Personalized Medication for Severe Ulcerative Colitis

Overseen By Queen Saunyama

Age: 18+

Sex: Female

Trial Phase: Phase 4

Sponsor: Berinstein, Jeffrey

Must be taking: Biologics

Must not be taking: CYP3A4 inducers/inhibitors

Disqualifiers: Pregnancy, Toxic megacolon, Severe infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 10 days

162 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores personalized treatments for individuals hospitalized with acute severe ulcerative colitis (ASUC). Researchers will test various combinations of medications, such as cyclosporine (available as both an injection and an oral product), methylprednisolone (an intravenous corticosteroid), and upadacitinib (an extended-release oral tablet), to identify the most effective treatment strategies. The ultimate goal is to help patients avoid colon removal surgery (colectomy) while ensuring their safety. Candidates for this study include those currently hospitalized with ulcerative colitis, experiencing frequent bloody bowel movements, and having tried other medications like adalimumab or infliximab.

As a Phase 4 trial, the treatment has already received FDA approval and proven effective, allowing researchers to understand how it benefits more patients.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it mentions that patients actively receiving strong CYP3A4 inducers or inhibitors, which are certain types of medications, are excluded from the study. It's best to discuss your current medications with the study team to see if any adjustments are needed.

What is the safety track record for these treatments?

Research shows that the treatments in this trial have different safety records from past studies.

**Methylprednisolone** is a steroid used to reduce inflammation. Studies have found it can increase the risk of infections. Patients should avoid contact with sick people and practice good hygiene. Use it carefully for ulcerative colitis, especially if there is a risk of complications like tears or infections in the intestines.

**Upadacitinib** has been researched for ulcerative colitis and other conditions. Evidence suggests it is generally safe, but there is a risk of serious infections. Long-term studies support its safety, but monitoring for signs of infection is important.

**Cyclosporine**, available as an injection or a pill, has been effective for severe ulcerative colitis, especially when steroids don't work. It is generally safe, but side effects increase with higher doses. Starting with lower doses is recommended.

These treatments have been tested for various conditions and have safety data to support them. However, reactions vary, so discussing potential risks and benefits with a healthcare provider is important. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for severe ulcerative colitis because they offer personalized medication strategies that could improve patient outcomes. Standard treatments often involve corticosteroids and immunosuppressants, but these new approaches combine drugs like Upadacitinib and Cyclosporine in different sequences to potentially enhance effectiveness. Upadacitinib is a unique feature, as it's a selective JAK inhibitor that targets specific pathways involved in inflammation, offering a different mechanism of action compared to traditional therapies. Additionally, the combination of intravenous and oral delivery methods aims to optimize drug absorption and patient response. By tailoring treatments to individual responses, this approach promises to be more effective than the one-size-fits-all methods commonly used today.

What evidence suggests that this trial's treatments could be effective for severe ulcerative colitis?

Research has shown that each treatment in this trial effectively addresses ulcerative colitis. Participants may receive Methylprednisolone, a steroid that helps about 60% of patients with severe cases. Another group may receive Upadacitinib, a newer drug that works for about 60-63% of patients, according to studies. Cyclosporine, often used when other treatments fail, is another option in this trial and proves effective in 62-92% of cases in the short term. These treatments have reduced symptoms and helped patients manage this challenging condition. ^{6 7 8 9 10}

Who Is on the Research Team?

Jeffrey Berinstein, MD, MSc

Principal Investigator

University of Michigan

Are You a Good Fit for This Trial?

This trial is for hospitalized patients with acute severe ulcerative colitis, who've had at least one dose of certain biologic treatments. They must be able to take oral meds, follow the study plan including daily symptom tracking, and women must use effective contraception during the study.

Inclusion Criteria

I have been diagnosed with ulcerative colitis confirmed by tests and symptoms.

I am currently in the hospital for ulcerative colitis and will start IV corticosteroids.

Stated willingness to comply with all study procedures and availability for the duration of the study

Exclusion Criteria

I have had or will have a major organ or bone marrow transplant within a year.

I do not have an ongoing infection, including TB.

I am not allergic to methylprednisolone, cyclosporine, tofacitinib, or upadacitinib.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive various combinations of Methylprednisolone, Upadacitinib, and Cyclosporine based on their response to initial treatments

Up to 10 days

Daily monitoring during hospital admission

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of clinical response and adverse events

90 days

Extension

Participants may continue to be monitored for long-term outcomes such as colectomy and steroid-free remission

Up to 100 days

What Are the Treatments Tested in This Trial?

Interventions

• Cyclosporine Injection (IV)
• Cyclosporine Oral Product
• Intravenous Methylprednisolone
• Prednisone Oral Product
• Upadacitinib Extended Release Oral Tablet

Trial Overview The trial aims to personalize treatment for ulcerative colitis using Upadacitinib tablets or Cyclosporine orally/injection along with standard steroids. It's testing if these strategies can prevent colectomy (surgical removal of the colon) safely before a larger trial.

