ss is defined as the steady-state maximum observed plasma concentration of the study drug at Day 28. |
| Part B: PK Parameter: Tmax of Seladelpar and Its Metabolites (M1, M2, and M3) | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose | Tmax is defined as the time to reach the maximum observed plasma concentration of the study drug. |
| Part B: PK Parameter: Tmax,ss of Seladelpar and Its Metabolites (M1, M2, and M3) | Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose | Tmax,ss is defined as the steady-state time to reach maximum observed plasma concentration of the study drug at Day 28. |
| Part B: PK Parameter: AUC0-24 of Seladelpar and Its Metabolites (M1, M2, and M3) | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose | AUC0-24 is defined as area under the concentration-time curve from time zero to 24 hours. |
| Part B: PK Parameter: AUC0-tau of Seladelpar and Its Metabolites (M1, M2, and M3) | Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose | AUCtau is defined as the area under the drug concentration versus time curve over the dosing interval. |
| Part B: PK Parameter: RCmax of Seladelpar and Its Metabolites (M1, M2, and M3) | Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose | RCmax is defined as the accumulation ratio based on Cmax, calculated as Cmax on Day 28/ Day 1. |
| Part B: PK Parameter: RAUC0-t of Seladelpar and Its Metabolites (M1, M2, and M3) | Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose | RAUC0-t is defined as the accumulation ratio based on AUC0-t, calculated as AUC0-tau on Day 28/ AUC0-24 on Day 1 for participants with dose once a day. |
| Percentage of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) and Study Drug-Related TEAEs | Part A: Up to Week 5; Part B: Up to Week 8 | An adverse event (AE) was defined as any medical occurrence in a participant administered to a pharmaceutical product in a clinical study, regardless of a causal relationship with this treatment. TEAEs were defined as AEs that commenced or worsened on or after the time of study drug administration in Part A until up to 30 days after study drug administration in Part A or before the first study drug administration in Part B (whichever is earlier). For Part B, TEAEs are defined as AEs that commence or worsen on or after the time of first study drug administration in Part B until up to 30 days after the last study drug administration in Part B. A drug-related TEAE was defined as TEAE which was related (reported as 'possible', 'probable', or 'definite') to study drug. Percentages were rounded off. |
| Percentage of Participants Who Experienced Any Grade and Grade 3 or 4 TEAEs | Part A: Up to Week 5; Part B: Up to Week 8 | TEAEs severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. Participants were counted at the highest AE grade experienced. The percentage of participants with any severity grade and severity grade of 3 or 4 were reported. Percentages were rounded off. |
| Percentage of Participants Who Experienced TEAEs of Special Interest | Part A: Up to Week 5; Part B: Up to Week 8 | TEAEs of special interest for this study were defined as AEs that met CTCAE version 5.0 or the most recent version Grade 2 criteria or higher for AEs of elevated alanine transaminase (ALT), aspartate aminotransferase (AST), bilirubin, creatinine kinase, lipase, or serum creatinine. Hepatic decompensation clinical events including ascites, jaundice, esophageal variceal bleeding, and hepatic encephalopathy, were also defined as TEAEs of special interest for this study. Percentages were rounded off. |
| Percentage of Participants With Clinically Significant Changes in Vital Signs | Part A: Up to Day 4; Part B: Up to Day 31 | Vital signs (including oral temperature, respiratory rate, seated blood pressure \[diastolic and systolic\], and heart rate) were evaluated. Percentage of participants with clinically significant changes in vital signs evaluations was reported. The clinically significant changes were based on investigator's judgement. |
| Percentage of Participants With Abnormal Clinically Significant 12-Lead Electrocardiogram (ECG) Findings | Part A: Up to Day 4; Part B: Up to Day 28 | ECG measurements included the parameters of heart rate, ventricular rate, PR interval, QRS duration, QT interval (uncorrected), and QT interval corrected for heart rate according to Fridericia's formula (QTcF). Per protocol, ECG findings were classified in 1 of 3 categories: normal, abnormal but not clinically significant, or abnormal and clinically significant. Any abnormality in ECG assessments which were deemed clinically significant by the investigator were reported. |
| Percentage of Participants Who Experienced Laboratory Abnormalities | Part A: Up to Day 4; Part B: Up to Day 31 | Clinical laboratory parameters included biochemistry, hematology, coagulation, and urinalysis. Abnormal laboratory values were graded according to the NCI CTCAE version 5.0.Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. The percentage of participants with a shift of ≥ 2 NCI CTCAE grade from baseline was reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: PK Parameter (Urine): Ae0-t of Seladelpar and Its Metabolites (M1, M2, and M3) | Day 1: Predose; 0-6 h, and 6-12 h postdose | Ae0-t is defined as the cumulative urinary excretion from time zero to time t, calculated as the sum of the amounts excreted over each collection interval. |
| Part A: PK Parameter (Urine): CLR of Seladelpar | Day 1: Predose; 0-6 h, and 6-12 h postdose | CLR is defined as the renal clearance, calculated as Ae0-t / AUC0-12. |
