Influence of HLA-DQA1*05 Genotype in Adults With Anti-TNF Treatment With Proactive Therapeutic Drug Monitoring. (Proa-DQ)

Influence of HLA-DQA1*05 Genotype in Adults With Inflammatory Bowel Disease and Anti-TNF Treatment With Proactive Therapeutic Drug Monitoring. A Prospective Multicenter Study.

HLA-DQA1*05 variant carriers are at risk of developing antibodies against infliximab and adalimumab with reduced TNF antagonist persistence.

The impact of proactive therapeutic drug monitoring (PTDM) on this association has been barely assessed.

Therefor, we propose a cohort study including adult patients with Crohn's disease and ulcerative colitis treated with TNF antagonists under proactive therapeutic drug monitoring.

Our hypothesis is that, proactive therapeutic drug monitoring could be an alternative to combination treatment with immunomodulators to increase TNF-antagonists' persistence in HLA-DQA1*05 carriers.

Study Overview

• Status: Recruiting
• Conditions: Inflammatory Bowel Diseases; Drug Monitoring
• Intervention / Treatment: Drug: Tumor necrosis factor (TNF)-alpha inhibitors

Detailed Description

Population study: patients with inflammatory bowel disease and initiation of anti-TNF therapy

Inclusion and exclusion criteria

The inclusion criteria are:

• Patient diagnosed with inflammatory bowel disease based on clinical, endoscopic, and pathological criteria according to ECCO criteria.
• Initiation of anti-TNf, including infliximab and adalimumab.
• Subjects naïve to biological treatment
• Age >18 years.

The exclusion criteria are:

• No determination of HLA DQA1*5 allele.
• No proactive drug monitoring
• Initiation of anti-TNF treatment as prevention of post-surgical recurrence in Crohn's disease during the first 12 months after surgery or, after that time, with a colonoscopy with a Rutgeerts 0-1
• Anti-TNF treatment with combined treatment with immunomodulator. Prior initiation of immunomodulator or prior use and suspension would not be a contraindication
• Initiation of anti-TNF treatment for extraintestinal manifestation
• Initiation of anti-TNF treatment during pregnancy.

Proactive drug monitoring was defined as standardized determination of drug levels during induction and maintenance, with optimization independently of the patient's clinical status, until reaching target levels.

• Study Type: Observational
• Enrollment (Estimated): 280

Contacts and Locations

• Study Contact: Name: Esteban Fuentes-Valenzuela, MD; Phone Number: +34 983 42 04 00; Email: estebanfuentes_2@hotmail.co

Study Locations

• Spain
  • Valladolid, Spain
    • Recruiting
    • Hospital Universitario Rio Hortega
    • Contact: Esteban Fuentes-Valenzuela

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Patients with a diagnosis of inflammatory bowel disease (Crohn's disease, ulcerative colitis and indeterminate colitis), who require starting anti-TNF for the first time.

Description

Inclusion Criteria:

• Diagnosis of inflammatory bowel disease according to ECCO criteria.
• Older than 18 years
• Subjects naïve to biological treatment
• Anti-TNF treatment initiation (infliximab or adalimumab) due to intestinal activity and/or perianal disease.
• Avaibility to evaluate HLA DQA1*05 status
• Proactive therapeutic drug monitoring of anti-TNF levels

Exclusion Criteria:

