Study of Tilpisertib Fosmecarbil in Participants With Moderately to Severely Active Ulcerative Colitis

Study Overview
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Brief Summary
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The goal of this study is to learn if tilpisertib fosmecarbil (formerly known as GS-5290) is effective and safe in treating participants with moderate to severe ulcerative colitis. The study will compare participants in different treatment groups treated with tilpisertib fosmecarbil with participants treated with placebo. The primary objective of this study is to demonstrate the efficacy of tilpisertib fosmecarbil, compared to placebo control, in achieving Clinical Response at Week 12.

Official Title
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A Phase 2, Double-Blinded, Randomized, Placebo-Controlled, Dose-Ranging Study Evaluating the Efficacy and Safety of GS-5290 in Participants With Moderately to Severely Active Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Tilpisertib Fosmecarbil
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Individuals assigned male at birth, or nonpregnant, nonlactating individuals assigned female at birth, 18 to 75 years of age based on the date of the screening visit. Ulcerative colitis (UC) of at least 90-day duration before randomization confirmed by endoscopy and histology at any time in the past AND a minimum disease extent of 15 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 with a modified Mayo Clinic Score based on the sum of Stool Frequency, Rectal Bleeding, and Endoscopic Finding of 5 to 9 points and an endoscopic subscore of 2 to 3 (determined by central reader). Previous treatment history of approved UC therapy with at least one advanced therapy mechanisms of action but failure (ie, loss of response or lack of response) of no more than 3 different advanced therapy mechanisms of action. Documentation of a surveillance colonoscopy in the 24 months prior to screening in individuals who have a history of UC for 8 or more years. Key Exclusion Criteria: Current diagnosis of Crohn's Disease (CD) or diagnosis of indeterminate colitis due to an enteric pathogen, lymphocytic or collagenous colitis. Individuals with disease limited to the rectum (ulcerative proctitis) during screening endoscopy. Requirement for ongoing therapy with or prior use of any prohibited medications. Active clinically significant infection, or any infection requiring hospitalization or treatment with intravenous anti-infectives within 8 weeks. of randomization; or any infection requiring oral anti-infective therapy within 6 weeks of randomization. History of opportunistic infection. Current diagnosis 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
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: Tilpisertib Fosmecarbil Dose A<br>Blinded Treatment Phase: Participants will receive tilpisertib fosmecarbil Dose A for up to 12 weeks. An efficacy assessment will be performed at Week 12. • Participants who achieve clinical response will receive tilpisertib fosmecarbil Dose B for up to Week 52. Non-responder Treatment Phase: • Participants who do not achieve clinical response at Week 12 will discontinue the Blinded Treatment Phase and have the option to enter into the Non-responder Treatment Phase. Participants will receive tilpisertib fosmecarbil Dose A for another 12 weeks. An efficacy assessment will be performed at Week 12 of the Non-responder Treatment Phase. Participants who achieved clinical response will receive tilpisertib fosmecarbil Dose B for up to Week 52. Participants who do not achieve clinical response at Non-responder Treatment Phase Week 12 will discontinue study drug. | Drug: Tilpisertib Fosmecarbil<br>* Tablets administered orally<br>* Other names: GS-5290;|
| Experimental: Tilpisertib Fosmecarbil Dose B<br>Blinded Treatment Phase: Participants will receive tilpisertib fosmecarbil Dose B for up to 12 weeks. An efficacy assessment will be performed at Week 12. • Participants who achieve clinical response will receive tilpisertib fosmecarbil Dose B for up to Week 52. Non-responder Treatment Phase: • Participants who do not achieve clinical response at Week 12 will discontinue the Blinded Treatment Phase and have the option to enter into the Non-responder Treatment Phase. Participants will receive tilpisertib fosmecarbil Dose B for another 12 weeks. An efficacy assessment will be performed at Week 12 of the Non-responder Treatment Phase. Participants who achieved clinical response will receive tilpisertib fosmecarbil Dose B for up to Week 52. Participants who do not achieve clinical response at Non-responder Treatment Phase Week 12 will discontinue study drug. | Drug: Tilpisertib Fosmecarbil<br>* Tablets administered orally<br>* Other names: GS-5290;|
