Study to Evaluate the Efficacy and Safety of Filgotinib in the Induction and Maintenance of Remission in Adults With Moderately to Severely Active Ulcerative Colitis

Study Overview
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Brief Summary
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The primary objectives of this study are to evaluate the efficacy of filgotinib in the induction and maintenance treatment of moderately to severely active ulcerative colitis (UC) in participants who are biologic-naive and biologic-experienced. Participants who complete the study, or met protocol specified efficacy discontinuation criteria will have the option to enter a separate, long-term extension (LTE) study (Gilead Study GS-US-418-3899: NCT02914535).

Official Title
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Combined Phase 2b/3, Double-Blind, Randomized, Placebo-Controlled Studies Evaluating the Efficacy and Safety of Filgotinib in the Induction and Maintenance of Remission in Subjects With Moderately to Severely Active Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Filgotinib
* Drug: PTM filgotinib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Males or non-pregnant, non-lactating females, ages 18 to 75 years, inclusive based on the date of the screening visit Documented diagnosis of UC of at least 6 months AND with a minimum disease extent of 15 cm from the anal verge. Documentation should include endoscopic and histopathologic evidence of UC. A surveillance colonoscopy is required at screening in individuals with a history of UC for 8 or more years, if one was not performed in the prior 24 months Moderately to severely active UC Previously demonstrated an inadequate clinical response, loss of response to, or intolerance to at least 1 of the following agents (depending on current country treatment recommendations/guidelines): corticosteroids, immunomodulators, tumor necrosis factor alpha (TNFa) antagonists, or vedolizumab Key Exclusion Criteria: Presence of Crohn's disease, indeterminate colitis, ischemic colitis, fulminant colitis, ulcerative proctitis, or toxic mega-colon Active tuberculosis (TB) or history of latent TB that has not been treated Use of any concomitant prohibited medications as described in the protocol Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induction Study (Cohort A): Filgotinib 200 mg<br>Participants in Cohort A (biologic-naive) received filgotinib 200 milligrams (mg) and placebo-to-match (PTM) filgotinib 100 mg orally once daily for 10 weeks. | Drug: Filgotinib<br>* Tablet(s) administered orally once daily<br>* Other names: GLPG0634;Drug: PTM filgotinib<br>* Tablet(s) administered orally once daily<br>|
| Experimental: Induction Study (Cohort A): Filgotinib 100 mg<br>Participants in Cohort A (biologic-naive) received filgotinib 100 mg and PTM filgotinib 200 mg orally once daily for 10 weeks. | Drug: Filgotinib<br>* Tablet(s) administered orally once daily<br>* Other names: GLPG0634;Drug: PTM filgotinib<br>* Tablet(s) administered orally once daily<br>|
| Placebo Comparator: Induction Study (Cohort A): Placebo<br>Participants in Cohort A (biologic-naive) received PTM filgotinib 200 mg and PTM filgotinib 100 mg orally once daily for 10 weeks. | Drug: PTM filgotinib<br>* Tablet(s) administered orally once daily<br>|
| Experimental: Induction Study (Cohort B): Filgotinib 200 mg<br>Participants in Cohort B (biologic-experienced) received filgotinib 200 mg and PTM filgotinib 100 mg orally once daily for 10 weeks. | Drug: Filgotinib<br>* Tablet(s) administered orally once daily<br>* Other names: GLPG0634;Drug: PTM filgotinib<br>* Tablet(s) administered orally once daily<br>|
| Experimental: Induction Study (Cohort B): Filgotinib 100 mg<br>Participants in Cohort B (biologic-experienced) received filgotinib 100 mg and PTM filgotinib 200 mg orally once daily for 10 weeks. | Drug: Filgotinib<br>* Tablet(s) administered orally once daily<br>* Other names: GLPG0634;Drug: PTM filgotinib<br>* Tablet(s) administered orally once daily<br>|