• Initiation of anti-TNF treatment as prevention of post-surgical recurrence in Crohn's disease during the first 12 months after surgery or, afterwards, if endoscopic recurrence with a Rutgeerts 0-1.
• Initiation of anti-TNF treatment under combo treatment with immunomodulator. Prior initiation of immunomodulator or prior use and suspension would not be a contraindication.
• Initiation of anti-TNF treatment due to extraintestinal activity.
• Initiation of anti-TNF treatment by a non-gastroenterologist specialist.
• Initiation of anti-TNF treatment during pregnancy.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
HLA-DQA1*05 variant carriers	Drug: Tumor necrosis factor (TNF)-alpha inhibitors; Proactive drug monitoring was defined as the assessment of trough concentrations to optimize dosing during induction therapy and intermittently thereafter regardless of symptoms or inflammatory markers. During induction, the following target concentrations are employed: 25-30 mcg/ml (week 2) and 20 mcg/ml (week 6) for Infliximab and > 10 mcg/ml (week 2 and 4) for Adalimumab. Checks are performed systematically at week 2 and 6 (infliximab) and at week 4 (adalimumab). During the maintenance, the targets are 5-10 mcg/ml for Infliximab and 8-12 mcg/ml for Adalimumab. In case of perianal disease, the targets are 7-20 mcg/ml.
HLA-DQA1*05 non-carriers	Drug: Tumor necrosis factor (TNF)-alpha inhibitors; Proactive drug monitoring was defined as the assessment of trough concentrations to optimize dosing during induction therapy and intermittently thereafter regardless of symptoms or inflammatory markers. During induction, the following target concentrations are employed: 25-30 mcg/ml (week 2) and 20 mcg/ml (week 6) for Infliximab and > 10 mcg/ml (week 2 and 4) for Adalimumab. Checks are performed systematically at week 2 and 6 (infliximab) and at week 4 (adalimumab). During the maintenance, the targets are 5-10 mcg/ml for Infliximab and 8-12 mcg/ml for Adalimumab. In case of perianal disease, the targets are 7-20 mcg/ml.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Corticosteroid-free clinical remission and treatment maintenance at week 54	Corticosteroid-free clinical remission was defined as Harvey Bradshaw score <5 for Crohn's disease or partial Mayo score ≤2 for ulcerative colitis with no item exceeding one point, without corticosteroid	Week 54

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Corticosteroid-free clinical response and remission at week 12.	Corticosteroid-free clinical response was defined as Harvey Bradshaw score < 5 or a decrease ≥ 3 points from baseline in Crohn's disease. For ulcerative colitis, a decrease in the partial Mayo Index of at least 3 points or 30% accompanied by a decrease in rectal bleeding by one point, without corticosteroid	week 12
Proportions of patients with ultrasound remission at week 12 and 24	Ultrasound remission was defined as SUS-CD 0 for Crohn's disease or a bowel wall thickness < 2.1 mm for ulcerative colitis	week 12 and 24
Proportions of patients with clinical-biochemical remission at week 54.	Clinical-biochemical remission was defined as CRP ≤ 5 mg/L and fecal calprotectin < 150 mg/kg	week 54
Proportions of endoscopic remission at week 54 between both groups.	For Crohn's disease endoscopic remission was defined as a SES-CD <3 points or absence of ulcerations (e.g. SES-CD ulceration subscores ¼ 0) For ulcerative colitis, a Mayo endoscopic subscore of 0 points, or UCEIS ≤1 points	week 54
Proportions of primary failure between both groups		week 12
To compare drug levels at week 6 (infliximab) and week 4 (adalimumab) in subjects with a standard induction	Drug monitoring at week 6 for infliximab and week 4 for adalimumab.	week 4 or 6
Proportion of subjects with anti-drug antibodies at the end of induction and week 54.	Anti-infliximab and anti-adalimumab antibodies at week 4 for adalimumab, at week 6 for infliximab and at week 54 for both.	week 54

Collaborators and Investigators

• Sponsor: Hospital del Rio Hortega
• Collaborators: Francisco Javier Garcia Alonso; Jesús Barrio

Study record dates

Study Major Dates

• Study Start (Actual): January 11, 2023
• Primary Completion (Estimated): February 1, 2024
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: May 1, 2023
• First Submitted That Met QC Criteria: August 8, 2023
• First Posted (Actual): August 14, 2023

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 8, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Anti-TNF; proactive therapeutic drug monitoring; HLA-DQA1*05 genotype
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Inflammatory Bowel Diseases; Intestinal Diseases
• Other Study ID Numbers: 22-EO033

Drug and device information, study documents

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