HIV
Conditions
Keywords
Phase 1, Renally Impaired
Brief summary
The primary objective of this study is to evaluate the pharmacokinetic (PK) profile of oral bictegravir (formerly GS-9883) in adults with impaired renal function relative to matched, healthy controls with normal renal function. Each participant in the renal impairment groups will be matched for age (± 10 years), gender, and body mass index \[BMI (± 20%, 18 ≤ BMI ≤ 40 kg/m\^2)\] with a participant in the control group.
Interventions
DRUGBictegravir
75 mg tablet administered orally
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: * Must have a calculated BMI from 18 to 40 kg/m\^2, inclusive, at screening * Individuals with impaired renal function * Chronic stable renal impairment without recent clinical change * Mild: Creatinine clearance (CrCl) = 60 - 89 mL/min * Moderate: CrCl = 30 - 59 mL/min * Severe: CrCl = 15 - 29 mL/min * Healthy individuals * CrCl ≥ 90 mL/min Key
Exclusion criteria
* All Individuals: * Pregnant or lactating females * HIV positive or chronic hepatitis B infected * Individuals with impaired renal function * Chronic liver disease * Dialysis or anticipated use of dialysis * Renal transplant Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK Parameter: Cmax of Bictegravir (Free) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 1 | Free Cmax was calculated based on unbound plasma bictegravir (Cmax × percentage unbound bictegravir ÷ 100 for each participant). |
| PK Parameter: AUClast of Bictegravir (Free) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 1 | Free AUClast was calculated based on unbound plasma bictegravir (AUClast × percentage unbound bictegravir ÷ 100 for each participant). |
| PK Parameter: Cmax of Bictegravir (Total) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 1 | Cmax is defined as the maximum observed plasma concentration of drug. |
| Pharmacokinetic (PK) Parameter: AUCinf of Bictegravir (Total) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 1 | AUCinf is defined as the area under the plasma concentration versus time curve extrapolated to infinite time. |
| PK Parameter: AUCinf of Bictegravir (Free) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 1 | Free AUCinf was calculated based on unbound plasma bictegravir (AUCinf × percentage unbound bictegravir ÷ 100 for each participant). |
| PK Parameter: AUClast of Bictegravir (Total) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 1 | AUClast is defined as the area under the plasma concentration versus time curve from time zero to the last quantifiable concentration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | First dose date to Day 31 | A treatment-emergent graded laboratory abnormality was defined as an increase of at least 1 abnormality grade from the predose assessment and occurring after the predose visit and on or before the date of the administration of study drug plus 30 days. The most severe graded abnormality from all tests was counted for each participant. Toxicity grade was defined as follows: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, and Grade 4 = Life-threatening. |
| Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | First dose date to Day 31 | Treatment-emergent adverse events (TEAEs) are defined as any adverse events (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 or any AEs leading to premature discontinuation of study drug. |
Countries
New Zealand, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States and New Zealand. The first participant was screened on 17 April 2015. The last study visit occurred on 13 July 2015.
Pre-assignment details
49 participants were screened. No participants were enrolled in the moderate or mild renal impairment adaptive cohorts as a review showed that PK data collected were sufficient to detect any differences between the 2 renal function groups.
Participants by arm
| Arm | Count |
|---|---|
| Severe Renal Impairment Participants with severe renal impairment (CrCl = 15 - 29 mL/min) received a single dose of bictegravir 75 mg tablet orally on Day 1 under fed conditions | 10 |
| Normal Renal Function Matched healthy control participants with normal renal function (CrCl ≥ 90 mL/min) received a single dose of bictegravir 75 mg tablet orally on Day 1 under fed conditions | 8 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Enrolled and Never Dosed | 1 | 0 |
Baseline characteristics
| Characteristic | Normal Renal Function | Total | Severe Renal Impairment |
|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 14.7 | 59 years STANDARD_DEVIATION 15.1 | 62 years STANDARD_DEVIATION 15.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 13 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 7 Participants | 14 Participants | 7 Participants |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Male | 6 Participants | 13 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 8 |
| other Total, other adverse events | 2 / 10 | 2 / 8 |
| serious Total, serious adverse events | 0 / 10 | 0 / 8 |
Outcome results
Primary
Pharmacokinetic (PK) Parameter: AUCinf of Bictegravir (Total)
AUCinf is defined as the area under the plasma concentration versus time curve extrapolated to infinite time.
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 1
Population: The PK Analysis Set included participants who took the single dose of bictegravir and had at least 1 nonmissing postdose concentration value for bictegravir.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Impairment | Pharmacokinetic (PK) Parameter: AUCinf of Bictegravir (Total) | 138169.7 h*ng/mL | Standard Deviation 61291.27 |
| Normal Renal Function | Pharmacokinetic (PK) Parameter: AUCinf of Bictegravir (Total) | 170105.6 h*ng/mL | Standard Deviation 42213.18 |
Comparison: A sample size of 8 evaluable participants in each group will provide at least 88% power to reject the null hypothesis that participants with severe impairment have at least 100% increase in bictegravir AUCinf, AUClast, or Cmax compared to participants with normal renal function.90% CI: [48.8, 108.1]
Primary
PK Parameter: AUCinf of Bictegravir (Free)
Free AUCinf was calculated based on unbound plasma bictegravir (AUCinf × percentage unbound bictegravir ÷ 100 for each participant).
