Comparison of Ustekinumab, Infliximab and Combination Therapy in Moderately to Severely Active Ulcerative Colitis

Inclusion Criteria:

1. Obtaining informed, written consent for the patient's participation in the in thestudy and for all planned procedures.

2. Age ≥ 18 years and ≤65 at the time of screening.

3. In the case of women of reproductive potential, agreement to not donate oocytes forthe entire period of participation in the in the study and 6 months after receivingthe last dose of the drug.

4. For women of reproductive potential, agreement to use effective contraception (Table

4. during the entire period, during which the patient participates in the study andfor a period counted from the last dose of 15 weeks if using UST (patients in arms Band C) or 6 months if using IFX (patients in arm A).

5. Negative serum or urine pregnancy test in women of childbearing age.

6. Diagnosis of UC a minimum of. 3 months prior to screening documented by:

(a) medical source documentation of the patient with the result of an endoscopicexamination that diagnosed features typical of UC.

(b) a histopathological examination result consistent with UC. In the absence of ahistopathological result, it is possible to take sections during the endoscopicexamination for histopathological evaluation at the time of eligibility for thestudy with subsequent sending of the material to the local pathomorphologylaboratory to confirm the diagnosis of UC before randomization.

7. UC with moderate or severe activity defined as a Mayo scale score (Appendix 2) of 7to 12 including the following sub-item values (each sub-item 0-3 points depending onthe severity of the lesions):

• Frequency of bowel movements

• Bowel bleeding

• Endoscopic image of the colonic mucosa

• General medical evaluation and:

• with inadequate response to standard treatment, including corticosteroids and 6-mercaptopurine or azathioprine, or.

• intolerant of treatment with corticosteroids and 6-mercaptopurine orazathioprine, or

• having contraindications to treatment with corticosteroids and 6-mercaptopurineor azathioprine, or

• with loss of response to standard treatment, including to treatment withcorticosteroids and 6-mercaptopurine or azathioprine, including patients:

• Steroid-resistant - in whom there is no clinical improvement despite the use ofa daily steroid up to 0.75 mg/kg prednisolone for 4 weeks;

• Steroid-dependent - in whom failure to reduce the steroid dose below 10 mg/day,converted to prednisolone, within 3 months of starting steroid therapy orrelapse of complaints within 3 months of steroid withdrawal.

• Refractory patients/about inadequate response to immunosuppressive treatment,defined as lack of remission or recurrence of complaints despiteimmunosuppressive treatment for at least 3 months at appropriate doses (azathioprine 2-2.5 mg/kg/day or 6-mercaptopurine 1-1.5 mg/kg/day).

8. Patients taking 5-ASA derivatives, corticosteroids, immunosuppressants may beincluded in the study if they are taking a fixed and specified dose of the abovedrugs 14 days before the day of randomization.

Exclusion Criteria:

1. Previous use of the study drug IFX or UST.

2. Hypersensitivity to the active substance or excipients.

3. Moderate or severe myocardial insufficiency (NYHA III or IV).

4. Unstable coronary artery disease.

5. History of serious cerebrovascular disease (stroke, intracranial hemorrhage,transient cerebral ischemia) within the last 24 weeks prior to screening.

6. Chronic respiratory failure.

7. Severe chronic renal failure.

8. Severe chronic liver failure.

9. Demyelinating syndrome or symptoms resembling the syndrome.

10. Alcoholic disease, post-alcoholic liver damage.

11. Diagnosis of malignant neoplasms, including within 5 years preceding the time ofeligibility for the program (except for carcinoma in situ of the cervix, andnon-melanoma skin cancers).

12 Complications requiring other management (e.g., surgery). 13. Current or recent (defined as an incident within 12 weeks prior to randomization) documented episode of fulminant colitis, or intra-abdominal abscess, or acute colonic distension, or bowel perforation.

14. Status after extensive colorectal resection, subtotal or total colectomy with orwithout colostomy, or J-pouch reservoir.

15. Indication of surgical intervention due to underlying disease or when there is asuspicion of need for such intervention during the course of the study.

16. History of current or previously documented unclassified colitis or ischemiccolitis.

17. History of colonic diverticulitis within the last 60 days prior to the randomizationvisit.

18. Current adenomatous polyps of the colon, small- or large-grade dysplasia in colonspecimens, or previously diagnosed foci of large-grade dysplasia that have not beentreated.

19. Enteral nutrition or total parenteral nutrition. 20. Pregnancy or breastfeeding. 21.Taking medications on the prohibited drugs list (Section 7.4.6). 22. daily dose ofprednisone> 40 mg (or equivalent other corticosteroid) or budesonide MMX > 9 mg.

20. Status after bone marrow transplantation. 24. Condition after apheresis 12 monthsprior to the randomization visit. 25. Period after administration of allowedbiologic drugs shorter than the drug's washout period from the body (Section 7.2).

21. Period after intestinal microbiota transplantation less than 8 weeks before signinginformed consent to participate in the study.

22. Active or latent form of tuberculosis. 28. HIV infection. 29. Treatment period foractive lesions of chronic infections (including pneumocystodosis, CMV, HPV, HSVinfection, atypical mycobacteriosis, invasive bacterial or fungal infections).

30 History of HSV, HPV, influenza virus, SARS-CoV2 infection within 12 weeks prior to randomization or history of disseminated or complicated HSV infection.

31. History of congenital or acquired immunodeficiency. 32. receipt of live vaccinewithin 30 days prior to randomization. 33. infection with HBV or HCV. 34. Clinicallysignificant changes on chest X-ray or ECG. 35 Clinically significant changesobserved in laboratory test results:

32. ALT activity >3x the upper limit of normal (GGN)

33. AST activity >3x GGN

34. Total bilirubin level >2x GGN (exception is Gilbert syndrome when other causes ofisolated hyperbilirubinemia are excluded).

35. ALP or GGTP activity >3x GGN

36. Creatinine level >2x GGN or impaired renal function (eGFR) <45mL/min calculated byMDRD formula.

37. Hemoglobin level <9g/dL

38. Absolute leukocyte count <3000/mm3

39. Absolute lymphocyte count <750/mm3

40. Neutrophil level <1000/mm3

41. Platelet level <100000/mm3. 36. Positive stool culture for bacteria/fungus (ifclinically relevant in the opinion of the investigator).

37.Positive stool culture for Clostridioides difficile. 38. Use of treatment notpermitted under this protocol.