Study to Evaluate the Pharmacokinetics of Filgotinib in Participants With Impaired Hepatic Function

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03417778
• Collaborator: Galapagos NV (Industry)
• Enrollment: 20
• Locations: 4
• Arms: 3
• Actual Duration (Months): 4.2
• Patients Per Site: 5
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the pharmacokinetics (PK) of filgotinib and its metabolite, GS-829845, in participants with varying degrees of impaired hepatic function relative to matched, healthy controls.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Filgotinib	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Open-Label Study to Evaluate the Pharmacokinetics of Filgotinib in Subjects With Impaired Hepatic Function
• Actual Study Start Date: Apr 3, 2018
• Actual Primary Completion Date: Aug 9, 2018
• Actual Study Completion Date: Aug 9, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Moderate Hepatic Impairment Participants with moderate hepatic impairment and matched healthy controls will receive a single dose of filgotinib on Day 1.	Drug: Filgotinib; 100 mg tablet administered orally; Other Names: GS-6034 GLPG0634
Experimental: Severe Hepatic Impairment Participants with severe hepatic impairment and matched healthy controls will receive a single dose of filgotinib on Day 1.	Drug: Filgotinib; 100 mg tablet administered orally; Other Names: GS-6034 GLPG0634
Experimental: Mild Hepatic Impairment Participants with mild hepatic impairment and matched healthy controls will receive a single dose of filgotinib on Day 1.	Drug: Filgotinib; 100 mg tablet administered orally; Other Names: GS-6034 GLPG0634

Outcome Measures

Primary Outcome Measures

1. Pharmacokinetic (PK) Parameter: AUClast of Filgotinib [Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 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.

2. PK Parameter: AUClast of GS-829845 [Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 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. GS-829845 is the primary metabolite of filgotinib.

3. PK Parameter: AUCinf of Filgotinib [Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1]

   AUCinf is defined as the concentration of drug extrapolated to infinite time.

4. PK Parameter: AUCinf of GS-829845 [Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1]

   AUCinf is defined as the concentration of drug extrapolated to infinite time. GS-829845 is the primary metabolite of filgotinib.

5. PK Parameter: Cmax of Filgotinib [Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1]

   Cmax is defined as the maximum observed concentration of drug.

6. PK Parameter: Cmax of GS-829845 [Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1]

   Cmax is defined as the maximum observed concentration of drug. GS-829845 is the primary metabolite of filgotinib.

Secondary Outcome Measures

1. Percentage of Participants Who Experienced Treatment-Emergent Adverse Events [Day 1 up to Day 31]

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Key Inclusion Criteria:

• Eligible individuals will be male and nonpregnant, nonlactating females, aged 18 to 70 years (inclusive), body mass index (BMI) between 18 and 36 kg/m^2 (inclusive), with either impaired hepatic function or normal hepatic function.

• Individuals will be current nonsmokers (no use of tobacco, nicotine-containing, or tetrahydrocannabinol [THC]-containing products within the last 14 days).

• Individuals with hepatic impairment will be categorized by the Child-Pugh-Turcotte (CPT) classification system indicating hepatic impairment as follows:

• Class A (mild): CPT score 5-6

• Class B (moderate): CPT score 7-9

• Class C (severe): CPT score 10-15

• Hepatic impairment must have been stable during the 3 months (90 days) prior to study drug. Each individual in the control group will be matched to a individual with impaired hepatic function by age (± 10 years), gender, and body mass index (± 15%).

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Pharmacology of Miami	Miami	Florida	United States	33014
2	American Research Corporation at the Texas Liver Institute	San Antonio	Texas	United States	78215
3	APEX GmbH	Munich		Germany	81241
4	Auckland Clinical Studies Ltd.	Grafton	Auckland	New Zealand	1010

Sponsors and Collaborators

• Gilead Sciences
• Galapagos NV

Investigators

• Study Director: Gilead Study Director, Gilead Sciences

Study Documents (Full-Text)

