Efficacy and Safety Comparison of Ustekinumab, Infliximab, and Dual Biological Therapy in Moderate to Severe Ulcerative Colitis: The COMBO-UC Trial

Trial ID: 2023-506452-25-00
Protocol: COMBO/2022/3
Sponsor: Medical University Of Lodz

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Diseases & Conditions

Colitis ulcerative

Objectives

The primary objective of this study is to evaluate the **efficacy** and **safety** of dual biological therapy in inducing remission in patients with moderate to severe **ulcerative colitis** (UC) compared to standard monotherapy with either **infliximab** (IFX) or **ustekinumab** (UST). This is clinically relevant as achieving remission in UC is crucial for improving patient outcomes and quality of life, and the study aims to determine if combination therapy offers superior benefits over existing monotherapies.

Participants

The clinical trial focuses on patients diagnosed with **ulcerative colitis** (UC) who are between the ages of 18 and 65. The study includes both male and female participants, with no vulnerable populations being selected. The sponsor has not provided the total number of participants. The trial population was selected based on specific criteria, including a documented diagnosis of UC for at least three months prior to screening, and a Mayo scale score indicating moderate to severe disease activity. Participants may be on stable doses of 5-ASA derivatives, glucocorticosteroids, or immunosuppressants. Women of reproductive potential are required to use effective contraception and have a negative pregnancy test prior to participation. The study does not focus on any particular lifestyle considerations such as diet or physical activity. Key inclusion criteria involve patients with an inadequate response, intolerance, or contraindications to standard treatments, including corticosteroids and immunosuppressants, or those with a loss of response to such treatments.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of dual biological therapy in inducing remission in patients with moderate to severe **ulcerative colitis** (UC) compared to standard monotherapy with either **ustekinumab** or **infliximab**. This is a randomized, double-blind, controlled trial, categorized as Phase 4, with an estimated duration extending until April 2028. The trial will commence recruitment in January 2024 and will involve a maximum treatment period of 44 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, diagnosis of UC, and previous treatment history. The inclusion criteria require participants to be between 18 and 65 years old, with a documented diagnosis of UC for at least three months prior to screening. Women of reproductive potential must agree to use effective contraception during the study and for a specified period after the last dose of the investigational product. The screening visit will also involve obtaining informed consent and conducting necessary medical evaluations.

Following the screening, eligible participants will be randomized into one of the treatment arms. The trial includes follow-up visits to monitor the participants' response to treatment and assess any adverse events. These visits will occur at regular intervals throughout the treatment period. The primary endpoint is the percentage of clinical and endoscopic remission after the remission induction phase. Secondary endpoints include clinical response and remission rates at 52 weeks, endoscopic improvement, laboratory remissions, and quality of life assessments.

The end-of-study visit will mark the conclusion of the participant's involvement in the trial, where final assessments will be conducted to evaluate the long-term effects of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The expected length of participant involvement is up to 44 weeks, with the possibility of early termination under specific conditions.

Treatment

The clinical trial involves the administration of **ustekinumab**, a biologic medication, in two different pharmaceutical forms. The first form is a **solution for injection in a pre-filled syringe**, designed for **subcutaneous** administration. The maximum daily dose for this form is 90 mg, with a total treatment period of up to 44 weeks. The second form of ustekinumab is a **concentrate for solution for infusion**, administered via **intravenous infusion**. This form allows for a maximum daily dose of 520 mg/kg, also over a treatment period of 44 weeks. Both forms of ustekinumab are utilized to evaluate their efficacy and safety in the treatment of moderately-to-severely active **ulcerative colitis**.

**Infliximab** is another biologic medication used in this trial, provided as a **powder for concentrate for solution for infusion**. It is administered through **intravenous infusion**. The maximum daily dose of infliximab is 100 mg, with a treatment duration of up to 44 weeks. This medication serves as a comparator treatment to assess its effectiveness against ustekinumab and the combination therapy in inducing remission in patients with moderate to severe ulcerative colitis.

The trial aims to compare the efficacy and safety of dual biological therapy, involving both ustekinumab and infliximab, against standard monotherapy with either infliximab or ustekinumab. Participant compliance is monitored throughout the study to ensure adherence to the dosing schedules and to evaluate the therapeutic outcomes accurately. No placebo is used in this study, as the focus is on comparing active treatments.

Efficacy

The efficacy of the clinical trial comparing **ustekinumab**, **infliximab**, and combination therapy in patients with moderately-to-severely active Ulcerative Colitis will be assessed using several primary and secondary endpoints. The primary endpoint is the percentage of clinical and endoscopic remission after the remission induction phase. Secondary endpoints include the percentage of clinical response after the remission induction phase, percentage of clinical response at 52 weeks, percentage of clinical remission at 52 weeks, and percentage of endoscopic remission or improvement after the remission induction phase and at 52 weeks. Additionally, the trial will evaluate the percentage of laboratory remissions, percentage of deep remissions, and comparison of patients' quality of life after the remission induction phase and at 52 weeks. The number and type of adverse events and serious adverse events will also be compared after the remission induction phase and at 52 weeks.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Obtain informed written consent for patient participation in the study and for all planned procedures.
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).
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).

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Exclusion Criteria

Previous use of the investigational drug IFX or UST.
Hypersensitivity to the active substance or excipients.
Moderate or severe myocardial insufficiency (NYHA III or IV).
Unstable coronary artery disease.
History of serious cerebrovascular disease (stroke, intracranial hemorrhage, transient cerebral ischemia) within the last 24 weeks prior to screening.
Chronic respiratory failure.
Severe chronic renal failure.
Severe chronic liver failure.
Demyelinating syndrome or symptoms resembling the syndrome.
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).
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.
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.
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.
Enteral nutrition or total parenteral nutrition.
Pregnancy or breastfeeding.
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 bone marrow transplantation.
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.
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).
History of HSV, HPV, influenza virus, SARS-CoV2 infection within 12 weeks prior to randomization or history of disseminated or complicated HSV infection.
History of congenital or acquired immunodeficiency.
Receipt of live vaccine within 30 days prior to randomization.
HBV or HCV infection.
Clinically significant changes on chest X-ray or ECG.
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.
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.