Chronic Hepatitis D Infection
Conditions
Brief summary
The goals of this study are to compare the amount of study drug, bulevirtide (BLV), that gets into the bloodstream and how long it takes for the body to eliminate it, measure the effect of BLV on bile acids, and evaluate the safety and tolerability of multiple doses of BLV in participants with normal or impaired renal (kidney) function.
Interventions
DRUGBulevirtide (BLV)
Administered via subcutaneous (SC) 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 at least ≥ 18.0 kg/m\^2 and ≤ 40.0 kg/m\^2 at screening. * No clinically significant abnormalities on electrocardiogram (ECG) * No known Liver Disease (Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)) ≤ 3 x upper limit of normal (ULN) at screening. Individuals with Renal Impairment (RI): * Have RI classification at screening that has been unchanged during the 90 days prior to study drug dosing. * Estimated Glomerular Filtration Rate (eGFR) must be the following (using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Inker 2021)) based on serum creatinine as measured at the screening evaluation: * Severe RI (Groups A and B): eGFR ≥ 15 to ≤ 29 mL/min/1.73 m\^2 * Moderate RI (Group C): eGFR ≥ 30 to ≤ 59 mL/min/1.73 m\^2 * Mild RI (Group D): eGFR ≥ 60 to ≤ 89 mL/min/1.73 m\^2 * Hemoglobin ≥ 9 g/dL at screening. * Individuals with cardiovascular disease, hypertension, diabetes mellitus, hyperlipidemia, hypothyroidism, osteoporosis, and many others) may be included provided that these diseases/conditions are clinically stable. Matched Control Individuals: * Have an eGFR of at least 90 mL/min/1.73 m\^2 (using the CKD-EPI equation) based on serum creatinine as measured at screening evaluation. * Matched for sex, age (± 10 years), and BMI (± 20%, 18.0 ≤ BMI ≤ 40.0 kg/m\^2) with the respective participant in the RI group. Key
Exclusion criteria
All Individuals: * Positive human immunodeficiency virus (HIV) test, hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody with detectable HCV viral ribonucleic acid (RNA) at screening. * Have any serious or active medical or psychiatric illness (including depression) that, in the opinion of the investigator, would interfere with participant treatment, assessment, or compliance with the protocol. Individuals with RI: * Recent history of reception of any blood or blood products or history of major bleeding within 4 weeks of dosing. * Positive test for drugs of abuse, including alcohol at screening or admission, with the exception of opioids and tetrahydrocannabinol (THC, marijuana) under prescription and verified by the investigator as for pain management. * Received treatment with trimethoprim or cimetidine or tenofovir prodrugs (tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF)) (affects elimination of creatinine) or with competitors of renal tubular excretion (eg, probenecid, chronic high-dose nonsteroidal anti-inflammatory drugs) within 28 days of Day -1. * Received known nephrotoxic drugs (eg, aminoglycosides, amphotericin B, vancomycin, cidofovir, foscarnet, cisplatin, pentamidine, cyclosporine, tacrolimus, herbal remedies (eg, compounds with aristolochic acid)) within 28 days of Day -1. * Individuals requiring or anticipated to require dialysis within 90 days of study entry. * Serum albumin concentration \<25 g/L. * Uncontrolled treated/untreated hypertension (defined as a mean of 3 repeated measurements for systolic blood pressure ≥180 mmHg and/or diastolic blood pressure ≥110 mmHg); current or documented history of repeated clinically significant hypotension or severe episodes of orthostatic hypotension (systolic blood pressure \<90 mmHg and/or diastolic blood pressure \<50 mmHg). Matched Control Individuals: * 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 Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic (PK) Parameter for Bulevirtide (BLV): AUCtau | Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose | AUCtau is defined as the area under the concentration versus time curve over the dosing interval at steady state at Day 6. |
| PK Parameter for BLV: Cmax ss | Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose | Cmax is defined as the maximum observed concentration of drug at steady state at Day 6. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK Parameter for BLV: Tmax | Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose; Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose | Tmax is defined as the time (observed time point) of Cmax. |