• Study Protocol - Dec 19, 2017
• Statistical Analysis Plan - Dec 10, 2018

More Information

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT03417778
• Other Study ID Numbers: GS-US-417-4048; 2017-000156-25
• First Posted: Jan 31, 2018
• Last Update Posted: Jan 15, 2021
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Arthritis; Arthritis, Rheumatoid

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at study sites in Germany, New Zealand, and United States. The first participant was screened on 03 April 2018. The last study visit occurred on 09 August 2018.
Pre-assignment Detail	38 participants were screened. Per protocol, participants in adaptive Cohort 2 (severe hepatic impairment) and Cohort 3 (mild hepatic impairment) were not enrolled following review of safety and pharmacokinetic (PK) data from participants in Cohort 1 (moderate hepatic impairment).

Arm/Group Title	Moderate Hepatic Impairment	Healthy Control
Arm/Group Description	Participants with moderate hepatic impairment received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.	Matched healthy control participants received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.
Period Title: Overall Study
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Moderate Hepatic Impairment	Healthy Control	Total
Arm/Group Description	Participants with moderate hepatic impairment received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.	Matched healthy control participants received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.	Total of all reporting groups
Overall Participants	10	10	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61 (6.9)	62 (5.3)	61 (6.1)
Sex: Female, Male (Count of Participants)
Female	7 70%	7 70%	14 70%
Male	3 30%	3 30%	6 30%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 50%	5 50%	10 50%
Not Hispanic or Latino	5 50%	5 50%	10 50%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	10 100%	10 100%	20 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
New Zealand	2 20%	2 20%	4 20%
United States	6 60%	6 60%	12 60%
Germany	2 20%	2 20%	4 20%

Outcome Measures

1. Primary Outcome

Title	Pharmacokinetic (PK) Parameter: AUClast of Filgotinib
Description	AUClast is defined as the concentration of drug from time zero to the last observable concentration.
Time Frame	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1

Outcome Measure Data

Analysis Population Description

The PK Analysis Set included all enrolled participants who received at least 1 dose of filgotinib and had at least 1 nonmissing postdose concentration value of filgotinib or its primary metabolite GS-829845 reported by the PK laboratory.

Arm/Group Title	Moderate Hepatic Impairment	Healthy Control
Arm/Group Description	Participants with moderate hepatic impairment received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.	Matched healthy control participants received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.
Measure Participants	10	10
Mean (Standard Deviation) [h*ng/mL]	2389.3 (530.85)	1981.9 (995.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate Hepatic Impairment, Healthy Control
	Comments	An analysis of variance (ANOVA) model was fitted to the natural logarithmic transformed values of the AUClast. Two-sided 90% confidence intervals (CI) were calculated for the geometric least-squares mean (GLSM) ratio of AUClast between hepatic impairment group versus the matched control (normal hepatic function) group.
	Type of Statistical Test	Other
	Comments	If the upper bound of the 2-sided 90% CIs of the GLSM ratio for AUClast of filgotinib falls within the [50%, 200%] bound, the null hypothesis that participants with hepatic impairment exhibit AUClast change of at least 2-fold for filgotinib compared with participants with normal liver function will be rejected.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GLSM Ratio
	Estimated Value	161.14
	Confidence Interval	(2-Sided) 90%; 80.77 to 321.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	PK Parameter: AUClast of GS-829845
Description	AUClast is defined as the concentration of drug from time zero to the last observable concentration. GS-829845 is the primary metabolite of filgotinib.
Time Frame	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1

Outcome Measure Data

Analysis Population Description

Participants in the PK Analysis Set were analyzed.

Arm/Group Title	Moderate Hepatic Impairment	Healthy Control
Arm/Group Description	Participants with moderate hepatic impairment received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.	Matched healthy control participants received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.
Measure Participants	10	10
Mean (Standard Deviation) [h*ng/mL]	32466.8 (10898.85)	31412.6 (13758.34)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate Hepatic Impairment, Healthy Control
	Comments	An ANOVA model was fitted to the natural logarithmic transformed values of the AUClast. Two-sided 90% CI were calculated for the GLSM ratio of AUClast between hepatic impairment group versus the matched control (normal hepatic function) group.
	Type of Statistical Test	Other
	Comments	If the upper bound of the 2-sided 90% CIs of the GLSM ratio for AUClast of GS-829845 falls within the [50%, 200%] bound, the null hypothesis that participants with hepatic impairment exhibit AUClast change of at least 2-fold for GS-829845 compared with participants with normal liver function will be rejected.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GLSM Ratio
	Estimated Value	122.08
	Confidence Interval	(2-Sided) 90%; 69.67 to 213.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	PK Parameter: AUCinf of Filgotinib
Description	AUCinf is defined as the concentration of drug extrapolated to infinite time.
Time Frame	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1

