Inflammatory Disease
Conditions
Brief summary
The primary objective of this study is to evaluate the pharmacokinetics (PK) of lanraplenib in participants with impaired renal function relative to matched healthy controls. Participants in this study will be enrolled using an adaptive design that includes up to 3 enrolled cohorts. Based on safety and/or PK data in Cohort 1, participants will be enrolled in adaptive Cohorts 2 and/or 3.
Interventions
DRUGLanraplenib.
20 mg (2 X 10 mg) tablets administered orally in a fasted state on Day 1
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: All Individuals * Have the ability to understand and sign a written informed consent form (ICF), which must be obtained prior to initiation of study procedures * Have a calculated body mass index (BMI) of ≥ 18 kg/m\^2 and ≤ 36 kg/m\^2 at screening * Females of childbearing potential must have a negative pregnancy test at screening and clinic admission (Day -1). * 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. * Have either a normal 12-lead electrocardiogram (ECG) or one with abnormalities that are considered clinically insignificant by the investigator in consultation with the sponsor * Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs For Individuals with Renal Impairment * Must have diagnosis of chronic (\> 6 months), stable renal impairment with no clinically significant change in renal function status within 90 days prior to study drug administration (Day 1). * Have a creatinine clearance (CLcr) \< 90 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at screening. For Healthy Matched Controlled Individuals (Individuals with Normal Renal Function) * Have a CLcr ≥ 90 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at screening * Match in age (± 10 years), gender, and body mass index (± 20%, 18 kg/m\^2 ≤ BMI ≤ 36 kg/m\^2). Key
Exclusion criteria
* Be a lactating female * Have received any investigational compound within 30 days prior to study dosing * Have current alcohol or substance abuse judged by the investigator to potentially interfere with individual's compliance or individual's safety as judged by the investigator * Have a positive test result for human immunodeficiency virus type 1 (HIV-1) antibody, hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus (HCV) antibody * Have poor venous access that limits phlebotomy For Individuals with Renal Impairment * Require or are anticipated to require dialysis within 90 days of study dosing * Require during the study or have received moderate or strong inhibitors or inducers of cytochrome P450 (CYP) 3A within 2 weeks prior to study drug administration. For Healthy Matched Controlled Individuals (Individuals with Normal Renal Function) * Have taken any prescription medications or over-the-counter medications, including herbal products and antacids, 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 and/or stable hormone replacement therapy in peri- /post-menopausal female Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic (PK) Parameter: AUClast of Lanraplenib Presented Based on Range of CLcr | 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose on Day 1 | AUClast is defined as the concentration of drug from time zero to the last observable concentration. CLcr was estimated using the CG equation for renal function as recommended by the FDA and international guidance documents. CG equation: For men: CLcr (mL/min) = (\[140-age in years\] × \[body weight in kg\])/(72 × serum creatinine in mg/dL) For women: CLcr (mL/min) = 0.85 × (\[140-age in years\] × \[body weight in kg\])/(72 × serum creatinine in mg/dL) Participants were classified based on estimated CLcr as: Moderate renal impairment: CLcr 30-59 mL/min Severe renal impairment: CLcr 15-29 mL/min Healthy control: CLcr ≥ 90 mL/min |
| PK Parameter: AUCinf of Lanraplenib Presented Based on Range of CLcr | 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose on Day 1 | AUCinf is defined as the concentration of drug extrapolated to infinite time. CLcr was estimated using the CG equation for renal function as recommended by the FDA and international guidance documents. CG equation: For men: CLcr (mL/min) = (\[140-age in years\] × \[body weight in kg\])/(72 × serum creatinine in mg/dL) For women: CLcr (mL/min) = 0.85 × (\[140-age in years\] × \[body weight in kg\])/(72 × serum creatinine in mg/dL) Participants were classified based on estimated CLcr as: Moderate renal impairment: CLcr 30-59 mL/min Severe renal impairment: CLcr 15-29 mL/min Healthy control: CLcr ≥ 90 mL/min |
| PK Parameter: Cmax of Lanraplenib Presented Based on Range of CLcr | 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose on Day 1 | Cmax is defined as the maximum concentration of drug. CLcr was estimated using the CG equation for renal function as recommended by the FDA and international guidance documents. CG equation: For men: CLcr (mL/min) = (\[140-age in years\] × \[body weight in kg\])/(72 × serum creatinine in mg/dL) For women: CLcr (mL/min) = 0.85 × (\[140-age in years\] × \[body weight in kg\])/(72 × serum creatinine in mg/dL) Participants were classified based on estimated CLcr as: Moderate renal impairment: CLcr 30-59 mL/min Severe renal impairment: CLcr 15-29 mL/min Healthy control: CLcr ≥ 90 mL/min |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | Day 1 up to Day 31 | — |
| Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Day 1 up to Day 31 | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant. The criteria used for grading was Common Terminology Criteria for Adverse Events (CTCAE) v 4.03. |
Countries
Germany, New Zealand, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in United States, New Zealand, and Germany. The first participant was screened on 21 November 2016. The last study visit occurred on 05 October 2018.
