Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial
Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial
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DOI：
10.1016/s0140-6736(14)62113-9
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发表时间：
2015-08-08
期刊：
影响因子：
168.9
通讯作者：
Wolk, Robert
中科院分区：
文献类型：
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作者：
Bachelez, Herve;van de Kerkhof, Peter C. M.;Wolk, Robert
背景：银屑病患者需要新的治疗方案。托法替尼是一种口服Janus激酶抑制剂，正在被研究用于治疗中到重度的慢性斑块型牛皮癣。在这项研究中，我们旨在比较两种托法替尼剂量与大剂量依那西普或安慰剂在该患者群体中的作用。方法在这个第三阶段，随机、多中心、双模拟、安慰剂对照、为期12周的非劣势试验，成年慢性稳定性斑块型银屑病患者(FOR>；从世界各地的122个皮肤病研究中心登记，他们接受系统治疗或光治疗，牛皮癣面积和严重程度指数(PASI)为12分或以上，医生的全球评估(PGA)为中或重度，对至少一种常规系统治疗没有反应，对至少一种传统系统治疗禁忌症，或对至少一种传统系统治疗不耐受。符合条件的患者按3：3：3：1的比例随机分配，接受托法替尼5 mg或10 mg每日两次，间隔约12小时，依那西普50 mg，每周两次，间隔约3-4天，或安慰剂。随机化是通过计算机生成的随机化时间表进行的，所有患者和研究人员都被掩蔽进行治疗分配。共同的主要终点是12周时PASI评分较基线下降至少75%的患者的比例(PASI75反应)，以及在完整分析集中分析的PGA评分达到“清楚”或“几乎清楚”的患者的比例(所有随机接受至少一剂研究药物的患者)。这项研究在ClinicalTrials.gov上注册，编号NCT01241591。在2010年11月29日至2012年9月13日期间，我们招募了1106名符合条件的成年慢性斑块型银屑病患者，并将他们随机分配到四个治疗组(330人每天两次托法替尼5 mg，332人每天两次托法替尼10 mg，336人每周两次服用依那西普50 mg，108人接受安慰剂治疗)。在这些患者中，1101人实际接受了他们分配的研究药物(托法替尼5毫克组329人，托法替尼10毫克组330人，依那西普组335人，安慰剂组107人)。12周时，托法替尼5毫克组329名患者中130名(39.5%)、托法替尼10毫克组330名患者中210名(63.6%)、依那西普组335名患者中197名(58.8%)和安慰剂组107名患者中6名(5.6%)有PASI75反应。329例患者中，托法替尼5 mg组155例(47.1%)，托法替尼10 mg组330例中225例(68.2%)，依那西普组335例中222例(66.3%)，安慰剂组107例中16例(15.0%)。四组患者的不良事件发生率相似，在329名患者中，托法替尼5毫克组有7名患者(2%)，托法替尼10毫克组330名患者中有5名(2%)，依那西普组335名患者中有7名(2%)，安慰剂组107名患者中有2名(2%)。托法替尼5毫克组329名患者中有3名患者(1%)，托法替尼10毫克组330名患者中有10名(3%)，依那西普组335名患者中有11名(3%)，安慰剂组107名患者中有4名(4%)因不良事件而终止分配的治疗。在中到重度斑块型银屑病患者中，每天两次服用托法替尼10毫克的疗效不逊于每周两次依那西普50毫克，优于安慰剂，但每天两次服用5毫克并不比每周两次依那西普50毫克更好。托法替尼和依那西普12周以上的不良事件发生率相似。这项研究表明，在未来，托法替尼可以为中到重度斑块型银屑病患者提供一种方便且耐受性良好的治疗选择。
Background New therapeutic options are needed for patients with psoriasis. Tofacitinib, an oral Janus kinase inhibitor, is being investigated as a treatment for moderate-to-severe chronic plaque psoriasis. In this study, we aimed to compare two tofacitinib doses with high-dose etanercept or placebo in this patient population.Methods In this phase 3, randomised, multicentre, double-dummy, placebo-controlled, 12-week, non-inferiority trial, adult patients with chronic stable plaque psoriasis (for >= 12 months) who were candidates for systemic or phototherapy and had a Psoriasis Area and Severity Index (PASI) score of 12 or higher and a Physician's Global Assessment (PGA) of moderate or severe, and had failed to respond to, had a contraindication to, or were intolerant to at least one conventional systemic therapy, were enrolled from 122 investigational dermatology centres worldwide. Eligible patients were randomly assigned in a 3: 3: 3: 1 ratio to receive tofacitinib 5 mg or 10 mg twice daily at about 12 h intervals, etanercept 50 mg subcutaneously twice weekly at about 3-4 day intervals, or placebo. Randomisation was done by a computer-generated randomisation schedule, and all patients and study personnel were masked to treatment assignment. The co-primary endpoints were the proportion of patients at week 12 with at least a 75% reduction in the PASI score from baseline (PASI75 response) and the proportion of patients achieving a PGA score of "clear" or "almost clear" (PGA response), analysed in the full analysis set (all patients who were randomised and received at least one dose of study drug). This study is registered with ClinicalTrials.gov, number NCT01241591.Findings Between Nov 29, 2010, and Sept 13, 2012, we enrolled 1106 eligible adult patients with chronic plaque psoriasis and randomly assigned them to the four treatment groups (330 to tofacitinib 5 mg twice daily, 332 to tofacitinib 10 mg twice daily, 336 to etanercept 50 mg twice weekly, and 108 to placebo). Of these patients, 1101 actually received their assigned study medication (329 in the tofactinib 5 mg group, 330 in the tofacitinib 10 mg group, 335 in the etanercept group, and 107 in the placebo group). At week 12, PASI75 responses were recorded in 130 (39.5%) of 329 patients in the tofacitinib 5 mg group, 210 (63.6%) of 330 in the tofacitinib 10 mg group, 197 (58.8%) of 335 in the etanercept group, and six (5.6%) of 107 in the placebo group. A PGA response was achieved by 155 (47.1%) of 329 patients in the tofacitinib 5 mg group, 225 (68.2%) of 330 in the tofacitinib 10 mg group, 222 (66.3%) of 335 in the etanercept group, and 16 (15.0%) of 107 in the placebo group. The rate of adverse events was similar across the four groups, with serious adverse events occurring in seven (2%) of 329 patients in the tofacitinib 5 mg group, five (2%) of 330 in the tofacitinib 10 mg group, seven (2%) of 335 in the etanercept group, and two (2%) of 107 in the placebo group. Three (1%) of 329 patients in the tofacitinib 5 mg group, ten (3%) of 330 in the tofacitinib 10 mg group, 11 (3%) of 335 in the etanercept group, and four (4%) of 107 patients in the placebo group discontinued their assigned treatment because of adverse events.Interpretation In patients with moderate-to-severe plaque psoriasis, the 10 mg twice daily dose of tofacitinib was non-inferior to etanercept 50 mg twice weekly and was superior to placebo, but the 5 mg twice daily dose did not show non-inferiority to etanercept 50 mg twice weekly. The adverse event rates over 12 weeks were similar for tofacitinib and etanercept. This study indicates that in the future tofacitinib could provide a convenient and well-tolerated therapeutic option for patients with moderate-to-severe plaque psoriasis.