Efficacy and Safety of Infliximab, Tofacitinib, and Vedolizumab in Induction-Resistant Ulcerative Colitis: A Comparative Analysis
- Trial ID
- 2023-506628-98-00
- Protocol
- ABM/RESPECT/2023
- Sponsor
- Agencja Badań Medycznych
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the efficacy of **infliximab** or **tofacitinib** monotherapy versus combination therapy with infliximab and **vedolizumab** or tofacitinib and vedolizumab in inducing sustained steroid-free remission in patients with **ulcerative colitis** after failure of vedolizumab treatment. This objective is clinically relevant as achieving sustained steroid-free remission is a critical goal in the management of ulcerative colitis, aiming to improve long-term patient outcomes and reduce the need for corticosteroids, which are associated with significant side effects.
Secondary objectives include: - Comparing the efficacy of infliximab or tofacitinib monotherapy versus combination therapy in achieving clinical response, clinical remission, and mucosal healing in patients with ulcerative colitis after vedolizumab treatment failure. - Evaluating the corticosteroid-sparing effect of these therapies. - Assessing the impact on quality of life and the safety profile of the therapies. - Comparing the efficacy in preventing death from ulcerative colitis and achieving histologic remission.
Participants
The clinical trial involves participants diagnosed with **ulcerative colitis**, specifically targeting individuals who have not achieved clinical remission despite 8 weeks of treatment with vedolizumab. The study population includes both male and female subjects aged between 18 to 75 years. Participants are required to have a confirmed diagnosis of ulcerative colitis through endoscopic or radiographic and histological criteria. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Eligible participants may continue certain treatments for ulcerative colitis, such as budesonide, other corticosteroids, and 5-Aminosalicylates, provided these are taken at stable doses prior to randomization. The trial includes a vulnerable population, and participants must adhere to specific contraceptive measures if they or their partners are of childbearing potential. The selection criteria ensure that participants have given informed consent and meet the age and health status requirements necessary for the study.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of dual biologic and/or small molecule therapy in patients with induction-resistant **ulcerative colitis**. This study is a randomized, double-blind, controlled trial, aiming to compare the efficacy of **infliximab** or **tofacitinib** monotherapy versus combination therapy with **infliximab** and **vedolizumab** or **tofacitinib** and **vedolizumab**. The primary objective is to induce sustained steroid-free remission in patients after the failure of **vedolizumab** treatment. The trial is set to commence recruitment on April 1, 2024, and is estimated to conclude by December 31, 2028.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, including age, diagnosis of **ulcerative colitis**, and previous treatment history. Following successful screening, participants will be randomized into one of the treatment arms. The trial will include follow-up visits at Week 8, Week 22, and Week 52 to assess primary and secondary endpoints, such as the percentage of sustained corticosteroid-free remissions and clinical response rates. The end-of-study visit will occur at Week 52, marking the completion of the participant's involvement in the trial.
The expected duration of participant involvement is approximately 52 weeks, with conditions for early termination including the occurrence of severe adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial will adhere to rigorous safety monitoring to ensure participant well-being throughout the study duration. The study's design and procedures are structured to provide robust data on the comparative efficacy of the treatment regimens, contributing valuable insights into the management of **ulcerative colitis**.
Treatment
The clinical trial involves the administration of **VEDOLIZUMAB**, a monoclonal antibody targeting the α4β7 integrin. This experimental medication is provided as a solution for infusion and is administered via **intravenous infusion**. The maximum daily dose is 300 mg, with a total maximum dose of 1800 mg over a treatment period of up to 40 weeks. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.
**INFLIXIMAB** is utilized as both a monotherapy and in combination therapy within the trial. It is a tumor necrosis factor alpha inhibitor, also classified as a monoclonal antibody. The pharmaceutical form is a powder for concentrate for solution for infusion, administered through intravenous infusion. The dosing regimen involves a maximum daily dose of 5 mg/kg, with a total maximum dose of 5 mg/kg over a treatment period of up to 46 weeks. Compliance with the dosing schedule is closely monitored to maintain the integrity of the trial results.
**TOFACITINIB** is employed in the trial as a comparator treatment. It is a small molecule that inhibits the activity of JAK kinases and is provided in the form of a film-coated tablet. The administration route is oral, with a maximum daily dose of 20 mg and a total maximum dose of 1120 mg over a treatment period of up to 8 weeks. In another regimen, the maximum daily dose is 10 mg, with a total maximum dose of 3080 mg over a treatment period of up to 44 weeks. Participant adherence to the oral dosing schedule is monitored to ensure accurate data collection and analysis.
