Rheumatoid Arthritis
Conditions
Brief summary
The primary objective of this study is to evaluate the effect of filgotinib on a mixed organic anion transporting polypeptide/cytochrome P450 3A (OATP/CYP3A), OATP/ breast cancer resistance protein (BCRP), and OATP substrates using phenotypic probes.
Interventions
DRUGRosuvastatin
Administered as single dose tablet orally.
DRUGFilgotinib
Administered as tablet orally once daily for 11 days.
DRUGAtorvastatin
Administered as single dose tablet orally.
DRUGPravastatin
Administered as single dose tablet orally.
Sponsors
Galapagos NV
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
Key Inclusion Criteria: * Be a nonsmoker. The use of nicotine or nicotine-containing products must be discontinued 90 days prior to the first dose of study drug. * Have a calculated body mass index (BMI) of greater than or equal to (≥) 19.0 and less than or equal to (≤) 30.0 kilogram per meter square (kg/m\^2) at screening. * Have a creatinine clearance (CLcr) ≥ 90 milliliters per minute (mL/min) (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at screening and upon admission. * Female participants of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at clinic admission. * Male participants must be surgically sterile. * Male participants and female participants of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception. * Screening laboratory evaluations and 12-lead electrocardiogram (ECG) evaluations must be without clinically significant abnormalities as assessed by the investigator. * Have liver biometric tests such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and total bilirubin below the upper limit of normal at screening. * Must be willing and able to comply with all study requirements. * Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs. * Participants must not have 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. Key
Exclusion criteria
* Positive serum pregnancy test (Female participants). * Lactating female. * Have received any investigational drug/device within 30 days prior to study dosing (or within 5 half-lives of the drug, whichever is longer). * Have current alcohol or substance abuse judged by the investigator to potentially interfere with participant compliance or participant safety, or a positive drug or alcohol test at screening or admission. * Have a positive test result for human immunodeficiency virus type 1 (HIV-1) antibody, hepatitis B virus (HBV) surface antigen (HBsAg), or hepatitis C virus (HCV) antibody at screening. * Have positive Coronavirus Disease 2019 (COVID-19) Real-Time Reverse. * Transcriptase-Polymerase Chain Reaction (RT-PCR) testing on screening and admission. * Have poor venous access that limits phlebotomy. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic (PK) Parameter: AUClast of ATV, PRA, and ROS | AB (Days 1,3,12,14) and BA (Days 6,8,18,20): Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 postdose; AB (Days 1,12) and BA (Days 6,18): 5,10,36 hours post dose; AB (Days 3,14) and BA (Days 8,20): 72 hours postdose | AUClast is defined as the concentration of drug from time zero to the last observable concentration. |
| PK Parameter: AUCinf of ATV, PRA, and ROS | AB (Days 1,3,12,14) and BA (Days 6,8,18,20): Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 postdose; AB (Days 1,12) and BA (Days 6,18): 5,10,36 hours post dose; AB (Days 3,14) and BA (Days 8,20): 72 hours postdose | AUCinf is defined as the concentration of drug extrapolated to infinite time. |
| PK Parameter: Cmax of ATV, PRA, and ROS | AB (Days 1,3,12,14) and BA (Days 6,8,18,20): Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 postdose; AB (Days 1,12) and BA (Days 6,18): 5,10,36 hours post dose; AB (Days 3,14) and BA (Days 8,20): 72 hours postdose | Cmax is defined as the maximum observed concentration of drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | Sequence AB: First dose up to 47 days, Sequence BA: First dose up to 50 days | An adverse event (AE) was any untoward medical occurrence in a participant administered a study drug, which did not necessarily have a causal relationship with the treatment. AE was therefore any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of the study drug, whether or not considered related to the study drug. TEAEs: AE with an onset date on or after the study drug start date and no later than 30 days after study drug stop date; or any AE leading to study drug discontinuation. |
| Percentage of Participants With Severity Grade 3 or Above Treatment-Emergent Laboratory Abnormalities | Sequence AB: First dose up to 47 days, Sequence BA: First dose up to 50 days | Treatment-emergent laboratory abnormalities were graded using Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 of Adverse Events and Laboratory abnormalities. Laboratory abnormalities were graded as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Life-threatening), Grade 5 (Death). Percentage of participants with Grade 3 or higher treatment-emergent laboratory abnormalities were reported. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at a study site in the United States. The first participant was screened on 04 November 2020. The last study visit occurred on 13 January 2021.
