Feasibility Pilot Sequential Multiple Assignment Randomized Trial (SMART) for Acute Severe Ulcerative Colitis
A Sequential Multiple Assignment Randomized Trial (SMART) Feasibility Pilot Developing and Optimizing Patient-Tailored Adaptive Treatment Strategies (ATS) for Acute Severe Ulcerative Colitis (ASUC)
Study Overview
Status
Conditions
Detailed Description
Group 1: SMART Intervention (n=62):
Adult patients (ages 18+) admitted with Acute Severe Ulcerative Colitis (ASUC) who meet all eligibility criteria and provide informed consent for the interventional component of the trial.
Cohort 2: Qualitative Patient Interviews (up to n=38) Eligible patients with ASUC who decline enrollment in the interventional component. These participants will undergo qualitative interviews to identify and characterize barriers to trial participation. Recruitment for this cohort will conclude once thematic saturation is achieved.
Cohort 3: Clinician Stakeholder Interviews (up to n=100) Clinicians (including attending physicians and house staff) providing direct care for participants enrolled in the interventional arm. Qualitative interviews will be conducted to assess the feasibility and acceptability of the study protocol within the clinical workflow. Recruitment will conclude once thematic saturation is achieved.
Cohort 4: Observational Comparator Group (up to n=500) A retrospective and prospective observational cohort of patients admitted with ASUC during the trial period who were not enrolled in the intervention. This group will serve as a contemporary control to provide comparative data on standard-of-care outcomes and help mitigate selection bias.
There was a major amendment (Ame00167573) submitted to the IRBMED and approved.
Changes included in the amendment (not all inclusive) were the primary feasibility and acceptability endpoints. New, more granular metrics were added for recruitment, retention, and adherence. These changes were made to provide a more robust and detailed assessment of feasibility, which is the primary goal of this pilot study. Additionally, efficacy outcomes were clarified and expanded as well as some eligibility criteria updated.
Study Type
Enrollment (Estimated)
Phase
- Phase 4
Contacts and Locations
Study Contact
- Name: Queen Saunyama
- Phone Number: 734-647-2564
- Email: saunayma@umich.edu
Study Locations
-
-
Michigan
-
Ann Arbor, Michigan, United States, 48109
- Recruiting
- University of Michigan
-
Contact:
- Queen Saunyama
- Phone Number: 734-647-2564
- Email: saunayma@umich.edu
-
Principal Investigator:
- Jeffrey Berinstein, MD, MSc
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria for Clinical trial patients:
- 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
Meeting the following definition of acute severe ulcerative colitis as defined as having ≥ 4 bowel movements per day with visible blood and one of the following:
a. Temperature > 37.8 Celsius b. Pulse > 90 Beats per minute (BPM) c. Hemoglobin < 10.5g/dL d. Erythrocyte sedimentation rate ≥ 30mm/h e. Weight loss > 5 lbs over 3 months f. C-reactive protein ≥ 3.0mg/dL g. Fecal calprotectin >782 mg/kg (within 4 weeks) h. Oral corticosteroid use for ≥ 14 days at a dose equivalent to ≥ 30mg/day
- 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
- Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, daily bowel movement symptoms surveys, and other study procedures
- Evidence of a personally signed and dated informed consent document indicating that the participant (or a legal representative) has been informed of all pertinent aspects 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 which include the following.
- Combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal, injectable) associated with the inhibition of ovulation, initiated at least 30 days prior to study baseline
- Progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation, initiated at least 30 days prior to study baseline
- Bilateral tubal occlusion/ligation (could be via hysteroscopy, provided a hysterosalpingogram confirmed success of the procedure)
- Vasectomized partner(s) provided the vasectomized partner had received medical confirmation of the surgical success and was the sole sexual partner of the trial participant
- Intrauterine device or intrauterine hormone-releasing system
- Lifestyle abstinence (refraining from heterosexual intercourse when this is in line with the preferred and usual lifestyle of the patient)
- Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods)
- Consistent use of barrier contraception
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 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)
- Known hypersensitivity to any of the following drugs or constituents: methylprednisolone, cyclosporine, tofacitinib, or upadacitinib
- Patients who had previous exposure to upadacitinib. Previous exposure to other Janus kinase (JAK) inhibitors (e.g., tofacitinib, baricitinib, or filgotinib) are permissible.
Patients with ongoing severe infection (as determined by the study team), including untreated or inadequately treated latent or active tuberculosis (TB)
a. Active Cytomegalovirus (CMV) colitis is defined as having > 5 CMV inclusion bodies per high powered field in any one ulcer at baseline. If CMV colitis is confirmed, the patient can remain in the trial if permissible by the infectious disease and primary treatment team and if concomitant anti-viral therapy is initiated.
b. Patients with a positive stool exam for enteric pathogens can remain in the trial. Initiation of treatment at the discretion of the treatment team and infectious disease team if needed.
