Ulcerative Colitis Acute
Conditions
Keywords
Acute Severe Ulcerative Colitis, Ulcerative colitis flare
Brief summary
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
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.
Interventions
DRUGCyclosporine Injection (IV)
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.
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.
DRUGUpadacitinib Extended Release Oral Tablet
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.
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).
DRUGPrednisone Oral Product
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).
Sponsors
Berinstein, Jeffrey
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study utilizes a Sequential Multiple Assignment Randomized Trial (SMART) design to evaluate adaptive treatment strategies for patients with Acute Severe Ulcerative Colitis (ASUC). Stage 1 Intervention: Upon enrollment, patients are randomized to an initial treatment arm. Clinical response is formally evaluated on Day 3 using pre-defined protocol criteria. Participants meeting response criteria at Day 3 will remain on their initially assigned Stage 1 therapy through the remainder of the induction period while participants identified as non-responders at Day 3 will undergo a second randomization to determine their Stage 2 therapy. The study will include semi-structured interviews with the inpatient clinical teams to evaluate the feasibility of the sequential randomization and the acceptability. The study will also include a Matched Temporal Control Group consisting of non-enrolled patients admitted with ASUC during the concurrent study period for a comparative analysis.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
for Clinical trial patients: 1. Patient ≥ 18 to 75 years of age at baseline 2. Diagnosis of ulcerative colitis (verified by a typical clinical history as well as characteristic appearance on endoscopy and histology) 3. 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 4. 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 5. 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 6. Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, daily bowel movement symptoms surveys, and other study procedures 7. 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 8. Ability to take oral medication and be willing to adhere to the study intervention regimen 9. 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. 1. 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 2. Progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation, initiated at least 30 days prior to study baseline 3. Bilateral tubal occlusion/ligation (could be via hysteroscopy, provided a hysterosalpingogram confirmed success of the procedure) 4. 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 5. Intrauterine device or intrauterine hormone-releasing system 6. Lifestyle abstinence (refraining from heterosexual intercourse when this is in line with the preferred and usual lifestyle of the patient) 7. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) 8. Consistent use of barrier contraception
Exclusion criteria
for Clinical trial patients: 1. Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, or clinical findings suggestive of Crohn's disease 2. On IV corticosteroids for ≥ 72 hours prior to enrollment continuously (at any institution) 3. Currently pregnant or breastfeeding 4. 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) 5. Known hypersensitivity to any of the following drugs or constituents: methylprednisolone, cyclosporine, tofacitinib, or upadacitinib 6. Patients who had previous exposure to upadacitinib. Previous exposure to other Janus kinase (JAK) inhibitors (e.g., tofacitinib, baricitinib, or filgotinib) are permissible. 7. 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. 8. 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. 9. Current malignancy with the exception of non-metastatic basal cell or squamous cell carcinoma of the skin. 10. Patients who had a history of colectomy (total or subtotal), ileoanal pouch, Kock pouch, or ileostomy or were planning bowel surgery 11. Moderate or severe renal, hematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac, neurological, or psychiatric condition including the following: 1. Neutropenia - Absolute Neutrophil Count (ANC) \<1200 cells/mm3 or Total white blood cell count \<2500/µL 2. Hemoglobin \< 7mg/dL without plans for a transfusion 3. Platelet count \<80,000/µL 4. Moderate/severe renal impairment with estimated glomerular filtration rate (eGFR) \<30milliliter (mL)/min/1.73m2 (by simplified four-variable Modification of Diet in Renal) 5. 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) 12. Cirrhosis with mild to severe hepatic impairment (defined as a Child-Pugh score ≥5) 13. History of uncontrolled hypertension (systolic blood pressure \>160 millimeters of mercury (mmHg) or diastolic blood pressure \> 100 millimeters of mercury (mmHg) despite anti-hypertensives) 14. 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) 15. 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 16. Patients with total cholesterol \<80 mg/dL at baseline 17. 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) 18. 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 19. Solid organ or bone marrow transplant within 1 year or expected transplant within 6 months 20. History of more than one episode of herpes zoster, a history of disseminated herpes zoster or disseminated herpes simplex 21. Current use of medications which significantly increase the risk of venous thromboembolic event as determined by the investigator including: 1. Hormone replacement therapy 2. Testosterone 3. Tamoxifen 22. 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. 23. 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. 24. 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 25. 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. 26. 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. 27. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Day 3 | 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 | Days 4 through day 10 (maximum 7 days from initiation of second stage of treatment) | Target ≥60% |