Efficacy
The clinical trial aims to assess the efficacy of different therapeutic regimens in patients with induction-resistant **ulcerative colitis**. The primary endpoint for evaluating efficacy is the percentage of sustained corticosteroid-free remissions at week 52, sustained from week 8 onward, with a maximum 11-week regimen of corticosteroids tapering. Clinical remission is defined as a total Mayo score of ≤ 2, with all subscores of ≤ 1 and a Mayo rectal bleeding subscore of 0.
Secondary endpoints include the percentage of clinical response at weeks 8, 22, and 52, defined as a decrease in the total Mayo score of at least 3 points and at least 30% from the baseline value, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. Additional secondary endpoints are the percentage of clinical remission at week 8, percentage of deaths from ulcerative colitis at weeks 8, 22, and 52, and the cumulative dose of corticosteroids used during the current flare of ulcerative colitis at week 52.
Further secondary endpoints include the percentage of patients achieving mucosal healing at weeks 8, 22, and 52, defined as the Mayo Endoscopic Score of ≤ 1, and the percentage of patients achieving histologic-endoscopic mucosal healing at the same time points, defined as achieving a combination of histologic remission and mucosal healing. Histologic remission is defined as an absolute Robarts Histopathological Index (RHI) score of 3 points or less, and mucosal healing is defined as the Mayo Endoscopic Score of ≤ 1.
Additional assessments include changes from baseline in quality of life measured by SIBDQ, PROMIS-29 v.2.1, WPAI:GH v.2.2, and PSQI questionnaires at weeks 8, 22, and 52. The occurrence of severe and non-severe adverse events, death from any cause, MACE events, tuberculosis, and hemiplegia at weeks 8, 22, and 52 will also be evaluated.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient has given written informed consent form to participate in the clinical trial.
- Patient is male or female aged 18 to 75 years, inclusive.
- Patient who has ulcerative colitis, confirmed by endoscopic or radiographic and histological criteria. Histopathology report supporting the diagnosis must be available in the source documents prior to the randomization.
- Patient who has not achieved clinical remission, defined as the total Mayo score of ≤ 2 with all subscores of ≤ 1 and Mayo rectal bleeding subscore of 0, despite 8-weeks of treatment with vedolizumab.
- Prior to initiation of vedolizumab treatment, the patient was biologic-naïve.
- The following treatment for ulcerative colitis is permitted: a. oral budesonide at a dose not exceeding 9 mg/day, if administered at a stable dose for at least 2 weeks prior to randomisation, b. other oral corticosteroids at a dose not exceeding 20 mg/day expressed as prednisone equivalent, if administered at a stable dose for at least 2 weeks prior to randomisation, c. oral 5-aminosalicylic acid (5-ASA) preparations, if administered at a stable dose for at least 4 weeks prior to randomisation. In the case of treatment with the following medicinal products: azathioprine, 6-mercaptopurine, methotrexate, such treatment was discontinued at least 8 weeks prior to randomisation.
- The use by women of childbearing potential, as well as by men and their partners of childbearing potential, of one of the following contraceptive methods during the study and for 6 months after the end of administration of the investigational medicinal product: a. Highly effective methods that are user-independent, with a failure rate of <1% per year when used consistently and correctly: i. progestogen-only hormonal contraceptive implants associated with inhibition of ovulation; ii. intrauterine device (IUD); iii. intrauterine hormone-releasing system (IUS); iv. bilateral tubal occlusion/ligation; v. a partner with documented vasectomy (provided that the partner is the sole sexual partner of the woman of childbearing potential and absence of sperm in semen has been confirmed); b. Highly effective user-dependent methods, with a failure rate of <1% per year when used consistently and correctly: i. progestogen-only hormonal contraception associated with inhibition of ovulation (oral or injectable); ii. combined (oestrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral intravaginal transdermal injectable c. complete declared sexual abstinence. The use of the above-mentioned methods also applies to women and men who have undergone surgical sterilisation within 6 months prior to the date of signing the informed consent form. A woman of childbearing potential is defined as a woman from menarche until the postmenopausal period (defined as age >45 years and complete absence of menstruation for at least 12 months with no medical cause), unless she is permanently infertile (following prior sterilisation – hysterectomy, bilateral salpingectomy, or bilateral oophorectomy). For women in the menopausal period, the criterion of the last menstruation occurring at least 12 months prior to the date of signing the informed consent form applies in order for them to be considered not of childbearing potential. Women and men who have undergone surgical sterilisation more than 6 months prior to signing the informed consent form are considered not of childbearing potential.