| Placebo Comparator: Induction Study (Cohort B): Placebo<br>Participants in Cohort B (biologic-experienced) received PTM filgotinib 200 mg and PTM filgotinib 100 mg orally once daily for 10 weeks. | Drug: PTM filgotinib<br>* Tablet(s) administered orally once daily<br>|
| Experimental: Maintenance Study: Filgotinib 200 mg From Induction Filgotinib 200 mg<br>Participants in the Filgotinib 200 mg arm who completed the Induction Study and achieved either Endoscopy/Bleeding/Stool Frequency (EBS) remission or Mayo Clinic Score (MCS) response at Week 10 were re-randomized at Week 11 into the Maintenance Study to receive filgotinib 200 mg and PTM filgotinib 100 mg for an additional 47 weeks (up to Week 58). | Drug: Filgotinib<br>* Tablet(s) administered orally once daily<br>* Other names: GLPG0634;Drug: PTM filgotinib<br>* Tablet(s) administered orally once daily<br>|
| Placebo Comparator: Maintenance Study: Placebo From Induction Filgotinib 200 mg<br>Participants in the Filgotinib 200 mg arm who completed the Induction Study and achieved either EBS remission or MCS response at Week 10 were re-randomized at Week 11 into the Maintenance Study to receive PTM filgotinib orally once daily for an additional 47 weeks (up to Week 58). | Drug: PTM filgotinib<br>* Tablet(s) administered orally once daily<br>|
| Experimental: Maintenance Study: Filgotinib 100 mg From Induction Filgotinib 100 mg<br>Participants in the Filgotinib 100 mg arm who completed the Induction Study and achieved either EBS remission or MCS response at Week 10 were re-randomized at Week 11 into the Maintenance Study to receive filgotinib 100 mg and PTM filgotinib 200 mg for an additional 47 weeks (up to Week 58). | Drug: Filgotinib<br>* Tablet(s) administered orally once daily<br>* Other names: GLPG0634;Drug: PTM filgotinib<br>* Tablet(s) administered orally once daily<br>|
| Placebo Comparator: Maintenance Study: Placebo From Induction Filgotinib 100 mg<br>Participants in the Filgotinib 100 mg arm who completed the Induction Study and achieved either EBS remission or MCS response at Week 10 were rerandomized at Week 11 into the Maintenance Study to receive PTM filgotinib orally once daily for an additional 47 weeks (up to Week 58). | Drug: PTM filgotinib<br>* Tablet(s) administered orally once daily<br>|
| Placebo Comparator: Maintenance Study: Placebo From Induction Placebo<br>Participants in the Placebo arm who completed the Induction Study and achieved either EBS remission or MCS response at Week 10 were re-randomized at Week 11 into the Maintenance Study to receive PTM filgotinib for an additional 47 weeks (up to Week 58). | Drug: PTM filgotinib<br>* Tablet(s) administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction Study: Percentage of Participants Who Achieved Endoscopy/Bleeding/Stool Frequency (EBS) Remission at Week 10 | EBS remission was defined as an endoscopic subscore of 0 or 1; rectal bleeding subscore of 0; and at least a 1-point decrease in stool frequency from baseline to achieve a subscore of 0 or 1. Endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease (spontaneous bleeding, ulceration); rectal bleeding subscore range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes; stool frequency subscore range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal. Total score for EBS ranged from 0 to 9 (sum of all subscores), with higher scores indicating more severe disease. | Week 10 | 
