Comparison of ustekinumab, infliximab and COMBinatiOn therapy in moderately-to-severely active Ulcerative Colitis – the head-to-head COMBO-UC trial.

Prior treatment

• Previous use of the investigational drug IFX or UST.
• Complications requiring other management (e.g., surgery).
• 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.
• History of current or previously documented unclassified colitis or ischemic colitis.
• History of diverticulitis within the last 60 days prior to the randomization visit.
• Current adenomatous polyps of the colon, small- or large-grade dysplasia in colon specimens, or previously diagnosed foci of large-grade dysplasia that have not been treated.
• Taking medications on the prohibited drug list (Section 7.4.6).
• Daily dose of prednisone> 40 mg (or equivalent other corticosteroid) or budesonide MMX > 9 mg.
• Condition after apheresis 12 months prior to the randomization visit.
• Period after administration of allowed biologics shorter than the drug's washout period from the body (Section 7.2).
• Period after intestinal microbiota transplantation less than 8 weeks before signing informed consent to participate in the study.
• History of HSV, HPV, influenza virus, SARS-CoV2 infection within 12 weeks prior to randomization or history of disseminated or complicated HSV infection.
• Receipt of live vaccine within 30 days prior to randomization.
• History of serious cerebrovascular disease (stroke, intracranial hemorrhage, transient cerebral ischemia) within the last 24 weeks prior to screening.

Other illness

• Alcoholic disease, post-alcoholic liver damage.
• Diagnosis of malignant neoplasms, including within 5 years preceding the time of eligibility for the program (except for carcinoma in situ of the cervix, and non-melanoma skin cancers).
• Condition after extensive colorectal resection, subtotal or total colectomy with or without emergent colostomy, or J-pouch reservoir.
• Indication for surgical intervention due to underlying disease or when there is a suspicion of need for such intervention during the course of the study.
• Hypersensitivity to the active substance or excipients.
• Condition after bone marrow transplantation.
• Active or latent form of tuberculosis.
• HIV infection.
• Treatment period for active lesions of chronic infections (including pneumocystodosis, CMV, HPV, HSV infection, atypical mycobacteriosis, invasive bacterial or fungal infections).
• Moderate or severe myocardial insufficiency (NYHA III or IV).
• History of congenital or acquired immunodeficiency.
• HBV or HCV infection.
• Unstable coronary artery disease.
• Chronic respiratory failure.
• Severe chronic renal failure.
• Severe chronic liver failure.
• Demyelinating syndrome or symptoms resembling the syndrome.

Lab values

• Clinically significant changes observed in laboratory test results, ie: a) ALT activity >3x upper limit of normal (GGN) b) AST activity >3x GGN c) Total bilirubin level >2x GGN (exception is Gilbert syndrome when other causes of isolated hyperbilirubinemia are excluded). d) ALP or GGTP activity >3x GGN e) Creatinine level >2x GGN or impaired renal function (eGFR) <45mL/min as calculated by the MDRD formula f) Hemoglobin level <9g/dL g) Absolute leukocyte count <3000/mm3 h) Absolute lymphocyte count <750/mm3 i) Neutrophil level <1000/mm3 j) Platelet level <100000/mm3 Note: for patients receiving treatment under this study, if any of the above parameters are outside the DGN or GGN, the test should be repeated within 7 days. Only after receiving another result outside the DGN /GGN will the Pharmacovigilance Team decide whether patients should remain.

Other

• Enteral nutrition or total parenteral nutrition.
• Pregnancy or breastfeeding.
• Clinically significant changes on chest X-ray or ECG.
• Positive stool culture for bacteria/fungus (if clinically relevant in the opinion of the investigator).
• Positive stool culture for Clostridioides difficile.
• Use of a treatment listed in section 7.4.6 that is not permitted under this protocol.

• Obtain informed written consent for patient participation in the study and for all planned procedures.
• Patients taking 5-ASA derivatives, glucocorticosteroids, immunosuppressants may be included in the study if they take a fixed and specified dose of the above drugs 14 days before the day of randomization (Section 7.4.5).
• Age ≥18 years and ≤65 at the time of screening.
• For women of reproductive potential * agree not to donate ova throughout the period of participation in the study and 6 months after receiving the last dose of the drug. *Patients of reproductive potential (able to become pregnant) are considered sexually mature, i.e. fertile, women after menarche (first menstrual period) until they enter the post-menopausal state, unless they are permanently infertile. Methods leading to irreversible infertility are considered to include removal of the uterus, bilateral excision of the ovaries, and bilateral excision of the fallopian tubes and ovaries. For the purposes of this study, post-menopausal condition is defined as the absence of menstruation for twelve (12) months, with no other (alternative) medical reason for its absence.
• For women of reproductive potential, agreement to use effective contraception (Table 4) during the entire period in which the patient is participating in the study and for a period counted from the last dose of 15 weeks for UST patients in arms B and C) or 6 months for IFX (patients in arm A).
• Negative serum or urine pregnancy test in women of childbearing age .
• Diagnosis of UC at least. 3 months prior to the start of screening documented by: a)medical source documentation of the patient with the result of an endoscopic examination that diagnosed features typical of UC b)a histopathological examination result consistent with UC. In the absence of a histopathological result, it is possible to take sections during the endoscopic examination for histopathological evaluation at the time of eligibility for the study with subsequent sending of the material to the local pathomorphology laboratory to confirm the diagnosis of UC before randomization.
• UC with moderate or severe activity defined as a Mayo scale score (Appendix 1, Table 3) of 7 to 12 containing the following sub-item values (each sub-item 0-3 points depending on the severity of the lesions): (a) Frequency of bowel movements ( b) Bleeding from the large intestine c) Endoscopic image of the colonic mucosa d) General medical evaluation and: (a) with inadequate response to standard treatment, including corticosteroids and 6-mercaptopurine or azathioprine, or (b) intolerant of treatment with corticosteroids and 6-mercaptopurine or azathioprine, or (c) having contraindications to treatment with corticosteroids and 6-mercaptopurine or azathioprine, or (d) with loss of response to standard treatment, including treatment with corticosteroids and 6-mercaptopurine or azathioprine.
• Patients with demonstrated failure of standard treatment for severe UC, defined as failure of 3-5 days of intravenous ICS. Patients included: Steroid-resistant - in whom there is no clinical improvement despite the use of a steroid at a daily dose of 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 or relapse of complaints within 3 months of steroid withdrawal.
• Patients refractory to/about inadequate response to immunosuppressive therapy, defined as lack of remission or relapse despite immunosuppressive therapy for at least 3 months at appropriate doses (azathioprine 2-2.5 mg/kg/day or 6-mercaptopurine 1-1.5 mg/kg/day).