A Trial for Acute Severe Ulcerative Colitis

Study Overview
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Brief Summary
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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.

Detailed Description
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It is anticipated that 62 participants will be enrolled on to the clinical trial and approximately 100 physicians caring for enrolled participants. There is also a third group that are eligible patients not enrolled in the trial (patients will only be interviewed and will not receive any active treatment) and will not be included in the enrollment numbers or outcome measures.

Official Title
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A Sequential Multiple Assignment Randomized Trial (SMART) Developing and Optimizing Patient-Tailored Adaptive Treatment Strategies (ATS) for Acute Severe Ulcerative Colitis

Conditions
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Ulcerative Colitis Acute

Intervention / Treatment
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* Drug: Cyclosporine Injection (IV)
* Drug: Cyclosporine Oral Product
* Drug: Upadacitinib Extended Release Oral Tablet
* Drug: Intravenous Methylprednisolone
* Drug: Prednisone Oral Product


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Clinical trial patients: 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 Intravenous (IV) corticosteroid initiation) Meeting definition of acute severe ulcerative colitis according to Truelove and Witt's Criteria (≥6 bowel movements per day with visible blood) and at least one of the following: (Temperature > 37.5 celsius, Pulse > 90 beats per minutes, hemoglobin < 10.5 grams per deciliter (g/dL), erythrocyte sedimentation rate > 30millimeters per hour (mm/h), c-reactive protein ≥ 4.5 milligrams per decilitre mg/dL) Prior history of receiving at least one dose of adalimumab, certolizumab, infliximab, or golimumab originator or biosimilars Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, daily bowel movement symptoms surveys, and other study procedures Stated willingness to comply with all study procedures and availability for the duration of the study Ability to take oral medication and be willing to adhere to the study intervention regimen For females of reproductive potential (i.e., females <55 years of age with intact ovaries and fallopian tubes) a negative pregnancy test on admission and intent to use highly effective contraception during 3-month follow-up period (per protocol). Exclusion Criteria for Clinical trial patients: 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 protocol. Known hypersensitivity to any of the following drugs or constituents: methylprednisone, cyclosporine, tofacitinib, or Upadacitinib Patients who had previous exposure to Upadacitinib. Previous exposure to other Janus kinase (JAK) inhibitors (eg, tofacitinib, baricitinib, or filgotinib) are permissible. Positive stool examinations for enteric pathogens, pathogenic ova or parasites, or Clostridium difficile toxin at screening Patients with ongoing infection, including untreated or inadequately treated latent or active tuberculosis (TB) Active Cytomegalovirus (CMV) colitis with >5 CMV inclusion bodies per high powered field in any one ulcer at baseline. If CMV colitis is confirmed on subsequent endoscopy the patient can remain in the trial if permissible by the infectious disease team and if concomitant anti-viral therapy is initiated. Patients who had received any investigational agent or procedure within 30 days or five half-lives prior to baseline, whichever is longer, or were enrolled in an interventional study Current malignancy or a history of malignancy, with the exception of adequately treated or excised non-metastatic basal cell or squamous cell carcinoma of the skin. Patients who had a history of colectomy (total or subtotal), ileoanal pouch, Kock pouch, or ileostomy or were planning bowel surgery Moderate or severe renal, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, neurological, or psychiatric condition per protocol. Mild to severe hepatic impairment: Child-Pugh score ≥5 History of uncontrolled hypertension (systolic blood pressure >160 millimetres of mercury (mmHg) or diastolic blood pressure > 100 millimetres of mercury (mmHg) despite anti-hypertensives) Certain cardiovascular or thrombotic conditions per protocol Patients with total cholesterol <80 mg/dL at baseline Patients who had a history of an allergic reaction or significant sensitivity to constituents of the treatment (and its excipients) and/or other products in the same class of medication (ex., tofacitinib) Patients who had hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infection defined per protocol. Solid organ or bone marrow transplant within 1 year or expected transplant within 6 months History of more than one episode of herpes zoster, a history of disseminated herpes zoster or disseminated herpes simplex Current use of medications which significantly increase the risk of venous thromboembolic event as determined by the investigator Vaccination with live or attenuated live vaccines within 6 weeks of baseline or scheduled to receive these vaccines during study period or within 140 days (20 weeks) after last dose of study medication. History of any lymphoproliferative disorder (such as Epstein-Barr virus (EBV)-related lymphoproliferative disorder), history of lymphoma, leukemia, myeloproliferative disorders, multiple myeloma, or signs and symptoms suggestive of current hematologic disease. Patients who had a history of spontaneous gastrointestinal (GI) perforation (other than appendicitis or mechanical injury), diverticulitis, or significantly increased risk of GI perforation per investigator's judgement Actively receiving strong CYP3A4 inducers or inhibitors prior to the first dose of study drug or are expected to receive any of these medications during the study period. The presence of any condition possibly affecting oral drug absorption (e.g., gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass). Procedures such as gastric banding that simply divide the stomach into separate chambers are not exclusionary. Patients who had a history of a clinically significant medical condition or any other reason which, in the opinion of the investigator, would have interfered with the patient's participation in this study, would have made the patient an unsuitable candidate to receive treatment, or would have put the patient at risk by participating in the protocol Inclusion criteria for Physicians: - Clinicians (Internal medicine residents, gastroenterology fellows, and attending gastroenterologists) caring for the patients enrolled in the clinical trial Exclusion criteria for Physicians: - Non-clinicians not caring for the enrolled patient

