Salvage Therapy With High/Low Methotrexate for Loss of Response to Infliximab Dose Escalation
Condition: Crohn's Disease
MeSH terms: Crohn Disease
Study type: Interventional
Phase: Phase 4

Summary: 
      The goal of the present study is to evaluate if addition of methotrexate can restore
      remission after loss of response to infliximab after dose escalation.

      another goal is to evaluate if low dose methotrexate can maintain remission achieved by
      regular dose methotrexate by 6 months.
    

Detailed description: 
      Background: IFX mono-therapy became the method of choice for treatment in pediatric CD,
      though this strategy has been called into question due to frequent loss of response to IFX
      requiring dose escalation of IFX or decreased intervals of IFX( up to 40% during the first
      year) (1). This loss of response has been attributed to development of ATIs and low trough
      levels of IFX, which can develop after the first infusions. This loss of response will often
      occur in patients with prior azathioprine exposure (2,3,4).

      Currently , the first step during loss of response to infliximab in children is dose
      escalation either by decreasing the interval between infusions or doubling the dose. However,
      patients with persistent antibodies or high titers are likely to fail even with dose
      escalation. The Sonic trial clearly demonstrated that combination therapy with a thiopurine
      may be more effective than Anti TNF alpha monotherapy (2). Ben Horin et al demonstrated that
      antidrug antibodies can be reversed and improved anti TNF trough levels obtained by adding an
      immunomodulator to failed monotherapy due to an antidrug antibody (3).

      We have previously shown that in patients with a previous loss of response to two biologics
      leading to cessation of both biologics can respond to reinduction with adalimumab and
      methotrexate . Among 12 patients (10 children and two adults) , 6 obtained complete
      remission. We subsequently lowered the does in several patients without loss of response, and
      tried stopping methotrexate in 3 patients. All 3 patients relapsed within months of complete
      cessation of methorexate.In this previous study we took two separate actions that restored
      response, re-induction and methotrexate therapy. In the current proposal we will take
      patients that are on escalated therapy and just add methotrexate, in order to evaluate if
      adding methotrexate once weekly can restore response after loss of response to infliximab
      after failed dose escalation.It is important to note that methotrexate does not increase the
      risk of malignancy as co-therapy as far as we know.

      Methods: It is a prospective open label phase 4, non randomized uncontrolled study in a small
      cohort of patients to evaluate if addition of methotrexate can restore remission after loss
      of response to infliximab after dose escalation in paediatric patients.
    

Intervention name(s): METHOTREXATE
Intervention type(s): Drug
Intervention description(s): Infliximab therapy after escalation. SC methotrexate at 15 mg/m2 , not to exceed 25 mg/m2 per week for 4 weeks. Patients in remission after 4 weeks reduce their dose by halve. patients not in remission will continue the full dose until 12 weeks.
Other intervention name(s): Rheumatrex; Trexall
Intervention MeSH terms: Methotrexate
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment