PROactive and Early Infliximab Monitoring and OPTimization in Inflammatory Bowel Disease (PROMPT-IBD)

Multicentric Evaluation of a Strategy for Early Infliximab Optimization Among Adult Inflammatory Bowel Disease Patients

Infliximab (IFX) is a Food and Drug administration (FDA)-appoved monoclonal antibody medication targeting tumor necrosis factor (TNF) widely used in inflammatory bowel disease (IBD) to treat intestinal inflammation and improve patient's symptoms. Intravenous (iv) IFX is effective to treat hospitalized IBD patients with moderate-to-severe flares who fail iv corticosteroids (CS). However, about one-third of IBD patients do not respond to this medications and a half will loss the response after an initial response. Researchers have shown that most of these phenomena occur due to low IFX concentrations sometimes accompanied by the development of anti-drug antiboides (ADA) againts IFX.

Blood concentrations of IFX are widely variable among IBD patients despite receiving the same weight-based dose. Several patient factors including laboratory parameters and severity of intestinal inflammation influence the way an individual's body proccesses and eliminate this type of medications. Dashboard software systems can take into account patient characteristics and IFX concentrations to modelate and facilitate dosing of IFX. By using pharmacokinetics (PK) models specifically developed to facilitate IFX dosing, these softwares can provide and recommend multiple dosing regimes to help the clinicians to select the appropriate dose to achieve target and optimal IFX concentrations.

The goal of this clinical trial is to learn if early measuring of IFX blood concentrations and dashboard-guided IFX dose adjustment in Chilean IBD patients starting IFX, increases the proportion of patients with optimal IFX levels and improves patient outcomes. Researchers will measure IFX concentrations before the second (week 2) and third dose (week 6) in a prospectively collected individual patient cohort and this information along with clinical data will be analyzed with a dashboard software system and multiple dosing regime options will be provide to the attending clinicians to facilitate the selection of the next IFX weight-based dose and interval of infusions. This group will be compared with IBD patients with standard of dosing where attending clinicians make the dosing decisions based on clinical parameters. The main goal is to analyze if IBD patients in the dashboard-guided dosing arm achieve a higher proportion of optimal IFX concentrations at week 14 of treatment, develop ADA less frequently and improve clinical outcomes compared with standard dosing group.

Participants will be asked to:

• Provide clinical data about their disease and other conditions
• Provide blood samples at enrollment and before each IFX infusion (IFN) during one year
• Maintain regular clinical assessments every 3 months for one year

Study Overview

• Status: Recruiting
• Conditions: Inflammatory Bowel Disease (IBD); Crohn Disease (CD); Ulcerative Colitis (UC)
• Intervention / Treatment: Drug: Infliximab; Drug: Infliximab

Detailed Description

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic diseases that entail important morbidity and frequently require high-cost medications such as biologic therapies. Monoclonal antibodies against tumoral necrosis factor (anti-TNF) are effective and can modify the progressive course of IBD. In Chile, given the high cost of anti-TNF therapy, this medication is provided by a national program with universal coverage. Unfortunately, a significant proportion of IBD patients never respond (primary non-response, PNR) or experience loss of response (secondary loss of response, SLR) to anti-TNF within the first year of therapy and current evidence support that the complex pharmacokinetics of anti-TNF is involved in both scenarios. Additionally, low trough levels (TL) are associated with the development of antidrug antibodies (ADA) which reduce anti-TNF efficacy and can cause anaphylactic reactions. This is particularly relevant for intravenous infliximab (IFX) which is usually indicated in IBD patients with acute severe disease not responding to iv corticosteroids. Therefore, IFX is frequently dose escalated in patients based on clinical parameters that are thought to be related to drug clearance with conflicting evidence supporting this strategy. Several studies have demonstrated that IFX TL between 7-20 mcg/ml at week 14 of treatment is a strong and independent predictor of therapy response. Furthermore, IFX dashboard-guided dose optimization based on clinical and pharmacokinetic (PK) parameters using adaptive Bayesian modeling have demonstrated to be more precise that empirical adjustments based on the clinician intuition alone. Therefore, the goal of this study is to analyze whether early therapeutic drug monitoring (TDM) and dose adjustment based on a Bayesian model (iDOSE) in CD and UC patients initiating IFX, increases the proportion of patients with therapeutic levels (7-20 mcg/ml), reducing immunogenicity and consequently increasing the rate of disease remission. A prospective multicentric randomized clinical trial (RCT) of Chilean adult IBD inpatients starting IFX due to moderate-to-severe disease refractory to corticosteroids will be carried out. Patients will be randomized 1:1 to:

1. - Dashboard-guided dosing arm. Patients will undergo proactive TDM during induction (TL at IFN 2 and 3) with dose adjustment based on iDOSE.
2. - Standard dosing arm. Patients will receive dose adjustment based solely on clinical parameters.

