Study to Evaluate the Efficacy and Safety of Tilpisertib in Adults With Moderately to Severely Active Ulcerative Colitis

Study Overview
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Brief Summary
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The primary objective of this study is to demonstrate the efficacy of tilpisertib (formerly GS-4875) compared with placebo control in achieving clinical remission per modified Mayo Clinic Score (MCS) in adults with moderately to severely active ulcerative colitis (UC).

Official Title
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A Phase 2, Blinded, Randomized, Placebo-Controlled Study Evaluating the Efficacy and Safety of GS-4875 in Subjects With Moderately to Severely Active Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Tilpisertib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Males, or non-pregnant, non-lactating females, at least 18 years of age based on the date of the screening visit. UC of at least 3 months duration before randomization confirmed by endoscopy and histology at any time in the past AND a minimum disease extent of 15 centimeter (cm) from the anal verge. Documentation of endoscopy and histology consistent with the diagnosis of UC must be available in the source documents prior to the initiation of screening. Moderately to severely active UC as determined during screening by a centrally read endoscopy score ≥ 2, a Rectal Bleeding subscore ≥ 1, a Stool Frequency subscore ≥ 1 and Physicians Global Assessment (PGA) of ≥ 2 as defined by the Mayo Clinic Score; total MCS must be between 6 and 12, inclusive. Previously demonstrated an inadequate response (primary non-response) or loss of response (secondary non-response) to a tumor necrosis factor-alpha (TNFα) inhibitor (ie, infliximab, adalimumab, golimumab, or biosimilars). The induction treatment regimen resulting in inadequate response or loss of response should have been in accordance with local prescribing information/guidelines or as outlined below. Infliximab: 5 mg/kg at Weeks 0, 2, and 6 Adalimumab: 160 mg on Day 1 (given in 1 day or split over consecutive days), followed by 80 mg 2 weeks later (Day 15), 40 mg 2 weeks later (Day 29) and every 2 weeks thereafter until Day 57 Golimumab: 200 mg on Day 1 followed by 100 mg at Week 2 May be receiving concomitant therapy for UC at the time of enrollment as specified in the protocol, provided the dose prescribed has been stable as indicated prior to randomization. Meet the following Tuberculosis (TB) screening criteria: No evidence of active TB, latent TB, or inadequately treated TB as evidenced by 1 of the following: A negative QuantiFERON test or equivalent assay reported by the central lab at screening or within 90 days prior to randomization date. OR A history of fully treated active or latent TB according to local standard of care. Investigator must verify adequate previous anti-TB treatment and provide documentation; these individuals do not require QuantiFERON testing and eligibility must be approved by the sponsor prior to enrollment in the study. AND A chest radiograph (views as per local guidelines with the report or films available for investigator review) taken at screening or within the 4 months prior to randomization without evidence of active or latent TB infection. Laboratory assessments at screening within the following parameters: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and total bilirubin ≤ 2 X upper limit of normal (ULN) Estimated glomerular filtration rate (eGFR) ≥ 60 ml/min (1.0 mL/sec) as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Cystatin C formula as described in protocol. Hemoglobin ≥ 8 g/dL (≥ 80 g/L) Absolute neutrophil count (ANC) ≥ 1.5 × 10^3/μL (≥ 1.5 GI/L) Platelets ≥ 100 × 10^3/μL (≥ 100 GI/L) White blood cells (WBC) ≥ 3 × 10^3/μL (≥ 3 GI/L) Absolute lymphocyte count ≥ 0.75 × 10^3/μL (≥ 0.75 GI/L) Key Exclusion Criteria: Currently displaying clinical signs of acute severe colitis, fulminant colitis, or toxic megacolon. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 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: Tilpisertib 300 mg<br>Participants will receive blinded tilpisertib 300 mg for up to 10 weeks. An efficacy assessment will be performed at Week 10. Participants who achieve MCS response will continue on the blinded treatment for up to 50 weeks. | Drug: Tilpisertib<br>* Tablets administered orally once daily<br>* Other names: GS-4875;|
| Experimental: Tilpisertib 100 mg<br>Participants will receive blinded tilpisertib 100 mg for up to 10 weeks. An efficacy assessment will be performed at Week 10. Participants who achieve MCS response will continue on the blinded treatment for up to 50 weeks. | Drug: Tilpisertib<br>* Tablets administered orally once daily<br>* Other names: GS-4875;|
| Placebo Comparator: Placebo<br>Participants will receive blinded tilpisertib matching placebo for up to 10 weeks. An efficacy assessment will be performed at Week 10. Participants who achieve MCS response will continue on the blinded treatment for up to 50 weeks. | Drug: Placebo<br>* Tablets administered orally once daily<br>|