| Part A: Rsq Between Plasma Seladelpar Cmax and Baseline Albumin | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | Rsq is defined as the R-squared value for the regression between Cmax and Baseline Albumin. |
| Part A: Rsq Between Plasma Seladelpar AUC0-inf and Baseline Albumin | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-inf and Baseline Albumin. |
| Part A: Rsq Between Plasma Seladelpar AUC0-t and Baseline Albumin | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-t and Baseline Albumin. |
| Part A: Rsq Between Plasma Seladelpar Cmax and Baseline Bilirubin | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | Rsq is defined as the R-squared value for the regression between Cmax and Baseline Bilirubin. |
| Part A: Rsq Between Plasma Seladelpar AUC0-inf and Baseline Bilirubin | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-inf and Baseline Bilirubin. |
| Part A: Rsq Between Plasma Seladelpar AUC0-t and Baseline Bilirubin | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-t and Baseline Bilirubin. |
| Part A: Rsq Between Plasma Seladelpar Cmax and Baseline Prothrombin Time | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | Rsq is defined as the R-squared value for the regression between Cmax and Baseline Prothrombin Time. |
| Part A: Rsq Between Plasma Seladelpar AUC0-inf and Baseline Prothrombin Time | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-inf and Baseline Prothrombin Time. |
| Part A: Rsq Between Plasma Seladelpar AUC0-t and Baseline Prothrombin Time | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-t and Baseline Prothrombin Time. |
| Part A: Rsq Between Plasma Seladelpar Cmax and CP Score | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | Rsq is defined as the R-squared value for the regression between Cmax and CP score of participants. |
| Part A: Rsq Between Plasma Seladelpar AUC0-inf and CP Score | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-inf and CP score of participants. |
| Part A: Rsq Between Plasma Seladelpar AUC0-t and CP Score | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 and 72 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-t and CP score of participants. |
| Part B: Rsq Between Plasma Seladelpar Cmax and Baseline Albumin | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose | Rsq is defined as the R-squared value for the regression between Cmax and baseline Albumin. |
| Part B: Rsq Between Plasma Seladelpar AUC0-t and Baseline Albumin | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose; Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-t and baseline Albumin. |
| Part B: Rsq Between Plasma Seladelpar AUC0-inf and Baseline Albumin | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-inf and baseline Albumin. |
| Part B: Rsq Between Plasma Seladelpar Cmax and Baseline Prothrombin Time | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose | Rsq is defined as the R-squared value for the regression between Cmax and baseline prothrombin time. |
| Part B: Rsq Between Plasma Seladelpar AUC0-t and Baseline Prothrombin Time | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose; Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-t and baseline prothrombin time. |
| Part B: Rsq Between Plasma Seladelpar AUC0-inf and Baseline Prothrombin Time | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-inf and baseline prothrombin time. |
| Part B: Rsq Between Plasma Seladelpar Cmax and Baseline Bilirubin | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose | Rsq is defined as the R-squared value for the regression between Cmax and baseline bilirubin. |
| Part B: Rsq Between Plasma Seladelpar AUC0-t and Baseline Bilirubin | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose; Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-t and baseline bilirubin. |
| Part B: Rsq Between Plasma Seladelpar AUC0-inf and Baseline Bilirubin | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-inf and baseline bilirubin. |
| Part B: Rsq Between Plasma Seladelpar Cmax and CP Score | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose | Rsq is defined as the R-squared value for the regression between Cmax and CP score of participants. |
| Part B: Rsq Between Plasma Seladelpar AUC0-t and CP Score | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose; Day 28: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48, and 72 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-t and and CP score of participants. |
| Part B: Rsq Between Plasma Seladelpar AUC0-inf and CP Score | Day 1: Predose; 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 hours postdose | Rsq is defined as the R-squared value for the regression between AUC0-inf and and CP score of participants. |
Countries
South Korea, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORGilead Study Director
Gilead Sciences
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States, South Korea, Spain, and the United Kingdom.
Pre-assignment details
37 participants were screened.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants |
| Age, Continuous | 59 years STANDARD_DEVIATION 8.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment South Korea | 1 Participants |
| Region of Enrollment Spain | 0 Participants |
| Region of Enrollment United Kingdom | 1 Participants |
| Region of Enrollment United States | 17 Participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 0 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 | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 1 | 0 / 5 | 0 / 1 | 0 / 5 |
| other Total, other adverse events | 0 / 6 | 2 / 6 | 1 / 6 | 0 / 6 | 0 / 1 | 2 / 5 | 0 / 1 | 3 / 5 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 1 | 1 / 5 | 0 / 1 | 0 / 5 |
Outcome results
None listed