Pre-assignment details
55 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Sequence AB Participants received a single oral dose of ATV 40 mg tablet on Day 1, followed by a washout period of 1 day, and then a single oral dose of PRA 40 mg + ROS 10 mg tablets on Day 3 in Treatment A, Period 1. In Treatment B, Period 2 participants received an oral dose of filgotinib 200 mg tablet once daily for 11 days, with a single oral dose of ATV 40 mg on Day 12 and a single oral dose of PRA 40 mg + ROS 10 mg tablets on Day 14. Period 1 and Period 2 were separated by a washout period of 3 days. | 14 |
| Sequence BA Participants received an oral dose of filgotinib 200 mg tablet once daily for 11 days, with a single oral dose of ATV 40 mg on Day 6 and a single oral dose of PRA 40 mg + ROS 10 mg tablets on Day 8 in Treatment B, Period 1. In Treatment A, Period 2 participants received single oral dose of ATV 40 mg tablet on Day 18, followed by a washout period of 1 day and a single oral dose of PRA 40 mg + ROS 10 mg tablets on Day 20. Period 1 and Period 2 were separated by a washout period of 6 days. | 13 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 (AB: 3 Days, BA: 11 Days) | Adverse Event | 0 | 1 |
| Period 1 (AB: 3 Days, BA: 11 Days) | Investigator's Discretion | 1 | 0 |
Baseline characteristics
| Characteristic | Sequence BA | Total | Sequence AB |
|---|---|---|---|
| Age, Continuous | 29 years STANDARD_DEVIATION 7.6 | 30 years STANDARD_DEVIATION 7.3 | 31 years STANDARD_DEVIATION 7.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 26 Participants | 14 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 | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 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 | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 9 Participants | 19 Participants | 10 Participants |
| Sex: Female, Male Female | 12 Participants | 26 Participants | 14 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 27 | 0 / 27 | 0 / 27 | 0 / 27 |
| other Total, other adverse events | 2 / 26 | 4 / 25 | 13 / 26 | 2 / 26 | 0 / 26 |
| serious Total, serious adverse events | 0 / 26 | 0 / 25 | 0 / 26 | 0 / 26 | 0 / 26 |
Outcome results
Primary
Pharmacokinetic (PK) Parameter: AUClast of ATV, PRA, and ROS
AUClast is defined as the concentration of drug from time zero to the last observable concentration.
Time frame: AB (Days 1,3,12,14) and BA (Days 6,8,18,20): Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 postdose; AB (Days 1,12) and BA (Days 6,18): 5,10,36 hours post dose; AB (Days 3,14) and BA (Days 8,20): 72 hours postdose
Population: Participants in the PK Analysis Set (all randomized participants who received at least 1 dose of study drug and had at least 1 non-missing PK concentration datum reported by PK laboratory for each respective analyte) with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | Pharmacokinetic (PK) Parameter: AUClast of ATV, PRA, and ROS | ATV | 78.8 h*ng/mL | Standard Deviation 39.1 |
| Pravastatin + Rosuvastatin | Pharmacokinetic (PK) Parameter: AUClast of ATV, PRA, and ROS | PRA | 199.5 h*ng/mL | Standard Deviation 115.64 |
| Pravastatin + Rosuvastatin | Pharmacokinetic (PK) Parameter: AUClast of ATV, PRA, and ROS | ROS | 62.6 h*ng/mL | Standard Deviation 29.03 |
| Filgotinib + Atorvastatin | Pharmacokinetic (PK) Parameter: AUClast of ATV, PRA, and ROS | ATV | 70.2 h*ng/mL | Standard Deviation 27.08 |
| Filgotinib + Pravastatin + Rosuvastatin | Pharmacokinetic (PK) Parameter: AUClast of ATV, PRA, and ROS | PRA | 232.5 h*ng/mL | Standard Deviation 137.76 |
| Filgotinib + Pravastatin + Rosuvastatin | Pharmacokinetic (PK) Parameter: AUClast of ATV, PRA, and ROS | ROS | 89.3 h*ng/mL | Standard Deviation 34.63 |
Primary
PK Parameter: AUCinf of ATV, PRA, and ROS
AUCinf is defined as the concentration of drug extrapolated to infinite time.
