Therapeutic Monitoring of Infliximab and Adalimumab

Therapeutic Monitoring of Infliximab and Adalimumab in Pediatric Chronic Inflammatory Diseases: Innovative Pharmacological Strategies for Predicting Response and Adverse Effects

Anti tumor necrosis factor (TNF agents), particularly infliximab and adalimumab, changed the way chronic inflammatory bowel disease (IBD) refractory to conventional therapies is treated, including in pediatric patients. However, approximately 10-30% of patients do not respond to initial therapy and up to 50% lose response over time. Variability in response to therapy may be influenced by multiple interacting factors at different levels. Recent studies showed that measurement of serum infliximab concentrations during induction therapy predicts treatment effects at one year. Therefore, therapeutic monitoring of infliximab is proposed as a useful strategy to improve clinical outcomes and optimize healthcare resources.

Most commercially available methods for infliximab quantification are based on the ELISA assay, which has an assay time of at least 8 hours. Recently, commercial point-of-care devices became available with assay times of less than one hour, enabling real-time therapeutic drug monitoring; however, validation of these devices in clinical settings and comparison with standard assays are still needed, particularly in pediatric patients. In addition, some studies suggest that loss of response in patients treated with anti-TNFs may be partly due to the emergence of specific anti-drug antibodies (AAFs). A limitation of the most widely used ELISA assays is the inability to quantify drug and AAF when they are simultaneously present. Recently, innovative ELISA assays have become available to overcome this problem. However, there is a lack of comparative studies between the classical and the specific method in terms of clinical response in pediatric patients. In patients who do not respond to infliximab, especially if they have high levels of AAF, guidelines call for the use of adalimumab. For this drug, the evidence in the literature regarding therapeutic monitoring of adalimumab concentrations and association with response in pediatric patients is still very preliminary. This study, carried out in in pediatric patients with IBD, aims to:

1. validate the "point of care" infliximab assay by comparing it with reference ELISA assays;
2. evaluate the correlation of infliximab and AAF levels, as measured by the innovative ELISA assays, with response to therapy, compared to traditional assays.
3. evaluate the association between adalimumab and AAF levels and response to therapy

Study Overview

• Status: Recruiting
• Conditions: Inflammatory Bowel Diseases
• Intervention / Treatment: Drug: Infliximab; Drug: Adalimumab

Detailed Description

Anti-TNF agents, particularly infliximab and adalimumab, changed the way chronic inflammatory bowel disease (IBD) refractory to conventional therapies is treated, including in pediatric patients. These biologic agents also appear promising as first-line treatment even in the early stages of the disease. However, approximately 10-30% of patients do not respond to initial therapy and up to 50% lose response over time. In addition, the widespread use of these drugs is limited by serious side effects and the high cost of therapy. Variability in response to therapy may be influenced by multiple interacting factors at different levels. Recent studies showed that measurement of serum infliximab concentrations during induction therapy predicts treatment effects at one year: in particular, patients with infliximab concentrations below 3 ug/ml at the end of induction (pre-dose IV infusion) have a reduced probability of response. Therefore, therapeutic monitoring of infliximab is proposed as a useful strategy to improve clinical outcomes and optimize healthcare resources.

Currently, most commercially available methods for infliximab quantification are based on the ELISA assay, which has an assay time of at least 8 hours, delaying therapeutic adjustment to the next drug infusion. Recently, commercial point-of-care devices became available with assay times of less than one hour, enabling real-time therapeutic drug monitoring; however, validation of these devices in clinical settings and comparison with standard assays are still needed, particularly in pediatric patients. In addition, some studies suggest that loss of response in patients treated with anti-TNFs, infliximab and adalimumab, may be partly due to the emergence of specific anti-drug antibodies (AAFs). A limitation of the most widely used ELISA assays is the inability to quantify drug and AAF when they are simultaneously present. Data from the literature suggest that in patients who lose response to anti-TNFs, classical ELISA assays may overestimate the percentage of patients with low levels of both drug and AAF; the use of specific ELISA assays allows accurate quantification of drug and AAF levels even in these patients, allowing the clinician to modify therapy accordingly. Recently, innovative ELISA assays have become available to overcome this problem. However, there is a lack of comparative studies between the classical and the specific method in terms of clinical response in pediatric patients. In patients who do not respond to infliximab, especially if they have high levels of AAF, guidelines call for the use of adalimumab. For this drug, the evidence in the literature regarding therapeutic monitoring of adalimumab concentrations and association with response in pediatric patients is still very preliminary. Thus, the research objectives are three, of equal importance:

1. to validate the "point of care" infliximab assay by comparing it with reference ELISA assays in pediatric patients with IBD;
2. to evaluate the correlation of infliximab and AAF levels, as measured by the above innovative ELISA assays, with response to therapy, compared to traditional assays, in pediatric patients with IBD.
3. to evaluate the association between adalimumab and AAF levels and response to therapy in pediatric patients with IBD.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Giuliana Decorti, MD; Phone Number: +390403785111; Email: giuliana.decorti@burlo.trieste.it
• Study Contact Backup: Name: Gabriele Stocco, MSC; Phone Number: +390403785111; Email: gabriele.stocco@burlo.trieste.it

Study Locations

• Italy
  • Bologna, Italy
    • Recruiting
    • Ospedale Maggiore
    • Contact: Patrizia Alvisi; Email: patrizia.alvisi@ausl.bologna.it
  • Treviso, Italy
    • Recruiting
    • Ospedale Ca' Foncello
    • Contact: Stefano Martelossi; Email: stefano.martelossi@aulss2.veneto.it
  • Trieste, Italy, 34137
    • Recruiting
    • IRCCS Burlo Garofolo
    • Contact: Gabriele Stocco; Email: gabriele.stocco@burlo.trieste.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: N/A

• Sampling Method: Non-Probability Sample

Study Population

Pediatric subjects with IBD suitable for treatment with infliximab or adalimumab

Description

Inclusion Criteria:

• IBD subjects
• age between 0 and 17 years
• suitable for treatment with infliximab or adalimumab

Exclusion Criteria:

• Pediatric subjects with IBD not suitable for treatment with infliximab or adalimumab

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
IBD group; Pediatric patients with IBD	Drug: Infliximab; Pediatric patients with IBD suitable for treatment with infliximab; Drug: Adalimumab; Pediatric patients with IBD suitable for treatment with adalimumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infliximab concentration	Assessed with the point-of-care assay and with the ELISA assay	Through study completion, an average of 5 years
Adalimumab concentration	Assessed with ELISA assay	Through study completion, an average of 5 years
AAF concentration	Assessed by the novel ELISA assays	Through study completion, an average of 5 years
Response to therapy assessed with validated score	Assessed by Pediatric Crohn's disease activity index (PCDAI) and Pediatric UlcerativeColitis Activity Index (PUCAI). PCDAI ranges from 0 to 100; higher scores indicate more active disease. Clinical remission was defined as PCDAI ≤ 10. PUCAI score ranges from 0 to 85, with disease remission less than 10, mild disease activity between 10-35, moderate disease activity from 35-65, and severe disease activity above 65	Through study completion, an average of 5 years

Collaborators and Investigators

• Sponsor: IRCCS Burlo Garofolo
• Investigators: Principal Investigator: Gabriele Stocco, MSC, IRCCS materno infantile Burlo Garofolo

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2018
• Primary Completion (Estimated): June 30, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: September 5, 2023
• First Submitted That Met QC Criteria: September 5, 2023
• First Posted (Actual): September 13, 2023

Study Record Updates

• Last Update Posted (Actual): June 14, 2024
• Last Update Submitted That Met QC Criteria: June 13, 2024
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Inflammatory Bowel Diseases; Infliximab; Adalimumab
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Inflammatory Bowel Diseases; Intestinal Diseases; Anti-Inflammatory Agents; Antirheumatic Agents; Gastrointestinal Agents; Dermatologic Agents; Tumor Necrosis Factor Inhibitors; Adalimumab; Infliximab
• Other Study ID Numbers: RC 01/17

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No