Department of Gastroenterology and Endoscopy, University Hospital Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.
Department of Gastroenterology and Hepatology, Amsterdam UMC, Vrije Universiteit Medical Centre, Amsterdam, Netherlands.
Lancet Gastroenterol Hepatol. 2019 Dec;4(12):960-970. doi: 10.1016/S2468-1253(19)30265-1. Epub 2019 Sep 4.
Refractory coeliac disease type 2 is a rare subtype of coeliac disease with high mortality rates; interleukin 15 (IL-15) is strongly implicated in its pathophysiology. This trial aimed to investigate the effects of AMG 714, an anti-IL-15 monoclonal antibody, on the activity and symptoms of refractory coeliac disease type 2.
This was a randomised, double-blind, placebo-controlled, phase 2a study of adults with a confirmed diagnosis of refractory coeliac disease type 2. Patients were randomly assigned at a 2:1 ratio to receive seven intravenous doses over 10 weeks of AMG 714 (8 mg/kg) or matching placebo. Biopsy samples were obtained at baseline and week 12 for cellular analysis and histology. The change in the proportion of aberrant intraepithelial lymphocytes from baseline to week 12 with respect to all intraepithelial lymphocytes was the primary endpoint and was quantified using flow cytometry. Secondary endpoints were the change in aberrant intraepithelial lymphocytes with respect to intestinal epithelial cells; intestinal histological scores (villous height-to-crypt depth ratio; VHCD); intraepithelial lymphocyte counts; Marsh score; and patient-reported symptom measures, including the Bristol stool form scale (BSFS) and gastrointestinal symptom rating scale (GSRS). Main analyses were done in the per-protocol population of patients who received their assigned treatment, provided evaluable biopsy samples, and did not have major protocol deviations; only patients with non-atypical disease were included in the analyses of aberrant intraepithelial lymphocytes, including the primary analysis. Safety was assessed in all patients who received at least one dose of study drug. This study is registered at ClinicalTrials.gov (NCT02633020) and EudraCT (2015-004063-36).
From April 13, 2016, to Jan 19, 2017, 28 patients were enrolled and randomly assigned to AMG 714 (n=19) and placebo (n=9). Six patients were not included in the primary analysis because of protocol deviation (one in the AMG 714 group), insufficient biopsy samples (one in the AMG 714 group), and atypical intraepithelial lymphocytes (three in the AMG 714 group and one in the placebo group). At 12 weeks, the least square mean difference between AMG 714 and placebo in the relative change from baseline in aberrant intraepithelial lymphocyte percentage was -4·85% (90% CI -30·26 to 20·56; p=0·75). The difference between the AMG 714 and placebo groups in aberrant intraepithelial lymphocytes with respect to epithelial cells at 12 weeks was -38·22% (90% CI -95·73 to 19·29; nominal p=0·18); the difference in change in Marsh score from baseline was 0·09% (95% CI -1·60-1·90; nominal p=0·92); the difference in VHCD ratio was 10·67% (95% CI -38·97 to 60·31; nominal p=0·66); and the difference in change in total intraepithelial lymphocyte count was -12·73% (95% CI -77·57-52·12); nominal p=0·69). Regarding symptoms, the proportion of patients with diarrhoea per the BSFS score decreased from ten (53%) of 19 at baseline to seven (37%) of 19 at week 12 in the AMG 714 group and increased from two (22%) of nine at baseline to four (44%) of nine at week 12 in the placebo group (nominal p=0·0008); and the difference between the groups in change in GSRS score was -0·14 (SE 0·19; nominal p=0·48). Eight (89%) patients in the placebo group and 17 (89%) in the AMG 714 group had treatment-emergent adverse events, including one (11%) patient in the placebo group and five (26%) in the AMG 714 group who had serious adverse events. The most common adverse event in the AMG 714 group was nasopharyngitis (eight [42%] patients vs one [11%] in the placebo group).
In patients with refractory coeliac disease type 2 who were treated with AMG 714 or placebo for 10 weeks, there was no difference between the groups in terms of the primary endpoint of aberrant intraepithelial lymphocyte reduction from baseline. Effects on symptoms and other endpoints suggest that further research of AMG 714 may be warranted in patients with refractory coeliac disease type 2.
