The goal of this trial is to create personalized treatments for each patient admitted to the hospital with acute severe ulcerative colitis (ASUC). The study will test the feasibility and acceptability of these treatment strategies among patients and physicians so that the study team can later do a larger trial to test whether the medication treatment pathways help patients avoid colectomy while ensuring patient's are safe.
Patient ≥ 18 to 75 years of age at baseline
Diagnosis of ulcerative colitis (verified by a typical clinical history as well as characteristic appearance on endoscopy and histology)
Current hospital admission for ulcerative colitis treatment (expecting IV corticosteroid initiation). Note this includes patients seen in emergency room who are expected to be admitted for UC treatment
Prior history of receiving at least one dose of adalimumab, certolizumab, infliximab, or golimumab originator or biosimilars or a prior history of receiving at least one approved systemic therapy in the event tumor necrosis factors blockers are clinically inadvisable
Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, or clinical findings suggestive of Crohn's disease
On IV corticosteroids for ≥ 72 hours prior to enrollment continuously (at any institution)
Currently pregnant or breastfeeding
Patients who meet diagnostic criteria for toxic megacolon during this current admission. This will be determined by the study team and inpatient treatment team according to the following supportive criteria: Having dilation of the colon > 6m and three of the following (Temperature>38 Celsius, Heart Rate >120 BPM, white blood cells (WBC) >10500/µL, Hemoglobin < 10.5mg/dL) and one of the following (dehydration, altered mental status, severe electrolyte disturbances, and hypotension)
Sequential
Cyclosporine Injection (IV)
DrugDrug be administered as weight-based continuous infusion (2mg/kg/day) during the second stage of treatment (if applicable). Cyclosporine monitoring will take place approximately 18-24 hours stage of treatment (Day 4 at the earliest). The goal is to achieve whole blood levels of 300 (range 200-400) ng/ml with adjustments according to the table in the protocol. The intravenous cyclosporine dosage is rarely raised above 4 mg/kg/day, in rare patients that are fast metabolizers.
Cyclosporine Oral Product
DrugOnce participants meet discharge criteria, participant's that received IV Cyclosporine (stage 2) will be transitioned to oral Cyclosporine. The oral dose is calculated to be approximately twice the daily intravenous dose or approximately 5 mg/kg, rounded to nearest 25 mg, and is administered every 12 hours (h). Oral cyclosporine solution will be administered as Sandimmune capsules available in 25mg 100mg capsules size. After the intervention period (during hospitalization after IV cyclosporine is complete) and during the follow-up period any cyclosporine adjustments are permissible under the current study protocol according to the discretion of the treating physician.
Upadacitinib Extended Release Oral Tablet
DrugThis will be administered orally once daily as 45mg (stage one) or twice daily as a 30mg oral tablet (first stage and second stage) of treatment (if applicable). Upon discharge a patient will be switched from Upadacitinib 30mg twice daily to 45mg daily for 8 weeks followed by 30mg or 15mg subsequently if Upadacitinib is to be continued after discharge. The choice of induction/maintenance agent initiated after discharge will be determined by inpatient treatment team and in consultation with the outpatient gastroenterologist. No patient will continue Upadacitinib 30mg twice daily after discharge from the hospital.
Intravenous Methylprednisolone
DrugDrug will be administered as 30mg twice daily during the first stage of treatment (if applicable) and through the second stage of treatment (if applicable). Prior to discharge a patient will be switched from IV Methylprednisolone to prednisone 40-60mg with plans to taper by 5mg/week (dose subject to adjustment by treating inpatient team and in consultation with the outpatient gastroenterologist).
Prednisone Oral Product
DrugPatients that received IV Methylprednisolone will be switched prior to discharge from IV Methylprednisolone to prednisone 40-60mg with plans to taper by 5mg/week (dose subject to adjustment by treating inpatient team and in consultation with the outpatient gastroenterologist).
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Treatment groupsSee each treatment group below.
Adherence to intervention based on the proportion of participants who received the assigned Adaptive Treatment Strategy (ATS) (without receiving added/removed therapy outside of assignment) during first stage of therapy
Target ≥60%
Adherence to intervention based on the proportion of participants who received the assigned Adaptive Treatment Strategy (ATS) (without receiving added/removed therapy outside of assignment) during second stage of therapy
Target ≥60%
Proportion of eligible enrolled patients who were randomized during the first stage of intervention and who received treatment (regardless of ATS assignment)
Target ≥ 80%
Proportion of eligible enrolled patients initiated on first stage therapy who were randomized during second stage of intervention and who received their assigned treatment (regardless of ATS assignment)
Target ≥ 60%
Proportion of participants in initial clinical response without rescue therapy or colectomy at 120 hours (5 days) after initiating first stage therapy
Proportion of enrolled patients meeting the definition of initial clinical response (reduction in bowel movements by ≥60% or \<4 BMs/day AND CRP \< 1 mg/dL).
Proportion of participants undergoing same-admission colectomy per first stage treatment and ATS
Proportion of enrolled patients who undergo colectomy during the index hospitalization.
Proportion of participants undergoing 90-day colectomy per first stage treatment and ATS
Proportion of enrolled patients who undergo colectomy during the index hospitalization.
Incidence and severity of adverse events
Incidence and severity of adverse events will be reported. Shingles, acne, major cardiovascular events, venous thromboembolic events, cancers and other infections are adverse events of special interest (AESI). The study team will also record the incidence of serious infections and incidence and severity of laboratory abnormalities between first treatment stage and adaptive treatment strategies. Adverse event will be graded as described in the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.
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Berinstein, Jeffrey
Lead sponsor
University of Michigan
Sponsor institution
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborator
