Infliximab Infusion Rates in Pediatric Inflammatory Bowel Disease

iRAPID: Infliximab Infusion Rate in Pediatric Inflammatory Bowel Disease. A Randomized Non-inferiority Trial of Infusion Reactions With Infliximab Infusion-rates of 30 Minutes and 60 Minutes

OBJECTIVES OF THE STUDY

1. Investigate whether there are just as few infusion reactions with infliximab infusions of 60 min and 30 min.
2. Investigate patient and nurse satisfaction with infusions of 60 min and 30 min.
3. Investigate resource use in terms of total length of stay and use of nursing resources.

Our primary objective in this study is to compare the incidence of infusion reactions of Infliximab when administered over 30 minutes versus 60 minutes. We hypothesize that there will be no significant differences between the two groups, demonstrating that 30-minute infusions are as safe and effective as the current standard of 60-minute infusions.

Secondary endpoints include evaluating patient and nurse satisfaction with both infusion rates, as well as assessing resource utilization by measuring total outpatient clinic stay and nursing staff allocation.

Additionally, we will explore whether satisfaction, infusion reactions and treatment effectiveness (asessed through clinical scoring systems, endoscopic findings and laboratory results) are affected by patient demographics (such as age, sex), disease type, infusion frequency, or co-treatment with immunomodulators.

Project methodology Study design and implementation Strategy The iRAPID study is designed as a prospective, randomized, open-label, non-inferiority crossover trial designed to compare the safety and effectiveness of 30-minute versus 60-minute infliximab infusions in pediatric IBD patients. The study will be conducted at the Akershus University Hospital Pediatric and Adolescent Outpatient Clinic, where all included patients already receive infliximab infusions for inflammatory bowel disease (IBD). Patients included in the study will be randomized to receiving four consecutive fast 30-minute infusions, or four consecutive standard 60-minute infusions, after which they will switch to the alternative regimen. Each patient will serve as their own control. Randomization will be performed using a validated computer-generated randomization program.

If the patient meets inclusion and exclusion criteria, they will be invited to participate in the study. Written consent will be obtained from parents for children under the age of 16, while patients aged 16 years or older will provide their own written consent. Participation is voluntary, and one may withdraw from the study and return to the standard infusion rate of 60 minutes at any time. Based on the power calculation, 60 patients will be included in the study. This sample size allows for adjustments in dosing, intervals, and concomitant medication according to standard clinical criteria, as well as a safety margin for dropouts.

Infusion reactions will be monitored by an experienced IBD-nurse before, during and after each infusion. Infusion reactions will be dichotomized as yes or no, and categorized as mild/localized, moderate or severe using predefined clinical criteria (See references Lichtenstein, J Crohns Colitis. 2015;9(9):806-15 and Jagt et al, J Pediatr Gastroenterol Nutr. 2023;77(3):373-80). The criteria are based on age-appropriate values from the Pediatric Early Warning Score (PEVS), which ensures consistency in event classification and facilitates reliable safety assessments. The nurse will record vital signs, including pulse, blood pressure and respiratory rate, in addition to observe for symptoms of an infusion reaction, in accordance with the already established standard procedure for infliximab infusions.

• Criteria for mild/localized infusion reaction: Transient and short-lived pruritus, flushing (facial erythema), myalgia or low-grade fever (37.5-37.9°C).
• Criteria for moderate infusion reaction: Fever (temperature >38°C), tachycardia (increase in heart rate >20 beats/min above age-appropriate values in the PEVS chart), sensation of breathlessness or chest tightness or angioedema.
• Criteria for severe infusion reaction: Bronchospasm or laryngospasm, decreased consciousness, hypotension (a drop in systolic blood pressure >20 mmHg from the normal value in the PEVS chart) or anaphylactic shock.

If an infusion reaction occurs, the patient will be assessed with a doctor, and appropriate intervention will follow standard clinical guidelines (Ref Lichtenstein, J Crohns Colitis. 2015;9(9):806-15). In case of an infusion reaction, clinical judgment will be used to assess whether there is an identifiable cause, whether the patient should continue the medication, whether additional treatment is necessary, and how the next infusion should be conducted. All adverse events, including symptoms, interventions, and assessments will be documented in the medical record and the study database.

• In the case of a mild infusion reaction, the infusion rate will be reduced and then gradually increased if tolerated.
• In the case of a moderate infusion reaction, the infusion will be stopped, pharmacological interventions will be considered and if the patient is deemed stable, the infusion will restart at a slower rate with gradual escalation.
• In the case of a severe infusion reaction, the infusion will be stopped immediately, and appropriate treatment will be administered.

Demographic data are recorded to describe the enrolled patients, including age, sex, weight and height, and disease-specific information such as IBD type, duration and extent, and previous treatment including other immunosuppressive treatment, treatment efficacy, and the duration and number of doses of infliximab therapy prior to study inclusion. At each infusion visit, the doctor will also document infliximab dose, infusion interval, and drug concentration. As part of the routine consultation, disease activity will be assessed using validated scoring systems: PUCAI for ulcerative colitis and short-PCDAI for Crohn's disease. Adjustments to treatment intervals and dosing will be made based on clinical jugdements and patient needs, independent of study participation.

Satisfaction will be evaluated using a custom-designed questionnaire completed by patients, parents and nurses. This assessment will provide qualitative insights into the impact of infusion time on both patient/caregiver experience and the clinical workflow.

The economic impact of infusion-rate will be assessed by recording:

• Total time spent in the outpatient clinic from arrival to discharge
• Total nursing time required for each infusion, including preparatory tasks (blood sampling, IV placement), infusion administration, monitoring of the patient and documentation.

Inclusion Criteria:

• Pediatric IBD patients on infliximab
• 1-17 years
• Received at least 5 infusions of infliximab prior to entry in the study

Exclusion Criteria:

• Receiving infliximab for non-IBD condition (reumatological or other causes)
• previous severe infliximab infusion reaction
• need for an interpreter
• heart failure with hemodynamic impact
• unwillingness to participate