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

Trial Summary

What is the purpose of this trial?

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.

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 data supports the effectiveness of the drug for severe ulcerative colitis?

Research shows that intravenous cyclosporine can be effective as a rescue therapy for severe ulcerative colitis, with a short-term success rate of up to 80% in avoiding surgery. However, it is associated with significant toxicity, and there are concerns about early relapse. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

Cyclosporine, used for severe ulcerative colitis, has shown promise but is associated with significant toxicity and potential for serious infections. Corticosteroids and immunosuppressive agents like cyclosporine have been used extensively, but their benefits must be weighed against possible adverse effects. ^{1 4 6 7 8}

How is the drug Cyclosporine Injection (IV) unique for treating severe ulcerative colitis?

Cyclosporine Injection (IV) is unique for treating severe ulcerative colitis because it is used as a rescue therapy for patients who do not respond to standard high-dose steroid treatments, showing promising short-term results in avoiding surgery. It is one of the few new therapies that have significantly impacted the management of this condition, despite its potential toxicity. ^{1 5 6 7 9}

Research Team

Jeffrey Berinstein, MD, MSc

Principal Investigator

University of Michigan

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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 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]

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 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]

References

1. Australia pubmed.ncbi.nlm.nih.gov

Infliximab or cyclosporine for acute severe ulcerative colitis: a retrospective analysis. [2015]

2. England pubmed.ncbi.nlm.nih.gov

Effect of oral tacrolimus (FK 506) on steroid-refractory moderate/severe ulcerative colitis. [2022]

3. England 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. [2019]

4. Netherlands pubmed.ncbi.nlm.nih.gov

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

5. England pubmed.ncbi.nlm.nih.gov

Intravenous cyclosporin as rescue therapy in severe ulcerative colitis: time for a reappraisal? [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Cyclosporine, tacrolimus, and mycophenolate mofetil in the treatment of inflammatory bowel disease. [2016]

7. England pubmed.ncbi.nlm.nih.gov

Safety of corticosteroids and immunosuppressive agents in ulcerative colitis. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Treatment of ulcerative colitis refractory to steroid therapy by oral microemulsion cyclosporine (Neoral). [2018]

9. Denmark pubmed.ncbi.nlm.nih.gov

[Cyclosporine treatment of patients with active ulcerative colitis refractory to high-dose glucocorticoid]. [2013]