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

描述(申请人提供)：顽固性胃食道反流病(GERD)在脑瘫(CP)和其他发育障碍的儿童中普遍存在，很难控制。它的发病率很高，经常住院。质子泵抑制剂(PPI)是治疗GERD的主要药物，在CP儿童中失败率很高，可能是因为它们不影响一过性下食道括约肌松弛(TLESR)的发生率，也不能控制或可能增加非酸反流的存在。最近出现的多通道管腔内阻抗(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GERD患者相比，胃底折叠术的并发症发生率是GERD的两倍，死亡率更高，发病率是GERD的3倍，再手术率是GERD的4倍。迫切需要找到专门针对TLESRs的新的医疗疗法，从而减少酸和非酸反流。巴氯芬是一种伽马氨基丁酸(GABA)激动剂，用于治疗脑性瘫痪儿童的痉挛，已在动物和人类中被证明可以减少TLESR，并可能有效地治疗GERD。这将是一项随机、安慰剂、对照的巴氯芬研究，用于治疗患有慢性胰腺炎的儿童的顽固性GERD。该研究的目的是：a)获得初步证据，证明巴氯芬与安慰剂治疗患有CP和难治性GERD的儿童的症状的有效性，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道功能试验(EFT)检测到的TLESR总数和继发于TLESR的反流方面的疗效，以及d)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岁的儿童将有资格参加。纳入后，他们将有2周的观察期，然后进入GCRC进行EFT和MII的36小时录影。然后，患者将随机服用巴氯芬或安慰剂。他们将在完成2周的治疗后返回接受评估，并将在巴氯芬治疗期间再次入院进行重复的EFT和MII。通过提供一种新的治疗方法和手术的替代方案，本研究可能对患有CP和难治性GERD的儿童的治疗产生重大影响。本研究将为巴氯芬治疗难治性胃食道反流病(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。这项研究将作为测试该药物在其他健康的GERD儿童中的基础。

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.