How Is the Trial Designed?

Group I: Oral Upadacitinib then Methylprednisolone plus cyclosporine infusion Experimental Treatment 3 Interventions

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.

Group II: Oral Upadacitinib then Methylprednisolone Experimental Treatment 3 Interventions

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.

Group III: Oral Upadacitinib Experimental Treatment 1 Intervention

Upadacitinib 30 mg BID

Group IV: Methylprednisolone then Upadacitinib Experimental Treatment 2 Interventions

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

Group V: Methylprednisolone then Cyclosporine Experimental Treatment 3 Interventions

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.

Group VI: Methylprednisolone plus Upadacitinib then increased Upadacitinib Experimental Treatment 3 Interventions

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.

Group VII: Methylprednisolone plus Upadacitinib then cyclosporine Experimental Treatment 3 Interventions

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.

Group VIII: Methylprednisolone plus Upadacitinib Experimental Treatment 2 Interventions

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

Group IX: Methylprednisolone Experimental Treatment 2 Interventions

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

Cyclosporine Injection (IV) is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cyclosporine for:

• Organ rejection prevention in transplant patients
• Rheumatoid arthritis
• Psoriasis
• Severe ulcerative colitis

Approved in European Union as Cyclosporin for:

• Organ rejection prevention in transplant patients
• Rheumatoid arthritis
• Psoriasis
• Severe ulcerative colitis
• Atopic dermatitis

Approved in Canada as Cyclosporine for:

• Organ rejection prevention in transplant patients
• Rheumatoid arthritis
• Psoriasis
• Severe ulcerative colitis

Approved in Japan as Cyclosporine for:

• Organ rejection prevention in transplant patients
• Rheumatoid arthritis
• Psoriasis
• Severe ulcerative colitis

Who Is Running the Clinical Trial?

Berinstein, Jeffrey

Lead Sponsor

Trials

1

Recruited

160+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

In a study of nine patients with steroid-refractory ulcerative colitis, oral tacrolimus was effective, with all patients responding within 1-2 weeks and 67% achieving complete remission after 12 weeks.

While oral tacrolimus may serve as a viable alternative to intravenous ciclosporin, careful monitoring for side effects is essential, as two patients experienced severe adverse effects during the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of oral tacrolimus (FK 506) on steroid-refractory moderate/severe ulcerative colitis. Högenauer, C., Wenzl, HH., Hinterleitner, TA., et al.[2022]

In a study of 55 patients with acute steroid-resistant ulcerative colitis, oral microemulsion cyclosporin was found to be more effective than intravenous cyclosporin, achieving a 100% short-term response compared to 65% for the intravenous group.

The oral microemulsion formulation had a significantly better safety profile, with no major toxicities reported, while 17% of patients receiving intravenous cyclosporin experienced major toxicity, including one fatality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and efficiency of oral microemulsion cyclosporin versus intravenous and soft gelatin capsule cyclosporin in the treatment of severe steroid-refractory ulcerative colitis: an open-label retrospective trial. Actis, GC., Aimo, G., Priolo, G., et al.[2019]

Corticosteroids are the primary treatment for acute ulcerative colitis, but in cases where the disease does not respond, immunosuppressive therapies like azathioprine and cyclosporin may be necessary.

While these treatments can be effective, their potential side effects and the risk of long-term complications, such as cancer in patients with chronic extensive colitis, must be carefully considered.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of corticosteroids and immunosuppressive agents in ulcerative colitis. Connell, WR., Taylor, AC.[2019]

In a study of 216 patients with acute severe ulcerative colitis (UC) who were resistant to standard steroid treatment, intravenous cyclosporin achieved a short-term remission rate of 56%.

However, the long-term effectiveness was lower, with only 40% of patients maintaining remission after a mean follow-up of 19 months, indicating that while cyclosporin can be beneficial, its effectiveness may not be as high as previously suggested.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous cyclosporin as rescue therapy in severe ulcerative colitis: time for a reappraisal? Hyde, GM., Thillainayagam, AV., Jewell, DP.[2019]

Immunosuppressive drugs like cyclosporine, tacrolimus, and mycophenolate mofetil are effective treatments for patients with severe forms of inflammatory bowel disease, including refractory Crohn's disease and severe ulcerative colitis.

The review highlights the importance of understanding the pharmacology, clinical trial results, and safety profiles of these medications, emphasizing the need for careful dosing and monitoring for potential toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclosporine, tacrolimus, and mycophenolate mofetil in the treatment of inflammatory bowel disease. Loftus, CG., Egan, LJ., Sandborn, WJ.[2016]

Intravenous cyclosporine showed a high initial response rate of 69% in 16 patients with acute ulcerative colitis who were refractory to steroids, indicating its efficacy as a rescue therapy.