- Patients who have received any investigational pharmacological agent or invasive investigational procedure within 30 days or five half-lives of study initiation with potential efficacy for UC or that could interact with study medications, as determined by the Principal Investigator. Participation in studies with non-invasive investigational procedures or standard-of-care invasive procedures are permitted.
- Current malignancy with the exception of 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 including the following:
- Neutropenia - Absolute Neutrophil Count (ANC) <1200 cells/mm3 or Total white blood cell count <2500/µL
- Hemoglobin < 7mg/dL without plans for a transfusion
- Platelet count <80,000/µL
- Moderate/severe renal impairment with estimated glomerular filtration rate (eGFR) <30milliliter (mL)/min/1.73m2 (by simplified four-variable Modification of Diet in Renal)
- Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) liver biochemistry levels that are ≥ 2 times the patient's baseline (as determined based on the principal investigator's judgement)
- Cirrhosis with mild to severe hepatic impairment (defined as a Child-Pugh score ≥5)
- History of uncontrolled hypertension (systolic blood pressure >160 millimeters of mercury (mmHg) or diastolic blood pressure > 100 millimeters of mercury (mmHg) despite anti-hypertensives)
Any of the following cardiovascular conditions:
a. Recent (within previous 6 months) cerebrovascular accident, myocardial infarction, or coronary stenting b. Recent (within previous 6 months) moderate-to-severe congestive heart failure (New York Heart Association class III or IV)
History of inherited or acquired conditions that predispose to hypercoagulability including the following. Please note, that patients with a remote history of provoked thrombotic event or recent thrombotic event on systemic anticoagulation are NOT exclusionary.
a. Antiphospholipid syndrome b. Factor V Leiden mutation c. Prothrombin G20210A mutations d. Deficiencies of antithrombin f. Deficiency of protein C g. Deficiency of protein S h. Heparin cofactor II deficiency i. Plasminogen and plasminogen activator inhibitor-1 j. Dysfibrinogenemia k. Factor XII deficiency
- 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 as:
a. HBV: hepatitis B surface antigen (HBsAg) positive with detectable deoxyribonucleic acid (DNA) not on therapy. Patients with serologic evidence of a resolved prior HBV infection (i.e., HBsAg-negative and anti-HB Core-positive) or patients with HBsAg positive on suppressive HBV therapy with low DNA (<105 copies/mL or <104 IU/mL negative) are not exclusionary b. HCV: HCV ribonucleic acid detectable in any patient with anti-HCV antibody c. HIV: Confirmed positive anti-HIV antibody with Cluster of Differentiation 4 (CD4) counts <350 cells/microliter (uL) or acquired immunodeficiency syndrome (AIDS)- defining opportunist infection
- 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 including:
- Hormone replacement therapy
- Testosterone
- Tamoxifen
- 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 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. This includes grapefruit and grapefruit juice.
- The presence of any condition significantly affecting oral drug absorption (e.g., gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass), as determined by the Principal Investigator. 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:
1. Clinicians (Internal medicine residents, gastroenterology fellows, and attending gastroenterologists or colorectal surgeons) caring for the patients enrolled in the clinical trial
Exclusion criteria for Physicians:
1. Non-clinicians not caring for the enrolled patient
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Sequential Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: Methylprednisolone
Methylprednisolone Intravenous (IV) 30 milligram (mg) twice a day (BID)
|
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).
Other Names:
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).
Other Names:
|
|
Experimental: Methylprednisolone plus Upadacitinib
Methylprednisolone IV 30mg BID plus Upadacitinib 45mg every day.
|
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).
Other Names:
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.
Other Names:
|
|
Experimental: Oral Upadacitinib
Upadacitinib 30 mg BID
|
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.
Other Names:
|
|
Experimental: Methylprednisolone then Cyclosporine
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 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).
Other Names:
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.
Other Names:
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.
Other Names:
|
|
Experimental: Methylprednisolone then Upadacitinib
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 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).
Other Names:
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.
Other Names:
|
|
Experimental: Oral Upadacitinib then Methylprednisolone
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 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).
Other Names:
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).
Other Names:
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.
Other Names:
|
|
Experimental: Oral Upadacitinib then Methylprednisolone plus cyclosporine infusion
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 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).
Other Names:
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).
Other Names:
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.
Other Names:
|
|
Experimental: Methylprednisolone plus Upadacitinib then cyclosporine
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 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).
Other Names:
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.
Other Names:
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.
Other Names:
|
|
Experimental: Methylprednisolone plus Upadacitinib then increased Upadacitinib
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 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).
Other Names:
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).