Outcome Measure Data

Analysis Population Description

Participants in the PK Analysis Set were analyzed.

Arm/Group Title	Moderate Hepatic Impairment	Healthy Control
Arm/Group Description	Participants with moderate hepatic impairment received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.	Matched healthy control participants received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.
Measure Participants	10	10
Mean (Standard Deviation) [h*ng/mL]	2417.0 (533.74)	1995.9 (997.88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate Hepatic Impairment, Healthy Control
	Comments	An ANOVA model was fitted to the natural logarithmic transformed values of the AUCinf. Two-sided 90% CI were calculated for the GLSM ratio of AUCinf between hepatic impairment group versus the matched control (normal hepatic function) group.
	Type of Statistical Test	Other
	Comments	If the upper bound of the 2-sided 90% CIs of the GLSM ratio for AUCinf of filgotinib falls within the [50%, 200%] bound, the null hypothesis that participants with hepatic impairment exhibit AUCinf change of at least 2-fold for filgotinib compared with participants with normal liver function will be rejected.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GLSM Ratio
	Estimated Value	159.15
	Confidence Interval	(2-Sided) 90%; 82.22 to 308.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	PK Parameter: AUCinf of GS-829845
Description	AUCinf is defined as the concentration of drug extrapolated to infinite time. GS-829845 is the primary metabolite of filgotinib.
Time Frame	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1

Outcome Measure Data

Analysis Population Description

Participants in the PK Analysis Set were analyzed.

Arm/Group Title	Moderate Hepatic Impairment	Healthy Control
Arm/Group Description	Participants with moderate hepatic impairment received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.	Matched healthy control participants received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.
Measure Participants	10	10
Mean (Standard Deviation) [h*ng/mL]	33296.5 (11568.33)	32060.0 (14329.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate Hepatic Impairment, Healthy Control
	Comments	An ANOVA model was fitted to the natural logarithmic transformed values of the AUCinf. Two-sided 90% CI were calculated for the GLSM ratio of AUCinf between hepatic impairment group versus the matched control (normal hepatic function) group.
	Type of Statistical Test	Other
	Comments	If the upper bound of the 2-sided 90% CIs of the GLSM ratio for AUCinf of GS-829845 falls within the [50%, 200%] bound, the null hypothesis that participants with hepatic impairment exhibit AUCinf change of at least 2-fold for GS-829845 compared with participants with normal liver function will be rejected.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GLSM Ratio
	Estimated Value	122.32
	Confidence Interval	(2-Sided) 90%; 69.90 to 214.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	PK Parameter: Cmax of Filgotinib
Description	Cmax is defined as the maximum observed concentration of drug.
Time Frame	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1

Outcome Measure Data

Analysis Population Description

Participants in the PK Analysis Set were analyzed.

Arm/Group Title	Moderate Hepatic Impairment	Healthy Control
Arm/Group Description	Participants with moderate hepatic impairment received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.	Matched healthy control participants received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.
Measure Participants	10	10
Mean (Standard Deviation) [ng/mL]	722.6 (293.24)	802.2 (485.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate Hepatic Impairment, Healthy Control
	Comments	An ANOVA model was fitted to the natural logarithmic transformed values of the Cmax. Two-sided 90% CI were calculated for the GLSM ratio of Cmax between hepatic impairment group versus the matched control (normal hepatic function) group.
	Type of Statistical Test	Other
	Comments	If the upper bound of the 2-sided 90% CIs of the GLSM ratio for Cmax of filgotinib falls within the [50%, 200%] bound, the null hypothesis that participants with hepatic impairment exhibit Cmax change of at least 2-fold for filgotinib compared with participants with normal liver function will be rejected.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GLSM Ratio
	Estimated Value	115.98
	Confidence Interval	(2-Sided) 90%; 58.75 to 228.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Primary Outcome