| PK Parameter for BLV: t1/2 | Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose; Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose | t1/2 is defined as the estimate of the terminal elimination half-life of the drug. |
| PK Parameter for BLV: CLss/F | Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose | CLss/F is defined as the apparent clearance at steady state at Day 6. CLss/F = Dose/AUCtau, where Dose is the dose of the drug per interval. |
| PK Parameter for BLV: Vss/F | Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose | Vss/F is defined as the apparent volume of distribution at steady state at Day 6. |
| PK Parameter for BLV: AUC0-24 | Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose | AUC0-24 is defined as the concentration of drug over time between time 0 hour and time 24 hours. |
| PD Parameter for Total BA: AUC0-24 | Days 1 and 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose | The PD effect of BLV was evaluated on plasma BA in participants with RI compared to matched control participants with normal renal function. AUC0-24 is defined as the concentration of total BA over time between time 0 hour and time 24 hours. The plasma bile acid panel includes 15 individual bile acids, and total BA is the sum of these 15 components. |
| PD Parameter for Total BA: NetAUC | Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose; Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose | The PD effect of BLV was evaluated on plasma BA in participants with RI compared to matched control participants with normal renal function. NetAUC is defined as positive portion of area under the baseline-adjusted biomarker concentration versus time curve over the dosing interval. The plasma bile acid panel includes 15 individual bile acids, and total BA is the sum of these 15 components. |
| Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | Up to 36 days | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. 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 if the AE onset date was the same as the date of study drug start date then the AE onset time must have been on or after the study drug start time. If the AE onset time was missing when the start dates was the same, the AE was considered treatment emergent.and/or any AEs leading to premature discontinuation of study drug. |
| Percentage of Participants Experiencing Laboratory Abnormalities | Up to 36 days | A treatment-emergent laboratory abnormality was any value that was outside the reference range at any time post baseline up to and including the date of last study drug dose plus 30 days. 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. Participants with at least a 1 grade increased from baseline for an individual laboratory test where the maximum post baseline laboratory abnormality was grade 1 or higher and grade 3 or higher were reported. The maximum post baseline toxicity grade across all tests for an individual participant was used in analysis. |
| Pharmacodynamic (PD) Parameter for Total Bile Acids (BA): Cmax | Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose; Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose | The PD effect of BLV was evaluated on plasma BA in participants with RI compared to matched control participants with normal renal function. Cmax is defined as the maximum observed concentration of total BA. The plasma bile acid panel includes 15 individual bile acids, and total BA is the sum of these 15 components. |
| PK Parameter for BLV: Cmax | Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose | Cmax is defined as the maximum observed concentration of drug. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States.
Pre-assignment details
98 participants were screened. The optional Groups C and D were not initiated and no participants were enrolled in these groups.
Participants by arm
| Arm | Count |
|---|---|
| Group A: BLV 2 mg (Severe RI Group) Participants with severe RI \[eGFR ≥ 15 to ≤ 29 mL/min/1.73 m\^2\] received BLV 2 mg, administered SC, QD, for 6 days. | 10 |
| Group A: BLV 2 mg (Matched Control) Participants with normal renal function (matched control group) \[eGFR ≥ 90 mL/min/1.73 m\^2\] received BLV 2 mg, administered SC, QD, for 6 days. | 10 |
| Group B: BLV 10 mg (Severe RI Group) Participants with severe RI \[eGFR ≥ 15 to ≤ 29 mL/min/1.73 m\^2\] received BLV 10 mg, administered SC, QD, for 6 days. | 11 |
