Model-Informed Precision Dosing of Vedolizumab and Ustekinumab in Maintaining Remission of Inflammatory Bowel Disease: A Randomized Controlled Trial

The primary objective of this study is to investigate whether dosage of **Vedolizumab** (VDZ) and **Ustekinumab** (UST) based on **Therapeutic Drug Monitoring** (TDM) is as effective in maintaining remission of **Inflammatory Bowel Diseases** (IBD), including **Crohn's disease** and **Ulcerative colitis**, as management based on the discretion of the treating physician. This is clinically relevant as it may optimize treatment strategies, potentially improving patient outcomes and resource utilization.

Secondary objectives include:

• Determining the cost-effectiveness of TDM-based treatment with Vedolizumab and Ustekinumab.
• Assessing whether treatment according to a pharmacokinetic (PK) model is superior in achieving mucosal healing compared to symptom-driven treatment.
• Evaluating if PK-model-based treatment results in better quality of life than physician-directed management, including the cost per quality-adjusted life year (QALY).
• Comparing the attainment of clinician-assessed clinical remission between PK-model-based treatment and physician-directed management.
• Assessing biochemical disease control in both treatment approaches.
• Evaluating drug persistency and the occurrence of flare-ups, defined as surgery or glucocorticoid use, during the study period.
• Assessing relief of fatigue and improvements in work productivity and daily activities with PK-model-based treatment compared to physician-directed management.

The clinical trial involves participants diagnosed with **Crohn's disease** or **ulcerative colitis**, with a minimum diagnosis period of three months prior to inclusion. The study population includes both male and female subjects aged 18 years and older. Participants are required to have stable treatment with Vedolizumab (VDZ) or Ustekinumab (UST) for at least three months before inclusion, with no changes in medical therapy during this period. The trial does not involve a vulnerable population. Participants must have stable disease activity, with mild activity defined by specific fecal calprotectin and PRO2 scores. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include the ability to understand patient information material and provide informed written consent.

The clinical trial is designed to evaluate the efficacy of **vedolizumab** and **ustekinumab** in maintaining remission in patients with **Crohn's disease** and **ulcerative colitis**. This is a randomized, controlled trial with a double-blind design, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The trial will span a total duration of 52 weeks, with an estimated recruitment start date in April 2025 and an anticipated end date in April 2027.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of **ulcerative colitis** or **Crohn's disease** for at least three months, stable treatment with **vedolizumab** or **ustekinumab** for a minimum of three months, and stable disease activity. Follow-up visits will occur periodically throughout the trial to monitor disease activity, treatment adherence, and any adverse events. The end-of-study visit will assess the primary endpoint, which is the fraction of patients in steroid-free remission at the end of the 48-week observation period.

Participant involvement is expected to last for the entire 52-week treatment period unless early termination is warranted. Conditions that may lead to early withdrawal from the study include significant adverse events, non-compliance with study procedures, or withdrawal of consent by the participant. The trial aims to provide valuable insights into the effectiveness of therapeutic drug monitoring compared to standard clinical evaluation in managing **inflammatory bowel diseases**.

The clinical trial involves the administration of **Vedolizumab**, an experimental medication used in the treatment of **Inflammatory Bowel Disease (IBD)**. Vedolizumab is a protein-based therapeutic agent, classified under the ATC code L04AA33. It is administered in the form of an intravenous infusion. The pharmaceutical form is identified as PHF00231MIG. The maximum daily dose of Vedolizumab is 10.71 mg, with a total maximum dose of 3900 mg over a treatment period of up to 52 weeks. The administration schedule is determined based on therapeutic drug monitoring (TDM) to ensure optimal dosing and efficacy. Participant compliance with the dosing regimen is monitored throughout the study.

Another experimental medication used in the trial is **Ustekinumab**, also a protein-based therapeutic agent, classified under the ATC code L04AC05. Ustekinumab is administered via subcutaneous injection, with the pharmaceutical form identified as PHF00230MIG. The maximum daily dose for Ustekinumab is 3.21 mg, with a total maximum dose of 1170 mg over a 52-week treatment period. Similar to Vedolizumab, the dosing of Ustekinumab is guided by therapeutic drug monitoring to maintain disease remission in participants with IBD. Compliance with the administration schedule is closely monitored to ensure adherence to the study protocol.

Both Vedolizumab and Ustekinumab are utilized as test products in this randomized controlled trial, with the primary objective of evaluating the efficacy of TDM-based dosing compared to standard physician-directed management in maintaining remission of IBD. No additional non-experimental treatments, such as placebo or comparator treatments, are specified in the study protocol. The trial is designed to provide insights into the precision dosing of these biologic agents, potentially enhancing therapeutic outcomes for patients with IBD.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the effectiveness of **Vedolizumab** and **Ustekinumab** in maintaining remission in patients with Inflammatory Bowel Disease (IBD). The primary endpoint is the fraction of patients achieving steroid-free remission at the end of the 48-week observation period. For Crohn's Disease (CD), this is defined by a PRO2 score of ≤ 4, and for Ulcerative Colitis (UC), a PRO2 score of 0, combined with a fecal calprotectin level of ≤ 200.

Secondary endpoints include the duration of steroid-free remission throughout the observation period, financial costs associated with the treatment strategies, and endoscopic healing of the mucosa assessed after 48 weeks. Endoscopic healing for CD will be evaluated using the Simple Endoscopic Score for Crohn's Disease (SES-CD) with a score of <3, and for UC using the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) with a score of ≤1. If the disease is primarily located in the small intestine, MRI or capsule endoscopy will be used, assessed by the simplified MaRIA score or Lewis score, respectively.

Additional secondary endpoints include quality of life assessments using the SIBDQ and EQ-5D-5L scales, the portion of the observational period in clinical remission, inflammatory burden assessed by CRP, albumin, hemoglobin, leukocyte measurements, and fecal calprotectin, as well as drug concentration analysis expenses and drug expenses. The trial will also evaluate the proportion of patients switching to another drug, consumption of steroids, fatigue assessed by VAS-F, and the impact of the disease on work productivity and daily activities using WPAI scores.