Salvage Therapy With High/Low Methotrexate for Loss of Response to Infliximab Dose Escalation
Information source: Wolfson Medical Center
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Crohn's Disease
Intervention: METHOTREXATE (Drug)
Phase: Phase 4
Status: Not yet recruiting
Sponsored by: Prof. Arie Levine Official(s) and/or principal investigator(s): Arie Levine, MD, Study Chair, Affiliation: Pediatric Gastroenterology and Nutrition Unit, The E. Wolfson MC, Tel-Aviv University, Holon, Israel
Overall contact: Arie Levine, MD, Phone: 972-3-5028808, Email: mailto:alevine@wolfson.health.gov.il
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.
Clinical Details
Official title: Phase 4, Open Lable Non Randomized un Controlled Study. Salvage Therapy With High/Low Methotrexate for Loss of Response to Infliximab Dose Escalation
Study design: Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: remission
Secondary outcome: RemissionTrough levels ATIs
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.
Eligibility
Minimum age: 8 Years.
Maximum age: 18 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. Informed consent
2. Established diagnosis of Crohns disease.
3. Age: 8 - 18 years ( inclusive)
4. Active disease PCDAI >10 at least two weeks after infusion.
5. On Infliximab with at least 3 prior infusions, and still active despite a decreased
dose interval ( ≤ 6 weeks) or increased dose of infliximab (≥7. 5 mg/kg /dose q 8
weeks).
Comment: Patients who are on combination therapy with a stable thiopurine>8 weeks can also
be included ( thiopurine will be stopped at enrollment).
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Exclusion Criteria:
1. Patients who are primary non responders after first two doses 2. Patients who have had
to stop infliximab due to side effects. 3. Patients with known intolerance to
methotrexate. 4. Elevated ALT >1. 5 normal. 5. Pregnancy.
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Locations and Contacts
Arie Levine, MD, Phone: 972-3-5028808, Email: mailto:alevine@wolfson.health.gov.il Additional Information
Starting date: July 2015
Last updated: May 14, 2015
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