Caterina Strisciuglio1†‡
Vincenzo Coppola2†‡Marina Russo2†‡Carlo Tolone1‡
Gian Luigi Marseglia3‡
Alberto Verrotti4‡Silvia Caimmi3‡Claudia Caloisi5‡
Valeria D'Argenio6,7‡Lucia Sacchetti6‡
Annamaria Staiano2*‡ 卡特琳娜·斯特里西尤格里奥1†‡ 文森佐·科波拉2†‡ 玛丽娜·鲁索2†‡ 卡洛·托隆1‡ 吉安·路易吉·马塞利亚3‡ 阿尔贝托·韦罗蒂4‡ 西尔维娅·凯米3‡ 克劳迪娅·卡洛伊西5‡ 瓦莱里娅·达吉尼奥6.7‡ 露西亚·萨凯蒂6‡ 安娜玛丽亚·斯塔亚诺2*‡- 1Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples, Italy
1意大利那不勒斯坎帕尼亚大学 “Luigi Vanvitelli” 妇女、儿童和普通外科和专业外科 - 2Department of Translational Medical Sciences, Section of Pediatric, University of Naples Federico II, Naples, Italy
阿拉伯数字意大利那不勒斯费德里科二世大学儿科转化医学科学系 - 3Maternal and Child Department, IRCCS Foundation Policlinico “S. Matteo” di Pavia, Pavia, Italy
3IRCCS 基金会妇幼部 Policlinico “S. Matteo” di Pavia， 帕维亚， 意大利 - 4Department of Pediatrics, University of Perugia, Perugia, Italy
4佩鲁贾大学儿科系，意大利佩鲁贾 - 5Department of Pediatrics, University of L'Aquila, L'Aquila, Italy
5意大利拉奎拉大学儿科 - 6CEINGE Biotecnologie Avanzate S. C. A R. L., Naples, Italy
6CEINGE Biotecnologie Avanzate S. C. A R. L.， 那不勒斯， 意大利 - 7Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Open University, Rome, Italy
7意大利罗马圣拉斐尔开放大学人文科学与生活质量促进系
Background: Polyethylene glycol (PEG) is recommended as first-line treatment of pediatric functional constipation. However, the oral route of administration is often poorly feasible in children mostly due to poor palatability. Promelaxin microenemas exert a topical evacuative action and may offer a valuable option in pediatric FC.
背景：聚乙二醇 （PEG） 被推荐作为儿童功能性便秘的一线治疗。然而，口服给药途径在儿童中通常不太可行，主要是由于适口性差。普罗美拉辛微灌肠具有局部排便作用，可能在儿科 FC 中提供有价值的选择。
Aim: To assess whether Promelaxin microenemas would be non-inferior to PEG 4000 in young children with FC.
目的：评估 Promelaxin 微灌肠是否不劣于 PEG 4000 治疗 FC 幼儿。
Methods: This is a randomized, open-label, multi-centric, non-inferiority trial enrolling infants and young children aged 6–48 months, with FC according to Rome III criteria. After 1 week of run in, children were randomized to 2 weeks of Promelaxin or PEG, followed by a 6-week on-demand treatment period. Primary endpoint was response rate to randomized treatment, with “response” defined as at least 3 evacuations per week and an average increase of at least one evacuation per week as compared to baseline. Safety, stool consistency and the analysis of fecal microbiota were secondary endpoints.
方法：这是一项随机、开放标签、多中心、非劣效性试验，根据罗马 III 标准招募了 6-48 个月大的 FC 婴幼儿。磨合期 1 周后，儿童被随机分配到 2 周的普罗美拉辛或 PEG，然后是 6 周的按需治疗期。主要终点是对随机治疗的反应率，“反应”定义为每周至少 3 次排空，与基线相比，每周平均增加至少 1 次排空。安全性、粪便稠度和粪便微生物群分析是次要终点。
Results: Out of the 158 patients who entered the trial, 153 patients were treated (77 and 76, PEG and Promelaxin arm, respectively). In the primary analysis, the 95% confidence interval (CI) for the treatment's effect lay entirely above the non-inferiority margin in both Full Set (FAS) and Per Protocol (PP) analyses, providing evidence of the non-inferiority of Promelaxin vs. PEG 4000 [response rate difference: 16.5% (CI 1.55–31.49%) and 11.03% (CI −5.58 to 27.64%), FAS and PP analyses, respectively]. Mean compliance to the randomized treatment was >80% in both arms. Secondary endpoints did not significantly differ between the two arms, except for the average number of total days of on-demand treatment that was significantly lower in the Promelaxin arm [14.6 (12.7) vs. 9.8 (9.1), mean (SD); primary endpoint responders in PEG and Promelaxin arm, respectively; p = 0.027]. Microbiota evenness significantly increased in the PEG 4000 arm at V4 as compared to the Promelaxin arm (p < 0.05). In addition, at V5, patients treated with PEG showed a significantly decreased microbiota density as compared to patients treated with Promelaxin (p = 0.036).
结果：在进入试验的 158 名患者中，153 名患者接受了治疗 （分别为 77 名和 76 名，PEG 组和 Promelaxin 组）。在初步分析中，在全套 （FAS） 和按方案 （PP） 分析中，治疗效果的 95% 置信区间 （CI） 完全高于非劣效性边缘，提供了 Promelaxin 与 PEG 4000 的非劣效性的证据 [反应率差异：16.5% （CI 1.55-31.49%） 和 11.03% （CI -5.58 至 27.64%），FAS 和 PP 分析， 分别]。两组对随机治疗的平均依从性均为 >80%。两组之间的次要终点没有显著差异，除了按需治疗的平均总天数显著降低，普罗美拉辛组 [14.6 （12.7） vs. 9.8 （9.1），平均值 （SD）;PEG 组和 Promelaxin 组的主要终点反应者分别为;p = 0.027]。与普罗美拉辛组相比，PEG 4000 组在 V4 时的微生物群均匀度显著增加 （p < 0.05）。此外，在 V5 时，与普罗美拉辛治疗的患者相比，PEG 治疗的患者表现出微生物群密度显著降低 （p = 0.036）。
Conclusions: Promelaxin microenemas are non-inferior to oral PEG in children with FC.
结论：普罗美拉辛微灌肠在 FC 患儿中不劣于口服 PEG。
Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02751411.
临床试验注册号：www.ClinicalTrials.gov，标识符：NCT02751411。
Introduction 介绍
Functional constipation (FC), defined as the infrequent (<2/week) and painful passage of stools associated with stool retention, is a common problem in childhood (1, 2). A 2018 systematic review and meta-analysis reported the worldwide pooled prevalence of FC in children to be 9.5% (95% CI 7.5–12.1%) (2, 3). Overall, 1 in 10 children may suffer from FC. The transition to solid food, toilet training and school entry are usually precipitating events associated with the onset of FC (3, 4).
功能性便秘 （FC），定义为与大便潴留相关的不频繁 （<2/周） 和疼痛排便，是儿童期的常见问题 （1， 2）。2018 年的一项系统评价和荟萃分析报告称，全球儿童 FC 的总体患病率为 9.5% （95% CI 7.5-12.1%） （2， 3）。总体而言，每 10 名儿童中就有 1 名可能患有 FC。过渡到固体食物、如厕训练和入学通常是与 FC 发作相关的诱发事件 （3， 4）。
In infants and toddlers, FC usually appears to originate from an acquired behavior of stool withholding after experiencing painful defecation (4). This makes the rectal fecal mass difficult to eliminate, thus amplifying the persistence of constipation. In order to avoid long-term FC, a successful integrated treatment strategy should be implemented at an early stage, combining pharmacological and non-pharmacological approaches (4). In fact, it is recommended to integrate early pharmacological treatment with non-pharmacological treatment, i.e., behavioral, psychological, dietary interventions (2, 5, 6), to interrupt the loop leading to the persistence of FC, fecal impaction, psychological problems, and a significant burden on children and parents (7). Considering that the median age for the onset of this condition is around 2 years (8), acting before or around that age becomes crucial, in order to interrupt the vicious loop leading to persistent FC and to avoid its complications, such as fecal impaction.
在婴幼儿中，FC 通常似乎起源于排便疼痛后后憋大便的后天行为 （4）。这使得直肠粪便肿块难以消除，从而放大了便秘的持续性。为了避免长期 FC，应在早期实施成功的综合治疗策略，结合药物和非药物方法 （4）。事实上，建议将早期药物治疗与非药物治疗相结合，即行为、心理、饮食干预 （2， 5， 6），以中断导致 FC 持续存在的循环、粪便嵌塞、心理问题以及儿童和父母的重大负担 （7）。考虑到这种情况发作的中位年龄约为 2 岁 （8），因此在该年龄之前或前后采取行动变得至关重要，以中断导致持续性 FC 的恶性循环并避免其并发症，例如粪便嵌塞。
Oral polyethylene glycol (PEG) is currently recommended as the first-line treatment of pediatric FC by the major international Societies (9). However, adherence to PEG can be sub-optimal especially in infants, often due to poor palatability (10) as reported by parents. Consistently, adherence as low as 37% has been reported in children on long-term treatment with PEG for persistent FC (11). Therefore, other treatment options with an efficacy comparable to PEG could be relevant in optimizing the treatment of FC, especially in young children.
口服聚乙二醇 （PEG） 目前被主要国际学会推荐为儿科 FC 的一线治疗 （9）。然而，对 PEG 的依从性可能不是最佳的，尤其是在婴儿中，通常是由于父母报告的适口性差 （10）。据报道，长期接受 PEG 治疗持续性 FC 的儿童依从性低至 37% （11）。因此，其他疗效与 PEG 相当的治疗选择可能与优化 FC 的治疗相关，尤其是在幼儿中。
Enemas are used in pediatric patients, with volumes adapted to the function (local or systemic effect) and to the age of the child (7, 12). A randomized trial in children suffering from fecal impaction, a condition that, triggers or complicates FC, compared oral PEG vs. enemas (60 ml of dioctyl sulfo-succinate-sodium, once-daily for 6 days) in children aged 4–6 years. The trial showed that enemas were as effective as high-dose oral PEG (13).
灌肠剂用于儿科患者，其体积适应功能（局部或全身效应）和儿童的年龄 （7， 12）。一项针对患有粪便嵌塞（一种诱发 FC 或使 FC 复杂化的疾病）的儿童的随机试验，比较了 4-6 岁儿童的口服 PEG 与灌肠剂（60 毫升丁磺基琥珀酸二辛酯钠，每天一次，持续 6 天）。试验表明，灌肠剂与高