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
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 发起方
- 入组人数
- 20
- 试验地点
- 1
- 主要终点
- Complete or partial LAR (lack of remission)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Crohns disease
- •Age: 6 - 18 years ( inclusive)
- •Active disease PCDAI >10, or any steroid dependence despite thiopurine use for >10 weeks.
- •Naïve to biologics
- •Informed consent
- •CRP ≥0.6 mg/dl
- •Neg. TB-Test, negative HBV- S Ag
- •Use of IMM at present or in past for at least 10 weeks ( for Withdraw only).
- •Negative stool culture, parasites and clostridium toxin current flare
- •Inclusion criteria Comments:
- •Patients receiving corticosteroids may be included if the disease is active and CRP elevated.
- •All other treatments such as 5ASA , , must be discontinued immediately after the first IFX infusion.
- •Patients may receive an antihistamine prior to any infusion.Use of corticosteroid pretreatment is allowed only during the first two infusions (single infusion on day of infliximab), or if an infusion reaction has occurred.
- •Partial enteral nutrition, accounting for less than 50% of daily required calories, may be supplied as needed.
- •Patients receiving antibiotics must cease use of antibiotics within the 14 days of receiving the first infusion.
- •ESR >20 can be alternative if the CRP <0.
- •Negative stool culture, parasites and clostridium toxin current flare will examined only if the patient has diarrhea.
- •Patients may be enrolled directly in to the Predict study , in which case duration of IMM is irrelevant , but patients must have received an IMM until week 2 as in the withdraw
排除标准
- •Intolerance to thiopurines/methotrexate
- •Contraindication for any of the drugs.
- •Leukopenia <4000 or absolute neutrophil count below 1200 on two consecutive tests during screening.
- •Hepatocellular Liver disease ( ALT > 60 ) or cirrhosis.
- •Renal Failure
- •Prior idiosyncratic side effects with thiopurines ( pancreatitis etc).
- •Current abscess ( < 14 days of antibiotics) or perforation of the bowel( <14 days antibiotics).
- •Small bowel obstruction within the last 3 months
- •Fixed non inflammatory stricture with predilatation with symptoms related to stricture
- •Complicated or heavily draining perianal fistula ( indolent non draining or scant draining fistula are not exclusion criteria)
- •Prior treatment with infliximab
- •Previous malignancy
- •Toxic Megacolon
- •Surgery related to Crohn's disease in previous 8 weeks.
- •Positive Hepatitis B surface antigen or evidence for TB.
- •Current bacterial infection
- •IBD unclassified
- •Exclusion criteria Comments:
- •Prior surgery or post operative recurrence are not exclusion criteria.
研究组 & 干预措施
Immunomodulator therapy 26 weeks
IFX 5mg/kg for 76 weeks, continuing immunomodulator for 6 months from first infusion
干预措施: AZATHIOPRINE or METHOTREXATE (Drug)
Immunomodulator therapy 2 weeks
IFX 5mg/kg induction for 76 weeks, discontinuing immunomodulator on day of second infusion( after 14 days).
干预措施: AZATHIOPRINE or METHOTREXATE (Drug)
结局指标
主要结局
Complete or partial LAR (lack of remission)
时间窗: 76 weeks
* 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.
次要结局
- Mean trough level(14 and 52 weeks)
- Hospitalizations for LOR (loss of response) or failure to obtain remission(Up to 76 weeks)
- Sustained steroid free remission(52 and 76 weeks)
- Corticosteroid free remission(14 weeks)
- Medication associated adverse events(Up to 76 weeks)
- Presence of ATI(52 weeks)
研究者
Prof. Arie Levine
Director, Pediatric Gastroenterology and Nutrition unit.
Wolfson Medical Center