Prospective Analysis of Pharmacokinetic Infliximab Data in Pediatric CD Patients (ProRAPID)
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Proportion of patients with IFX Trough Levels ≥ 5 µg/mL at week 12 without treatment escalation
研究概览
简要总结
Rationale: Crohn's disease (CD) is a chronic, debilitating inflammatory bowel disease (IBD) which is diagnosed during childhood in up to one in ten patients. The use of anti-tumor necrosis factor (TNF)-α agents has significantly ameliorated CD management. Infliximab (IFX) is the first anti-TNF-α agent registered for pediatric CD. The current dosing recommendation of IFX is extrapolated from adult studies, and it is a weight-based dose (5 mg/kg) delivered during induction (infusion at weeks 0, 2, and 6) and maintenance (every 8 weeks). However, pediatric patients have a 25-40% lower drug exposure compared to adults, particularly children under 10 years of age, resulting in diminished efficacy and an increased risk of developing a complicated disease course. The investigators hypothesize that an intensified IFX induction scheme (instead of the current dosing recommendation) is more effective in the treatment of pediatric CD patients.
Objective: The primary study objective of our study is to assess the efficacy of an IFX intensified induction scheme vs. a standard dosing schedule in improving drug exposure without treatment escalation in pediatric CD patients. Secondary objectives are clinical and biochemical remission without treatment escalation, development of antibodies to IFX (ATI) and adverse reactions.
Study design: An international, multicenter, prospective, open-label trial. Study population: Anti-TNF-α naïve children (age 3-15 years) with CD and an indication to start IFX treatment.
Intervention: IFX will be given intravenously at 10 mg/kg at week 0, and 5 mg/kg at weeks 2, 4, and 8 to all patients (induction). Maintenance will start at week 12, and then ideally continue every 6 weeks till week 24 (end of study). IFX trough levels will be measured at weeks 4, 12, and 24. During the maintenance, the IFX dose and/or interval adjustments, the IFX discontinuation or the start of a co-medication (i.e., an immunomodulator) will be possible on indication (i.e., primary nonresponse, secondary loss of response, intolerance to study medication) at the physicians' discretion. Follow-up will continue for the duration of the study (week 24).
Main endpoint: Proportion of patients with IFX TL ≥ 5 µg/mL at week 12 without treatment escalation.
详细描述
INTRODUCTION AND RATIONALE
Definition of the problem
Crohn's disease (CD) is a chronic, debilitating inflammatory bowel disease (IBD) which is diagnosed during childhood in up to one in ten patients. Pediatric CD patients often have more severe and extensive disease compared to adults. Prospective studies in pediatric CD are scarce; therefore, many questions remain unanswered in the treatment of pediatric CD. The discovery of anti-tumor necrosis factor (TNF)-α agents opened up a new window in the pharmacological management of this condition. Infliximab (IFX) was the first anti-TNF-α agent to be approved for use in the treatment of CD. Several clinical studies showed its efficacy in inducing mucosal healing and improving long-term outcomes, even as a first-line treatment. Efficacy of IFX has been related to IFX trough levels, which are dependent on clearance of IFX. Lower IFX trough levels (TLs) are associated with increased immunogenicity and increased risk of developing complicated disease course of time. The clearance of IFX is influenced by many factors. Clearance of IFX in IBD can be influenced by disease severity (i.e., local vs. systemic inflammation), increased intestinal permeability, increased proteatic activity, the presence of antibodies to IFX (ATI), and the use of a concomitant immunomodulatory. Furthermore, the study of Dotan el al. showed that clearance of IFX is not linearly related weight, meaning that patients with lower body weight might need higher IFX doses.
Despite these data, the current dosing recommendation of IFX is still a weight-based dose (5 mg/kg) during induction (infusion at weeks 0, 2, and 6) and the maintenance phase (every 8 weeks) extrapolated from adult studies. However, recent evidence indicates that pediatric patients have a 25-40% lower drug exposure compared to adults. Particularly in children under 10 years of age, Jongsma et al. showed in a retrospective cohort a median IFX TLs at week 14 of 3.1 µg/mL in a subset of young CD patients (age < 10 years), which is far below the recently recommended target trough level > 5 µg/mL at week 14. Based on this data, young children probably need higher IFX dosing to obtain optimal IFX trough levels.
However, up till now no prospective trials have been performed using an intensified dosing scheme for younger CD patients. As stated above, adult data on intensified dosing schemes cannot be directly extrapolated to children due to pharmacokinetic differences. Therefore, a prospective trial within children with CD is necessary to identify a possible new dosing scheme for these patients. This study is innovative, as it will be the first prospective trial to determine if an IFX intensified induction scheme is more effective than standard dose in pediatric CD. This study will provide additional knowledge whether an intensified induction scheme in younger patients will indeed result in higher trough levels and better disease outcomes.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 3 Years 至 15 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Anti-TNF-α naïve children (age 3-15 years) with CD and an indication to start IFX treatment will be eligible for inclusion after a diagnosis of CD is made based on the Porto criteria. Indications of starting IFX treatment as per ECCO-ESPGHAN guidelines include non-response after induction with exclusive enteral nutrition or steroids, non-response to immunomodulators, severe growth delay, extensive disease and/or structuring or penetrating disease, with or without perianal disease. Evaluation of the indication to start IFX is performed at the discretion of the attending physician.
排除标准
- •Established monogenetic IBD
- •Fistulizing/perianal disease at start of IFX treatment
- •Severe comorbidity (not related to IBD)
- •Immediate need for surgery (i.e., symptomatic stenosis or stricture in the bowel)
- •Severe infection such as sepsis or opportunistic infections, positive tuberculin test or a chest radiograph consistent with tuberculosis or malignancy
- •Pregnancy, suspected or definitive
- •Treatment with anti-TNF or other biological drugs in the past
- •Start of corticosteroids, Exclusive/Partial Enteral Nutrition, other CD dietary therapy or mesalazine less than 2 weeks prior to first IFX infusion
研究组 & 干预措施
Intensified induction scheme with Infliximab
Intensified induction scheme with Infliximab. IFX will be given intravenously at 10 mg/kg at week 0, and 5 mg/kg at weeks 2, 4, and 8 to all patients (induction). Maintenance will start at week 12, and then ideally continue every 6 weeks.
干预措施: Infliximab (Drug)
结局指标
主要结局
Proportion of patients with IFX Trough Levels ≥ 5 µg/mL at week 12 without treatment escalation
时间窗: 12 weeks
Treatment escalation is defined as any additional CD-related medication or IBD-related abdominal surgery
次要结局
- Evaluation of quality of life(24 weeks)
- Prediction of reponders versus non-responders to IFX based on proteomic analysis.(24 weeks)
- Proportion of patients with IFX Trough Levels ≥ 5 µg/mL at week 24 without the need for treatment escalation(24 weeks)
- Clinical and biochemical remission at weeks 4, 12, and 24 without the need for treatment escalation in patients with TL ≥ 5 µg/mL and in patients with TL < 5 µg/mL.(24 weeks)
- Predictors of IFX Trough Levels at weeks 4, 12, and 24. Factors included in this analysis will be sex, age, body mass index (BMI), wPCDAI, IBD laboratory values, antibodies to Infliximab (ATI), dose, and interval of IFX infusions.(24 weeks)
- Development of antibodies to IFX until week 24(24 weeks)
研究者
Lissy de Ridder
Medical Doctor; Associate Professor
Erasmus Medical Center