Identification of Biomarkers of Janus Kinase Inhibitor Therapy in Patients With Ulcerative Colitis

Study Overview
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Brief Summary
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This study aims to provide new mechanistic insights into the molecular determinants of response or nonresponse to Janus Kinase inhibitor therapy and the biological heterogeneity that exists in Ulcerative Colitis. This study will include patients who are initiating Janus Kinase inhibitor therapy according to standard of care. This study consists of: Part 1: 8 or 10 week induction therapy followed by an 8-week maintenance therapy Part 2: Patients who continue Janus Kinas inhibitor therapy after part 1 will be followed further for a total of 2 years, or until discontinuation of Janus Kinase inhibitor therapy (whichever is first)

Official Title
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PhaRmacOkinetics and PHarmacodynamic BiomarkErs of Janus Kinase Inhibitor Therapy in PatIents With Ulcerative Colitis (PROPHETIC)

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Janus Kinase Inhibitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 1.18 years of age or older. 2.Male or nonpregnant, nonlactating females. 3.Diagnosis of Ulcerative Colitis for at least 3 months prior to screening. 4.Moderately to severely active Ulcerative Colitis (total Mayo Clinic Score ≥ 6), with objective evidence of inflammation defined by a Mayo endoscopic subscore (MES) ≥ 2 and disease extending > 15 cm from the anal verge. 5.Physician plans to administer Janus Kinase inhibitor for at least 8 weeks of induction therapy as part of Standard of Care (SOC). 6.Documentation of a negative test result for latent tuberculosis within the last 12 months, or according to routine clinical practice. 7.Able to participate fully in all aspects of this clinical trial, including collection of tissue biopsies. 8.Written informed consent must be obtained and documented. Exclusion Criteria: Diagnosis of Crohn's disease or indeterminate colitis. An active, serious infection, including localized infections. Concomitant administration of biological therapies for Ulcerative Colitis or potent immunosuppressants, such as azathioprine and cyclosporine. Subjects with previous exposure to these treatments should undergo an appropriate washout period according to local practice prior to starting Janus Kinase inhibitor, in keeping with routine clinical practice. Hematology laboratory (e.g., absolute lymphocyte count, absolute neutrophil count, and hemoglobin that contraindicate the product label. Interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. Serious underlying disease other than Ulcerative Colitis that in the opinion of the investigator may interfere with the subject's ability to participate fully in the study.

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Open-Label Group<br>Eligible patients will include those who will be prescribed Janus Kinase inhibitor as part of their routine medical care. | Drug: Janus Kinase Inhibitor<br>* Janus Kinase inhibitor induction therapy will be administered according to Standard Of Care (SOC)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identify predictive fecal biomarkers that are associated with a change from baseline in UC-100 score | The UC-100 is a composite disease activity index consisting of clinical, endoscopic, and histological findings. The UC-100 is calculated by summing the weighted Mayo Clinic Score (MCS) stool frequency and endoscopy subscores, and the Robarts Histopathology Index (RHI) score as follows: UC-100 Score = 1 + (16 X stool frequency) + (6 X endoscopic subscore) + (RHI score). The total UC-100 score ranges from 1 to 100, with higher scores representing more severe disease activity. | 8 or 10 weeks; 24 weeks | 
| Identify predictive blood biomarkers that are associated with a change from baseline in UC-100 score |  | 8 or 10 weeks; 24 weeks | 
| Identify predictive tissue biomarkers that are associated with a change from baseline in UC-100 score |  | 8 or 10 weeks; 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identify pharmacodynamic fecal biomarkers that are associated with a change from baseline in UC-100 score |  | 8 or 10 weeks, 24 weeks | 
| Identify pharmacodynamic blood biomarkers that are associated with a change from baseline in UC-100 score |  | 8 or 10 weeks, 24 weeks | 
| Identify pharmacodynamic tissue biomarkers that are associated with a change from baseline in UC-100 score |  | 8 or 10 weeks, 24 weeks | 
| Identify a fecal biomarker signature as a surrogate measure for change from baseline in UC-100 score |  | 8 or 10 weeks, 24 weeks | 
| Identify a blood biomarker signature as a surrogate measure for change from baseline in UC-100 score |  | 8 or 10 weeks, 24 weeks | 
| Identify a tissue biomarker signature as a surrogate measure for change from baseline in UC-100 score |  | 8 or 10 weeks, 24 weeks | 
| Identify whether colonic tissue pSTAT at week 8 and/or 24 correlates with change from baseline in UC-100 score |  | 8 or 10 weeks, 24 weeks | 
| Determine the time-concentration profile of Janus Kinase inhibitor at steady state in stool samples. |  | 24 weeks | 
| Determine the time-concentration profile of Janus Kinase inhibitor at steady state in serum samples. |  | 24 weeks | 
| Determine the time-concentration profile of Janus Kinase inhibitor at steady state in tissue samples. |  | 24 weeks | 
| Evaluate correlation of exposure of Janus Kinase inhibitor between stool samples following SOC induction therapy and at Week 24. |  | 8 or 10 weeks, 24 weeks | 
| Evaluate correlation of exposure of Janus Kinase inhibitor between serum samples following SOC induction therapy and at Week 24. |  | 8 or 10 weeks, 24 weeks | 
| Evaluate correlation of exposure of Janus Kinase inhibitors between tissue samples following SOC induction therapy and at Week 24. |  | 8 or 10 weeks, 24 weeks | 
| Explore the exposure-response relationship of Janus Kinase inhibitors with exposure measured in stool samples and response defined as tissue PD biomarkers following SOC induction therapy and at Week 24. |  | 8 or 10 weeks, 24 weeks | 
| Explore the exposure-response relationship of Janus Kinase inhibitors with exposure measured in serum samples and response defined as tissue PD biomarkers following SOC induction therapy and at Week 24. |  | 8 or 10 weeks, 24 weeks | 
| Explore the exposure-response relationship of Janus Kinase inhibitors with exposure measured in tissue samples and response defined as tissue PD biomarkers following SOC induction therapy and at Week 24. |  | 8 or 10 weeks, 24 weeks | 
| Develop an exposure-response model of Janus Kinase inhibitors to characterize the relationships between local and systemic drug exposure and clinical, endoscopic, histologic, or biologic response to therapy. |  | 24 weeks | 
| Identify potential demographic and disease factors affecting the most relevant JAKi exposure-response relationships and determine target threshold of systemic exposure associated with relevant clinical, endoscopic, histologic, and/or biologic outcomes. |  | 8 or 10 weeks, 24 weeks | 
| Evaluate long-term hospitalization rates, surgery rates, and corticosteroid use after initiation of Janus Kinase inhibitor therapy and identify baseline or early biomarker signatures associated with these long-term healthcare resource use outcomes |  | 2 years | 
| Measure adverse drug reactions, clinical, endoscopic, and histologic response and remission rates to Janus Kinase inhibitors in a real-world population |  | 24 weeks |