Impact of Early Proactive Therapeutic Drug Monitoring on the Durability and Efficacy of Infliximab Therapy in Pediatric Inflammatory Bowel Disease: a Multicenter Open-label Randomized-control Trial
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 发起方
- 入组人数
- 86
- 试验地点
- 1
- 主要终点
- Frequency of IFX discontinuation or need for treatment intensification due to non-response or LOR during the first year of treatment.
研究概览
简要总结
The purpose of the study is to assess whether a proactive therapeutic drug monitoring strategy, introduced early during treatment, improves Infliximab (IFX) durability, efficacy and safety in children and young adults with inflammatory bowel disease. Patients with an indication to receive IFX, based on current clinical practice recommendations, will receive the drug either based on IFX concentrations determined before every IFX infusion, starting from the third infusion, or at standard dosing. Approximately 90 patients will be included in this research study. Patients enrolled will be in the study for approximately 12 months.
详细描述
Inflammatory Bowel Disease (IBD) are relapsing disorders with progressive bowel damage leading to long-term disability.
Infliximab (IFX), is a highly effective and commonly used biologic in IBD. However, up to 40% of patients do not respond to treatment or lose response over time. Low-serum IFX concentrations and the development of antibodies to IFX (ATI) are two major factors affecting IFX efficacy, durability and safety. Standard IFX dose is administered as an IV (in the vein) infusion at 5 mg/kg in a 0, 2, and 6 weeks induction regimen followed by a maintenance regimen with infusions every 8 weeks. This standard dosing is extrapolated from adult studies. IFX has a highly variable pharmacokinetic and pharmacodynamics that is dependent on body weight, disease extent, levels of inflammation and the presence of ATI. In children and young adults with IBD all these factors often result in low-serum IFX concentrations.
Proactive therapeutic drug monitoring, consists in the measurement of drug concentrations on patient's blood, in order to adjust the following administrations (dosing or interval) and maintain a desired concentration of the medication in the body.
This study seeks to determine whether a proactive therapeutic drug monitoring strategy can improve IFX durability, efficacy and safety in children and young adults with IBD. The study will involve approximately 90 patients, aged 6 to 17 years, with IBD. All the patients enrolled in the study will receive IFX at 5mg/kg at week 0, 2 and 6. At week 6 patients will be randomly assigned to receive IFX treatment either based on IFX concentrations determined before every IFX infusion (intervention group) or at standard dosing (control group). Patients will participate in the study for 54 weeks (approximately 12 months) or until IFX discontinuation. During the study, patients will visit the study center at the time of every IFX infusion or in case of disease flares.
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 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Anti-TNF naïve children and adolescents, 6-17 years, with a diagnosis of IBD confirmed by a prior endoscopic biopsy that is consistent with the diagnosis
- •Indication to start anti-TNF therapy in accordance with current pediatric guidelines for the treatment of pediatric IBD
- •Active inflammation supported by CRP > 5mg/L and /or FC > 150 μg/g before the 1st IFX dose
排除标准
- •Consent withdrawal,
- •Stenosing or penetrating disease requiring surgery, abdominal abscess, symptomatic stricture,
- •Abdominal surgery within the previous 6 months,
- •Acute severe ulcerative colitis attack defined by a PUCAI score Ñ 65,
- •Infective contraindication to IFX treatment including positive tuberculin skin test or Quantiferon-TB test, recent opportunistic infection, infection with hepatitis B (HBV), C (HCV), human immunodeficiency virus (HIV),
- •Previous exposure to anti-TNF;
- •Exposure to concomitant prohibited medications including other biologics (including but not limited to ustekinumab, vedolizumab, abatacept, anakinra..), thalidomide, investigational drugs
- •Pregnancy or lactation
研究组 & 干预措施
Early-Proactive Therapeutic Drug Monitoring (E-pTDM)
Infliximab (IFX) at 5mg/kg, IV at week 0, 2 and 6. From week 6, the infusion interval will be adjusted based on pre-infusion IFX concentrations to target a trough level grater or equal to (>=) 5 mcg/ml (> 10 μg/ml in patients with perianal disease). For IFX concentrations below target, the infusion interval will be shortened (minimum interval 2 weeks). IFX dose increase will be performed as a second step.
干预措施: Infliximab (Drug)
Standard dosing
Infliximab (IFX) at 5mg/kg, IV at week 0, 2 and 6 followed by 5mg/kg infusions every 8 weeks.
干预措施: Infliximab (Drug)
结局指标
主要结局
Frequency of IFX discontinuation or need for treatment intensification due to non-response or LOR during the first year of treatment.
时间窗: 54 weeks
Composite outcome. Treatment intensification is defined as adjunction of rescue therapies, including corticosteroids systemic or topical, azathioprine (AZA), methotrexate (MTX), 5-aminosalicylate (5-ASA) systemic or topical, or rescue IFX escalation or surgery; treatment response is defined as a decrease in Pediatric Crohn's Disease Activity Index (PCDAI) by 12.5 point or in Pediatric Ulcerative Colitis Activity Index (PUCAI) by 10 points with decrease in C reactive protein (CRP) by 50% after induction, evaluated between 12-14 weeks; loss of response (LOR) is defined as PCDAI \>= 10 or PUCAI \> 10 with CRP \> 0.5mg/dl and/or fecal calprotectin (FC) \>250 microg/g in a patient who previously responded to induction treatment.
次要结局
- Cumulative probability of IFX discontinuation(54 weeks)
- Cumulative probability of Loss of Response(54 weeks)
- Frequency of infusion reactions(54 weeks)
- Frequency of Anti-Infliximab Antibodies(54 weeks)
- Frequency of clinical and biochemical remission at week 14(Week 14)
- Frequency of endoscopic remission(54 weeks)
- Frequency of patients with clinical remission at 14 weeks(Week 14)
- Frequency of subtherapeutic IFX concentrations(54 weeks)
- Frequency of patients with treatment response at the end of induction between 12 and 14 weeks(Week 14)