| Group B: BLV 10 mg (Matched Control) Participants with normal renal function (matched control group) \[eGFR ≥ 90 mL/min/1.73 m\^2\] received BLV 10 mg, administered SC, QD, for 6 days. | 10 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 |
| Overall Study | Participant Decision | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Group B: BLV 10 mg (Severe RI Group) | Total | Group B: BLV 10 mg (Matched Control) | Group A: BLV 2 mg (Severe RI Group) | Group A: BLV 2 mg (Matched Control) |
|---|---|---|---|---|---|
| Age, Continuous | 63 years STANDARD_DEVIATION 11.1 | 59 years STANDARD_DEVIATION 11.9 | 57 years STANDARD_DEVIATION 10.6 | 59 years STANDARD_DEVIATION 15.1 | 55 years STANDARD_DEVIATION 10.6 |
| Age, Customized >=65 years | 6 Participants | 13 Participants | 2 Participants | 4 Participants | 1 Participants |
| Age, Customized Between 18 and 65 years | 5 Participants | 28 Participants | 8 Participants | 6 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 31 Participants | 8 Participants | 7 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 10 Participants | 2 Participants | 3 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| 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 | 4 Participants | 6 Participants | 0 Participants | 2 Participants | 0 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 | 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 |
| Race (NIH/OMB) White | 7 Participants | 35 Participants | 10 Participants | 8 Participants | 10 Participants |
| Region of Enrollment United States | 11 Participants | 41 Participants | 10 Participants | 10 Participants | 10 Participants |
| Sex: Female, Male Female | 3 Participants | 14 Participants | 3 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 8 Participants | 27 Participants | 7 Participants | 6 Participants | 6 Participants |
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 / 10 | 0 / 10 | 0 / 11 | 0 / 10 |
| other Total, other adverse events | 4 / 10 | 2 / 10 | 2 / 11 | 3 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 1 / 11 | 0 / 10 |
Outcome results
Primary
Pharmacokinetic (PK) Parameter for Bulevirtide (BLV): AUCtau
AUCtau is defined as the area under the concentration versus time curve over the dosing interval at steady state at Day 6.
Time frame: Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose
Population: The plasma PK Analysis Set included all enrolled participants who received at least 1 dose of BLV and had at least 1 measurable plasma PK concentration data reported by PK laboratory for the respective analyte. Participants in the PK Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: BLV 2 mg (Severe RI Group) | Pharmacokinetic (PK) Parameter for Bulevirtide (BLV): AUCtau | 94.6 hours(h)*nanograms per milliliter(ng/mL) | Standard Deviation 29.8 |
| Group A: BLV 2 mg (Matched Control) | Pharmacokinetic (PK) Parameter for Bulevirtide (BLV): AUCtau | 112 hours(h)*nanograms per milliliter(ng/mL) | Standard Deviation 32.6 |
| Group B: BLV 10 mg (Severe RI Group) | Pharmacokinetic (PK) Parameter for Bulevirtide (BLV): AUCtau | 1880 hours(h)*nanograms per milliliter(ng/mL) | Standard Deviation 642 |
| Group B: BLV 10 mg (Matched Control) | Pharmacokinetic (PK) Parameter for Bulevirtide (BLV): AUCtau | 1810 hours(h)*nanograms per milliliter(ng/mL) | Standard Deviation 560 |
90% CI: [60.1, 119]
90% CI: [80.8, 133]
Primary
PK Parameter for BLV: Cmax ss
Cmax is defined as the maximum observed concentration of drug at steady state at Day 6.
Time frame: Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose
Population: Participants in the PK Analysis Set with available data were analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: BLV 2 mg (Severe RI Group) | PK Parameter for BLV: Cmax ss | 15.0 ng/mL | Standard Deviation 8.11 |
| Group A: BLV 2 mg (Matched Control) | PK Parameter for BLV: Cmax ss | 14.6 ng/mL | Standard Deviation 9.35 |
| Group B: BLV 10 mg (Severe RI Group) | PK Parameter for BLV: Cmax ss | 311 ng/mL | Standard Deviation 110 |
| Group B: BLV 10 mg (Matched Control) | PK Parameter for BLV: Cmax ss | 307 ng/mL | Standard Deviation 156 |
90% CI: [63.6, 175]
90% CI: [77.8, 151]
Secondary
PD Parameter for Total BA: AUC0-24
The PD effect of BLV was evaluated on plasma BA in participants with RI compared to matched control participants with normal renal function. AUC0-24 is defined as the concentration of total BA over time between time 0 hour and time 24 hours. The plasma bile acid panel includes 15 individual bile acids, and total BA is the sum of these 15 components.