Pre-assignment details
75 participants were screened. Participants in adaptive Cohort 3 (Mild renal impairment) were not enrolled following review of safety and pharmacokinetic (PK) data from participants in Cohort 1 (moderate renal impairment).
Participants by arm
| Arm | Count |
|---|---|
| Moderate Renal Impairment Participants with moderate renal impairment received a single oral dose of lanraplenib 20 mg (2 x 10 mg tablets) in a fasted state, on Day 1. | 10 |
| Severe Renal Impairment Participants with severe renal impairment received a single oral dose of 20 mg (2 x 10 mg tablets) lanraplenib tablets in a fasted state, on Day 1. | 9 |
| Healthy Control Matched healthy control participants received a single oral dose of 20 mg (2 x 10 mg tablets) lanraplenib tablets in a fasted state, on Day 1. | 16 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Enrolled but Never Treated | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Moderate Renal Impairment | Total | Healthy Control | Severe Renal Impairment |
|---|---|---|---|---|
| Age, Continuous | 67 years STANDARD_DEVIATION 5.5 | 62 years STANDARD_DEVIATION 9.3 | 61 years STANDARD_DEVIATION 9.4 | 59 years STANDARD_DEVIATION 11.6 |
| Estimated Creatinine Clearance (CLcr) | 45.3 mL/min STANDARD_DEVIATION 11.46 | 66.5 mL/min STANDARD_DEVIATION 37.96 | 104.0 mL/min STANDARD_DEVIATION 16.21 | 23.4 mL/min STANDARD_DEVIATION 4.31 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 10 Participants | 5 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 25 Participants | 11 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black | 1 Participants | 4 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Race White | 9 Participants | 29 Participants | 12 Participants | 8 Participants |
| Region of Enrollment Germany | 0 Participants | 9 Participants | 5 Participants | 4 Participants |
| Region of Enrollment New Zealand | 2 Participants | 8 Participants | 3 Participants | 3 Participants |
| Region of Enrollment United States | 8 Participants | 18 Participants | 8 Participants | 2 Participants |
| Sex: Female, Male Female | 5 Participants | 18 Participants | 9 Participants | 4 Participants |
| Sex: Female, Male Male | 5 Participants | 17 Participants | 7 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 9 | 0 / 16 |
| other Total, other adverse events | 6 / 10 | 5 / 9 | 2 / 16 |
| serious Total, serious adverse events | 0 / 10 | 0 / 9 | 0 / 16 |
Outcome results
Primary
Pharmacokinetic (PK) Parameter: AUClast of Lanraplenib Presented Based on Range of CLcr
AUClast is defined as the concentration of drug from time zero to the last observable concentration. CLcr was estimated using the CG equation for renal function as recommended by the FDA and international guidance documents. CG equation: For men: CLcr (mL/min) = (\[140-age in years\] × \[body weight in kg\])/(72 × serum creatinine in mg/dL) For women: CLcr (mL/min) = 0.85 × (\[140-age in years\] × \[body weight in kg\])/(72 × serum creatinine in mg/dL) Participants were classified based on estimated CLcr as: Moderate renal impairment: CLcr 30-59 mL/min Severe renal impairment: CLcr 15-29 mL/min Healthy control: CLcr ≥ 90 mL/min
Time frame: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose on Day 1
Population: PK Analysis Set included all enrolled participants who took study drug, had at least 1 nonmissing postdose concentration value reported by PK lab for corresponding analytes, based on CLcr. Some healthy control participants matched to participants with moderate renal impairment were also used as matches to participants with severe renal impairment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Moderate Renal Impairment | Pharmacokinetic (PK) Parameter: AUClast of Lanraplenib Presented Based on Range of CLcr | 2317.8 h*ng/mL | Standard Deviation 813.83 |
