Safety and Efficacy Study of TLL018 in the Treatment of Ulcerative Colitis

Study Overview
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Brief Summary
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A study to investigate the safety and efficacy of TLL018 compared with placebo in subjects with moderate to severe ulcerative colitis.

Detailed Description
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This is a phase 2, multicenter, randomized, double-blind, parallel dose groups, placebo-controlled dose ranging study to evaluate the safety and efficacy of 3 doses of TLL018 as an induction therapy in subjects with moderate to severe UC. Eligible subjects will be randomized to receive one of the following treatments: TLL018 low dose, TLL018 middle dose, TLL018 high dose, or placebo. All subjects may remain on a stable dose of conventional therapy used prior to enrollment. Subjects will be assessed for safety, tolerability, and response to treatment. Samples for pharmacokinetics (PK) and pharmacodynamics (PD) biomarker analyses will be collected throughout the study according to the Schedule of Assessments (SoA) for potential correlation to clinical outcomes. Further participation may continue beyond the initial 8 weeks for another 5-week Extension Period of therapy.

Official Title
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A Phase 2 Multicenter, Randomized, Double Blind, Placebo Controlled Study to Evaluate the Safety and Efficacy of TLL018 for Induction Therapy in Subjects With Moderate to Severe Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: TLL018
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects ≥ 18 and ≤ 75 years of age at baseline. Capable of giving informed consent and complying with study procedures. Normal renal function or mild renal impairment as determined by the Investigator following review of clinical laboratory test results. Laboratory and medical history parameters within the protocol-defined ranges. Diagnosis of UC for 90 days or greater prior to baseline, confirmed by colonoscopy during the screening period, with exclusion of current infection, colonic dysplasia, and/or malignancy. Appropriate documentation of biopsy results consistent with the diagnosis of UC, in the assessment of the Investigator, must be available. Active UC with a full Mayo score of 6 to 12 points and endoscopic subscore of 2 or higher confirmed by central reader. Subject must have received COVID-19 vaccine >2 months before first dose of study drug. Exclusion Criteria: Pregnant or nursing women. Clinically significant history of cardiovascular, hematologic, renal, hepatic, bronchopulmonary, immunologic, lipid metabolism disorders, or drug hypersensitivity as determined by the Investigator. Current and/or recent history of a clinically significant infection. Any history of malignancies, except for non-melanoma skin cancers (unless it is metastatic). Positive blood screen for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibody. Any condition or finding that in the Investigator's opinion would put the subjects or study conduct at risk if the subjects were to participate in the study. Current diagnosis of Crohn's disease (CD) or diagnosis of indeterminate colitis (IC). Current diagnosis of fulminant colitis and/or toxic megacolon, or active Clostridium difficile colitis. Subject with disease limited to the rectum (ulcerative proctitis) during the screening endoscopy. Subject with previous exposure to JAK inhibitor (eg, tofacitinib, baricitinib, filgotinib, upadacitinib).

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose TLL018,BID<br>Drug: TLL018 all subjects will receive TLL018 for 8 weeks | Drug: TLL018<br>* a TYK2/JAK1 inhibitor<br>|
| Experimental: Middle dose TLL018,BID<br>Drug: TLL018 all subjects will receive TLL018 for 8 weeks | Drug: TLL018<br>* a TYK2/JAK1 inhibitor<br>|
| Experimental: High dose TLL018,BID<br>Drug: TLL018 all subjects will receive TLL018 for 8 weeks | Drug: TLL018<br>* a TYK2/JAK1 inhibitor<br>|
| Placebo Comparator: Placebo<br>Placebo twice daily for 8 weeks. | Other: Placebo<br>* a TLL018 Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects who achieved clinical remission per adapted Mayo score at Week 8 |  | Baseline to Week 8 | 
| Number of treatment-emergent adverse events (TEAEs) | TEAE defined as adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug. | Up to 8 weeks | 
| Incidence of Adverse Events (AEs) and Adverse Events of Special Interest (AESIs) |  | Up to 8 weeks | 
| Number of Participants With Clinically Significant Changes in clinical laboratory data | Laboratory investigation included hematology, biochemistry, urinalysis and coagulation. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in laboratory parameters were reported. | Up to 8 weeks | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | Vital signs included body temperature, systolic and diastolic blood pressure, pulse rate, respiratory rate, weight and height. Clinical significance was determined by the investigator. The number of participants with clinically significant changes from baseline in vital signs were reported. | Up to 8 weeks | 
| Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Findings | Clinically significant ECG criteria included QT interval corrected using the Fridericia's formula (QTCF) value 450 msec and 30<=change<60. | Up to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects with endoscopic improvement at Week 8 |  | Week 8 | 
| Percentage of subjects with endoscopic remission at Week 8 |  | Week 8 | 
| Percentage of subjects achieving clinical response per adapted Mayo score at Week 8 |  | Week 8 | 
| Percentage of subjects achieving clinical response per partial adapted Mayo score at Week 2 |  | Week 2 | 
| Percentage of subjects who achieved histologic-endoscopic mucosal improvement (as defined by endoscopic subscore and Geboes score) at Week 8 |  | Week 8 | 
| Percentage of subjects with mucosal healing (as defined by the endoscopic and histologic variables) at Week 8 |  | Week 8 | 
| Percentage of subjects who achieved histologic improvement (as defined by Geboes score) at Week 8 |  | Week 8 | 
| Percentage of subjects who reported no bowel urgency (as monitored electronically via a handheld device) at Week 8 |  | Week 8 | 
| Change From Baseline in the Inflammatory Bowel Disease Questionnaire (IBDQ) Score | The IBDQ is used to measure disease specific quality of life on a 32 Likert-scaled items questionnaire. The IBDQ scale contains 4 component subscales: bowel symptoms, systemic symptoms, emotional function and social function with scores ranging from 10 to 70, 5 to 35, 12 to 84 and 5 to 35 respectively and the total score ranges from 32 to 224. Higher scores indicate better health related quality of life. | Baseline to Week 8 | 
| Change in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Questionnaire Score | The FACIT system is a collection of quality of life (QOL) questionnaires targeted to the management of cancer and other chronic illnesses. | Baseline to Week 8 | 
| Time to improvement as measured by rectal bleeding via handheld device |  | Baseline to Week 8 |