Time frame: AB (Days 1,3,12,14) and BA (Days 6,8,18,20): Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 postdose; AB (Days 1,12) and BA (Days 6,18): 5,10,36 hours post dose; AB (Days 3,14) and BA (Days 8,20): 72 hours postdose
Population: Participants in the PK Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | PK Parameter: AUCinf of ATV, PRA, and ROS | ATV | 80.8 h*ng/mL | Standard Deviation 39.76 |
| Pravastatin + Rosuvastatin | PK Parameter: AUCinf of ATV, PRA, and ROS | PRA | 201.3 h*ng/mL | Standard Deviation 116.38 |
| Pravastatin + Rosuvastatin | PK Parameter: AUCinf of ATV, PRA, and ROS | ROS | 66.0 h*ng/mL | Standard Deviation 29.53 |
| Filgotinib + Atorvastatin | PK Parameter: AUCinf of ATV, PRA, and ROS | ATV | 71.8 h*ng/mL | Standard Deviation 27.3 |
| Filgotinib + Pravastatin + Rosuvastatin | PK Parameter: AUCinf of ATV, PRA, and ROS | PRA | 234.8 h*ng/mL | Standard Deviation 137.43 |
| Filgotinib + Pravastatin + Rosuvastatin | PK Parameter: AUCinf of ATV, PRA, and ROS | ROS | 92.3 h*ng/mL | Standard Deviation 34.94 |
Primary
PK Parameter: Cmax of ATV, PRA, and ROS
Cmax is defined as the maximum observed concentration of drug.
Time frame: AB (Days 1,3,12,14) and BA (Days 6,8,18,20): Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 postdose; AB (Days 1,12) and BA (Days 6,18): 5,10,36 hours post dose; AB (Days 3,14) and BA (Days 8,20): 72 hours postdose
Population: Participants in the PK Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Atorvastatin | PK Parameter: Cmax of ATV, PRA, and ROS | ATV | 19.7 ng/mL | Standard Deviation 13.5 |
| Pravastatin + Rosuvastatin | PK Parameter: Cmax of ATV, PRA, and ROS | PRA | 84.2 ng/mL | Standard Deviation 56.6 |
| Pravastatin + Rosuvastatin | PK Parameter: Cmax of ATV, PRA, and ROS | ROS | 7.5 ng/mL | Standard Deviation 4.17 |
| Filgotinib + Atorvastatin | PK Parameter: Cmax of ATV, PRA, and ROS | ATV | 15.0 ng/mL | Standard Deviation 7.81 |
| Filgotinib + Pravastatin + Rosuvastatin | PK Parameter: Cmax of ATV, PRA, and ROS | PRA | 99.2 ng/mL | Standard Deviation 65.68 |
| Filgotinib + Pravastatin + Rosuvastatin | PK Parameter: Cmax of ATV, PRA, and ROS | ROS | 12.3 ng/mL | Standard Deviation 6 |
Secondary
Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a participant administered a study drug, which did not necessarily have a causal relationship with the treatment. AE was therefore any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of the study drug, whether or not considered related to the study drug. TEAEs: AE with an onset date on or after the study drug start date and no later than 30 days after study drug stop date; or any AE leading to study drug discontinuation.
Time frame: Sequence AB: First dose up to 47 days, Sequence BA: First dose up to 50 days
Population: All randomized participants who received at least 1 dose of that particular study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atorvastatin | Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 19.2 percentage of participants |
| Pravastatin + Rosuvastatin | Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 24.0 percentage of participants |
| Filgotinib + Atorvastatin | Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 65.4 percentage of participants |
| Filgotinib + Pravastatin + Rosuvastatin | Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 7.7 percentage of participants |
| Filgotinib + Pravastatin + Rosuvastatin | Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | 11.5 percentage of participants |
Secondary
Percentage of Participants With Severity Grade 3 or Above Treatment-Emergent Laboratory Abnormalities
Treatment-emergent laboratory abnormalities were graded using Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 of Adverse Events and Laboratory abnormalities. Laboratory abnormalities were graded as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Life-threatening), Grade 5 (Death). Percentage of participants with Grade 3 or higher treatment-emergent laboratory abnormalities were reported.
Time frame: Sequence AB: First dose up to 47 days, Sequence BA: First dose up to 50 days
Population: Participants randomized and received at least 1 dose of that particular study drug with available data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Atorvastatin | Percentage of Participants With Severity Grade 3 or Above Treatment-Emergent Laboratory Abnormalities | 0 percentage of participants |
| Pravastatin + Rosuvastatin | Percentage of Participants With Severity Grade 3 or Above Treatment-Emergent Laboratory Abnormalities | 0 percentage of participants |
| Filgotinib + Atorvastatin | Percentage of Participants With Severity Grade 3 or Above Treatment-Emergent Laboratory Abnormalities | 3.8 percentage of participants |
| Filgotinib + Pravastatin + Rosuvastatin | Percentage of Participants With Severity Grade 3 or Above Treatment-Emergent Laboratory Abnormalities | 0 percentage of participants |
| Filgotinib + Pravastatin + Rosuvastatin | Percentage of Participants With Severity Grade 3 or Above Treatment-Emergent Laboratory Abnormalities | 0 percentage of participants |