| Experimental: Open-label Tilpisertib 300 mg<br>Based on the efficacy assessment results at Week 10, participants who do not achieve MCS response will have the option to receive open-label tilpisertib 300 mg for up to 50 weeks. | Drug: Tilpisertib<br>* Tablets administered orally once daily<br>* Other names: GS-4875;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Clinical Remission Per Modified Mayo Clinic Score (MCS) at Week 10 | The modified MCS is a scoring system for assessment of ulcerative colitis (UC) activity and is 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 or more stools more than normal), and physician's global assessment (PGA) (range: 0 to 3, where 0 = normal and 3 = severe disease). Total score for MCS ranges from 0 to 12 (sum of all subscores), with higher scores indicating higher disease activity. Clinical remission per modified MCS is defined as stool frequency subscore ≤ 1 and not greater than baseline, rectal bleeding subscore of 0, and endoscopic subscore ≤ 1 at Week 10. | Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Endoscopic Response at Week 10 | Endoscopic response was defined as an endoscopic subscore of ≤ 1 at Week 10. Endoscopic subscore is a part of the modified MCS which is a scoring system for assessment of UC activity. Endoscopic subscore range: 0 to 3, where 0 = normal or inactive disease, 1 = mild disease (erythema, decreased vascular pattern), 2 = moderate disease (marked erythema, lack of vascular pattern, friability, erosions), and 3 = severe disease (spontaneous bleeding, ulceration). | Week 10 | 
| Percentage of Participants Who Achieved MCS Response at Week 10 | The modified MCS is a scoring system for assessment of UC activity and is 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 or more stools more than normal), and PGA (range: 0 to 3, where 0 = normal and 3 = severe disease). Total score for MCS ranges from 0 to 12 (sum of all subscores), with higher scores indicating higher disease activity. MCS response is defined as a decrease from baseline of ≥ 3 points and at least 30% in MCS, in addition to a ≥ 1 point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore ≤ 1 at Week 10. | Week 10 | 
| Percentage of Participants Who Achieved MCS Remission at Week 10 | The modified MCS is a scoring system for assessment of UC activity and is 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 or more stools more than normal), and PGA (range: 0 to 3, where 0 = normal and 3 = severe disease). Total score for MCS ranges from 0 to 12 (sum of all subscores), with higher scores indicating higher disease activity. MCS remission is defined as a MCS score of ≤ 2 and no individual subscore > 1 at Week 10. | Week 10 | 
| Percentage of Participants Who Achieved Histologic Remission Based Upon the Geboes Scale at Week 10 | Geboes histologic remission was assessed using the Geboes histologic scores to identify histologic changes in ulcerative colitis. 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). Histologic remission 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. Geboes score ranges from 0 to 5.4. Lower values indicate better outcome. | Week 10 | 
| Percentage of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | Treatment-emergent adverse events (TEAEs) for the Blinded Treatment phase are either defined as AEs with an onset date on or after the Blinded Treatment phase study drug start date and no later than 30 days after permanent discontinuation of the Blinded Treatment phase study drug if no Open-label Treatment phase study drug was taken, or any AEs with an onset date on or after the Blinded Treatment phase study drug start date and before the Open-label Treatment phase study drug start date if Open-label Treatment phase study drug was taken and/or any AEs leading to premature discontinuation of Blinded Treatment phase study drug. TEAEs for the Open-label Treatment phase are either defined as AEs with an onset date on or after the Open-label Treatment phase study drug start date and no later than 30 days after permanent discontinuation of the Open-lab Treatment phase study drug and/or any AEs leading to premature discontinuation of Open-label Treatment phase study drug. | Blinded Treatment phase: First dose date up to 50.6 weeks plus 30 days; Open-label phase: First dose date up to 50.7 weeks plus 30 days | 
| Percentage of Participants Who Experienced Laboratory Abnormalities | Treatment-emergent laboratory abnormalities for Blinded Treatment phase are defined as values that increase at least 1 toxicity grade from baseline at any postbaseline time point, up to and including the date of last dose of Blinded Treatment phase study drug plus 30 days for participants who permanently discontinued Blinded Treatment phase study drug or before the first dose of Open-label Treatment phase study drug. For the Open-label Treatment phase, treatment-emergent laboratory abnormalities are defined as values that increase at least 1 toxicity grade from Open-label baseline at any postbaseline time point, up to and including the date of last dose of Open-label Treatment phase study drug plus 30 days for participants who permanently discontinued Open-label phase study drug. For maximum postbaseline toxicity grade, the most severe graded abnormality from all tests was counted for each patient. Grade 1: mild; Grade 2: moderate; Grade 3: severe; Grade 4: life-threatening. | Blinded Treatment phase: First dose date up to 50.6 weeks plus 30 days; Open-label phase: First dose date up to 50.7 weeks plus 30 days |