Clinical trial NCT05765344: Study of Bulevirtide in Participants Who Have Normal or Impaired Liver Function
Official title: A Phase 1, Open-label, Parallel-group, Multiple-dose Study to Evaluate the Pharmacokinetics of Bulevirtide in Participants With Normal and Impaired Hepatic Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Hepatitis D Infection
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2023-03-13
Enrollment: 74
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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%, 19 ≤ BMI ≤ 40 kg/m\^2) with a 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/Exclusion criteria may apply.

Primary outcomes:
measure: Pharmacokinetic (PK) Parameter: AUCtau of Bulevirtide (BLV)
timeFrame: Day 6: Predose and up to 24 hours postdose
measure: PK Parameter: Cmax,ss of BLV
timeFrame: Day 6: Predose and up to 24 hours postdose
Secondary outcomes:
measure: PK Parameter: AUC0-24h of BLV
timeFrame: Day 1: Predose and up to 24 hours postdose
measure: PK Parameter: Tmax of BLV
timeFrame: Days 1 and 6: Predose and up to 24 hours postdose
measure: PK Parameter: Cmax of BLV
timeFrame: Day 1: Predose and up to 24 hours postdose
measure: PK Parameter: t1/2 of BLV
timeFrame: Day 1: Predose and up to 24 hours postdose; Day 6: Predose and up to 48 hours postdose
measure: PK Parameter: CLss/F of BLV
timeFrame: Day 6: Predose and up to 48 hours postdose
measure: PK Parameter: Vss/Fv of BLV
timeFrame: Day 6: Predose and up to 48 hours postdose
measure: PK Parameter: Ctrough of Total Bile Acid (BA)
timeFrame: Day 2 up to Day 5 (predose), Day 7, and Day 8
measure: PK Parameter: Cmax of Total BA
timeFrame: Days 1 and 6: Predose and up to 24 hours postdose
measure: PK Parameter: AUC0-24h of Total BA
timeFrame: Days 1 and 6: Predose and up to 24 hours postdose
measure: PK Parameter: Tmax of Total BA
timeFrame: Days 1 and 6: Predose and up to 24 hours postdose
measure: Percentage of Participants with Treatment-emergent Adverse Events
timeFrame: First dose date up to 6 days plus 7 days
measure: Percentage of Participants with Laboratory Abnormalities
timeFrame: First dose date up to 6 days plus 7 days
Other outcomes:
Locations:
city: Lake Forest
country: United States
facility: Orange County Research Center
state: California
city: Miami
country: United States
facility: Clinical Pharmacology of Miami, LLC
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Orlando
country: United States
facility: Orlando Clinical Research Center
state: Florida
city: San Antonio
country: United States
facility: Texas Liver Institute
state: Texas
city: San Antonio
country: United States
facility: Pinnacle Clinical Research LLC
state: Texas
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References: