Ignite Creation Date:
2025-12-25 @ 1:19 AM
Ignite Modification Date:
2026-01-07 @ 2:38 AM
Study NCT ID:
NCT01802593
Status:
TERMINATED
Last Update Posted:
2015-12-22
First Post:
2012-12-24
Is NOT Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Comparison of 2 Immunomodulator Withdrawal Schemes for Infliximab Monotherapy in Active Pediatric Crohn's Disease After Thiopurine Failure
Sponsor:
Prof. Arie Levine
Organization:
Study Overview
Official Title:
Phase 4, Open Label Multicenter Randomized Controlled Trial. Comparison of 2 Immunomodulator Withdrawal Schemes for Infliximab Monotherapy in Active Pediatric Crohn's Disease After Immunomodulator Failure
Status:
TERMINATED
Status Verified Date:
2015-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
lack of budget and failure to reach milestones
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
WITHDRAW
Brief Summary:
The goal of the present study is to evaluate the best regimen for infliximab monotherapy, and to evaluate if limited combination therapy with IFX and an Immunomodulator for the first 6 months of therapy, in prior Immunomodulator failures, is superior to monotherapy with Immunomodulator cessation from the second infusion, in preventing loss of remission to IFX.
Detailed Description:
Background: Current data from studies and registries involving pediatric Crohn's disease indicate that 50-80% of children will receive an immunomodulator (IMM) as a maintenance therapy within 12 months of diagnosis, and between 60-80% by 18 months. The common use of IMM early in the disease also leads to a high proportion of patients with active disease despite IMM (IMMfailure).
Infliximab has become a standard of care in North America, Europe and Israel, and is recommended at present for steroid dependent or refractory patients, fistulizing disease, active disease despite an immunomodulator.
Infliximab was originally prescribed as an add on therapy to IMM, because of concerns regarding IFX side effects and loss of response due to development of antibodies to infliximab (ATIs). An early study clearly showed an advantage in long term remission with thiopurine co administration.However, subsequent studies in adults with CD showed that with scheduled IFX treatment, AZA could be safely discontinued after the first 6 months of therapy , lowering the risks associated with dual immunosuppressive therapies, and the risks of co-therapy. Monotherapy subsequently became the recommended method of treatment with IFX, despite a decrease in trough levels among those who discontinued IMM.
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. This loss of response has been attributed to development of ATIs and low trough levels of IFX, which can develop after the first infusions. Low trough levels of infliximab at 14 weeks were predictive of LOR. The second reason for questioning IFX mono-therapy is a trial that compared mono-therapy to combined AZA+IFX therapy in adults with moderate to severe thiopurine naïve disease. This study clearly showed improved long term remission rates and mucosal healing in an unselected cohort of patients with combination therapy. Conversely, mono-therapy was associated with low levels of sustained mucosal healing, which is troublesome. Lastly, some excellent results obtained in a pediatric cohort treated with combined therapy, along with the relatively low risk of HTSCL, has left pediatric gastroenterologists at a loss; Should we recommend primary mono-therapy , or use IMM for a limited period of time before discontinuing therapy ? When should the IMM be discontinued, after the first infusion or after several months? There are no controlled data in pediatric IBD to answer this pressing question.
There is also a movement towards increased use of methotrexate instead of thiopurines as immunomodulators because of concerns about neoplasia.
Recent studies have shown that by adding an immunomodulator to a biologic after LOR, trough levels can be improved and ATIs or ADAs decreased, suggesting that IMM may inhibit antibody formation.
The investigators hypothesize that by continuing IMM with IFX for the first 6 months, the investigators will detect a benefit . The investigators hypothesize that early cessation of an IMM will increase the risk of LOR (Loss of response), decrease trough levels at 14 weeks, and be associated with lower rates of corticosteroid free sustained remission by one year.
In a parallel study , using the same data base, We also hypothesize that low trough levels at week 14 ( parallel study) will predict LOR- This study, called Predict Study; Prediction of Loss of Response to Infliximab in Crohn's Disease Based on Week 14 Trough Levels.will enable open label enrolment of patients receiving infliximab with an immunomodulator, but will not require randomization, and patients may be allocated to group one or group 2 at the physicians or patients discretion.
Methods: It is a prospective open label phase 4 RCT in pediatric patients with active CD, defined by the Porto criteria, despite \>10 weeks of prior treatment with an immunomodulator (thiopurines/Methotrexate) ,requiring infliximab, involving 2 arms, and intention to treat analysis after the first infusion.
Infliximab has become a standard of care in North America, Europe and Israel, and is recommended at present for steroid dependent or refractory patients, fistulizing disease, active disease despite an immunomodulator.
Infliximab was originally prescribed as an add on therapy to IMM, because of concerns regarding IFX side effects and loss of response due to development of antibodies to infliximab (ATIs). An early study clearly showed an advantage in long term remission with thiopurine co administration.However, subsequent studies in adults with CD showed that with scheduled IFX treatment, AZA could be safely discontinued after the first 6 months of therapy , lowering the risks associated with dual immunosuppressive therapies, and the risks of co-therapy. Monotherapy subsequently became the recommended method of treatment with IFX, despite a decrease in trough levels among those who discontinued IMM.
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. This loss of response has been attributed to development of ATIs and low trough levels of IFX, which can develop after the first infusions. Low trough levels of infliximab at 14 weeks were predictive of LOR. The second reason for questioning IFX mono-therapy is a trial that compared mono-therapy to combined AZA+IFX therapy in adults with moderate to severe thiopurine naïve disease. This study clearly showed improved long term remission rates and mucosal healing in an unselected cohort of patients with combination therapy. Conversely, mono-therapy was associated with low levels of sustained mucosal healing, which is troublesome. Lastly, some excellent results obtained in a pediatric cohort treated with combined therapy, along with the relatively low risk of HTSCL, has left pediatric gastroenterologists at a loss; Should we recommend primary mono-therapy , or use IMM for a limited period of time before discontinuing therapy ? When should the IMM be discontinued, after the first infusion or after several months? There are no controlled data in pediatric IBD to answer this pressing question.
There is also a movement towards increased use of methotrexate instead of thiopurines as immunomodulators because of concerns about neoplasia.
Recent studies have shown that by adding an immunomodulator to a biologic after LOR, trough levels can be improved and ATIs or ADAs decreased, suggesting that IMM may inhibit antibody formation.
The investigators hypothesize that by continuing IMM with IFX for the first 6 months, the investigators will detect a benefit . The investigators hypothesize that early cessation of an IMM will increase the risk of LOR (Loss of response), decrease trough levels at 14 weeks, and be associated with lower rates of corticosteroid free sustained remission by one year.
In a parallel study , using the same data base, We also hypothesize that low trough levels at week 14 ( parallel study) will predict LOR- This study, called Predict Study; Prediction of Loss of Response to Infliximab in Crohn's Disease Based on Week 14 Trough Levels.will enable open label enrolment of patients receiving infliximab with an immunomodulator, but will not require randomization, and patients may be allocated to group one or group 2 at the physicians or patients discretion.
Methods: It is a prospective open label phase 4 RCT in pediatric patients with active CD, defined by the Porto criteria, despite \>10 weeks of prior treatment with an immunomodulator (thiopurines/Methotrexate) ,requiring infliximab, involving 2 arms, and intention to treat analysis after the first infusion.
Study Oversight
Has Oversight DMC:
True
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?: