A Phase II Study in Patients With Moderate to Severe Active Ulcerative Colitis.

Study Overview
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Brief Summary
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The proposed study is a randomized, double-blind,placebo-controlled, multicenter phase II study to investigate the safety and efficacy of SHR0302 in patients with moderate to severe active ulcerative colitis. The study aims to evaluate the optimal dose of SHR0302 and time needed to induce clinical response in active ulcerative colitis patients. This is an 8+8 weeks study, in which participants who complete the first 8 weeks treatment phase, will have the option to enter a blinded active arms 8-week extension phase. Early withdrawn subjects during the first treatment phase can not enter the extension phase. The total duration of the study participation, including extension and follow-up, will be approximately 18 weeks. SHR0302 is a Janus kinase 1(JAK1) inhibitor, capable of blocking Janus kinase-signal transducer and activator of transcription (JAK-STATs) pathway and controlling inflammation. Therefore it has the potential to be a treatment for ulcerative colitis.

Official Title
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A Phase II Randomized, Placebo Controlled, Double-blind, 4 Arms Dose-ranging Study to Evaluate the Efficacy and Safety of SHR0302 Compared to Placebo in Patients With Moderate to Severe Active Ulcerative Colitis.

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: SHR0302
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and Female subject age ≥ 18 and ≤75 years of age at randomization. Active ulcerative colitis with a 9-point modified Mayo score of 5 to 9 points and endoscopic subscore of 2 to 3 (The duration of the time between endoscopy and baseline should not exceed 10 days and allow central over read turn over before randomization). Subject should have at least three-month history of Ulcerative Colitis diagnosis at randomization. Exclusion Criteria: Diagnosis of indeterminate colitis, or clinical findings suggestive of Crohn's disease. Subjects with ulcerative colitis, which is confined to a proctitis (distal 15 cm or less). Treatment naïve subjects diagnosed with ulcerative colitis (without previous exposure to treatment).