Exclusion Criteria
- Allergies to any of the excipients of infliximab or tofacitinib or any other murine and/or human proteins or has hypersensitivity to immunoglobulin products.
- Patient who has received any of the following treatments: a. Within 2 weeks prior to the randomization: - budesonide taken orally in excess of 9 mg/day, - other GCSs taken orally in excess of 20 mg/day prednisone, - GCSs administered parenterally, - rectally administered medications containing corticosteroids or 5-ASA b. Within 3 weeks prior to the randomization: - apheresis (e.g., Adacolumn apheresis), c. Within 4 weeks prior to the randomization administration of parenteral antibiotics d. Within 8 weeks prior to the randomization initiation of treatment with the following drugs: - azathioprine, - 6-mercaptopurine (6-MP), - methotrexate (MTX),
- Patient who has received any of the following treatments due to ulcerative colitis or other disease: a. within 8 weeks prior to the randomization: cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, b. within 12 months prior to the randomization: alkylating agents, c. at any time: any other biologic medicinal product or so-called “small molecule”, except for vedolizumab administered immediately prior to the start of the study.
- Currently require or are anticipated to require surgical intervention for ulcerative colitis during the study.
- Abdominal surgery for, including but not limited to, active gastrointestinal bleeding, peritonitis, intestinal obstruction, gastrointestinal resection, or intra-abdominal or pancreatic abscess requiring surgical drainage within 4 months prior to the randomization.
- Extensive colonic resection (subtotal and total colectomy) prior to the randomization.
- Stoma (e.g., ileostomy or colostomy) within 6 months prior to the randomization.
- Nonautologous stem cell therapy (e.g. Prochymal) within 12 months prior to the randomization.
- Use of total parenteral nutrition within a month prior to the randomization.
- Use of exclusive enteral nutrition for more than 3 consecutive days within a month or any single day of exclusive enteral nutrition within 2 weeks prior to the randomization.
- Live or live - attenuated vaccine within 4 weeks prior to the randomization.
- Abnormalities in laboratory tests performed at screening: a. Serum creatinine ≥ 1.5 × upper limit of normal (ULN) or an estimated creatinine clearance level (eGFR) ≤ 50 ml/min (calculated from the Cockcroft-Gault formula), b. Serum alanine aminotransferase ≥ 2.0 × ULN, c. Serum aspartate aminotransferase ≥ 2.0 × ULN, d. Serum total bilirubin ≥ 1.5 × ULN, e. Hemoglobin < 8.5 g/dl (SI units: < 85 g/l or 5.28 mmol/l ), f. White blood cell count < 3.5 × 10^3 cells/μl (SI units: <3.5×10^9 cells/l), g. Neutrophil count < 1.5 × 10^3 cells/μl (SI units: <1.5×10^9 cells/l), h. Platelet count < 100 × 10^3 cells/μl (SI units: <100×10^9 cells/l). i. Positive HBsAg result, j. Positive HBV DNA result, k. Positive HCV RNA result, l. Positive anti-HIV result, m. Positive or twice inconclusive Quantiferon-TB Gold test result.