Title	PK Parameter: Cmax of GS-829845
Description	Cmax is defined as the maximum observed concentration of drug. GS-829845 is the primary metabolite of filgotinib.
Time Frame	Predose and 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 18, 24, 36, 48, 72, 96, and 120 hours postdose on Day 1

Outcome Measure Data

Analysis Population Description

Participants in the PK Analysis Set were analyzed.

Arm/Group Title	Moderate Hepatic Impairment	Healthy Control
Arm/Group Description	Participants with moderate hepatic impairment received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.	Matched healthy control participants received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.
Measure Participants	10	10
Mean (Standard Deviation) [ng/mL]	972.5 (256.09)	1122.6 (447.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Moderate Hepatic Impairment, Healthy Control
	Comments	An ANOVA model was fitted to the natural logarithmic transformed values of the Cmax. Two-sided 90% CI were calculated for the GLSM ratio of Cmax between hepatic impairment group versus the matched control (normal hepatic function) group.
	Type of Statistical Test	Other
	Comments	If the upper bound of the 2-sided 90% CIs of the GLSM ratio for Cmax of GS-829845 falls within the [50%, 200%] bound, the null hypothesis that participants with hepatic impairment exhibit Cmax change of at least 2-fold for GS-829845 compared with participants with normal liver function will be rejected.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	GLSM Ratio
	Estimated Value	102.85
	Confidence Interval	(2-Sided) 90%; 60.12 to 175.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Participants Who Experienced Treatment-Emergent Adverse Events
Time Frame	Day 1 up to Day 31

Outcome Measure Data

Analysis Population Description

The Safety Analysis Set included all enrolled participants who received at least 1 dose of study drug.

Arm/Group Title	Moderate Hepatic Impairment	Healthy Control
Arm/Group Description	Participants with moderate hepatic impairment received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.	Matched healthy control participants received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.
Measure Participants	10	10
Number [percentage of participants]	30.0 300%	10.0 100%

8. Secondary Outcome

Title	Percentage of Participants Who Experienced Graded Laboratory Abnormalities
Description	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.
Time Frame	Day 1 up to Day 31

Outcome Measure Data

Analysis Population Description

Participants in the Safety Analysis Set were analyzed.

Arm/Group Title	Moderate Hepatic Impairment	Healthy Control
Arm/Group Description	Participants with moderate hepatic impairment received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.	Matched healthy control participants received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.
Measure Participants	10	10
Any Laboratory Abnormality	90.0 900%	70.0 700%
Grade 3 or 4 Laboratory Abnormalities	60.0 600%	0.0 0%

Adverse Events

Time Frame	Day 1 up to Day 31
Adverse Event Reporting Description	The Safety Analysis Set included all enrolled participants who received at least 1 dose of study drug.
Arm/Group Title	Moderate Hepatic Impairment		Healthy Control
Arm/Group Description	Participants with moderate hepatic impairment received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.		Matched healthy control participants received a single dose of filgotinib 100 mg administered orally on Day 1, in a fasted state.
All Cause Mortality
	Moderate Hepatic Impairment		Healthy Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Serious Adverse Events
	Moderate Hepatic Impairment		Healthy Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Moderate Hepatic Impairment		Healthy Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/10 (30%)		1/10 (10%)
Gastrointestinal disorders
Diarrhoea	1/10 (10%)		0/10 (0%)
General disorders
Chest discomfort	1/10 (10%)		0/10 (0%)
Infections and infestations
Rhinitis	0/10 (0%)		1/10 (10%)
Respiratory, thoracic and mediastinal disorders
Cough	1/10 (10%)		0/10 (0%)
Dyspnoea	1/10 (10%)		0/10 (0%)
Skin and subcutaneous tissue disorders
Rash papular	1/10 (10%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or The study has been completed at all study sites for at least 2 years