Tofacitinib Versus Cyclosporine for Steroid Refractory Acute Severe Ulcerative Colitis

Study Overview
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Brief Summary
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This randomised trial plans to compare oral tofacitinib with intravenous cyclosporine in patients with acute severe ulcerative colitis who have failed to respond to intravenous steroids

Official Title
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Tofacitinib Versus Cyclosporine for Steroid Refractory Acute Severe Ulcerative Colitis: An Open Label Randomized Study

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: Tofacitinib
* Drug: Cyclosporine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients admitted with Acute severe ulcerative colitis as defined by Modified Truelove and Witts Criteria WITH Failure to respond to intravenous steroids (Hydrocortisone 100 mg IV QID OR IV Methylprednisolone 60 mg IV OD) as defined by Day 3 non-response as per Oxford criteria (stool frequency of > 8/day, OR stool frequency between 3-8 with CRP > 45 mg/L PLUS Ongoing activity as defined by Partial Mayo Score of > 3 (rectal bleeding sub-score of >1) Decision to start second line therapy (within 5-7 days of starting intravenous steroids) Exclusion Criteria: Age <18, Age > 65 years E1 disease (involvement distal to rectosigmoid junction only) Crohn's disease Contraindication to intravenous cyclosporine or oral tofacitinib Renal failure, uncontrolled hypertension, seizure disorder,and uncorrected hypomagnesemia (<1.5 mg/L) Previous thrombosis, or prothrombotic state, on oral contraceptive, history of herpes zoster, active TB, active hepatitis, past opportunistic infections, h/o diverticulitis, Age >50 plus at least one cardiac risk factor Patient wants treatment with intravenous infliximab or wants surgery Underlying sepsis or active infection (Enteric infections, Clostridium difficile, active hepatitis B or C, Tuberculosis, zoster, CMV disease) Toxic megacolon, previous dysplasia or any indication of immediate surgery Known malignancy Pregnancy or Lactation Unwilling to provide consent or for follow-up

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A<br>Group A: Intravenous Cyclosporine 2 mg/kg continuous infusion for 5-7 days and then shifted to oral cyclosporine 4 mg/kg/day in two divided doses for 12 weeks | Drug: Cyclosporine<br>* : Intravenous Cyclosporine 2 mg/kg continuous infusion for 5-7 days and then shifted to oral cyclosporine 4 mg/kg/day in two divided doses for 12 weeks.Those who respond with intravenous cyclosporine will be shifted to oral cyclosporine 4 mg/kg for 12 weeks while the thiopurine dose is adjusted to the patient's weight<br>|
| Experimental: Group B<br>Oral Tofacitinib 10 mg TDS for 3 days, and then 10 mg BD to complete 8 weeks followed by 5 mg BD till follow-up (14 weeks) | Drug: Tofacitinib<br>* For the tofacitinib the dose of 10 mg BD will be administered for 8 weeks (10 mg TDS for initial three days) and then reduced to 5 mg BD for the period of study<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment failure | I) At Day 7 Absence of clinical response at day 7 (as defined by Partial Mayo of > 3) II) By Day 98 Relapse (Partial Mayo Score of 3 or more) between day 7 and day 98 requiring additional therapy Absence of steroid free remission at 14 weeks (Mayo < 2 with MES 1 or less) Need for colectomy, third line medical rescue or biologics or mortality Serious adverse effect needing interruption of treatment | 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical response | Partial Mayo <4 | 7 days | 
| Absence of steroid free remission | Mayo score of more than 2 with endoscopic sub-score of more than 1 | day 98 | 
| Colectomy free survival | No need for colectomy | 98 days | 
| Time to clinical response | Partial Mayo of 3 or less | 98 days | 
| Endoscopic healing | Mayo endoscopic sub-score of 1 or less | Day 98 | 
| Serious adverse effects | requiring hospitalization, cessation of treatment and events like cardiovascular events, pulmonary embolism, venous thrombosis, any infection, malignancy, gastrointestinal perforation | 98 days |