Time frame: Days 1 and 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose
Population: Participants in the PD Biomarker Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A: BLV 2 mg (Severe RI Group) | PD Parameter for Total BA: AUC0-24 | AUC0-24 (Day 1) | 166 h*µmol/L | Standard Deviation 109 |
| Group A: BLV 2 mg (Severe RI Group) | PD Parameter for Total BA: AUC0-24 | AUC0-24 (Day 6) | 581 h*µmol/L | Standard Deviation 442 |
| Group A: BLV 2 mg (Matched Control) | PD Parameter for Total BA: AUC0-24 | AUC0-24 (Day 1) | 108 h*µmol/L | Standard Deviation 58.8 |
| Group A: BLV 2 mg (Matched Control) | PD Parameter for Total BA: AUC0-24 | AUC0-24 (Day 6) | 705 h*µmol/L | Standard Deviation 324 |
| Group B: BLV 10 mg (Severe RI Group) | PD Parameter for Total BA: AUC0-24 | AUC0-24 (Day 1) | 1290 h*µmol/L | Standard Deviation 613 |
| Group B: BLV 10 mg (Severe RI Group) | PD Parameter for Total BA: AUC0-24 | AUC0-24 (Day 6) | 2120 h*µmol/L | Standard Deviation 1050 |
| Group B: BLV 10 mg (Matched Control) | PD Parameter for Total BA: AUC0-24 | AUC0-24 (Day 6) | 2710 h*µmol/L | Standard Deviation 669 |
| Group B: BLV 10 mg (Matched Control) | PD Parameter for Total BA: AUC0-24 | AUC0-24 (Day 1) | 1450 h*µmol/L | Standard Deviation 573 |
Comparison: Day 190% CI: [87.8, 221]
Comparison: Day 690% CI: [37.3, 120]
Comparison: Day 190% CI: [54.5, 135]
Comparison: Day 690% CI: [49.4, 100]
Secondary
PD Parameter for Total BA: NetAUC
The PD effect of BLV was evaluated on plasma BA in participants with RI compared to matched control participants with normal renal function. NetAUC is defined as positive portion of area under the baseline-adjusted biomarker concentration versus time curve over the dosing interval. The plasma bile acid panel includes 15 individual bile acids, and total BA is the sum of these 15 components.
Time frame: Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose; Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose
Population: Participants in the PD Biomarker Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A: BLV 2 mg (Severe RI Group) | PD Parameter for Total BA: NetAUC | NetAUC (Day 6) | 496 h*µmol/L | Standard Deviation 433 |
| Group A: BLV 2 mg (Severe RI Group) | PD Parameter for Total BA: NetAUC | NetAUC (Day 1) | 54.9 h*µmol/L | Standard Deviation 40.4 |
| Group A: BLV 2 mg (Matched Control) | PD Parameter for Total BA: NetAUC | NetAUC (Day 6) | 662 h*µmol/L | Standard Deviation 330 |
| Group A: BLV 2 mg (Matched Control) | PD Parameter for Total BA: NetAUC | NetAUC (Day 1) | 66.1 h*µmol/L | Standard Deviation 57.6 |
| Group B: BLV 10 mg (Severe RI Group) | PD Parameter for Total BA: NetAUC | NetAUC (Day 1) | 1240 h*µmol/L | Standard Deviation 598 |
| Group B: BLV 10 mg (Severe RI Group) | PD Parameter for Total BA: NetAUC | NetAUC (Day 6) | 2060 h*µmol/L | Standard Deviation 1020 |
| Group B: BLV 10 mg (Matched Control) | PD Parameter for Total BA: NetAUC | NetAUC (Day 6) | 2660 h*µmol/L | Standard Deviation 666 |
| Group B: BLV 10 mg (Matched Control) | PD Parameter for Total BA: NetAUC | NetAUC (Day 1) | 1400 h*µmol/L | Standard Deviation 572 |
Comparison: Day 190% CI: [32.7, 217]
Comparison: Day 690% CI: [30.1, 112]
Comparison: Day 190% CI: [54.1, 135]
Comparison: Day 690% CI: [48.9, 99.2]
Secondary
Percentage of Participants Experiencing Laboratory Abnormalities
A treatment-emergent laboratory abnormality was any value that was outside the reference range at any time post baseline up to and including the date of last study drug dose plus 30 days. 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. Participants with at least a 1 grade increased from baseline for an individual laboratory test where the maximum post baseline laboratory abnormality was grade 1 or higher and grade 3 or higher were reported. The maximum post baseline toxicity grade across all tests for an individual participant was used in analysis.
