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

描述（由申请人提供）：脑瘫（CP）和其他发育障碍儿童的难治性胃食管反流病（GERD）很普遍，难以控制。其发病率高，住院率高。质子泵抑制剂（PPI）是GERD治疗的主要药物，在CP儿童中具有较高的失败率，可能是因为它们不影响一过性下食管括约肌松弛（TLESR）的发生率，并且不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，与其他健康的GERD患者相比，在CP儿童中，胃底折叠术的并发症发生率为2倍，死亡率更高，发病率为3倍，再次手术率为4倍。迫切需要确定专门针对TLESR的新型药物疗法，从而减少酸和非酸反流。巴氯芬是一种γ-氨基丁酸（GABA）激动剂，用于CP儿童治疗痉挛，已在动物和人类中显示可减少TLESR，并可能有效治疗GERD。这将是一项巴氯芬治疗CP儿童难治性GERD的随机、安慰剂、对照研究。这项研究的目的是：A）获得巴氯芬与安慰剂相比在患有CP和难治性GERD的儿童中施用两周治疗GERD症状的功效的初步证据，B）评估巴氯芬与安慰剂相比在减少通过MII检测的反流事件的数量方面的功效，c）评估巴氯芬相对于安慰剂在减少通过食管功能测试（EFT）检测到的总TLESR和继发于TLESR的反流的数量方面的功效，以及评估巴氯芬治疗CP和难治性GERD儿童的安全性和耐受性。3至18岁的儿童将有资格。入组后，他们将有2周的观察期，随后进入GCRC进行36小时的EFT和MII，并进行录像。然后将患者随机分配至巴氯芬或安慰剂组。他们将在完成2周治疗后返回进行评估，并将在巴氯芬治疗期间再次入院进行重复EFT和MII。本研究可能会对CP和难治性GERD儿童的治疗产生重大影响，提供一种新的治疗方法和手术的替代方案。本研究将为巴氯芬治疗难治性胃食管返流病（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。这项研究将作为在其他健康的GERD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.