Efficacy and Safety of Infliximab, Ustekinumab, and Vedolizumab Combination Therapy in Refractory Crohn's Disease Resistant to Vedolizumab Induction
- Trial ID
- 2023-506626-37-00
- Protocol
- ABM/FLAMING/2023
- Sponsor
- Agencja Badań Medycznych
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the efficacy of **infliximab** or **ustekinumab** monotherapy versus combination therapy with infliximab and **vedolizumab** or ustekinumab and vedolizumab in inducing sustained steroid-free remission in patients with **Crohn's disease** after failure of vedolizumab treatment. This is clinically relevant as achieving sustained steroid-free remission is a critical goal in the management of Crohn's disease, 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 ustekinumab monotherapy versus combination therapy in achieving clinical response and inducing clinical remission in patients with Crohn's disease after vedolizumab treatment failure.
- Evaluating the corticosteroid-sparing effect of monotherapy relative to combination treatment.
- Assessing the efficacy in achieving endoscopic response and remission.
- Evaluating the impact on the quality of life of patients.
- Comparing the safety profile of monotherapy versus combination treatment.
- Assessing the efficacy in preventing death from Crohn's disease.
Participants
The clinical trial focuses on patients diagnosed with **Crohn's disease**, specifically targeting individuals who have experienced failure with vedolizumab treatment. The study population includes both male and female participants aged between 18 and 75 years. Participants are required to have a confirmed diagnosis of Crohn's disease for at least three months prior to randomization, with active disease characterized by a Crohn's Disease Activity Index (CDAI) score of at least 220. The trial allows for the inclusion of patients who are on stable doses of certain medications such as azathioprine, 6-mercaptopurine, methotrexate, budesonide, other corticosteroids, and 5-aminosalicylates. The trial population is selected based on these criteria, and participants must provide written informed consent. Both genders are included, and the study considers vulnerable populations. However, the sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of dual biological therapy in patients with refractory **Crohn's disease** resistant to induction. This is a Phase 4, randomized, double-blind, controlled trial. The trial aims to compare the efficacy of infliximab or ustekinumab monotherapy versus combination therapy with infliximab and vedolizumab or ustekinumab and vedolizumab in inducing sustained steroid-free remission in patients after failure of vedolizumab treatment. The trial is expected to commence on April 1, 2024, and conclude by December 31, 2028.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, confirmed diagnosis of Crohn's disease, and previous treatment history. Following randomization, participants will attend follow-up visits at Week 8, Week 22, and Week 52 to monitor clinical response, remission, and any adverse events. The primary endpoint is the percentage of sustained corticosteroid-free remissions at Week 52, with secondary endpoints including clinical response and remission rates, endoscopic outcomes, and quality of life assessments.
The expected length of participant involvement is approximately 52 weeks, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial will employ a rigorous methodology to ensure the reliability and validity of the results, with all procedures conducted in accordance with ethical standards and regulatory requirements.
Treatment
The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy and safety in patients with refractory **Crohn's disease**. **Ustekinumab** is utilized in multiple formulations within the study. It is administered as a **solution for injection in a pre-filled syringe** with a maximum daily dose of 90 mg and a total dose of 360 mg over a treatment period of 36 weeks. The route of administration is **subcutaneous**. Additionally, ustekinumab is also provided as a **solution for infusion**, with a maximum daily and total dose of 520 mg, administered via **intravenous infusion** over a single treatment period. Ustekinumab functions as an **interleukin inhibitor** and is classified as a **monoclonal antibody**.
**Vedolizumab** is another experimental medication used in the trial. It is administered as a **solution for infusion** with a maximum daily dose of 300 mg and a total dose of 1800 mg over a treatment period of 40 weeks. The route of administration is **intravenous infusion**. Vedolizumab acts as a **monoclonal antibody** against **α4β7 integrin**.
**Infliximab** is included as a comparator treatment in the study. It is provided as a **powder for concentrate for solution for infusion**. The dosing regimen involves a maximum daily and total dose of 5 mg/kg, administered via **intravenous infusion** over a treatment period of 46 weeks. Infliximab is a **tumor necrosis factor alpha inhibitor** and is also classified as a **monoclonal antibody**.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols. The study aims to compare the efficacy of infliximab or ustekinumab monotherapy versus combination therapy with infliximab and vedolizumab or ustekinumab and vedolizumab in inducing sustained steroid-free remission in patients with Crohn's disease after failure of vedolizumab treatment.
Efficacy
The clinical trial aims to assess the efficacy of dual biological therapy in patients with refractory **Crohn's disease** resistant to induction. 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 an absolute Crohn's Disease Activity Index (CDAI) score of less than 150 points.
Secondary endpoints include the percentage of clinical response at weeks 8, 22, and 52, defined as a CDAI-100 response (a decrease in CDAI score of 100 points or more from the baseline value) and CDAI-70 (a decrease in CDAI score of 70 points or more from the baseline value). Additionally, the percentage of patients achieving endoscopic remission and response at the same time points will be evaluated. Endoscopic remission is defined by a Simple Endoscopic Score for Crohn's Disease (SES-CD) score of 4 points or less, with at least a 2-point reduction from baseline and subscores of 1 point or less in all individual components. The trial will also measure changes in quality of life using SIBDQ, PROMIS-29 v.2.1, WPAI:GH v.2.2, and PSQI questionnaires at weeks 8, 22, and 52.
Data collection will occur at specified intervals, including weeks 8, 22, and 52, to ensure comprehensive assessment of the treatment's efficacy. The analysis will focus on the comparison of monotherapy with infliximab or ustekinumab versus combination therapy with infliximab and vedolizumab or ustekinumab and vedolizumab. The trial is designed to provide robust data on the potential benefits of dual biological therapy in achieving sustained remission in patients with Crohn's disease.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient has given written informed consent from to participate in the clinical trial.
- Patient is male or female aged 18 to 75 years, inclusive.
- Patient who has CD, confirmed at any time in the past by radiography, histology, or endoscopy, of at least 3 months prior to the randomization.
- Patients with active Crohn's Disease (CD) who have at least moderately active CD, defined by an absolute CDAI score of at least ≥220, despite 12-weeks of treatment with vedolizumab (VEDO).
- Prior to initiation of vedolizumab treatment, the patient was biologic-naïve.
- The following treatments for CD are allowed: a. azathioprine (AZA), 6-mercaptopurine (6-MP) or methotrexate (MTX), if taken at a stable dose for more than 8 weeks prior to the randomization, b. budesonide taken orally at a dose not exceeding 9 mg/day, if taken at a stable dose for at least 2 weeks prior to the randomization, c. other corticosteroids taken orally at a dose not exceeding 20 mg/day of prednisone, if taken at a stable dose for at least 2 weeks prior to the randomization, d. 5-Aminosalicylates (5-ASA), if taken at a stable dose for at least 4 weeks prior to the randomization.
- 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 ustekinumab or any other murine and/or human proteins or has hypersensitivity to immunoglobulin products.
- Patient who has received any of following treatments: a. Within 2 weeks prior to randomization: - budesonide taken orally in excess of 9 mg/day, - other GCSs taken orally in excess of 20 mg/day prednisone, - GCSs administered parenterally, - antibiotics for the primary treatment of CD (e.g., ciprofloxacin, metronidazole) 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, - methotrexate.
- Patient who has received any of following treatments due to CD or other disease: a. within 4 weeks prior to randomization: janus kinase (JAK) inhibitors, including but not limited to tofacitinib and baricitinib, b. within 8 weeks prior to randomization: cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, c. within 12 months prior to randomization: alkylating agents, d. 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 CD 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.
- History of more than 3 small-bowel resection procedures.
- 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 × 103 cells/μl (SI units: <3.5×109 cells/l), g. Neutrophil count < 1.5 × 103 cells/μl (SI units: <1.5×109 cells/l), h. Platelet count < 100 × 103 cells/μl (SI units: <100×109 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 2 weeks or parenteral injection within 4 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 3 months 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 Quantiferon-TB-Gold 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. Diagnose of UC (ulcerative colitis) or indeterminate colitis. b. Short bowel syndrome. c. Evidence of fixed symptomatic stenosis or obstruction of the large or small intestine. d. Active entero-vesical, entero-retroperitoneal, entero-cutaneous or entero-vaginal fistulae within 6 months prior to the randomization. Entero-enteral fistulae without clinically significant symptoms in the invesigator’s opinion and anal fistulae without draining problems are allowed. 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 | 192 |
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 |
|---|---|---|---|---|---|---|
USTEKINUMAB | Comparator | — | SUBCUTANEOUS | 90 | 36 | SUB27761 |
USTEKINUMAB | Comparator | — | INTRAVENIOUS INFUSION | 520 | 1 | SUB27761 |
USTEKINUMAB | Test | — | SUBCUTANEOUS | 90 | 36 | SUB27761 |
USTEKINUMAB | Test | — | INTRAVENIOUS INFUSION | 520 | 1 | SUB27761 |
VEDOLIZUMAB | Test | — | INTRAVENIOUS INFUSION | 300 | 40 | SUB30452 |
INFLIXIMAB | Test | — | INTRAVENIOUS INFUSION | 5 | 46 | SUB02681MIG |
INFLIXIMAB | Comparator | — | INTRAVENIOUS INFUSION | 5 | 46 | SUB02681MIG |