PROactive and Early Infliximab Monitoring and OPTimization in Inflammatory Bowel Disease

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:

• - Dashboard-guided dosing arm. Patients will undergo proactive TDM during induction (TL at IFN 2 and 3) with dose adjustment based on iDOSE.
• - 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

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