Comparison of 2 Immunomodulator Withdrawal Schemes for Inflixiamb Monotherapy in Active Pediatric Crohn's Disease After Thiopurine Failure (WITHDRAW)
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase 4,Open Lable Multicenter Randomized Controlled Trial. Comparison of 2 Immunomodulator Withdrawal Schemes for Inflixiamb Monotherapy in Active Pediatric Crohn's Disease After Immunomodulator Failure|
- Complete or partial LAR (lack of remission) [ Time Frame: 76 weeks ] [ Designated as safety issue: No ]
- Complete LAR- Patient failing to achieve remission after first 3 scheduled doses , or absence of remission 7 days after an infliximab infusion in a patient who had achieved remission after any previous infusion, and unresponsive to dose escalation or dose interval change, or relapse occurring less than 4 weeks after last infusion
- Partial LAR- Relapse 4-8 weeks after previous infusion, with requirement for dose escalation or shortening of infliximab schedule, and remission with change in dosing or interval.
- Mean trough level [ Time Frame: 14 and 52 weeks ] [ Designated as safety issue: No ]
- Sustained steroid free remission [ Time Frame: 52 and 76 weeks ] [ Designated as safety issue: No ]
- Presence of ATI [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
- Corticosteroid free remission [ Time Frame: 14 weeks ] [ Designated as safety issue: No ]
- Hospitalizations for LOR (loss of response) or failure to obtain remission [ Time Frame: Up to 76 weeks ] [ Designated as safety issue: No ]
- Medication associated adverse events [ Time Frame: Up to 76 weeks ] [ Designated as safety issue: No ]
|Study Start Date:||February 2013|
|Estimated Study Completion Date:||September 2015|
|Estimated Primary Completion Date:||September 2015 (Final data collection date for primary outcome measure)|
Experimental: Immunomodulator therapy 26 weeks
IFX 5mg/kg for 76 weeks, continuing immunomodulator for 6 months from first infusion
Drug: AZATHIOPRINE or METHOTREXATE
Patients should continue azathioprine or 6 MP or methotrexate at their previous doses for 6 months IMM therapy 26 weeks
Other Name: 6 MERCAPTOPURINE
Experimental: Immunomodulator therapy 2 weeks
IFX 5mg/kg induction for 76 weeks, discontinuing immunomodulator on day of second infusion( after 14 days).
Drug: AZATHIOPRINE or METHOTREXATE
Patients should continue the same dose of azathioprine or 6 MP or methotrexate until the day of the second infusion (week 2)
Thiopurine therapy 2 weeks
Other Name: 6 MERCAPTOPURINE
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 immuno-suppressive therapies, and the risks of co-therapy. Mono-therapy 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.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01802593
|Contact: Arie Levine Levine, MDfirstname.lastname@example.org|
|The E. Wolfson.Medical Center||Recruiting|
|Holon, Israel, 58100|
|Contact: Arie Levine, MD 972-3-5028808 email@example.com|
|Principal Investigator: Arie Levine, MD|
|Study Chair:||Arie Levine, MD||Pediatric Gastroenterology and Nutrition Unit, The E. Wolfson MC, Tel-Aviv University, Holon, Israel|
|Study Director:||Dan Turner, MD, PhD||Pediatric Gastroenterology and Nutrition Unit, The Hebrew University of Jerusalem, Shaare Zedek MC, Jerusalem, Israel|
|Principal Investigator:||Raanan Shamir, MD||Schneider Childrens Hospital|
|Principal Investigator:||Michal Kori, MD||Kaplan Medical Center|
|Principal Investigator:||Michael Wilshanski, MD||Hadassah Medical Center|
|Principal Investigator:||Ron Shaoul, MD||Meyer Childrens Hospital Rambam, Haifa, Israel|
|Principal Investigator:||Shlomi Cohen, MD||Tel Aviv Medical Center|
|Principal Investigator:||Batia Weiss, MD||Sheba Medical Center|
|Principal Investigator:||Sarit Peleg, MD||Afula Hospital|
|Principal Investigator:||Baruch Yerushalmi, MD||Soroka Medical Center|
|Principal Investigator:||Efrat Broide, MD||Asaf Harofe Medical Center|
|Principal Investigator:||Avi On, MD||Poriah Hospital|
|Principal Investigator:||Hussein Chemali, MD||Nazheret Hospital|
|Principal Investigator:||Aharon Lerner, MD||Carmel Hospital|