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: SHR0302 8mg QD<br>Participants randomized in this arm will receive SHR0302 8mg QD for the treatment phase. All participants that had completed the 8-week treatment phase (non-responders or responders) had the option to enter a blinded 8-week extension phase to continue to receive SHR0302 8mg QD. Those who had completed the first 8-week of the treatment phase, but decided not to enter into the extension phase were also required to attend the 2-week follow-up visit. Participants who immaturely withdrew during the first treatment phase could not enter the extension phase. SHR0302: The study drug, SHR0302, is designed to block the activity of an enzyme protein called JAK (known as a JAK inhibitor). | Drug: SHR0302<br>* The study drug, SHR0302, is designed to block the activity of an enzyme protein called JAK (known as a Janus kinase inhibitor).<br>* Other names: Ivarmacitinib;|
| Experimental: SHR0302 4mg BD<br>Participants randomized in this arm will receive SHR0302 4mg BD for the treatment phase. All participants that had completed the 8-week treatment phase (non-responders or responders) had the option to enter a blinded 8-week extension phase to continue to receive SHR0302 4mg BD. Those who had completed the first 8-week of the treatment phase, but decided not to enter into the extension phase were also required to attend the 2-week follow-up visit. Participants who immaturely withdrew during the first treatment phase could not enter the extension phase. SHR0302: The study drug, SHR0302, is designed to block the activity of an enzyme protein called JAK (known as a JAK inhibitor). | Drug: SHR0302<br>* The study drug, SHR0302, is designed to block the activity of an enzyme protein called JAK (known as a Janus kinase inhibitor).<br>* Other names: Ivarmacitinib;|
| Experimental: SHR0302 4mg QD<br>Participants randomized in this arm will receive SHR0302 4mg QD for the treatment phase. All participants that had completed the 8-week treatment phase (non-responders or responders) had the option to enter a blinded 8-week extension phase to continue to receive SHR0302 4mg QD. Those who had completed the first 8-week of the treatment phase, but decided not to enter into the extension phase were also required to attend the 2-week follow-up visit. Participants who immaturely withdrew during the first treatment phase could not enter the extension phase. SHR0302: The study drug, SHR0302, is designed to block the activity of an enzyme protein called JAK (known as a JAK inhibitor). | Drug: SHR0302<br>* The study drug, SHR0302, is designed to block the activity of an enzyme protein called JAK (known as a Janus kinase inhibitor).<br>* Other names: Ivarmacitinib;|
| Placebo Comparator: placebo<br>Participants randomized in this arm will receive the placebo until week 8, and then will be re-randomized into one of the 3 active arms ( 4mg QD, 4mg BD, 8mg QD of SHR0302) in a 1:1:1 allocation ratio until the end of the study at week 16. Those who had completed the first 8-week of the treatment phase, but decided not to enter into the extension phase were also required to attend the 2-week follow-up visit. Participants who immaturely withdrew during the first treatment phase could not enter the extension phase. SHR0302: The study drug, SHR0302, is designed to block the activity of an enzyme protein called JAK (known as a JAK inhibitor). Placebos: Placebo Oral Tablet | Drug: SHR0302<br>* The study drug, SHR0302, is designed to block the activity of an enzyme protein called JAK (known as a Janus kinase inhibitor).<br>* Other names: Ivarmacitinib;Drug: Placebo<br>* Placebo Oral Tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Subject Achieve Clinical Response at Week 8 | Clinical response is defined as a decrease from baseline in a 9-point modified Mayo score of at least 2 points and at least 30%, with an accompanying reduction in the subscore for rectal bleeding of at least 1 point or absolute subscore for rectal bleeding of 0 or 1. The 9-point modified Mayo score is the Mayo score excluding the Physician Global Assessment sub-score, hence the maximum is 9 points and the minimum is 0 point, includes: Stool Frequency 0 = Normal = 1-2 stools/day more than normal = 3-4 stools/day more than normal = 5 or more stools/day than normal Rectal bleeding 0 = None = Visible blood with stool less than half the time = Visible blood with stool half of the time or more = Passing blood alone Mucosal appearance at endoscopy 0 = Normal or inactive disease = Mild disease (erythema, decreased vascular pattern, mild friability = Moderate disease (marked erythema, absent vascular pattern, friability, erosio | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Percentage of Subjects Achieve Clinical Remission | Clinical remission was defined as a total Mayo score of 2 points or lower, with no individual sub-score exceeding 1 point. The percentage of subjects who achieve clinical remission per 9-point modified Mayo score at week 8, where stool frequency subscore ≤ 1, rectal bleeding subscore of 0, and endoscopic subscore ≤ 1. 9-point modified Mayo score includes: Stool Frequency 0 = Normal = 1-2 stools/day more than normal = 3-4 stools/day more than normal = 5 or more stools/day than normal Rectal bleeding 0 = None = Visible blood with stool less than half the time = Visible blood with stool half of the time or more = Passing blood alone Mucosal appearance at endoscopy 0 = Normal or inactive disease = Mild disease (erythema, decreased vascular pattern, mild friability = Moderate disease (marked erythema, absent vascular pattern, friability, erosions) = Severe disease (spontaneous bleeding, ulceration) | Week 8 | 
| The Percentage of Subjects Achieve Clinical Remission at Week 8 | Clinical remission was defined as a total Mayo score of 2 points or lower, with no individual sub-score exceeding 1 point. The percentage of subjects achieve clinical remission at week 8 as per a total Mayo score of 2 points or lower ≤2, with no individual subscore exceeding 1 point and a rectal bleeding subscore of 0. The 9-point modified Mayo score includes: Stool Frequency 0 = Normal = 1-2 stools/day more than normal = 3-4 stools/day more than normal = 5 or more stools/day than normal Rectal bleeding 0 = None = Visible blood with stool less than half the time = Visible blood with stool half of the time or more = Passing blood alone Mucosal appearance at endoscopy 0 = Normal or inactive disease = Mild disease (erythema, decreased vascular pattern, mild friability = Moderate disease (marked erythema, absent vascular patt | Week 8 | 
| The Percentage of Subjects Achieve Endoscopic Remission (Mucosal Healing) at Week 8 | Endoscopic remission was defined by Mayo endoscopic subscore ≤ 1 point. Mayo endoscopic subscore defines score 0 as normal or inactive disease, score 1 as mild disease (erythema, decreased vascular pattern, mild friability); score 2 as moderate disease (marked erythema, absent vascular pattern, friability, erosions)； score 3 as severe disease (spontaneous bleeding, ulceration). | Week 8 |