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

Phase 2TerminatedNCT04130919

Gilead Sciences19 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Ulcerative Colitis

Interventions

TilpisertibDRUG

Tablets administered orally once daily

PlaceboDRUG

Tablets administered orally once daily

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (49)

Outcomes

Primary Outcomes

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.

Time frame: Week 10

Secondary Outcomes

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).

Time frame: 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.

Data from ClinicalTrials.gov

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Gut P.C., dba Digestive Health Specialists of the Southeast

Dothan, Alabama, United States

Om Research LLC

Lancaster, California, United States

United Medical Doctors

Murrieta, California, United States

Alliance Clinical Research

Poway, California, United States

Alliance Medical Research

Coral Springs, Florida, United States

Encore Borland-Groover Clinical Research

Jacksonville, Florida, United States

A Plus Research, Inc

Miami, Florida, United States

BRCR Medical Center Inc.

Plantation, Florida, United States

Advanced Medical Research Center

Port Orange, Florida, United States

Gastrointestinal Specialists of Georgia

Marietta, Georgia, United States

...and 39 more locations

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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