Long-term follow-up revealed that 56% of patients were able to avoid surgery by using a combination of cyclosporine and azathioprine for maintenance, suggesting that this treatment regimen can be effective and relatively safe for managing ulcerative colitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination immunomodulatory therapy with cyclosporine and azathioprine in corticosteroid-resistant severe ulcerative colitis: the Edinburgh experience of outcome. Campbell, S., Ghosh, S.[2019]

In a study of 38 patients with steroid-refractory ulcerative colitis, infliximab was associated with a significantly lower colectomy rate at 3 months (21%) compared to cyclosporine (63%), indicating better short-term efficacy.

At 12 months, infliximab also showed a trend towards lower colectomy rates (37% vs. 68% for cyclosporine), and patients treated with infliximab had shorter hospital stays and lower steroid dependence, suggesting it may be a safer and more effective option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infliximab or cyclosporine for acute severe ulcerative colitis: a retrospective analysis. Dean, KE., Hikaka, J., Huakau, JT., et al.[2015]

In a study of 19 patients with corticosteroid-refractory ulcerative colitis, Neoral (cyclosporine in microemulsion form) showed an 85% response rate and a 75% remission rate after 3.5 and 13 days, respectively, indicating its efficacy in this challenging condition.

The study also highlighted that Neoral's safety profile is similar to that of intravenous cyclosporine, with mild side effects like transient renal impairment and hypertension, and emphasized the importance of monitoring blood levels to avoid toxicity, recommending target levels of 100 ng/mL for fasting and 700 ng/mL two hours post-administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of ulcerative colitis refractory to steroid therapy by oral microemulsion cyclosporine (Neoral). Weber, A., Fein, F., Koch, S., et al.[2018]

In a review of 23 patients with acute severe ulcerative colitis who were unresponsive to high-dose glucocorticoids, intravenous cyclosporine led to clinical remission in 57% of cases after a median of nine days.

This suggests that about one-third of patients with refractory ulcerative colitis may benefit from adding intravenous cyclosporine to their treatment regimen, potentially improving long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Cyclosporine treatment of patients with active ulcerative colitis refractory to high-dose glucocorticoid]. Kjeldsen, J., Wilson, BV., Knudsen, T.[2013]

Citations

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Short- and longevity outcome of cyclosporin rescue therapy ... Previous data on the short-term effectiveness of CsA treatment showed a clinical response rate of 62%–92% supporting our results.6,8,10,13,14,16 ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38164363

Long-term outcomes of cyclosporin induction and ... Combination of cyclosporin and ustekinumab therapy allowed nearly half of ASUC patients to reach clinical and endoscopic remission after 52 weeks, warranting ...

3. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT05219656

Efficacy of Cyclosporine Rescue Therapy in Acute ... The efficacy and safety of Cyclosporine A as rescue therapy for acute severe ulcerative colitis in long-term follow-up. Detailed Description. All UC patients ...

4. sciencedirect.com sciencedirect.com/science/article/pii/014067369091521B

cyclosporin in treatment of severe active ulcerative colitis In the acute phase of the open trial, eleven patients (73%) improved and avoided colectomy; the mean response time was 5·8 days. Patients who responded were ...

5. tandfonline.com tandfonline.com/doi/full/10.1080/00365521.2022.2143727

Long-term outcomes of patients with acute severe ... CyA induces remission in up to 85% of patients with ASUC but overall colectomy rates still remain high [Citation10–12]. The long-term efficacy ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/16368919/

Cyclosporine for severe ulcerative colitis There is evidence to support the use of intravenous cyclosporine for patients with severe ulcerative colitis who are refractory to corticosteroid therapy.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5350574/

The Role of Cyclosporine Therapy in Ulcerative Colitis ... 80% response rate to cyclosporine was observed in a population of patients who had failed steroid therapy, and who would otherwise be slated for colectomy.

8. nejm.org nejm.org/doi/full/10.1056/NEJM199406303302601

Cyclosporine in Severe Ulcerative Colitis Refractory to ... We conclude that intravenous cyclosporine therapy is effective and safe in severely ill patients with ulcerative colitis that has not responded ...

9. journals.lww.com journals.lww.com/ajg/fulltext/2008/10000/safety_and_efficacy_of_cyclosporine_therapy_in.39.aspx

Safety and Efficacy of Cyclosporine Therapy in ... We report our experience of cyclosporine therapy in steroid-resistant ulcerative colitis (UC). One hundred five UC patients were treated at our unit between ...

10. tgh.amegroups.org tgh.amegroups.org/article/view/5363/html

A novel player: cyclosporine therapy in the management of ... Cyclosporine has progressed from strictly a transplant drug, to a novel therapeutic agent for the management of inflammatory bowel disease (IBD).