Efficacy of Upadacitinib Re-induction Therapy in Patients With Ulcerative Colitis Who Lost Response to 30 mg Maintenance Dose

A Single Arm, Multicenter Open-Label Interventional to Evaluate the Efficacy of Upadacitinib Re-induction Therapy in Patients With Ulcerative Colitis Who Lost Response to 30 mg Maintenance Dose

ReCOUP is a multicenter clinical study designed to evaluate the efficacy of upadacitinib (Rinvoq®) in patients with ulcerative colitis whose disease has become active again despite maintenance treatment with upadacitinib 30 mg.

This study involves adult patients aged 18 to 64 years with active ulcerative colitis, who are being treated with upadacitinib and are not participating in another interventional clinical trial.

Participation in this study will depend on the patients' response to treatment during the 52-week maintenance period.

Several follow-up visits will be scheduled throughout the study according to a timetable defined by the protocol, and additional visits may be arranged if necessary depending on patients' health status.

Inclusion Criteria:

1. Subjects must voluntarily sign and date an informed consent, approved by an IEC/IRB, prior to the initiation of any screening or study-specific procedures.

2. Individuals at least 18 years old and less than 65 years.

3. Laboratory values meeting the following criteria within the screening period prior to the first dose of study drug:

   • Serum alanine transaminase (ALT) < 2 × ULN;
   • Serum aspartate aminotransferase (AST) < 2 x ULN;
   • Estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula > 0 mL/min/1.73 m2;
   • Total white blood cell (WBC) count > 2,500/μL;
   • Absolute neutrophil count (ANC) > 1,500/μL;
   • Platelet count > 100,000/μL;
   • Absolute lymphocyte count > 850/μL;
   • Hemoglobin > 10 g/dL.

4. Are willing and able to comply with procedures required in this protocol.

5. Subjects must not be incarcerated and must be freely willing and able to provide informed consent. Examples of subjects unable to freely provide informed consent may include some adults under legal protection measures (e.g., under guardianship/curatorship) or unable to express their consent and select adults under psychiatric care. Investigator's discretion should be applied.

6. Diagnosis of moderate to severe active ulcerative colitis with a documented initial response to upadacitinib treatment (defined as adapted Mayo score of 5-9) and subsequent documented loss of response to upadacitinib 30 mg QD dose. This should be within 8 weeks of screening. This will allow for short term non-UC related flares to self-resolve, while at the same time allowing for adequate time interval between appointments.

7. Subject has documented diagnosis of moderate to severe active UC with a modified Mayo score of 5 to 9 points and endoscopic subscore of 2 to 3 at the time of screening.

8. Pregnancy testing in females of childbearing potential/individuals of childbearing potential; Contraception Recommendations of this protocol :

   Females of childbearing potential/Individuals of childbearing potential must have a negative serum pregnancy test at the Screening Visit.

9. Female subjects of childbearing potential must practice at least 1 protocol-specified method of birth control, from Study Day 1 through at least 30 days after the last dose of study drug. Female subjects of nonchildbearing potential do not need to use birth control.

Exclusion Criteria:

1. Subject with current diagnosis of Crohn's Disease or diagnosis of indeterminate colitis.

2. Current diagnosis of fulminant colitis and/or toxic megacolon.

3. History of clinically significant (per investigator's judgment) drug or alcohol abuse within the last 6 months.

4. Conditions that could interfere with drug absorption including but not limited to short bowel syndrome.

5. History of colectomy (total or subtotal), ileoanal pouch, Kock pouch, or ileostomy or is planning bowel surgery.

6. Subject has active TB or latent TB.

7. Subject who received fecal microbial transplantation within 30 days prior to Baseline.

8. Subject with new or chronic systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong CYP3A inducers while on UPA therapy should be evaluated by caring physician as to possibility of this medication being responsible for the loss of response to UPA. Herbal therapies and other traditional medicines are defined as any herbal formulation that is intended to treat or prevent health problems and may include supplements based on herbs which the subject is taking.

9. Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN at any time during study treatment.

10. Subject with positive C. difficile toxin stool assay during screening.

11. Infection(s) requiring treatment with intravenous anti-infectives within 30 days prior to the Baseline visit or oral/intramuscular anti-infectives within 14 days prior to the baseline visit.

12. Chronic recurring infection and/or active viral infection that, based on the investigator's clinical assessment, makes the subject an unsuitable candidate for the study

13. Subject has current or past history of recurrent or disseminated (even a single episode) herpes zoster

14. Subject has current or past history of disseminated (even a single episode) herpes simplex

15. Prior or current gastrointestinal (GI) dysplasia, other than completely removed dysplastic lesion in any biopsy performed during or before the screening endoscopy.

16. History of any malignancy, except for successfully treated nonmelanoma skin cancer (NMSC) or localized carcinoma in situ of the cervix.

17. History of gastrointestinal (GI) perforation (other than due to appendicitis or mechanical injury), diverticulitis, or significantly increased risk of GI perforation per investigator's judgment.

18. History of an allergic reaction or significant sensitivity to constituents of upadacitinib (and its excipients)

19. Subject who previously received stem cell transplantation

20. Subject has been a previous recipient of an organ transplant which requires continued immunosuppression.

21. History of cerebrovascular accident, myocardial infarction, coronary stenting, or aortocoronary bypass stenting or retinal vein occlusion; however, if the investigator determines there are no suitable treatment alternatives available for a subject who has experienced one of these events more than 6 months prior to the Baseline visit, the investigator must document a favorable benefit-risk assessment to justify the subject's inclusion in the study.

    In patients with known VTE risk factors other than cardiovascular or alignancy risk factors, participation in this clinical trial is considered the most suitable treatment option among treatment alternatives and the risks and benefits have been discussed with the subject.

22. A serious AE or AE that is identified or a possible risk of UPA during prior treatment with upadacitinib that is deemed to have a causal relationship with upadacitinib by Investigator

23. Subjects who have been treated with any investigational drug of chemical or biologic nature within 30 days or five half-lives (whichever is longer) prior to the first dose of study treatment or who are currently enrolled in another interventional clinical study.

24. Received treatment with rectal aminosalicylates or corticosteroids, other enemas/suppositories (other than required for endoscopy), within 7 days prior to the Screening endoscopy and during the remainder of the Screening Period.

25. Received cyclosporine, tacrolimus, mycophenolate mofetil or thalidomide within 30 days prior to Baseline.

26. Subjects who received azathioprine or 6-mercaptopurine within 10 days of Baseline.

27. Subjects who received intravenous corticosteroids within 14 days prior to screening or during the screening period.

28. Subjects who require corticosteroids to remain in the study

29. Subject who received non-steroidal anti-inflammatory drugs (NSAIDs) (except topicalNSAIDs and the useof low dose aspirin for cardiovascular [CV] protection) within 7 days prior to baseline