| Proportion of eligible enrolled patients who were randomized during the first stage of intervention and who received treatment (regardless of ATS assignment) | Randomized day 0 - up to day 3 | 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) | Days 4 through day 10 | Target ≥ 60% |
| Proportion of eligible enrolled patients who initiated first stage therapy who successfully transitioned to the second stage of intervention | 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%. |
| 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 | 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. |
| Proportion of eligible patients who enroll (not including screen failures) in the trial throughout the enrollment period | 5 years | Target ≥50% |
| Proportion of eligible enrolled participants followed until discharge or colectomy (whichever comes first) | up to approximately 10 days | The proportion is regardless of ATS adherence (target ≥ 70%) |
| Proportion of eligible enrolled participants without colectomy that were followed for 90 days with completion of one of the required study items | 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%). |
| 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 | 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%). |
| Percentage of participants with complete colectomy status and safety data via 90-day chart review | 90 days | Target ≥ 90% |
| 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) | up to approximately 10 days | Target ≥ 50% completion across all eligible days |
| Proportion of eligible enrolled participants without colectomy that were followed for 90 days with completion of all requested study items | Day 30, Day 60, Day 90 | Completion of all requested study items at Day 30, Day 60, and Day 90 (target ≥ 50%) |
| Proportion of participants who were enrolled prior to receiving their first dose of intravenous (IV) methylprednisolone | Baseline | Target ≥ 70% |
| Proportion of participants who were enrolled who satisfied Truelove and Witts' disease severity criteria as measured by stool frequency | 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%). |
| Proportion of eligible enrolled patients who initiated first stage therapy (regardless of ATS adherence) within 12 hours of randomization | up to 12 hours after randomization | Target ≥ 50% |
| Proportion of enrolled participants who completed endoscopic evaluation within 72 hours of enrollment and had an endoscopic Mayo score ≥ 2 | up to 72 hours | This excludes those that did not complete endoscopic evaluation within 1 week of enrollment. Target ≥75% |
| Proportion of eligible enrolled participants reporting trial design acceptable as measured by semi-structured interviews | 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%) |
| Proportion of inpatient physicians interviewed reporting trial design acceptable | 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%) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of participants in initial clinical response without rescue therapy or colectomy at 120 hours (5 days) after initiating first stage therapy | 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). |
| Proportion of participants undergoing same-admission colectomy per first stage treatment and ATS | Day 0 to Day 4 | Proportion of enrolled patients who undergo colectomy during the index hospitalization. |
| Proportion of participants undergoing 90-day colectomy per first stage treatment and ATS | 90 days from enrollment | Proportion of enrolled patients who undergo colectomy during the index hospitalization. |
| Incidence and severity of adverse events | 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. |
| Proportion of participants who are in steroid-free remission at 90 days per first stage treatment and ATS. | At 90-day follow-up | Proportion of participants without steroid use within 14 days prior to the 90-day follow-up point. |
| Proportion of participants without rescue therapy during intervention period or colectomy within 90 days per first stage treatment and ATS. | 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. |
| Proportion of participants meeting first stage response criteria per first-stage treatment | 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. |
| Proportion of first stage non-responders who are re-randomized who avoid colectomy within 90 days | 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. |
| Proportion of patients who are steroid-free at 90 days among eligible enrolled patients in SMART compared to non-enrolled patients | 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. |
| Proportion of patients who experience a UC-related readmission within 90 days among eligible enrolled patients in SMART compared to non-enrolled patients | 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. |
| Proportion of patients without rescue therapy during hospitalization among eligible enrolled patients in SMART compared to non-enrolled patients | 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. |
| Proportion of patients without rescue therapy during hospitalization or colectomy within 90 days among eligible enrolled patients in SMART compared to non-enrolled patients | 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. |
Countries
United States
Contacts
CONTACTQueen Saunyama
PRINCIPAL_INVESTIGATORJeffrey Berinstein, MD, MSc
University of Michigan
Outcome results
None listed