| Experimental: Tilpisertib Fosmecarbil Dose C<br>Blinded Treatment Phase: Participants will receive tilpisertib fosmecarbil Dose C for up to 12 weeks. An efficacy assessment will be performed at Week 12. • Participants who achieve clinical response will receive tilpisertib fosmecarbil Dose C for up to Week 52. Non-responder Treatment Phase: • Participants who do not achieve clinical response at Week 12 will discontinue the Blinded Treatment Phase and have the option to enter into the Non-responder Treatment Phase. Participants will receive tilpisertib fosmecarbil Dose B for another 12 weeks. An efficacy assessment will be performed at Week 12 of the Non-responder Treatment Phase. Participants who achieved clinical response will receive tilpisertib fosmecarbil Dose B for up to Week 52. Participants who do not achieve clinical response at Non-responder Treatment Phase Week 12 will discontinue study drug. | Drug: Tilpisertib Fosmecarbil<br>* Tablets administered orally<br>* Other names: GS-5290;|
| Placebo Comparator: Tilpisertib Fosmecarbil Placebo<br>Blinded Treatment Phase: Participants will receive tilpisertib fosmecarbil placebo for up to 12 weeks. An efficacy assessment will be performed at Week 12. • Participants who achieve clinical response will receive tilpisertib fosmecarbil Dose C for up to Week 52. Non-responder Treatment Phase: • Participants who do not achieve clinical response at Week 12 will discontinue the Blinded Treatment Phase and have the option to enter into the Non-responder Treatment Phase. Participants will receive tilpisertib fosmecarbil Dose A for another 12 weeks. An efficacy assessment will be performed at Week 12 of the Non-responder Treatment Phase. Participants who achieved Clinical Response will receive tilpisertib fosmecarbil Dose B for up to Week 52. Participants who do not achieve Clinical Response at Non-responder Treatment Phase Week 12 will discontinue study drug. | Drug: Tilpisertib Fosmecarbil<br>* Tablets administered orally<br>* Other names: GS-5290;Drug: Placebo<br>* Tablets administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Achieving Clinical Response Per Modified Mayo Clinic Score at Week 12 | Clinical Response is defined as a decrease from baseline of ≥ 2 points and at least 30% in 3 components of the modified Mayo Clinic Score, Stool Frequency, Rectal Bleeding, and Endoscopic Findings, in addition to a ≥ 1 point decrease from baseline in the Rectal Bleeding subscore or Rectal Bleeding subscore of ≤ 1. The modified Mayo Clinic Score 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), and stool frequency (range: 0 to 3, where 0 = normal number of stools and 3 = at least 5 or more stools more than normal). Total score for modified Mayo Clinic Score ranges from 0 to 9 (sum of all subscores), with higher scores indicating higher disease activity. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Achieving Clinical Remission Per Modified Mayo Clinic Score at Week 12 | Clinical Remission is defined as a Stool Frequency subscore ≤ 1 and not greater than baseline, Rectal Bleeding subscore of 0, and Endoscopic Findings subscore ≤ 1 at Week 12. The modified Mayo Clinic Score 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). Total score for modified Mayo Clinic Score ranges from 0 to 9 (sum of all subscores), with higher scores indicating higher disease activity. | Week 12 | 
| Proportion of Participants Achieving Endoscopic Response at Week 12 | Endoscopic Response is defined as an Endoscopic Findings subscore ≤ 1 at Week 12. Endoscopic subscore is a part of the modified Mayo Clinic Score 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). Higher scores indicate higher disease activity. | Week 12 | 
| Proportion of Participants Achieving Histologic Endoscopic Mucosal Improvement at Week 12 | Histologic Endoscopic Mucosal Improvement is defined as an Endoscopic Findings subscore ≤ 1 and Geboes score ≤ 3.1 (indicating neutrophil infiltration in < 5% of crypts, no crypt destruction and no erosions, ulcerations, or granulation tissue). Endoscopic subscore is a part of the modified Mayo Clinic Score 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). Geboes histologic remission is assessed using the Geboes histologic scores to identify histologic changes in ulcerative colitis. Possible scores are graded as Grade 0 to Grade 5, with higher grade representing higher levels of disease activity. | Week 12 | 
| Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) |  | First dose date up to Week 52 (responders) or Week 64 (non-responders) plus 30 days | 
| Percentage of Participants Experiencing Clinically Significant Laboratory Abnormalities |  | First dose date up to Week 52 (responders) or Week 64 (non-responders) plus 30 days |