Other Names:
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.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
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
Time Frame: Day 3
|
Target ≥60%
|
Day 3
|
|
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
Time Frame: Days 4 through day 10 (maximum 7 days from initiation of second stage of treatment)
|
Target ≥60%
|
Days 4 through day 10 (maximum 7 days from initiation of second stage of treatment)
|
|
Proportion of eligible enrolled patients who were randomized during the first stage of intervention and who received treatment (regardless of ATS assignment)
Time Frame: Randomized day 0 - up to day 3
|
Target ≥ 80%
|
Randomized day 0 - up to day 3
|
|
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)
Time Frame: Days 4 through day 10
|
Target ≥ 60%
|
Days 4 through day 10
|
|
Proportion of eligible enrolled patients who initiated first stage therapy who successfully transitioned to the second stage of intervention
Time Frame: Day 3 - Day 4
|
Intervention (randomized and received treatment if deemed to be a non-responder or continued treatment/were discharged if deemed to be first stage responder) Target ≥ 50%.
|
Day 3 - Day 4
|
|
Proportion of eligible enrolled patients with complete data records for C-Reactive Protein (CRP) and Ulcerative Colitis Patient reported outcomes (UC-PRO) prior to second stage allocation
Time Frame: Day 0 to Day 3 of intervention
|
Target ≥ 60% with CRP and UC-PRO recorded on Day 3 or day of intervention phase completion if occurring before Day 3.
|
Day 0 to Day 3 of intervention
|
|
Proportion of eligible patients who enroll (not including screen failures) in the trial throughout the enrollment period
Time Frame: 5 years
|
Target ≥50%
|
5 years
|
|
Proportion of eligible enrolled participants followed until discharge or colectomy (whichever comes first)
Time Frame: up to approximately 10 days
|
The proportion is regardless of ATS adherence (target ≥ 70%)
|
up to approximately 10 days
|
|
Proportion of eligible enrolled participants without colectomy that were followed for 90 days with completion of one of the required study items
Time Frame: 90 days
|
Participants followed for 90 days with completion of one of the required study items at Day 90 (UC-PRO, Complete Blood Count (CBC), Comprehensive Metabolic Panel (CMP), CRP, fecal calprotectin (FCP), research stool) (target ≥ 70%).
|
90 days
|
|
Proportion of eligible enrolled participants without colectomy that were followed for 90 days with completion of all of the required study items at Day 90
Time Frame: 90 days
|
Proportion of eligible enrolled participants without colectomy that were followed for 90 days with completion of all of the required study items at Day 90 (UC-PRO, CBC, CMP, CRP, FCP, research stool) (target ≥ 50%).
|
90 days
|
|
Percentage of participants with complete colectomy status and safety data via 90-day chart review
Time Frame: 90 days
|
Target ≥ 90%
|
90 days
|
|
Proportion of eligible enrolled participants with complete UC-PROs on each day of hospitalization from enrollment to discharge or colectomy (whichever comes first regardless of intervention phase completion/ATS adherence)
Time Frame: up to approximately 10 days
|
Target ≥ 50% completion across all eligible days
|
up to approximately 10 days
|
|
Proportion of eligible enrolled participants without colectomy that were followed for 90 days with completion of all requested study items
Time Frame: Day 30, Day 60, Day 90
|
Completion of all requested study items at Day 30, Day 60, and Day 90 (target ≥ 50%)
|
Day 30, Day 60, Day 90
|
|
Proportion of participants who were enrolled prior to receiving their first dose of intravenous (IV) methylprednisolone
Time Frame: Baseline
|
Target ≥ 70%
|
Baseline
|
|
Proportion of participants who were enrolled who satisfied Truelove and Witts' disease severity criteria as measured by stool frequency
Time Frame: Baseline
|
This is measured by stool frequency > 6 Bowel Movements (BMs)/day with blood and 1 feature of systemic disturbance (fever >37.8 Celsius, pulse >90 beats/minute, hemoglobin >10.5 grams per deciliter (g/dL), or erythrocyte sedimentation rate >30 millimetres per hour (mm/h) or C-reactive protein >30 mg/L) (target ≥ 50%).