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

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: Sequential Assignment
Interventional Model Description: Patients will be randomized to stage 1 and then be evaluated day 3. If patients are non-responders (defined by protocol) re-randomization for the second stage will take place. Patients that are responders at day 3 will continue with stage 1 treatment. Response to the second-stage of treatment will be calculated 72 hours after initiation of second-stage treatment and on every day up to day 10. If a patient meets any of the second-stage treatment failure criteria (per protocol) on day 6 through day 10, the patient will be considered to have failed second-stage therapy and will be referred for colectomy. If a patient does not meet criteria for second-stage treatment failure or criteria for safe discharge (see the protocol) the patient will be permitted to continue second-stage treatment for a maximum of 7 days (day 10 of intervention). Physicians care for patients enrolled in our study will be interviewed to evaluate acceptability and feasibility.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methylprednisolone<br>Methylprednisolone Intravenous (IV) 30 milligram (mg) twice a day (BID) | Drug: Intravenous Methylprednisolone<br>* Drug 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).<br>* Other names: Solu-Medrol;Drug: Prednisone Oral Product<br>* Patients 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).<br>* Other names: Rayos;|
| Experimental: Methylprednisolone plus Upadacitinib<br>Methylprednisolone IV 30mg BID plus Upadacitinib 45mg every day. | Drug: Upadacitinib Extended Release Oral Tablet<br>* This 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.<br>* Other names: Rinvoq;Drug: Intravenous Methylprednisolone<br>* Drug 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).<br>* Other names: Solu-Medrol;|
| Experimental: Oral Upadacitinib<br>Upadacitinib 30 mg BID | Drug: Upadacitinib Extended Release Oral Tablet<br>* This 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.<br>* Other names: Rinvoq;|
| Experimental: Methylprednisolone then Cyclosporine<br>Methylprednisolone IV 30 mg BID Stage 1 and if determined to be a non-responder to Methylprednisolone, patient will receive rescue Cyclosporine (2milligram/kilogram (mg/kg) per day aiming for levels 200-400 nanograms per milliliter (ng/mL)) in addition to continuing Methylprednisolone for stage 2. | Drug: Cyclosporine Injection (IV)<br>* Drug 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.<br>* Other names: Sandimmune;Drug: Cyclosporine Oral Product<br>* Once 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.<br>* Other names: Sandimmune;Drug: Intravenous Methylprednisolone<br>* Drug 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).<br>* Other names: Solu-Medrol;|
| Experimental: Methylprednisolone then Upadacitinib<br>Methylprednisolone IV 30mg twice a day Stage 1 and if determined to be a non-responder to Methylprednisolone, patient will receive rescue Upadacitinib 30mg BID in addition to continuing Methylprednisolone for stage 2 | Drug: Upadacitinib Extended Release Oral Tablet<br>* This 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.<br>* Other names: Rinvoq;Drug: Intravenous Methylprednisolone<br>* Drug 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).<br>* Other names: Solu-Medrol;|
| Experimental: Oral Upadacitinib then Methylprednisolone<br>Oral Upadacitinib 30mg BID for stage 1 then for patients that are non-responders, add rescue Methylprednisolone IV 30mg twice a day in addition to continuing Upadacitinib for stage 2. | Drug: Upadacitinib Extended Release Oral Tablet<br>* This 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.<br>* Other names: Rinvoq;Drug: Intravenous Methylprednisolone<br>* Drug 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).<br>* Other names: Solu-Medrol;Drug: Prednisone Oral Product<br>* Patients 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).<br>* Other names: Rayos;|
