Healthy, Hepatic Impairment
Conditions
Brief summary
The goals of this study are to measure the amount of bulevirtide (BLV) that gets into the blood stream and how long it takes to get rid of it, measure the effect of BLV on bile acids, and evaluate the safety and tolerability of multiple doses of BLV in participants with normal and impaired hepatic (liver) function.
Interventions
DRUGBulevirtide
2 mg administered via subcutaneous injections.
Sponsors
Gilead Sciences
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
Key Inclusion Criteria: All individuals: * Body mass index (BMI) of 18 ≤ BMI ≤ 40 kg/m\^2 at screening. * Have a calculated creatinine clearance (CLcr) of at least 60 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at screening. * Individuals assigned male at birth and individuals assigned female at birth and of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception as described in the protocol. * Individuals have not donated blood within 56 days of study entry or plasma within 7 days of study entry and must refrain from blood donation from clinic admission, throughout the study period, and continuing for at least 30 days following the last dose of study drug. * 12-lead electrocardiogram (ECG) evaluations at screening must be without clinically significant abnormalities as assessed by the investigator. * Aside from hepatic impairment among the individuals with hepatic impairment, the individual must, in the opinion of the investigator, be sufficiently healthy for study participation based upon medical history, physical examination, vital signs, and screening laboratory evaluations. * Must be willing and able to comply with all study requirements. Individuals With Hepatic Impairment: * Have a diagnosis of chronic (\> 6 months), stable hepatic impairment (moderate or severe based upon the Child-Pugh-Turcotte (CPT) classification system for moderate or severe hepatic impairment \[CPT Class B or C, respectively\]) with no clinically significant change in hepatic status (as determined by the investigator) within the 2 months (60 days) prior to screening. * Individuals with moderate or severe hepatic impairment must have a score of 7 to 9 or 10 to 15 on the CPT classification system at screening. If an individual's score changes during the study, the score at screening will be used for classification. * Must meet all of the following laboratory parameters at screening: * alanine aminotransferase (ALT) ≤ 10 × upper limit of normal (ULN) * aspartate aminotransferase (AST) ≤ 10 × ULN * platelets ≥ 25,000/mm\^3 * hemoglobin ≥ 9 g/dL * Individuals with hepatic impairment who have not been on a stable dose of concomitant medications for at least 4 weeks prior to screening (or 5 half-lives, whichever is longer) and/or for whom dose changes are likely to occur during the study should have their medications reviewed and approved by the sponsor. Matched Control Individuals With Normal Hepatic Function: * Have alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, international normalized ratio, and total bilirubin at or below the ULN; and albumin above the lower limit of normal at screening and at admission. * Must be matched for age (± 10 years), sex (assigned at birth), and BMI (± 20%, 18 ≤ BMI ≤ 40 kg/m\^2) with an individual in the hepatic impairment group. Key
Exclusion criteria
All Individuals: * Positive serum pregnancy test at screening and at admission. * Breastfeeding individual. * Have received any study drug within 30 days prior to study dosing. * Have current alcohol or substance abuse judged by the investigator to potentially interfere with individual compliance or individual safety, or a positive drug or alcohol test at screening or admission. * Have poor venous access that limits phlebotomy. * Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic agents within 3 months prior to screening or is expected to receive these agents during the study. * Have a history of any of the following: * Significant serious skin disease, such as but not limited to rash, food allergy, eczema, psoriasis, or urticaria. * Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity). * Known hypersensitivity to the study drugs, their metabolites, or to formulation excipients. * Significant cardiac disease (including history of myocardial infarction based on ECG and/or clinical history, any history of ventricular tachycardia, congestive heart failure, or dilated cardiomyopathy with left ventricular ejection fraction ≤ 40%); or a family history of long QT syndrome, or unexplained death in an otherwise healthy individual between the ages of 1 and 30 years. * Syncope, palpitations, or unexplained dizziness. * Implanted defibrillator or pacemaker. * Have any serious or active medical or psychiatric illness (including depression). * Requirement for ongoing therapy with or prior use of any prohibited medications listed in the protocol. Individuals With Hepatic Impairment: * Have a positive test result for human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody with detectable HCV ribonucleic acid (RNA) at screening. * Suspicion of hepatocellular carcinoma (ie, if alpha-fetoprotein \> 20 ng/mL at screening). * Anticipated changes in concomitant medications or dosage used to treat symptoms of hepatic impairment or associated comorbid conditions that could lead to clinically significant changes in medical conditions during the study. * Use of known hepatotoxic medications, clinical organic anion transporting polypeptide (OATP)1B1/3 inhibitors, or sodium-taurocholate cotransporting polypeptide (NTCP) inhibitors (half-maximal inhibitory concentration (IC50) or kinetic inhibition constant \[Ki\] \< 20 μM). * Positive test for drugs of abuse, including alcohol at screening or admission, with the exception of opioids and tetrahydrocannabinol (marijuana) under prescription and verified by the investigator as for pain management. Matched Control Individuals With Normal Hepatic Function: * Have a positive test result for HIV antibody, HBsAg, or HCV antibody. * Have a history of liver disease including Gilbert's disease. * Have taken any prescription medications or over-the-counter medications, including herbal products, within 28 days prior to start of study drug dosing, with the exception of vitamins and/or acetaminophen and/or ibuprofen and/or hormonal contraceptive medications. