PLACEBO CONTROLLED STUDY OF BACLOFEN FOR GERD IN CHILDREN WITH CEREBRAL PALSY

描述（由申请人提供）：顽固性胃食管反流病（GERD）在脑瘫（CP）和其他发育障碍儿童中普遍存在且难以控制。它具有高发病率和频繁的住院治疗。质子泵抑制剂（PPIs）是治疗胃食管反流的主要方法，但在CP患儿中失败率很高，可能是因为它们不影响短暂性食管下括约肌松弛（TLESRs）的发生率，也不能控制或可能增加非酸反流的存在。最近出现的多通道腔内阻抗（MII）监测显示，在其他健康儿童和CP儿童中，33-74%的反流是非酸性的。然而，在患有CP的儿童中，与其他健康的反流患者相比，盆底重叠的并发症发生率是其两倍，死亡率更高，发病率是其三倍，再手术率是其四倍。迫切需要确定专门针对tlesr的新型医学疗法，从而减少酸反流和非酸反流。巴氯芬是一种γ -氨基丁酸（GABA）激动剂，用于儿童CP治疗痉挛，已在动物和人类中显示可降低tlesr，并可能有效治疗反流。这将是一项随机、安慰剂、巴氯芬治疗CP患儿难治性胃食管反流的对照研究。该研究的目的是：A)与安慰剂相比，获得巴氯芬治疗CP合并难治性GERD患儿两周的疗效的初步证据；b)评估巴氯芬与安慰剂在减少MII检测到的反流事件数量方面的疗效。c)评估巴氯芬与安慰剂在减少食管功能测试（EFT）检测到的tlesr总数量和tlesr继发反流方面的疗效；d)评估巴氯芬治疗CP和难治性胃食管反流儿童两周的安全性和耐受性。3至18岁的儿童将有资格参加。纳入后，他们将有2周的观察期，随后36小时进入GCRC进行EFT和MII录像。然后，患者将随机接受巴氯芬或安慰剂治疗。他们将在完成2周治疗后返回进行评估，并在巴氯芬治疗期间再次接受EFT和MII治疗。本研究通过提供一种新的治疗方法和手术的替代方案，可能对儿童CP和顽固性反流的治疗产生重大影响。本研究将为巴氯芬治疗难治性胃食管反流病（GERD）的有效性和安全性提供证据，并可能代表一种新的治疗方法。本研究将作为在其他健康的反流儿童中测试药物的基础。

DESCRIPTION (provided by applicant): Intractable gastroesophageal reflux disease (GERD) in children with cerebral palsy (CP) and other development disabilities is prevalent and difficult to control. It carries a high morbidity with frequent hospitalizations. Proton pump inhibitors (PPIs), the mainstay of therapy for GERD, have a high failure rate in children with CP, presumably because they do not affect the rate of transient lower esophageal sphincter relaxations (TLESRs) and do not control or may increase the presence of non-acid reflux. The recent emergence of multichannel intraluminal impedance (MII) monitoring has revealed that 33-74% of reflux in otherwise healthy children and children with CP is non-acidic. However in children with CP, fundoplication is associated with twice the complication rate, a higher mortality, three times the morbidity, and four times the re-operation rate, as compared with otherwise healthy patients with GERD. Identifying novel medical therapies that specifically target TLESRs, and therefore decrease both acid and non-acid reflux, are urgently needed. Baclofen, a gamma-amino butyric acid (GABA) agonist used in children with CP to treat spasticity, has been shown in animals and humans to decrease TLESRs and may be effective in treating GERD. This will be a randomized, placebo, controlled study of baclofen to treat intractable GERD in children with CP. The aims of the study will be to: A) Gain preliminary evidence of the efficacy of baclofen to treat symptoms of GERD, in comparison with placebo, administered for two weeks in children with CP and intractable GERD , b) Assess the efficacy baclofen versus placebo in reducing the number of reflux events detected by MII, c) Assess the efficacy of baclofen versus placebo in reducing the number of total TLESRs and reflux secondary to TLESRs detected by esophageal function testing (EFT) and d) Assess the safety and tolerability of baclofen administered over two weeks to treat children with CP and intractable GERD. Children 3 to 18 years old will be eligible. After inclusion they will have a 2 week observation period, followed by a 36 hour admission to the GCRC for an EFT and MII with videorecording. Patients will then be randomized to baclofen or placebo. They will return for evaluation after completing 2 weeks of therapy, and will be readmitted for repeat EFT and MII while on baclofen therapy. The present study could have a major impact on the treatment of children with CP and intractable GERD by providing a new therapy and an alternative to surgery. This study will provide evidence about the efficacy and safety of baclofen for the treatment of intractable gastroesophageal relfux disease (GERD), and may represent a new treatment. This study will serve as a basis to test the medication in otherwise healthy children with GERD.