Time frame: Up to 36 days
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A: BLV 2 mg (Severe RI Group) | Percentage of Participants Experiencing Laboratory Abnormalities | Grade 1 or Higher | 100 percentage of participants |
| Group A: BLV 2 mg (Severe RI Group) | Percentage of Participants Experiencing Laboratory Abnormalities | Grade 3 or Higher | 50.0 percentage of participants |
| Group A: BLV 2 mg (Matched Control) | Percentage of Participants Experiencing Laboratory Abnormalities | Grade 3 or Higher | 0 percentage of participants |
| Group A: BLV 2 mg (Matched Control) | Percentage of Participants Experiencing Laboratory Abnormalities | Grade 1 or Higher | 90.0 percentage of participants |
| Group B: BLV 10 mg (Severe RI Group) | Percentage of Participants Experiencing Laboratory Abnormalities | Grade 1 or Higher | 100 percentage of participants |
| Group B: BLV 10 mg (Severe RI Group) | Percentage of Participants Experiencing Laboratory Abnormalities | Grade 3 or Higher | 45.5 percentage of participants |
| Group B: BLV 10 mg (Matched Control) | Percentage of Participants Experiencing Laboratory Abnormalities | Grade 1 or Higher | 90.0 percentage of participants |
| Group B: BLV 10 mg (Matched Control) | Percentage of Participants Experiencing Laboratory Abnormalities | Grade 3 or Higher | 0 percentage of participants |
Secondary
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. 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 if the AE onset date was the same as the date of study drug start date then the AE onset time must have been on or after the study drug start time. If the AE onset time was missing when the start dates was the same, the AE was considered treatment emergent.and/or any AEs leading to premature discontinuation of study drug.
Time frame: Up to 36 days
Population: The Safety Analysis Set included all enrolled participants who received at least 1 dose of study drug BLV.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A: BLV 2 mg (Severe RI Group) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 40.0 percentage of participants |
| Group A: BLV 2 mg (Matched Control) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 20.0 percentage of participants |
| Group B: BLV 10 mg (Severe RI Group) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 27.3 percentage of participants |
| Group B: BLV 10 mg (Matched Control) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 30.0 percentage of participants |
Secondary
Pharmacodynamic (PD) Parameter for Total Bile Acids (BA): Cmax
The PD effect of BLV was evaluated on plasma BA in participants with RI compared to matched control participants with normal renal function. Cmax is defined as the maximum observed concentration of total BA. The plasma bile acid panel includes 15 individual bile acids, and total BA is the sum of these 15 components.
