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)
Temperature > 37.5C
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>38C, HR >120 BPM, 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.
Proportion of randomly allocated participants to first stage of intervention
The study team will assess the ability of the investigators to execute the SMART, as well as the ability to treat participants with each of three first stages of intervention.
Proportion of randomly assigned patients who completed study period and 90-day follow-up
The study team will assess the ability of the investigators to execute the SMART, as well as the ability to treat participants to complete one of the adaptive treatment strategies and complete the SMART study (including the intervention and follow-up period).
Proportion of patients with completed CRP and daily bowel movements recorded on Day 2 or Day 3 prior to sequentially randomized allocation
To assess the feasibility of using bowel movements and CRP as the study primary tailoring variable to determine if these are too long or burdensome, and if these variables can be obtained in a timely and complete fashion.
Proportion of patients who successfully underwent the second randomization (or transition to the second stage among those not re-randomized)
The study will assess the feasibility of using real-time sequentially randomized allocation performed successfully by the treatment team.
Proportion of patients undergoing same-admission colectomy
Colectomy events prior to discharge from index admission will be recorded as yes/no and compared between adaptive treatment strategies.
Proportion of patients undergoing colectomy within follow-up
Colectomy events within follow-up of index admission will be recorded as yes/no and compared between arms.
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.
Proportion of patients in steroid-free remission at 90 days
Patients will be assessed for on-going steroid use (any dose) at the 90-day follow-up and will be recorded as yes/no and compared between arms.
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Berinstein, Jeffrey
Lead sponsor
University of Michigan
Sponsor institution
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborator
