Researchers initiated a randomized, multicenter trial to evaluate the safety and efficacy of ustekinumab, infliximab, and combination therapy in patients with moderate to severe active ulcerative colitis. The COMBO-UC trial aimed to determine whether combining two different modes of action could improve treatment outcomes in this patient population.

In the prospective study, published in Frontiers in Medicine, the researchers begun enrolling patients in 2024, and planned to involve 172 adult participants across eight gastroenterology centers in Poland. The patients were randomly assigned in a 1:1:2 ratio to receive infliximab (IFX) monotherapy, ustekinumab (UST) monotherapy, or IFX plus UST combination therapy.

The trial design included a 14 to 16 week remission induction phase followed by a 52-week maintenance phase. The primary endpoint of the trial was the percentage of patients achieving clinical and endoscopic remission after the induction phase.

Key details of the study protocol included:

• Inclusion criteria encompassed adults aged 18 to 80 years with moderately to severely active ulcerative colitis (UC) (total Mayo score: 7 to 12) and inadequate response to standard treatments. Exclusion criteria included previous exposure to IFX or UST, certain comorbidities, and recent use of specific medications.
• Treatment arms: arm A (IFX monotherapy) at 5 mg/kg intravenously at weeks 0, 2, 6, and every 8 weeks thereafter; arm B (UST monotherapy) with weight-based intravenous doses at week 0, 90 mg SC at week 8, and every 8 or 12 weeks thereafter; and arm C (IFX plus UST combination) with IFX administered as in arm A plus UST administered as in arm B.
• Primary endpoint: clinical and endoscopic remission following induction (week 14 for arm A, week 16 for arms B and C; secondary endpoint: clinical response, endoscopic response/remission, biochemical remission, histological remission, quality of life, and safety assessments at various time points
• Assessments: disease activity with the Mayo Score, including endoscopic subscore; quality of life with the Inflammatory Bowel Disease Questionnaire and 36-Item Short Form Health Survey; and safety with adverse events and serious adverse events.
• Sample size: 172 patients (43 in arm A, 43 in arm B, 86 in arm C) to detect a difference in remission rates of 20% vs 40% with 80% power and α = 0.05.
• Statistical analysis: primary analysis planned to compare the combined IFX plus UST arm to monotherapy arms using Pearson's χ2 test. Secondary endpoints were to be analyzed similarly.

Definitions of outcomes:

• • Clinical remission: PRO-2 score ≤ 1 point or total Mayo score < 3
  • Endoscopic remission: endoscopic Mayo score ≤ 1
  • Clinical response: reduction in PRO-2 score ≥ 50% or reduction in total Mayo score ≥ 3 points
  • Endoscopic response: reduction in endoscopic Mayo score ≥ 1 point
  • Biochemical remission: calprotectin level ≤ 125 μg/g of stool
  • Deep remission: PRO-2 score = 0 points, endoscopic Mayo score = 0 points, and Picasso Histologic Remission Index = 0 points.

Additional details from the study protocol included:

• Exploratory analyses: the researchers planned to use classification models based on logistic regression, decision trees, ROC curves, and discriminant analyses to identify predictive indicators for therapy success or failure and adverse event occurrence.
• Missing data handling: the study protocol specified the use of Last Observation Carried Forward imputation for missing data at visits in weeks 2 to 48. For continuous variables, the average value from preceding and subsequent observations would be adopted.
• Monitoring: the trial included on-site, remote, and risk-based monitoring to ensure compliance with the protocol, ICH GCP, and regulatory requirements.
• Biochemical assessments: the study planned to measure drug levels and evaluate drug antibodies at specific time points.

The COMBO-UC trial was funded by the Medical Research Agency (grant no. 2022/ABM/03/00013) and received approval from the Independent Bioethics Committee and the President of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products (EU CT number 2023-506452-25-00).

The trial was scheduled to conclude by the end of 2028, with findings to be disseminated through publications in leading gastroenterology journals and presentations at national and international conferences.

A conflict of interest statement can be found in the study.