|
Baseline
|
|
Proportion of eligible enrolled patients who initiated first stage therapy (regardless of ATS adherence) within 12 hours of randomization
Time Frame: up to 12 hours after randomization
|
Target ≥ 50%
|
up to 12 hours after randomization
|
|
Proportion of enrolled participants who completed endoscopic evaluation within 72 hours of enrollment and had an endoscopic Mayo score ≥ 2
Time Frame: up to 72 hours
|
This excludes those that did not complete endoscopic evaluation within 1 week of enrollment. Target ≥75% |
up to 72 hours
|
|
Proportion of eligible enrolled participants reporting trial design acceptable as measured by semi-structured interviews
Time Frame: up to approximately 10 days (prior to discharge)
|
Interviews will assess perceptions of the ATS, trial burden, and willingness to participate in a similar study again (target ≥ 60%)
|
up to approximately 10 days (prior to discharge)
|
|
Proportion of inpatient physicians interviewed reporting trial design acceptable
Time Frame: Up to approximately 10 days
|
Interviews assess the feasibility, practicality, complexity, workload imposed by the SMART design and clarity, and clinical appropriateness of the ATS (target ≥ 60%)
|
Up to approximately 10 days
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Incidence and severity of adverse events
Time Frame: Up to 100 days (intervention plus follow-up)
|
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 participants in initial clinical response without rescue therapy or colectomy at 120 hours (5 days) after initiating first stage therapy
Time Frame: 5 days
|
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).
|
5 days
|
|
Proportion of participants undergoing same-admission colectomy per first stage treatment and ATS
Time Frame: Day 0 to Day 4
|
Proportion of enrolled patients who undergo colectomy during the index hospitalization.
|
Day 0 to Day 4
|
|
Proportion of participants undergoing 90-day colectomy per first stage treatment and ATS
Time Frame: 90 days from enrollment
|
Proportion of enrolled patients who undergo colectomy during the index hospitalization.
|
90 days from enrollment
|
|
Proportion of participants who are in steroid-free remission at 90 days per first stage treatment and ATS.
Time Frame: At 90-day follow-up
|
Proportion of participants without steroid use within 14 days prior to the 90-day follow-up point.
|
At 90-day follow-up
|
|
Proportion of participants without rescue therapy during intervention period or colectomy within 90 days per first stage treatment and ATS.
Time Frame: 90 days
|
Proportion of enrolled patients who did not receive non-protocol rescue therapy during the intervention period and did not undergo colectomy within 90 days of enrollment.
|
90 days
|
|
Proportion of participants meeting first stage response criteria per first-stage treatment
Time Frame: Day 3
|
Proportion of participants who met the criteria for being a "responder" at the end of the first stage, out of all participants who received that specific first stage treatment.
|
Day 3
|
|
Proportion of first stage non-responders who are re-randomized who avoid colectomy within 90 days
Time Frame: 90 days
|
Among the subgroup of participants who were non-responders at the end of stage 1 and were re-randomized, the proportion who did not undergo colectomy within 90 days of initial enrollment.
|
90 days
|
|
Proportion of patients who are steroid-free at 90 days among eligible enrolled patients in SMART compared to non-enrolled patients
Time Frame: 90 days
|
Non-enrolled patients 18-75 years of age, with a verified diagnosis of UC, hospitalized with ASUC (according to the study eligibility criteria) and are expecting IV steroids.
|
90 days
|
|
Proportion of patients who experience a UC-related readmission within 90 days among eligible enrolled patients in SMART compared to non-enrolled patients
Time Frame: 90 days
|
Non-enrolled patients 18-75 years of age, with a verified diagnosis of UC, hospitalized with ASUC (according to study eligibility criteria) and are expecting IV steroids.
|
90 days
|
|
Proportion of patients without rescue therapy during hospitalization among eligible enrolled patients in SMART compared to non-enrolled patients
Time Frame: Day 0 up to Day 10
|
Non-enrolled patients 18-75 years of age, with a verified diagnosis of UC, hospitalized with ASUC (according to study eligibility criteria) and are expecting IV steroids.
|
Day 0 up to Day 10
|
|
Proportion of patients without rescue therapy during hospitalization or colectomy within 90 days among eligible enrolled patients in SMART compared to non-enrolled patients
Time Frame: 90 days
|
Non-enrolled patients 18-75 years of age, with a verified diagnosis of UC, hospitalized with ASUC (according to our eligibility criteria) and are expecting IV steroids.
|
90 days
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Jeffrey Berinstein, MD, MSc, University of Michigan
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Intestinal Diseases
- Digestive System Diseases
- Gastrointestinal Diseases
- Colonic Diseases
- Gastroenteritis
- Inflammatory Bowel Diseases
- Colitis
- Colitis, Ulcerative
- Ulcer
- Peptides
- Amino Acids, Peptides, and Proteins
- Polycyclic Compounds
- Pregnadienes
- Pregnanes
- Steroids
- Fused-Ring Compounds
- Pregnadienetriols
- Pregnadienediols
- Macrocyclic Compounds
- Peptides, Cyclic
- Cyclosporins
- Methylprednisolone
- Prednisolone
- Prednisone
- Methylprednisolone Hemisuccinate
- Cyclosporine
- upadacitinib
Other Study ID Numbers
- HUM00228245
- K23DK134764 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Data sharing plan includes:
* de-identified dataset will be placed in a public repository after publication.
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- ICF
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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