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 1
Population: Participants in the PK Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Impairment | PK Parameter: AUCinf of Bictegravir (Free) | 830.6 h*ng/mL | Standard Deviation 266.59 |
| Normal Renal Function | PK Parameter: AUCinf of Bictegravir (Free) | 824.5 h*ng/mL | Standard Deviation 203.49 |
Comparison: A sample size of 8 evaluable participants in each group will provide at least 88% power to reject the null hypothesis that participants with severe impairment have at least 100% increase in bictegravir AUCinf, AUClast, or Cmax compared to participants with normal renal function.90% CI: [79.49, 124.04]
Primary
PK Parameter: AUClast of Bictegravir (Free)
Free AUClast was calculated based on unbound plasma bictegravir (AUClast × percentage unbound bictegravir ÷ 100 for each participant).
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 1
Population: Participants in the PK Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Impairment | PK Parameter: AUClast of Bictegravir (Free) | 822.5 h*ng/mL | Standard Deviation 263.22 |
| Normal Renal Function | PK Parameter: AUClast of Bictegravir (Free) | 818.6 h*ng/mL | Standard Deviation 201.18 |
Comparison: A sample size of 8 evaluable participants in each group will provide at least 88% power to reject the null hypothesis that participants with severe impairment have at least 100% increase in bictegravir AUCinf, AUClast, or Cmax compared to participants with normal renal function.90% CI: [79.24, 123.74]
Primary
PK Parameter: AUClast of Bictegravir (Total)
AUClast is defined as the area under the plasma concentration versus time curve from time zero to the last quantifiable concentration.
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 1
Population: Participants in the PK Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Impairment | PK Parameter: AUClast of Bictegravir (Total) | 136956.4 h*ng/mL | Standard Deviation 60557.34 |
| Normal Renal Function | PK Parameter: AUClast of Bictegravir (Total) | 168876.8 h*ng/mL | Standard Deviation 41706.37 |
Comparison: A sample size of 8 evaluable participants in each group will provide at least 88% power to reject the null hypothesis that participants with severe impairment have at least 100% increase in bictegravir AUCinf, AUClast, or Cmax compared to participants with normal renal function.90% CI: [48.54, 108.07]
Primary
PK Parameter: Cmax of Bictegravir (Free)
Free Cmax was calculated based on unbound plasma bictegravir (Cmax × percentage unbound bictegravir ÷ 100 for each participant).
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 1
Population: Participants in the PK Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Impairment | PK Parameter: Cmax of Bictegravir (Free) | 37.7 ng/mL | Standard Deviation 8.15 |
| Normal Renal Function | PK Parameter: Cmax of Bictegravir (Free) | 35.0 ng/mL | Standard Deviation 9.94 |
Comparison: A sample size of 8 evaluable participants in each group will provide at least 88% power to reject the null hypothesis that participants with severe impairment have at least 100% increase in bictegravir AUCinf, AUClast, or Cmax compared to participants with normal renal function.90% CI: [87.46, 137.85]
Primary
PK Parameter: Cmax of Bictegravir (Total)
Cmax is defined as the maximum observed plasma concentration of drug.
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, 72, 96, 120 and 144 hours postdose on Day 1
Population: Participants in the PK Analysis Set were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Severe Renal Impairment | PK Parameter: Cmax of Bictegravir (Total) | 5977.0 ng/mL | Standard Deviation 2079.57 |
| Normal Renal Function | PK Parameter: Cmax of Bictegravir (Total) | 7227.5 ng/mL | Standard Deviation 2135.56 |
Comparison: A sample size of 8 evaluable participants in each group will provide at least 88% power to reject the null hypothesis that participants with severe impairment have at least 100% increase in bictegravir AUCinf, AUClast, or Cmax compared to participants with normal renal function.90% CI: [59.56, 108.3]
Secondary
Percentage of Participants Who Experienced Treatment-Emergent Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as any adverse events (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 or any AEs leading to premature discontinuation of study drug.
Time frame: First dose date to Day 31
Population: The Safety Analysis Set included participants who received the single dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Severe Renal Impairment | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 20.0 percentage of participants |
| Normal Renal Function | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 25.0 percentage of participants |
Secondary
Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities
A treatment-emergent graded laboratory abnormality was defined as an increase of at least 1 abnormality grade from the predose assessment and occurring after the predose visit and on or before the date of the administration of study drug plus 30 days. The most severe graded abnormality from all tests was counted for each participant. Toxicity grade was defined as follows: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, and Grade 4 = Life-threatening.
Time frame: First dose date to Day 31
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Severe Renal Impairment | Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Grade 1 | 20.0 percentage of participants |
| Severe Renal Impairment | Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Grade 2 | 40.0 percentage of participants |
| Severe Renal Impairment | Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Grade 3 | 40.0 percentage of participants |
| Severe Renal Impairment | Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Grade 4 | 0 percentage of participants |
| Normal Renal Function | Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Grade 4 | 0 percentage of participants |
| Normal Renal Function | Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Grade 1 | 25.0 percentage of participants |
| Normal Renal Function | Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Grade 3 | 0 percentage of participants |
| Normal Renal Function | Percentage of Participants Who Experienced Treatment-Emergent Laboratory Abnormalities | Grade 2 | 25.0 percentage of participants |