Feasibility Pilot Sequential Multiple Assignment Randomized Trial (SMART) for Acute Severe Ulcerative Colitis

NCT05867329 | Recruiting Phase 4 FDA Drug

• 2 other identifiers: HUM002282451K23DK134764-01
• Study Type: interventional
• Target: 162
• Locations: 1 country
• Sites: 1

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.

Conditions

Ulcerative Colitis Acute

Keywords

Acute Severe Ulcerative Colitis; Ulcerative colitis flare

Outcome Measures

Primary Outcomes (7)

• 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 patients who completed study period and 90-day follow-up

  The study team will assess the ability of the investigators to execute the SMART, as well as the ability to treat participants to complete one of the adaptive treatment strategies and complete the SMART study (including the intervention and follow-up period).

  Up to 100 days (intervention plus follow-up)

• Proportion of patients with completed CRP and daily bowel movements recorded on Day 2 or Day 3 prior to sequentially randomized allocation

  To assess the feasibility of using bowel movements and CRP as the study primary tailoring variable to determine if these are too long or burdensome, and if these variables can be obtained in a timely and complete fashion.

  Day 2 or Day 3 (prior to sequentially randomized allocation)

• Proportion of patients who successfully underwent the second randomization (or transition to the second stage among those not re-randomized)

  The study will assess the feasibility of using real-time sequentially randomized allocation performed successfully by the treatment team.

  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)

• Proportion of patients who complete the trial who successfully underwent the second randomization (non-responders) or continued current therapy (responders) of all enrolled patients.

  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)

Secondary Outcomes (6)

• Proportion of patients undergoing same-admission colectomy

  Approximately 10 days (prior to discharge from index admission)

• Proportion of patients undergoing colectomy within follow-up

  Up to 100 days (intervention plus follow-up)

• Incidence and severity of adverse events

  Up to 100 days (intervention plus follow-up)

• Proportion of patients in steroid-free remission at 90 days

  At 90-day follow-up

• Proportion of patients in initial clinical response (C-reactive protein and number of bowel movements) without non-trial rescue therapy or colectomy at 120 hours (5 days) after initiating first stage therapy per to treatment and ATS.

  5 days from randomization

Study Arms (9)

Methylprednisolone

EXPERIMENTAL

Methylprednisolone Intravenous (IV) 30 milligram (mg) twice a day (BID)

Drug: Intravenous Methylprednisolone; Drug: Prednisone Oral Product

Methylprednisolone plus Upadacitinib

EXPERIMENTAL

Methylprednisolone IV 30mg BID plus Upadacitinib 45mg every day.

Drug: Upadacitinib Extended Release Oral Tablet; Drug: Intravenous Methylprednisolone

Oral Upadacitinib

EXPERIMENTAL

Upadacitinib 30 mg BID

Drug: Upadacitinib Extended Release Oral Tablet

Methylprednisolone then Cyclosporine

EXPERIMENTAL

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); Drug: Cyclosporine Oral Product; Drug: Intravenous Methylprednisolone

Methylprednisolone then Upadacitinib

EXPERIMENTAL

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; Drug: Intravenous Methylprednisolone

Oral Upadacitinib then Methylprednisolone

EXPERIMENTAL

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; Drug: Intravenous Methylprednisolone; Drug: Prednisone Oral Product

Oral Upadacitinib then Methylprednisolone plus cyclosporine infusion

EXPERIMENTAL

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; Drug: Intravenous Methylprednisolone; Drug: Prednisone Oral Product

Methylprednisolone plus Upadacitinib then cyclosporine

EXPERIMENTAL

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); Drug: Cyclosporine Oral Product; Drug: Intravenous Methylprednisolone

Methylprednisolone plus Upadacitinib then increased Upadacitinib

EXPERIMENTAL

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; Drug: Intravenous Methylprednisolone; Drug: Prednisone Oral Product

Interventions

Cyclosporine Injection (IV) DRUG

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.

Also known as: Sandimmune

Methylprednisolone plus Upadacitinib then cyclosporine; Methylprednisolone then Cyclosporine

Cyclosporine Oral Product DRUG

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.

Also known as: Sandimmune

Methylprednisolone plus Upadacitinib then cyclosporine; Methylprednisolone then Cyclosporine

Upadacitinib Extended Release Oral Tablet DRUG

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.

Also known as: Rinvoq

Methylprednisolone plus Upadacitinib; Methylprednisolone plus Upadacitinib then increased Upadacitinib; Methylprednisolone then Upadacitinib; Oral Upadacitinib; Oral Upadacitinib then Methylprednisolone; Oral Upadacitinib then Methylprednisolone plus cyclosporine infusion

Intravenous Methylprednisolone DRUG

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).

Also known as: Solu-Medrol

Methylprednisolone; Methylprednisolone plus Upadacitinib; Methylprednisolone plus Upadacitinib then cyclosporine; Methylprednisolone plus Upadacitinib then increased Upadacitinib; Methylprednisolone then Cyclosporine; Methylprednisolone then Upadacitinib; Oral Upadacitinib then Methylprednisolone; Oral Upadacitinib then Methylprednisolone plus cyclosporine infusion

Prednisone Oral Product DRUG

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).

Also known as: Rayos

Methylprednisolone; Methylprednisolone plus Upadacitinib then increased Upadacitinib; Oral Upadacitinib then Methylprednisolone; Oral Upadacitinib then Methylprednisolone plus cyclosporine infusion

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• 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:
• Temperature \> 37.5C
• Pulse \> 90 BPM
• Hemoglobin \< 10.5g/dL
• Erythrocyte sedimentation rate ≥ 30mm/h
• Weight loss \> 5 lbs over 3 months
• C-reactive protein ≥ 3.0mg/dL
• Fecal calprotectin \>782 mg/kg (within 4 weeks)
• 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
• 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

You may not qualify if:

• Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, or clinical findings suggestive of Crohn's disease
• On IV corticosteroids for ≥ 72 hours prior to enrollment continuously (at any institution)
• Currently pregnant or breastfeeding
• Patients who meet diagnostic criteria for toxic megacolon during this current admission. This will be determined by the study team and inpatient treatment team according to the following supportive criteria: Having dilation of the colon \> 6m and three of the following (Temperature\>38C, HR \>120 BPM, WBC\>10500/µL, Hemoglobin \< 10.5mg/dL) and one of the following (dehydration, altered mental status, severe electrolyte disturbances, and hypotension)
• 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 (eg, 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)
• 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 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 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 - ANC \<1200 cells/mm3 or Total white blood cell count \<2500/µL
• Hemoglobin \< 8mg/dL
• Platelet count \<80,000/µL

Sponsors & Collaborators

• Berinstein, Jeffrey: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

University of Michigan

Ann Arbor, Michigan, 48109, United States

RECRUITING

MeSH Terms

Interventions

Cyclosporine; upadacitinib; Methylprednisolone Hemisuccinate; Prednisone

Intervention Hierarchy (Ancestors)

Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Methylprednisolone; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Pregnadienediols

Study Officials

• Jeffrey Berinstein, MD, MSc

  University of Michigan

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Queen Saunyama

CONTACT

734-647-2564; saunayma@umich.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant Professor Internal Medicine

Model Details: 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.

Study Record Dates

• First Submitted: April 18, 2023
• First Posted: May 22, 2023
• Study Start: September 30, 2023
• Primary Completion: May 1, 2026
• Study Completion: May 1, 2026
• Last Updated: April 15, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF

Locations

US (1)