Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial
Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double-blind controlled trial
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DOI：
10.1016/s0140-6736(16)31203-x
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发表时间：
2016-09-24
期刊：
影响因子：
168.9
通讯作者：
Danese, Silvio
中科院分区：
文献类型：
--
作者：
Panes, Julian;Garcia-Olmo, Damian;Danese, Silvio
背景：克罗恩病并发复杂肛周瘘管的治疗具有挑战性。异体、扩增的脂肪来源干细胞（Cx601）是一种很有前途的新治疗方法。我们的目的是评估Cx601治疗克罗恩病患者难治性复杂肛周瘘的安全性和有效性。方法：2012年7月6日至2015年7月27日，我们在7个欧洲国家和以色列的49家医院进行了这项随机、双盲、平行组、安慰剂对照研究。患有克罗恩病和难治性引流复杂肛周瘘的成年患者（>= 18岁）使用预先建立的随机列表随机分配（1:1），单次病灶内注射1.2亿个Cx601细胞或24 mL生理盐水溶液（安慰剂），并根据伴随的基线治疗进行分层。治疗由一名不戴面具的外科医生进行，由一名戴面具的胃肠病学家和放射科医生评估治疗效果。主要终点是第24周的联合缓解（即，临床评估所有治疗后的外部开口在基线时的闭合情况，以及经掩盖的中央MRI证实治疗后的肛周瘘管没有收集物（约2厘米））。在意向治疗人群（ITT）和修改后的ITT人群中评估疗效；在安全人群中进行安全性评估。本研究已在ClinicalTrials.gov注册，注册号为NCT01541579。212例患者被随机分配：107例接受Cx601治疗，105例接受安慰剂治疗。与安慰剂相比，接受Cx601治疗的患者在ITT（107人中的53人[50%]对105人中的36人[34%]；差异15.2%,97.5% CI 0.2-30.3; p=0.024）和改良ITT人群（103人中的53人[51%]对101人中的36人[36%]；15.8%,0.5-31.2;p=0.021）中获得联合缓解。Cx601组103例患者中有18例（17%）出现治疗相关不良事件，安慰剂组103例中有30例（29%）出现治疗相关不良事件，其中最常见的是肛门脓肿（Cx601组6例，安慰剂组9例）和直肠痛（5例，安慰剂组9例）。Cx601是一种有效且安全的治疗方法，用于对传统或生物治疗或两者均无反应的克罗恩病患者的复杂肛周瘘。
Background Complex perianal fistulas in Crohn's disease are challenging to treat. Allogeneic, expanded, adipose-derived stem cells (Cx601) are a promising new therapeutic approach. We aimed to assess the safety and efficacy of Cx601 for treatment-refractory complex perianal fistulas in patients with Crohn's disease.Methods We did this randomised, double-blind, parallel-group, placebo-controlled study at 49 hospitals in seven European countries and Israel from July 6, 2012, to July 27, 2015. Adult patients (>= 18 years) with Crohn's disease and treatment-refractory, draining complex perianal fistulas were randomly assigned (1: 1) using a pre-established randomisation list to a single intralesional injection of 120 million Cx601 cells or 24 mL saline solution (placebo), with stratification according to concomitant baseline treatment. Treatment was administered by an unmasked surgeon, with a masked gastroenterologist and radiologist assessing the therapeutic effect. The primary endpoint was combined remission at week 24 (ie, clinical assessment of closure of all treated external openings that were draining at baseline, and absence of collections >2 cm of the treated perianal fistulas confirmed by masked central MRI). Efficacy was assessed in the intention-to-treat (ITT) and modified ITT populations; safety was assessed in the safety population. This study is registered with ClinicalTrials.gov, number NCT01541579.Findings 212 patients were randomly assigned: 107 to Cx601 and 105 to placebo. A significantly greater proportion of patients treated with Cx601 versus placebo achieved combined remission in the ITT (53 of 107 [50%] vs 36 of 105 [34%]; difference 15.2%, 97.5% CI 0.2-30.3; p=0.024) and modified ITT populations (53 of 103 [51%] vs 36 of 101 [36%]; 15.8%, 0.5-31.2; p=0.021). 18 (17%) of 103 patients in the Cx601 group versus 30 (29%) of 103 in the placebo group experienced treatment-related adverse events, the most common of which were anal abscess (six in the Cx601 group vs nine in the placebo group) and proctalgia (five vs nine).Interpretation Cx601 is an effective and safe treatment for complex perianal fistulas in patients with Crohn's disease who did not respond to conventional or biological treatments, or both.