目标:利那洛肽,鸟苷酸环化酶-C激动剂,最近在美国被批准用于治疗患有功能性便秘(FC)的6-17岁儿童。这项研究评估了剂量反应,安全,与安慰剂相比,利那洛肽在2-5岁FC儿童中的4周疗效。
方法:在这个阶段2,随机,双盲,安慰剂对照,多剂量研究,35名FC儿童(基于罗马III标准)以3:1随机分配接受利那洛肽(18、36或72μg,对于第1、2和3组)和5:1分别接受利那洛肽9、18、36或72μg(第4组),或匹配的安慰剂。关键终点是总体自发排便(SBM)频率(SBM/周)相对于基线的变化,大便稠度,和紧张,以及研究干预期间大便失禁天数的比例。记录不良事件(AE)。
结果:在随机分组的患者中,34(97.1%)完成了治疗期,33(94.3%)完成了治疗期。四个关键功效终点中的三个在治疗期间从基线的平均变化显示利那洛肽72μg组相对于安慰剂的更大改善。在接受利那洛肽的患者中,粪便稠度呈剂量反应趋势。四名随机接受利那洛肽治疗的患者经历了治疗引起的AE,其中之一是治疗相关的(轻度腹泻)。所有不良事件均为轻度或中度,无严重不良事件。
结论:利那洛肽在该儿科人群中具有良好的耐受性,与安慰剂相比,利那洛肽72μg具有疗效趋势。
OBJECTIVE: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for the treatment of children 6-17 years of age with functional constipation (FC). This study evaluated the dose-response, safety, and efficacy of 4 weeks of linaclotide compared with placebo in children 2-5 years of age with FC.
METHODS: In this phase 2, randomized, double-blind, placebo-controlled, multidose study, 35 children with FC (based on Rome III criteria) were randomized 3:1 to receive linaclotide (18, 36, or 72 μg, for groups 1, 2, and 3, respectively) and 5:1 to receive linaclotide 9, 18, 36, or 72 μg (group 4), or matching placebo. Key endpoints were the changes from baseline in overall spontaneous bowel movement (SBM) frequency (SBMs/week), stool consistency, and straining, as well as the proportion of days with fecal incontinence during the study intervention period. Adverse events (AEs) were recorded.
RESULTS: Of the randomized patients, 34 (97.1%) completed the treatment period and 33 (94.3%) completed the posttreatment period. Mean change from baseline over the treatment period for three of the four key efficacy endpoints showed greater improvement in the linaclotide 72 μg group versus placebo. A dose-response trend was seen for stool consistency in patients receiving linaclotide. Four patients randomized to linaclotide experienced treatment-emergent AEs, one of which was treatment-related (mild diarrhea). All AEs were mild or moderate and none were severe.
CONCLUSIONS: Linaclotide was well tolerated in this pediatric population and an efficacy trend was seen with linaclotide 72 μg versus placebo.