Time frame: Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose; Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose
Population: The plasma PD Biomarker Analysis Set included all enrolled participants who received at least 1 dose of study drug BLV and had at least 1 measurable plasma PD concentration value reported for each respective analyte. Participants in the PD Biomarker Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group A: BLV 2 mg (Severe RI Group) | Pharmacodynamic (PD) Parameter for Total Bile Acids (BA): Cmax | Cmax (Day 1) | 13.5 micromoles per liter (µmol/L) | Standard Deviation 8.58 |
| Group A: BLV 2 mg (Severe RI Group) | Pharmacodynamic (PD) Parameter for Total Bile Acids (BA): Cmax | Cmax (Day 6) | 48.1 micromoles per liter (µmol/L) | Standard Deviation 35.4 |
| Group A: BLV 2 mg (Matched Control) | Pharmacodynamic (PD) Parameter for Total Bile Acids (BA): Cmax | Cmax (Day 6) | 58.2 micromoles per liter (µmol/L) | Standard Deviation 24.5 |
| Group A: BLV 2 mg (Matched Control) | Pharmacodynamic (PD) Parameter for Total Bile Acids (BA): Cmax | Cmax (Day 1) | 8.54 micromoles per liter (µmol/L) | Standard Deviation 7.02 |
| Group B: BLV 10 mg (Severe RI Group) | Pharmacodynamic (PD) Parameter for Total Bile Acids (BA): Cmax | Cmax (Day 1) | 110 micromoles per liter (µmol/L) | Standard Deviation 50.6 |
| Group B: BLV 10 mg (Severe RI Group) | Pharmacodynamic (PD) Parameter for Total Bile Acids (BA): Cmax | Cmax (Day 6) | 168 micromoles per liter (µmol/L) | Standard Deviation 83.4 |
| Group B: BLV 10 mg (Matched Control) | Pharmacodynamic (PD) Parameter for Total Bile Acids (BA): Cmax | Cmax (Day 1) | 121 micromoles per liter (µmol/L) | Standard Deviation 53.6 |
| Group B: BLV 10 mg (Matched Control) | Pharmacodynamic (PD) Parameter for Total Bile Acids (BA): Cmax | Cmax (Day 6) | 207 micromoles per liter (µmol/L) | Standard Deviation 52.1 |
Comparison: Day 190% CI: [97.2, 263]
Comparison: Day 690% CI: [35, 124]
Comparison: Day 190% CI: [53.3, 141]
Comparison: Day 690% CI: [50.4, 105]
Secondary
PK Parameter for BLV: AUC0-24
AUC0-24 is defined as the concentration of drug over time between time 0 hour and time 24 hours.
Time frame: Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose
Population: Participants in the PK Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: BLV 2 mg (Severe RI Group) | PK Parameter for BLV: AUC0-24 | 46.5 h*ng/mL | Standard Deviation 13.3 |
| Group A: BLV 2 mg (Matched Control) | PK Parameter for BLV: AUC0-24 | 53.4 h*ng/mL | Standard Deviation 6.77 |
| Group B: BLV 10 mg (Severe RI Group) | PK Parameter for BLV: AUC0-24 | 843 h*ng/mL | Standard Deviation 480 |
| Group B: BLV 10 mg (Matched Control) | PK Parameter for BLV: AUC0-24 | 876 h*ng/mL | Standard Deviation 458 |
90% CI: [67.4, 104]
90% CI: [56.2, 179]
Secondary
PK Parameter for BLV: CLss/F
CLss/F is defined as the apparent clearance at steady state at Day 6. CLss/F = Dose/AUCtau, where Dose is the dose of the drug per interval.
Time frame: Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose
Population: Participants in the PK Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: BLV 2 mg (Severe RI Group) | PK Parameter for BLV: CLss/F | 29.9 milliliters per hour (mL/h) | Standard Deviation 13.4 |
| Group A: BLV 2 mg (Matched Control) | PK Parameter for BLV: CLss/F | 19.1 milliliters per hour (mL/h) | Standard Deviation 7.54 |
| Group B: BLV 10 mg (Severe RI Group) | PK Parameter for BLV: CLss/F | 5.80 milliliters per hour (mL/h) | Standard Deviation 1.69 |
| Group B: BLV 10 mg (Matched Control) | PK Parameter for BLV: CLss/F | 6.09 milliliters per hour (mL/h) | Standard Deviation 2.22 |
Secondary
PK Parameter for BLV: Cmax
Cmax is defined as the maximum observed concentration of drug.
