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