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic (PK) Parameter: AUCtau of Bulevirtide (BLV) | Day 6: Predose and up to 24 hours postdose | AUCtau was defined as the area under the concentration versus time curve (AUC) over the dosing interval at steady state. |
| PK Parameter: Cmax,ss of BLV | Day 6: Predose and up to 24 hours postdose | Cmax,ss was defined as the maximum observed concentration of drug at steady state. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK Parameter: AUC0-24h of BLV | Day 1: Predose and up to 24 hours postdose | AUC0-24h was defined as the partial area under the concentration versus time curve from time zero to time 24 hours. |
| PK Parameter: Tmax of BLV | Days 1 and 6: Predose and up to 24 hours postdose | Tmax was defined as the time (observed time point) of Cmax. |
| PK Parameter: Cmax of BLV | Day 1: Predose and up to 24 hours postdose | Cmax was defined as the maximum observed plasma concentration of drug. |
| PK Parameter: t1/2 of BLV | Day 6: Predose and up to 48 hours postdose | t1/2 was defined as estimate of the terminal elimination half-life of the drug in plasma, calculated by dividing the natural log of 2 by the terminal elimination rate constant (λz). |
| PK Parameter: CLss/F of BLV | Day 6: Predose and up to 48 hours postdose | CLss/F was defined as the apparent clearance at the steady state (CLss) after administration of the drug: CLss/F = Dose/AUCtau, where "Dose" is the dose of the drug per interval. |
| PK Parameter: Vss/F of BLV | Day 6: Predose and up to 48 hours postdose | Vss/F was defined as the apparent steady-state volume of distribution of the drug. |
| Pharmacodynamic (PD) Parameter: Ctrough of Total Bile Acids (BA) | Predose on Days 2, 3, 4, 5, 7, and 8 | Ctrough was defined as the concentration of total BA at the end of the dosing interval. |
| PD Parameter: Cmax of Total BA | Days 1 and 6: Predose and up to 24 hours postdose | Cmax was defined as the maximum observed concentration of total BA. |
| PD Parameter: AUC0-24h of Total BA | Days 1 and 6: Predose and up to 24 hours postdose | AUC0-24 was defined as the partial area under the concentration versus time curve from time "0" to time "24" hours for total BA. |
| PD Parameter: NetAUC of Total BA | Days 1 and 6: Predose and up to 24 hours postdose | NetAUC was defined as the positive portion of area under the baseline-adjusted biomarker concentration versus time curve over the dosing interval. |
| PD Parameter: Tmax of Total BA | Days 1 and 6: Predose and up to 24 hours postdose | Tmax was defined as the time (observed time point) of Cmax of total BA. |
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | First dose date up to Day 6 plus 30 days | TEAEs were defined as any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug and/or any AEs leading to premature discontinuation of study drug. If the AE onset date is the same as the date of study drug start date then the AE onset time must be on or after the study drug start time. If the AE onset time is missing when the start dates were the same, the AE were considered treatment emergent. An AE was any untoward medical occurrence in a clinical study participant administered a study drug that did not necessarily had a causal relationship with the treatment. |
| Percentage of Participants With Laboratory Abnormalities | First dose date up to Day 6 plus 30 days | Treatment-emergent laboratory abnormalities were defined as values that increase at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last dose of study drug plus 30 days. If the relevant baseline laboratory value is missing, any abnormality of at least Grade 1 observed within the time frame specified above will be considered treatment emergent. Grading categories are determined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Grade 1: mild, Grade 2: moderate, Grade 3: severe or medically significant, Grade 4: life-threatening; Grade 5: Death. |
Countries
United States
Contacts
STUDY_DIRECTORGilead Study Director
Gilead Sciences
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States.
Pre-assignment details
124 participants were screened.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Age, Continuous | 55 years STANDARD_DEVIATION 10.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 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 | 68 Participants |
| Region of Enrollment United States | 8 Participants |
| Sex: Female, Male Female | 26 Participants |
| Sex: Female, Male Male | 7 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 / 11 | 0 / 11 | 0 / 8 | 0 / 8 | 0 / 10 | 0 / 10 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 3 / 11 | 1 / 11 | 2 / 8 | 1 / 8 | 2 / 10 | 2 / 10 | 2 / 8 | 2 / 8 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 | 0 / 8 | 0 / 8 | 0 / 10 | 0 / 10 | 0 / 8 | 0 / 8 |
Outcome results
None listed