| Maintenance Study: Percentage of Participants Who Achieved EBS Remission at Week 58 | EBS remission was defined as an endoscopic subscore of 0 or 1; rectal bleeding subscore of 0; and at least a 1-point decrease in stool frequency from baseline to achieve a subscore of 0 or 1. Endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease (spontaneous bleeding, ulceration); rectal bleeding subscore range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes; stool frequency subscore range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal. Total score for EBS ranged from 0 to 9 (sum of all subscores), with higher scores indicating more severe disease. | Week 58 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction Study: Percentage of Participants Who Achieved MCS Remission at Week 10 | MCS remission was defined as having a MCS of 2 or less and no single subscore higher than 1. The MCS was composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease [spontaneous bleeding, ulceration]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal), and physician's global assessment (PGA). The PGA acknowledged the participant's daily recollection of abdominal discomfort and general sense of wellbeing, and other observations, such as physical findings and the participant's performance status. The PGA score ranged from 0 to 3 with higher score indicating the severe disease. Total score for MCS ranged from 0 to 12 (sum of all subscores), with higher scores indicating more severe disease. | Week 10 | 
| Induction Study: Percentage of Participants Who Achieved an Endoscopic Subscore of 0 at Week 10 | Endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease (spontaneous bleeding, ulceration). | Week 10 | 
| Induction Study: Percentage of Participants Who Achieved Geboes Histologic Remission at Week 10 | Geboes histologic remission was assessed using the Geboes histologic scores for evaluation of disease severity in ulcerative colitis and classifies histologic changes. Remission was defined as having Grade 0 of <= 0.3, Grade 1 of <= 1.1, Grade 2A of <= 2A.3, Grade 2B of 2B.0, Grade 3 of 3.0, Grade 4 of 4.0, and Grade 5 of 5.0. Possible scores are Grade 0: Architectural changes (0.0=No abnormality to 0.3=Severe diffuse or multifocal abnormalities); Grade 1: Chronic inflammatory infiltrate (1.0=No increase to 1.3=Marked increase); Grade 2A: Eosinophils in lamina propria (2A.0=No increase to 2A.3-=Marked increase; Grade 2B: Neutrophils in lamina propria (2B.0= No increase to 2B.3=Marked increase); Grade 3: Neutrophils in epithelium (3.0=None to 3.3=>50% crypts involved); Grade 4: Crypt destruction (4.0=none to 4.3=Unequivocal crypt destruction), and Grade 5: Erosions and ulcerations: (5.0=No erosion, ulceration or granulation to 5.4=Ulcer or granulation tissue). | Week 10 | 
| Induction Study: Percentage of Participants Who Achieved MCS Remission (Alternative Definition) at Week 10 | MCS remission (alternative definition) was defined as having rectal bleeding, stool frequency, and PGA subscores of 0 and an endoscopic subscore of 0 or 1; overall MCS of ≤ 1. MCS possible subscores: rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal), PGA subscore (range: 0 to 3 with higher score indicating the severe disease), and an endoscopic subscore (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease [spontaneous bleeding, ulceration]. Total score for MCS ranged from 0 to 12 (sum of all subscores), with higher scores indicating more severe disease. | Week 10 | 
| Induction Study: Pharmacokinetic (PK) Parameter: Cmax of Filgotinib and Its Metabolite GS-829845 | Cmax is defined as the maximum observed concentration of drug. | Predose and at 0.5, 1, 2, 3, 4 and 6 hours postdose at a single visit between Week 2 and Week 10 | 
| Induction Study: PK Parameter: Tmax of Filgotinib and Its Metabolite GS-829845 | Tmax is defined as the time to reach maximum observed concentration of drug. | Predose and at 0.5, 1, 2, 3, 4 and 6 hours postdose at a single visit between Week 2 and Week 10 | 
| Induction Study: PK Parameter: AUCtau of Filgotinib and Its Metabolite GS-82984 | AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Predose and at 0.5, 1, 2, 3, 4 and 6 hours postdose at a single visit between Week 2 and Week 10 | 
| Induction Study: PK Parameter: AUClast of Filgotinib and Its Metabolite GS-82984 | AUClast is defined as the concentration of drug from time zero to the last observable concentration. | Predose and at 0.5, 1, 2, 3, 4 and 6 hours postdose at a single visit between Week 2 and Week 10 | 