| Cohort 1: Healthy Control | Pharmacokinetic (PK) Parameter: AUClast of Lanraplenib Presented Based on Range of CLcr | 2027.4 h*ng/mL | Standard Deviation 424.52 |
| Cohort 2: Severe Renal Impairment | Pharmacokinetic (PK) Parameter: AUClast of Lanraplenib Presented Based on Range of CLcr | 2076.3 h*ng/mL | Standard Deviation 812.99 |
| Cohort 2: Healthy Control | Pharmacokinetic (PK) Parameter: AUClast of Lanraplenib Presented Based on Range of CLcr | 1871.6 h*ng/mL | Standard Deviation 519.06 |
Comparison: The Estimate statement was used to produce the point estimate and the corresponding 90% confidence interval of the difference in PK parameters of interest on a logarithmic scale.90% CI: [86.94, 143.47]
Comparison: The Estimate statement was used to produce the point estimate and the corresponding 90% CI of the difference in PK parameters of interest on a logarithmic scale.90% CI: [78.47, 146.02]
Primary
PK Parameter: AUCinf of Lanraplenib Presented Based on Range of CLcr
AUCinf is defined as the concentration of drug extrapolated to infinite time. CLcr was estimated using the CG equation for renal function as recommended by the FDA and international guidance documents. CG equation: For men: CLcr (mL/min) = (\[140-age in years\] × \[body weight in kg\])/(72 × serum creatinine in mg/dL) For women: CLcr (mL/min) = 0.85 × (\[140-age in years\] × \[body weight in kg\])/(72 × serum creatinine in mg/dL) Participants were classified based on estimated CLcr as: Moderate renal impairment: CLcr 30-59 mL/min Severe renal impairment: CLcr 15-29 mL/min Healthy control: CLcr ≥ 90 mL/min
Time frame: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose on Day 1
Population: Participants in the PK Analysis Set were analyzed, based on CLcr. Some healthy control participants matched to participants with moderate renal impairment were also used as matches to participants with severe renal impairment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Moderate Renal Impairment | PK Parameter: AUCinf of Lanraplenib Presented Based on Range of CLcr | 2478.7 h*ng/mL | Standard Deviation 908.61 |
| Cohort 1: Healthy Control | PK Parameter: AUCinf of Lanraplenib Presented Based on Range of CLcr | 2153.0 h*ng/mL | Standard Deviation 435.44 |
| Cohort 2: Severe Renal Impairment | PK Parameter: AUCinf of Lanraplenib Presented Based on Range of CLcr | 2223.4 h*ng/mL | Standard Deviation 855.97 |
| Cohort 2: Healthy Control | PK Parameter: AUCinf of Lanraplenib Presented Based on Range of CLcr | 1994.2 h*ng/mL | Standard Deviation 528.55 |
Comparison: The Estimate statement was used to produce the point estimate and the corresponding 90% CI of the difference in PK parameters of interest on a logarithmic scale.90% CI: [86.92, 144.12]
Comparison: The Estimate statement was used to produce the point estimate and the corresponding 90% CI of the difference in PK parameters of interest on a logarithmic scale.90% CI: [79.63, 145.65]
Primary
PK Parameter: Cmax of Lanraplenib Presented Based on Range of CLcr
Cmax is defined as the maximum concentration of drug. CLcr was estimated using the CG equation for renal function as recommended by the FDA and international guidance documents. CG equation: For men: CLcr (mL/min) = (\[140-age in years\] × \[body weight in kg\])/(72 × serum creatinine in mg/dL) For women: CLcr (mL/min) = 0.85 × (\[140-age in years\] × \[body weight in kg\])/(72 × serum creatinine in mg/dL) Participants were classified based on estimated CLcr as: Moderate renal impairment: CLcr 30-59 mL/min Severe renal impairment: CLcr 15-29 mL/min Healthy control: CLcr ≥ 90 mL/min
