Efficacy & Safety of TD-1473 in Ulcerative Colitis

Study Overview
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Brief Summary
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A Phase 2b/3 set of studies to evaluate the efficacy and safety of induction and maintenance therapy with TD-1473 in subjects with moderately-to-severely active ulcerative colitis with up to 60 weeks of treatment.

Detailed Description
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This protocol consists of 3 separate studies: an 8-week Phase 2b dose-finding induction study, an 8-week dose-confirming Phase 3 induction study, and a 44-week Phase 3 maintenance study. Subjects who respond to induction will enter the maintenance study; those who do not will receive TD-1473 during extended induction. The safety and efficacy data of the Phase 2b study will be analyzed to select the induction and maintenance dose regimens for the confirmatory Phase 3 studies. Participants who have disease relapse or complete the maintenance study may be eligible to enter a separate long-term safety study. Efficacy, pharmacokinetic, biomarkers, and safety will be evaluated in all 3 studies. 240 subjects are planned for the Phase 2b and the planned Primary Completion Date for this portion of the study is JULY 2021. 640 subjects are planned for the Phase 3 portion of the study.

Official Title
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A Phase 2b/3 Multi-Center, Randomized, Double-Blind, Multi-Dose, Placebo-Controlled, Parallel-Group Set of Studies to Evaluate the Efficacy and Safety of Induction and Maintenance Therapy With TD-1473 in Subjects With Moderately-to-Severely Active Ulcerative Colitis

Conditions
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Ulcerative Colitis (UC)

Intervention / Treatment
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* Drug: TD-1473 Dose A
* Drug: TD-1473 Dose B
* Drug: TD-1473 Dose C
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is at least 18 years of age at screening Has a history of UC for at least 3 months prior to screening Has moderately-to-severely active UC, as defined by a Mayo endoscopic subscore of ≥2 points and an adapted Mayo score between 4 - 9 points inclusive Is corticosteroid-dependent or has demonstrated inadequate response, or intolerance to conventional therapy (aminosalicylates, corticosteroids, immunomodulators) or biologics Willing to use highly-effective methods of contraception during the study and for 7 days after the last dose Additional inclusion criteria apply Exclusion Criteria: Has symptoms suggestive of fulminant colitis, megacolon or intestinal perforation Likely to require surgery for UC or other major surgeries Has previously received / is currently receiving prohibited medications within specified timeframe Is refractory to 3 biologics with ≥2 mechanisms of action Has a current bacterial, parasitic, fungal, or viral infection Has clinically significant abnormalities in laboratory evaluations Has had any prior exposure to an approved Janus kinase (JAK) inhibitor or potential exposure to an investigational JAK inhibitor that was stopped due to intolerance or lack of efficacy Additional exclusion criteria 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
Interventional Model Description: Integrated and Adaptive Design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active Treatment TD-1473 Dose A<br>Participants will be randomized to receive an oral daily dose of TD-1473. Responders will be re-randomized into the Phase 3 Maintenance portion of the study. Non-responders may participate in an extended induction. | Drug: TD-1473 Dose A<br>* See Arm description<br>|
| Experimental: Active Treatment TD-1473 Dose B<br>Participants will be randomized to receive an oral daily dose of TD-1473. Responders will be re-randomized into the Phase 3 Maintenance portion of the study. Non-responders may participate in an extended induction. | Drug: TD-1473 Dose B<br>* See Arm description<br>|
| Experimental: Active Treatment TD-1473 Dose C<br>Participants will be randomized to receive an oral daily dose of TD-1473. Responders will be re-randomized into the Phase 3 Maintenance portion of the study. Non-responders may participate in an extended induction. | Drug: TD-1473 Dose C<br>* See Arm description<br>|
| Placebo Comparator: Placebo<br>Participants will be randomized to receive an oral daily dose of placebo. Participants who received Placebo (and were non-responders) may move to an extended induction. Subjects who are on placebo will be assigned to active TD-1473 for the extended induction (they will be blinded to dose). | Drug: Placebo<br>* See Arm description<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total Mayo Score (tMS) at Week 8 | Total Mayo Score (tMS) was calculated as the sum of four components: rectal bleeding (0-3), stool frequency (0-3), physician's global assessment (0-3) and Mayo endoscopic subscore (0-3). tMS was reported as a 0-12 point score with 12 reflecting the highest severity. | Baseline to Week 8 | 
| Phase 3 Maintenance: Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Maintenance Week (mWeek) 44 | Clinical remission by Adapted Mayo score was defined based on Adapted Mayo score components within specific ranges: stool frequency score of 0 or 1, a rectal bleeding subscore of 0 and a Mayo endoscopy subscore of 0 or 1. The Adapted Mayo score was the sum of three components: rectal bleeding, stool frequency, and Mayo endoscopic subscore, each measured on a scale of 0-3 with higher scores reflecting higher severity. Participants with missing Week 44 values were imputed as non-responders. | mWeek 44 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Demonstrated Clinical Remission by Adapted Mayo Score Components at Week 8 | Clinical remission by Adapted Mayo score was defined based on Adapted Mayo score components within specific ranges: stool frequency score of 0 or 1, a rectal bleeding subscore of 0 and a Mayo endoscopy subscore of 0 or 1. The Adapted Mayo score was the sum of three components: rectal bleeding, stool frequency, and Mayo endoscopic subscore, each measured on a scale of 0-3 with higher scores reflecting higher severity. | Week 8 | 
| Phase 3 Maintenance: Number of Participants Who Demonstrated a Clinical Response by Adapted Mayo Score Components at mWeek 44 | Clinical response was defined as a reduction from baseline in adapted Mayo score of ≥ 2 points and ≥ 30% relative to baseline. It also required ≥ 1 reduction in the rectal bleeding subscore or an absolute subscore ≤ 1. The Adapted Mayo score was the sum of three components: rectal bleeding, stool frequency, and Mayo endoscopic subscore, each measured on a scale of 0-3 with higher scores reflecting higher severity. Participants with missing Week 44 values were imputed as non-responders. | Baseline to mWeek 44 | 
| Phase 3 Maintenance: Number of Participants Who Demonstrated Endoscopic Remission by Adapted Mayo Score Components at mWeek 44 | Endoscopic remission was defined as an endoscopic subscore ≤ 1. Endoscopic subscore was measured using scale of 0-3, where higher numbers reflected greater severity. | mWeek 44 | 
| Phase 3 Maintenance: Number of Participants Who Demonstrated Symptomatic Remission by Adapted Mayo Score Components at mWeek 44 | Symptomatic remission was defined as a stool frequency score ≤ 1 and a rectal bleeding subscore of 0. Stool frequency score and rectal bleeding score were each measured using scale of 0-3, where higher numbers reflected greater severity. Participants with missing Week 44 values were imputed as non-responders. | mWeek 44 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TD-1473, Janus kinase inhibitor, JAK inhibitor, Inflammatory Bowel Disease, IBD, Ulcerative colitis, UC, Gut selective