Time frame: Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose
Population: Participants in the PK Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: BLV 2 mg (Severe RI Group) | PK Parameter for BLV: Cmax | 12.3 ng/mL | Standard Deviation 4.91 |
| Group A: BLV 2 mg (Matched Control) | PK Parameter for BLV: Cmax | 13.1 ng/mL | Standard Deviation 6.49 |
| Group B: BLV 10 mg (Severe RI Group) | PK Parameter for BLV: Cmax | 121 ng/mL | Standard Deviation 86.2 |
| Group B: BLV 10 mg (Matched Control) | PK Parameter for BLV: Cmax | 146 ng/mL | Standard Deviation 83.9 |
90% CI: [65.1, 143]
90% CI: [42.7, 142]
Secondary
PK Parameter for BLV: t1/2
t1/2 is defined as the estimate of the terminal elimination half-life of the drug.
Time frame: Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose; Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose
Population: Participants in the PK Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group A: BLV 2 mg (Severe RI Group) | PK Parameter for BLV: t1/2 | t1/2 (Day 1) | 2.47 h |
| Group A: BLV 2 mg (Severe RI Group) | PK Parameter for BLV: t1/2 | t1/2 (Day 6) | 3.98 h |
| Group A: BLV 2 mg (Matched Control) | PK Parameter for BLV: t1/2 | t1/2 (Day 6) | 4.60 h |
| Group A: BLV 2 mg (Matched Control) | PK Parameter for BLV: t1/2 | t1/2 (Day 1) | 3.95 h |
| Group B: BLV 10 mg (Severe RI Group) | PK Parameter for BLV: t1/2 | t1/2 (Day 1) | 2.86 h |
| Group B: BLV 10 mg (Severe RI Group) | PK Parameter for BLV: t1/2 | t1/2 (Day 6) | 2.79 h |
| Group B: BLV 10 mg (Matched Control) | PK Parameter for BLV: t1/2 | t1/2 (Day 1) | 3.03 h |
| Group B: BLV 10 mg (Matched Control) | PK Parameter for BLV: t1/2 | t1/2 (Day 6) | 2.75 h |
Secondary
PK Parameter for BLV: Tmax
Tmax is defined as the time (observed time point) of Cmax.
Time frame: Day 1: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours postdose; Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose
Population: Participants in the PK Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Group A: BLV 2 mg (Severe RI Group) | PK Parameter for BLV: Tmax | Tmax (Day 1) | 1.00 h |
| Group A: BLV 2 mg (Severe RI Group) | PK Parameter for BLV: Tmax | Tmax (Day 6) | 1.00 h |
| Group A: BLV 2 mg (Matched Control) | PK Parameter for BLV: Tmax | Tmax (Day 6) | 1.50 h |
| Group A: BLV 2 mg (Matched Control) | PK Parameter for BLV: Tmax | Tmax (Day 1) | 1.00 h |
| Group B: BLV 10 mg (Severe RI Group) | PK Parameter for BLV: Tmax | Tmax (Day 1) | 4.00 h |
| Group B: BLV 10 mg (Severe RI Group) | PK Parameter for BLV: Tmax | Tmax (Day 6) | 3.00 h |
| Group B: BLV 10 mg (Matched Control) | PK Parameter for BLV: Tmax | Tmax (Day 1) | 4.00 h |
| Group B: BLV 10 mg (Matched Control) | PK Parameter for BLV: Tmax | Tmax (Day 6) | 3.00 h |
Secondary
PK Parameter for BLV: Vss/F
Vss/F is defined as the apparent volume of distribution at steady state at Day 6.
Time frame: Day 6: Predose (≤ 30 minutes before dose), 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 24, and 48 hours postdose
Population: Participants in the PK Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group A: BLV 2 mg (Severe RI Group) | PK Parameter for BLV: Vss/F | 222 mL | Standard Deviation 175 |
| Group A: BLV 2 mg (Matched Control) | PK Parameter for BLV: Vss/F | 121 mL | Standard Deviation 69.4 |
| Group B: BLV 10 mg (Severe RI Group) | PK Parameter for BLV: Vss/F | 24.4 mL | Standard Deviation 10.7 |
| Group B: BLV 10 mg (Matched Control) | PK Parameter for BLV: Vss/F | 25.0 mL | Standard Deviation 14.2 |