- Patient who has a current or history of any of the following infections: a. Known infection with hepatitis B or hepatitis C (active or carrier state). However, a patient who is without cirrhosis of liver and recovered from a past hepatitis B or hepatitis C infection can be enrolled. A patient with a history of cured hepatitis B or C who does not have cirrhosis of liver can be enrolled but the following conditions must be met on screening: -a negative HBsAg and HBV DNA result for a patient with hepatitis B, - a negative HCV RNA result in the case of a patient with hepatitis C. b. Known infection with human immunodeficiency virus (HIV). c. Acute infection requiring oral antibiotics within 7 days or parenteral injection within 2 weeks prior to the randomization. d. Recurrent hemiplegia. e. Other recurrent or chronic infection, significant in the investigator’s opinion, within 6 weeks prior to the randomization. f. Current or past granulomatous infections or opportunistic infections (e.g., Pneumocystis carinii, aspergillosis, or mycobacteriosis [infection caused by nontuberculous mycobacteria]) or invasive fungal infection (e.g., histoplasmosis). g. Known cytomegalovirus infection within 6 months prior to the randomization. h. Evidence of Clostridioides difficile toxin in stool within 30 days prior to the randomization. i. Patient who has a current diagnosis of active TB or a history of active TB. Patient who has any evidence of history of active TB cannot be enrolled despite sufficient documentation of complete resolution of active TB. j. Patient who has had exposure to person(s) with active TB (e.g., first-degree relative, co-worker, roommate). k. Current diagnosis of latent TB at screening (defined as a positive interferon gamma assay [IGRA] without clinical signs of active tuberculosis and with a negative examination of chest x-ray from the qualifying visit for vedolizumab treatment). l. Other serious infections, in the investigator’s opinion, within 6 months prior to the randomization.
- Medical condition including 1 or more of the following: a. Evidence of toxic megacolon b. Diagnose of Crohn’s disease or indeterminate colitis. c. Evidence of fixed symptomatic stenosis or obstruction of the large intestine d. Evidence of colonic mucosal dysplasia or adenomatous polyps. However, a patient whose adenomatous polyps are completely removed and free of polyps at the randomization can be enrolled. For a patient who has an increased risk for colorectal cancer, it is necessary to confirm the absence of adenomatous polyps and mucosal dysplasia with a colonoscopy (the result must be available in the source documentation): - if the patient is ≥ 45 years of age, a colonoscopy within 5 years prior to the randomization is required - if the patient, regardless of age, has extensive colitis for ≥ 8 years or disease limited to left side of colon (distal to splenic flexure) for ≥10 years, a colonoscopy performed within 1 year prior to the randomization is required e. Body mass index ≥ 35 kg/m2. f. Uncontrolled diabetes mellitus. g. Uncontrolled hypertension (as defined by systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg). h. A known malignancy within 5 years prior to the randomization, except completely excised and cured squamous carcinoma in situ of the uterine cervix, cutaneous basal cell carcinoma, or cutaneous squamous cell carcinoma. i. History of lymphoma, lymphoproliferative disease, or bone marrow hyperplasia. j. New York Heart Association (NYHA) class III or IV heart failure, severe uncontrolled cardiac disease (unstable angina or clinically significant electrocardiogram [ECG] abnormalities), or myocardial infarction within 6 months prior to the randomization. k. History of organ transplantation, including corneal graft/transplantation. l. Any uncontrolled, clinically significant respiratory disease in the investigator’s opinion, including but not limited to chronic obstructive pulmonary disease, asthma, bronchiectasis, or pleural effusion. m. Previous diagnosis or symptoms suggestive of demyelinating disorders, including multiple sclerosis and Guillain-Barré syndrome. n. Any condition significantly affecting the nervous system (e.g., neuropathic conditions or nervous system damage). o. Any other serious acute or chronic medical, or psychiatric conditions that may increase the risk associated with study participation or investigational product administration or that may interfere with the interpretation of study results.
- Current or history of alcohol abuse within 12 months prior to the randomization.
- Treatment with any other investigational device or medical product within 4 weeks prior to the randomization or 5 half-lives of the drug, whichever is longer.
- Female patients who are currently pregnant or planning to become pregnant within 6 months of the last dose of study drug.
- Female patients who are currently breastfeeding planning to breastfeed within 6 months of the last dose of study drug.
- Lack of cooperation from the patient.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Recruiting | 01 Apr 2024 | 180 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TOFACITINIB | Comparator | — | ORAL | 20 | 8 | SUB33104 |
TOFACITINIB | Test | — | ORAL | 20 | 8 | SUB33104 |
INFLIXIMAB | Comparator | — | INTRAVENIOUS INFUSION | 5 | 46 | SUB02681MIG |
TOFACITINIB | Comparator | — | ORAL | 10 | 44 | SUB33104 |
TOFACITINIB | Test | — | ORAL | 10 | 44 | SUB33104 |
INFLIXIMAB | Test | — | INTRAVENIOUS INFUSION | 5 | 46 | SUB02681MIG |
VEDOLIZUMAB | Test | — | INTRAVENIOUS INFUSION | 300 | 40 | SUB30452 |