Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
Inflamm Bowel Dis. 2010 Jul;16(7):1203-8. doi: 10.1002/ibd.21204.
Improving granulocyte function may represent an effective therapy for Crohn's disease (CD). We performed a Phase I-2 trial of sargramostim (SRG) in children with CD.
This was multicenter, open-label study in 6-16-year-old patients with moderate to severely active CD. Patients received either 4 or 6 microg/kg SRG subcutaneously daily for 8 weeks, with and without concomitant corticosteroids (CS). The primary endpoint was identification of a safe and tolerable dose in children. The secondary endpoint was establishment of the pharmacokinetics (PK). Efficacy, a tertiary endpoint, was measured by the Pediatric CD Activity Index (PCDAI). Response was defined as a decrease from baseline of > or =12.5 points and remission as absolute PCDAI of < or =10.
In all, 22 patients were enrolled: 12 and 10 received 4 and 6 mg/kg, respectively; 19 completed the course. Both doses were found to be safe and well tolerated. Mild injection-site reactions occurred in 90% of patients. Three patients required dose reductions due to elevated absolute neutrophil counts. Following 4 microg/kg the mean area under the curve (AUC) was 2.64 and 2.80 ngh/mL for the 6-11- and 12-16-year-old groups, respectively. The mean half-life (t(1/2)) was 1.22 and 1.59 hours, respectively. Following 6 microg/kg, the mean AUC was 5.01 ngh/mL for the 12-16-year-old group, a 1.8-fold increase. A total of 16/18 patients (88%) achieved remission or response.
Sargramostim at both 4 and 6 mg/kg was well tolerated. PK analysis suggested dose proportionality unaffected by CS exposure. Remission and response data are encouraging, but further trials are needed to assess efficacy.
改善粒细胞功能可能是克罗恩病（CD）的有效治疗方法。我们对 CD 患儿进行了沙格司亭（SRG）的 I-2 期临床试验。
这是一项多中心、开放性研究，纳入 6-16 岁的中重度 CD 患儿。患者接受每日皮下注射 4 或 6μg/kg 的 SRG，持续 8 周，同时或不合并使用皮质类固醇（CS）。主要终点是确定儿童的安全和耐受剂量。次要终点是建立药代动力学（PK）。疗效，即 tertiary 终点，通过儿科 CD 活动指数（PCDAI）进行测量。缓解定义为与基线相比下降≥12.5 分，完全缓解定义为绝对 PCDAI<10。
共纳入 22 例患者：12 例和 10 例分别接受 4 和 6mg/kg 的剂量；19 例完成了疗程。两个剂量均安全且耐受良好。90%的患者出现轻微的注射部位反应。由于绝对中性粒细胞计数升高，有 3 例患者需要减少剂量。4μg/kg 时，6-11 岁和 12-16 岁组的平均 AUC 分别为 2.64 和 2.80ng/mL。平均半衰期（t(1/2)）分别为 1.22 和 1.59 小时。6μg/kg 时，12-16 岁组的平均 AUC 为 5.01ng/mL，增加了 1.8 倍。共有 16/18 例（88%）患者达到缓解或应答。
4 和 6mg/kg 的 SRG 均耐受良好。PK 分析表明，CS 暴露不受剂量比例影响。缓解和应答数据令人鼓舞，但仍需进一步试验评估疗效。