Both groups will be followed-up after induction with clinical visits, TL and ADA at week 14 (INF 4), 26 and 52. Researchers expect that a higher proportion of patients in the dashboard-guided dosing arm will achieve therapeutic TL of IFX (7-20 mcg/ml) at week 14 of treatment (Primary outome). Secondary outcomes will include clinical and laboratory parameters related to therapy response at week 52 of treatment, proportion of patients experiencing PNR and SLR, patients developing ADA, as well as, adverse events, hospitalization and surgery

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Cristian Hernández-Rocha Cristian Hernández-Rocha, MD; Phone Number: 56-22-3543838; Email: caherna4@uc.cl
• Study Contact Backup: Name: Carolina Pavez Carolina Pavez, MD; Phone Number: 56-22-3543838; Email: cdpavez@uc.cl

Study Locations

• Chile
  • Santiago, Chile
    • Recruiting
    • Pontificia Universidad Catolica of Chile
    • Contact: Maria Balcells E, MD; Phone Number: +56955048170; Email: proyectos.didemuc@uc.cl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult inpatients with Crohn's disease, ulcerative colitis or inflammatory bowel disease-unclassified.
• Moderate-to-severe flare who fail to iv steroids and require infliximab as per standard of care by treating gastroenterologist

Exclusion Criteria:

• Participant younger than 18 years
• Non-controlled infectious diseases
• Permanent ileostomy or Ileal pouch-anal anastomosis
• Pregnancy
• Patients do not consent to participate in study
• Patients unable to comply with protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Dashboad-guided dosing; Eligible patients will receive IFX with proactive therapeutic drug monitoring during induction (week 2 and 6) and dashboard-guided dosing options will be suggested to their attending gastroenterologists	Drug: Infliximab; IFX therapeutic drug monitoring before the second and third infusion and subsequent dashboard-guided dosing regimes suggested to attending gastroenterologists based on clinical and pharmacokinetics data; Drug: Infliximab; No IFX therapeutic drug monitoring before the second and third infusion and subsequent dosing regimes based on clinical data
Other: Standard dosing; Eligible patients will receive IFX standard dosing during induction based solely on clinical data	Drug: Infliximab; IFX therapeutic drug monitoring before the second and third infusion and subsequent dashboard-guided dosing regimes suggested to attending gastroenterologists based on clinical and pharmacokinetics data; Drug: Infliximab; No IFX therapeutic drug monitoring before the second and third infusion and subsequent dosing regimes based on clinical data

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infliximab optimal concentration	Proportion of patients who achieve infliximab trough levels between 7-20 mcg/ml at week 14 of treatment	Week 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical remission	Proportion of subjects in clinical remission at week 52 (CDAI <150 for CD or partial Mayo score < 2 for UC).	Week 52
Corticosteroid-free clinical remission	Proportion of subjects in Corticosteroid (CS)-free clinical remission at week 52 (CDAI <150 for CD or partial Mayo score < 2 for UC and no use of CS within previous 6 months).	Week 52
Sustained corticosteroid-free clinical remission	Proportion of subjects with sustained CS-free clinical remission at week 52 (CDAI <150 for CD or partial Mayo score < 2 for UC and no CS use from week 14 through week 52).	Week 52
CRP normalization	Proportion of subjects with normalisation of C-reactive protein (CRP) at week 52 (decrease from ≥1 at baseline to <1 mg/dL).	Week 52
Fecal calprotectin normalization	Proportion of subjects with normalisation of fecal calprotectin at week 52 (decrease from >250μg/g at baseline to ≤250mcg/g).	Week 52
Primary non-response	Proportion of subjects who are primary non-responders (≤70-point decrease in CDAI score for CD or decrease in partial Mayo score of ≥2 points and ≥25% for UC from baseline) and at least one of: CRP ≥1mg/dL or FC >250μg/g; or need for rescue therapy prior to week 14).	Week 14
Secondary loss of response	Proportion of subjects exhibiting secondary loss of response (CDAI >220 or partial Mayo score >4 and at least one of: CRP ≥1mg/dL or FC >250μg/g; or need for rescue therapy) during maintenance.	Week 14 through 52
Antibodies to infliximab-free survival	Proportion of subjects with no antibodies to infliximab (ATI).	Week 2 through 52
Proportion of subjetcs with antibodies to infliximab	Proportion of subjects with antibodies to infliximab (ATI)	Week 2 through 52
Time to antibodies to infliximab	Time to antibodies to infliximab (ATI) development.	Week 2 through 52
Adverse events	Proportion of subjects with any treatment-related adverse event.	Week 0 through 52
Surgery	Proportion of subjects with CD or UC-related surgery	Week 0 through 52
Time to surgery	Time to CD or UC-related surgery	Week 0 through 52
Hospitalization	Proportion of subjects with CD or UC-related hospitalisation.	Week 0 through 52
Time to hospitalization	Time to CD or UC-related hospitalisation	Week 0 through 52

Collaborators and Investigators

• Sponsor: Pontificia Universidad Catolica de Chile
• Collaborators: University of Chile; Universidad de La Frontera; Clinica Indisa; Clínica Universidad de los Andes; Hospital San Juan de Dios,Chile

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2025
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: December 26, 2024
• First Submitted That Met QC Criteria: December 26, 2024
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 25, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Inflammatory Bowel Disease; Infliximab; therapeutic drug monitoring; dashboard-guided dosing
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Crohn Disease; Intestinal Diseases; Inflammatory Bowel Diseases; Tumor Necrosis Factor Inhibitors; Anti-Inflammatory Agents; Gastrointestinal Agents; Antirheumatic Agents; Dermatologic Agents; Infliximab
• Other Study ID Numbers: 240320009; SA24I0002 (Other Grant/Funding Number: The Chilean National Research and Development Agency (ANID))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No