| Experimental: Oral Upadacitinib then Methylprednisolone plus cyclosporine infusion<br>Upadacitinib 30 mg BID for stage 1. If a patient is a non-responder to Upadacitinib 30 mg, then the study team will stop Upadacitinib and initiate Methylprednisolone IV 30mg twice a day plus Cyclosporine (2 milligram/kilogram (mg/kg) per day aiming for levels 200-400 nanograms per milliliter (ng/mL)) for stage 2. | Drug: Upadacitinib Extended Release Oral Tablet<br>* This 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.<br>* Other names: Rinvoq;Drug: Intravenous Methylprednisolone<br>* Drug 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).<br>* Other names: Solu-Medrol;Drug: Prednisone Oral Product<br>* Patients 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).<br>* Other names: Rayos;|
| Experimental: Methylprednisolone plus Upadacitinib then cyclosporine<br>Methylprednisolone IV 30mg BID and Oral Upadacitinib 45mg everyday stage 1 and then Cyclosporine 2 mg/kg per day aiming for levels 200-400ng/mL for stage 2. | Drug: Cyclosporine Injection (IV)<br>* Drug 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.<br>* Other names: Sandimmune;Drug: Cyclosporine Oral Product<br>* Once 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.<br>* Other names: Sandimmune;Drug: Intravenous Methylprednisolone<br>* Drug 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).<br>* Other names: Solu-Medrol;|
| Experimental: Methylprednisolone plus Upadacitinib then increased Upadacitinib<br>Methylprednisolone IV 30mg BID and Oral Upadacitinib 45mg everyday stage 1 and if determined to be a non-responder to Methylprednisolone and 45 mg Oral Upadacitinib, patient will receive rescue Upadacitinib 30mg BID in addition to continuing Methylprednisolone for stage 2. | Drug: Upadacitinib Extended Release Oral Tablet<br>* This 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.<br>* Other names: Rinvoq;Drug: Intravenous Methylprednisolone<br>* Drug 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).<br>* Other names: Solu-Medrol;Drug: Prednisone Oral Product<br>* Patients 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).<br>* Other names: Rayos;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Approximately 100 Days (intervention plus 90 days of follow-up) | 
| Proportion of randomly assigned participants that completed intervention and follow-up period up to 100 days | 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). | Up to 100 days (intervention plus follow-up) | 
| Proportion of participants with completed C-Reactive Protein (CRP) and daily bowel movements recorded 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. | Day 2 or Day 3 (prior to sequentially randomized allocation) | 
| Proportion of enrolled patients that successfully underwent the second randomization (or transition to the second-stage among participants not re-randomized) | The study will assess the feasibility of using real-time sequentially randomized allocation performed successfully by the treatment team. | Up to 10 days | 
| Proportion of patients reporting trial design acceptable | This will be measured by semi-structured interviews with patients and clinicians at the end of study period. One question for this outcome will be asked the study was acceptable (yes or no). | Approximately Day 10 (end of study treatment period) | 
| Proportion of inpatient physicians reporting trial design acceptable | This will be measured by semi-structured interviews with patients and clinicians at the end of study period. One question for this outcome will be asked the study was acceptable (yes or no). | Approximately Day 10 (end of study treatment period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Approximately 10 days (prior to discharge from index admission) | 
| 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. | Up to 100 days (intervention plus follow-up) | 
| 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. | Up to 100 days (intervention plus follow-up) | 
| 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. | At 90-day follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Severe Ulcerative Colitis, Ulcerative colitis flare