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Salvage Therapy With High/Low Methotrexate for Loss of Response to Infliximab Dose Escalation

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ClinicalTrials.gov Identifier: NCT02269358
Recruitment Status : Completed
First Posted : October 21, 2014
Last Update Posted : October 18, 2018
Sponsor:
Information provided by (Responsible Party):
Prof. Arie Levine, Wolfson Medical Center

Brief 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.


Condition or disease Intervention/treatment Phase
Crohn's Disease Drug: METHOTREXATE Phase 4

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : July 2015
Actual Primary Completion Date : October 9, 2018
Actual Study Completion Date : October 9, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Addition of methotrexate
Addition SC methotrexate at 15 mg/m2, not to exceed 25 mg/m2 . Patients in remission after 4 weeks will reduce their dose by halve. patients not in remission will continue the full dose until 12 weeks.
Drug: METHOTREXATE
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 Names:
  • Rheumatrex
  • Trexall




Primary Outcome Measures :
  1. remission [ Time Frame: at 12 weeks ]
    remission without additional therapy.


Secondary Outcome Measures :
  1. Remission [ Time Frame: 6 months ]
  2. Trough levels [ Time Frame: week 12 ]
  3. ATIs [ Time Frame: week 12 ]


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Ages Eligible for Study:   8 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. 6. Patients who have insulin-dependent diabetes 7. Patients who have significantly impaired renal function 8. Current bacterial infection/ inflammation including Hepatitis B or C and Pneumonia.

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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02269358


Locations
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Israel
The E. Wolfson.Medical Center
Holon, Israel, 58100
Sponsors and Collaborators
Prof. Arie Levine
Investigators
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Study Chair: Arie Levine, MD Pediatric Gastroenterology and Nutrition Unit, The E. Wolfson MC, Tel-Aviv University, Holon, Israel

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Responsible Party: Prof. Arie Levine, Director, Pediatric Gastroenterology and Nutrition unit., Wolfson Medical Center
ClinicalTrials.gov Identifier: NCT02269358     History of Changes
Other Study ID Numbers: 0143-14-WOMC
First Posted: October 21, 2014    Key Record Dates
Last Update Posted: October 18, 2018
Last Verified: October 2018

Additional relevant MeSH terms:
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Crohn Disease
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Methotrexate
Infliximab
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors
Gastrointestinal Agents