Celimmune and Amgen.
难治性乳糜泻 2 型是一种罕见的乳糜泻亚型，死亡率较高；白细胞介素 15（IL-15）强烈参与其病理生理学过程。本试验旨在研究 AMG 714（一种抗 IL-15 单克隆抗体）对难治性乳糜泻 2 型的活动和症状的影响。
这是一项随机、双盲、安慰剂对照、2a 期临床试验，纳入了已确诊的难治性乳糜泻 2 型成人患者。患者按 2:1 的比例随机分配，接受 7 次静脉注射，为期 10 周，分别给予 AMG 714（8mg/kg）或匹配的安慰剂。在基线和第 12 周时获取活检样本，用于细胞分析和组织学检查。主要终点是从基线到第 12 周时，异常上皮内淋巴细胞相对于所有上皮内淋巴细胞的比例变化，使用流式细胞术进行定量分析。次要终点是异常上皮内淋巴细胞相对于肠上皮细胞的变化；绒毛高度-隐窝深度比（VHCD）；上皮内淋巴细胞计数；Marsh 评分；以及患者报告的症状测量，包括布里斯托尔粪便形态量表（BSFS）和胃肠道症状评分量表（GSRS）。主要分析是在接受治疗、提供可评估的活检样本且无主要方案偏差的患者中进行的，仅包括非典型疾病的患者进行异常上皮内淋巴细胞分析，包括主要分析。所有至少接受一剂研究药物的患者均进行安全性评估。该研究在 ClinicalTrials.gov（NCT02633020）和 EudraCT（2015-004063-36）注册。
2016 年 4 月 13 日至 2017 年 1 月 19 日期间，共纳入 28 例患者并随机分配至 AMG 714 组（n=19）和安慰剂组（n=9）。由于方案偏差（1 例在 AMG 714 组）、活检样本不足（1 例在 AMG 714 组）和非典型上皮内淋巴细胞（3 例在 AMG 714 组和 1 例在安慰剂组），有 6 例患者未纳入主要分析。在第 12 周时，AMG 714 组和安慰剂组从基线开始的异常上皮内淋巴细胞百分比的相对变化的最小二乘均数差值为-4.85%（90%CI-30.26 至 20.56；p=0.75）。第 12 周时，AMG 714 组和安慰剂组异常上皮内淋巴细胞与上皮细胞的差异为-38.22%（90%CI-95.73 至 19.29；名义 p=0.18）；从基线开始的 Marsh 评分变化差异为 0.09%（95%CI-1.60 至 1.90；名义 p=0.92）；VHCD 比值的差异为 10.67%（95%CI-38.97 至 60.31；名义 p=0.66）；总上皮内淋巴细胞计数变化的差异为-12.73%（95%CI-77.57 至 52.12；名义 p=0.69）。关于症状，BSFS 评分的腹泻患者比例从基线时的 19 例中有 10 例（53%）下降到第 12 周时的 19 例中有 7 例（37%），而安慰剂组从基线时的 9 例中有 2 例（22%）上升到第 12 周时的 9 例中有 4 例（44%）（名义 p=0.0008）；GSRS 评分变化的组间差异为-0.14（SE 0.19；名义 p=0.48）。安慰剂组有 8 例（89%）和 AMG 714 组有 17 例（89%）患者发生治疗相关不良事件，其中安慰剂组有 1 例（11%）和 AMG 714 组有 5 例（26%）发生严重不良事件。AMG 714 组最常见的不良事件是鼻咽炎（8 例[42%]与安慰剂组的 1 例[11%]）。
在接受 AMG 714 或安慰剂治疗 10 周的难治性乳糜泻 2 型患者中，两组在异常上皮内淋巴细胞从基线减少的主要终点方面没有差异。症状和其他终点的影响表明，在难治性乳糜泻 2 型患者中进一步研究 AMG 714 可能是合理的。
Celimmune 和 Amgen。