Time frame: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96 and 120 hours postdose on Day 1
Population: Participants in the PK Analysis Set were analyzed, based on CLcr. Some healthy control participants matched to participants with moderate renal impairment were also used as matches to participants with severe renal impairment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: Moderate Renal Impairment | PK Parameter: Cmax of Lanraplenib Presented Based on Range of CLcr | 134.4 ng/mL | Standard Deviation 35.47 |
| Cohort 1: Healthy Control | PK Parameter: Cmax of Lanraplenib Presented Based on Range of CLcr | 131.6 ng/mL | Standard Deviation 33.71 |
| Cohort 2: Severe Renal Impairment | PK Parameter: Cmax of Lanraplenib Presented Based on Range of CLcr | 118.0 ng/mL | Standard Deviation 38.97 |
| Cohort 2: Healthy Control | PK Parameter: Cmax of Lanraplenib Presented Based on Range of CLcr | 130.5 ng/mL | Standard Deviation 30.77 |
Comparison: The Estimate statement was used to produce the point estimate and the corresponding 90% CI of the difference in PK parameters of interest on a logarithmic scale.90% CI: [81.42, 127.79]
Comparison: The Estimate statement was used to produce the point estimate and the corresponding 90% CI of the difference in PK parameters of interest on a logarithmic scale.90% CI: [68.14, 113.13]
Secondary
Percentage of Participants Who Experienced Graded Laboratory Abnormalities
Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant. The criteria used for grading was Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.
Time frame: Day 1 up to Day 31
Population: Participants in the Safety Analysis Set were analyzed. Grouping for the analysis was done based on CLcr.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1: Moderate Renal Impairment | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Any Graded Laboratory Abnormality | 80.0 percentage of participants |
| Cohort 1: Moderate Renal Impairment | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Grade 3 or above Laboratory Abnormalities | 30.0 percentage of participants |
| Cohort 1: Healthy Control | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Any Graded Laboratory Abnormality | 100.0 percentage of participants |
| Cohort 1: Healthy Control | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Grade 3 or above Laboratory Abnormalities | 44.4 percentage of participants |
| Cohort 2: Severe Renal Impairment | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Any Graded Laboratory Abnormality | 81.3 percentage of participants |
| Cohort 2: Severe Renal Impairment | Percentage of Participants Who Experienced Graded Laboratory Abnormalities | Grade 3 or above Laboratory Abnormalities | 0 percentage of participants |
Secondary
Percentage of Participants Who Experienced Treatment-Emergent Adverse Events
Time frame: Day 1 up to Day 31
Population: The Safety Analysis Set included all enrolled participants who received lanraplenib. Grouping for the analysis was done based on CLcr.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Moderate Renal Impairment | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 60.0 percentage of participants |
| Cohort 1: Healthy Control | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 55.6 percentage of participants |
| Cohort 2: Severe Renal Impairment | Percentage of Participants Who Experienced Treatment-Emergent Adverse Events | 12.5 percentage of participants |