| Induction Study: PK Parameter: Ctau of Filgotinib and Its Metabolite GS-82984 | Ctau is defined as the observed drug concentration at the end of the dosing interval. | Predose and at 0.5, 1, 2, 3, 4 and 6 hours postdose at a single visit between Week 2 and Week 10 | 
| Maintenance Study: Percentage of Participants Who Achieved MCS Remission at Week 58 | MCS remission was defined as having a MCS of 2 or less and no single subscore higher than 1. The MCS was composed of subscores from endoscopy (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease [spontaneous bleeding, ulceration]), rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal), and PGA. The PGA acknowledged the participant's daily recollection of abdominal discomfort and general sense of wellbeing, and other observations, such as physical findings and the participant's performance status. The PGA score ranged from 0 to 3 with higher score indicating the severe disease. Total score for MCS ranged from 0 to 12 (sum of all subscores), with higher scores indicating more severe disease. | Week 58 | 
| Maintenance Study: Percentage of Participants Who Achieved Sustained EBS Remission at Week 58 | Sustained EBS remission was defined as having achieved EBS remission at both Weeks 10 and 58. | Week 58 | 
| Maintenance Study: Percentage of Participants Who Achieved 6-Month Corticosteroid-Free EBS Remission at Week 58 | Six-month corticosteroid-free EBS remission at Week 58 was defined as achieving EBS remission with no corticosteroid use for the indication of ulcerative colitis for at least 6 months prior to Week 58. | Week 58 | 
| Maintenance Study: Percentage of Participants Who Achieved Endoscopic Subscore of 0 at Weeks 58 | Endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease (spontaneous bleeding, ulceration). | Week 58 | 
| Maintenance Study: Percentage of Participants Who Achieved Geboes Histologic Remission at Week 58 | Geboes histologic remission was assessed using the Geboes histologic scores for evaluation of disease severity in ulcerative colitis and classifies histologic changes. Remission was defined as having Grade 0 of <= 0.3, Grade 1 of <= 1.1, Grade 2A of <= 2A.3, Grade 2B of 2B.0, Grade 3 of 3.0, Grade 4 of 4.0, and Grade 5 of 5.0. Possible scores are Grade 0: Architectural changes (0.0=No abnormality to 0.3=Severe diffuse or multifocal abnormalities); Grade 1: Chronic inflammatory infiltrate (1.0=No increase to 1.3=Marked increase); Grade 2A: Eosinophils in lamina propria (2A.0=No increase to 2A.3-=Marked increase; Grade 2B: Neutrophils in lamina propria (2B.0= No increase to 2B.3=Marked increase); Grade 3: Neutrophils in epithelium (3.0=None to 3.3=>50% crypts involved); Grade 4: Crypt destruction (4.0=none to 4.3=Unequivocal crypt destruction), and Grade 5: Erosions and ulcerations: (5.0=No erosion, ulceration or granulation to 5.4=Ulcer or granulation tissue). | Week 58 | 
| Maintenance Study: Percentage of Participants Who Achieved MCS Remission (Alternative Definition) at Week 58 | MCS remission (alternative definition) was defined as having rectal bleeding, stool frequency, and PGA subscores of 0 and an endoscopic subscore of 0 or 1; overall MCS of ≤ 1. MCS possible subscores: rectal bleeding (range: 0 to 3, where 0 = no blood seen and 3 = blood alone passes), stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 stools more than normal), PGA subscore (range: 0 to 3 with higher score indicating the severe disease), and an endoscopic subscore (range: 0 to 3, where 0 = normal or inactive disease and 3 = severe disease [spontaneous bleeding, ulceration]. Total score for MCS ranged from 0 to 12 (sum of all subscores), with higher scores indicating more severe disease. | Week 58 | 
| Maintenance Study: Plasma Concentration of Filgotinib and Its Metabolite GS-829845 | Plasma concentration is defined as the measured drug concentration of filgotinib and its metabolite GS-829845. Lower limit of quantitation (LLOQ) was defined as 1 ng/mL for analyte filgotinib and 2 ng/mL for analyte GS-829845. | Week 26 (any Time) and Week 58 (predose) |