Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial.
Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial.
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DOI：
10.1016/s2213-2600(16)30152-7
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发表时间：
2016-09
影响因子：
76.2
通讯作者：
Elashoff, Robert M.
中科院分区：
文献类型：
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作者：
Tashkin, Donald P.;Roth, Michael D.;Clements, Philip J.;Furst, Daniel E.;Khanna, Dinesh;Kleerup, Eric C.;Goldin, Jonathan;Arriola, Edgar;Volkmann, Elizabeth R.;Kafaja, Suzanne;Silver, Richard;Steen, Virginia;Strange, Charlie;Wise, Robert;Wigley, Fredrick;Mayes, Maureen;Riley, David J.;Hussain, Sabiha;Assassi, Shervin;Hsu, Vivien M.;Patel, Bela;Phillips, Kristine;Martinez, Fernando;Golden, Jeffrey;Connolly, M. Kari;Varga, John;Dematte, Jane;Hinchcliff, Monique E.;Fischer, Aryeh;Swigris, Jeffrey;Meehan, Richard;Theodore, Arthur;Simms, Robert;Volkov, Suncica;Schraufnagel, Dean E.;Scholand, Mary Beth;Frech, Tracy;Molitor, Jerry A.;Highland, Kristin;Read, Charles A.;Fritzler, Marvin J.;Kim, Grace Hyun J.;Tseng, Chi-Hong;Elashoff, Robert M.
与安慰剂相比，口服环磷酰胺（CYC）12个月可改变硬皮病相关间质性肺病（SSc-ILD）的进展。然而，毒性是一个问题，如果不继续治疗，疗效在24个月内消失。我们假设，两年疗程的霉酚酸酯（MMF）比CYC更安全，耐受性更好，改善持续时间更长。在14家医学中心进行的一项双盲、两组试验中，将符合规定的呼吸困难、肺功能和高分辨率计算机断层扫描（HRCT）标准的SSc-ILD患者随机分组。MMF（目标剂量1500 mg，每日两次），一组给药24个月，（目标剂量2.0 mg/kg/d）给药12个月，然后另一组给予安慰剂12个月。主要终点是24个月期间用力肺活量变化占预测正常值的百分比（FVC %），在改良的意向治疗分析中进行评估，使用推理联合模型，结合纵向结局的混合效应模型和处理不可验证缺失数据的生存模型。本研究在ClinicalTrials.gov注册，编号为NCT 00883129，现已关闭。2009年11月至2013年1月期间，142例患者接受了随机化。126例基线HRCT研究可接受且至少有一项结局指标的患者（63例MMF; 63例CYC）纳入分析。从基线至24个月，MMF组校正的FVC %（主要终点）改善了2.17（95% CI，0.53-3.84），CYC组改善了2.86（95%置信区间1.19 - 4.58），治疗间无显著差异（p= 0.24），表明试验的主要终点为阴性。然而，在主要终点的事后分析中，CYC和MMF组均观察到从基线至24个月的治疗内改善。CYC组中提前停用研究药物（32 vs 20）和治疗失败（2 vs 0）的患者数量多于MMF组，CYC组中至停止治疗的时间显著缩短（p=0·019）。发生了16例死亡（11例CYC; 5例MMF），大多数是由于进行性ILD。接受CYC治疗的患者更常发生白细胞减少症（30 vs 4例患者）和血小板减少症（4 vs 0例患者）。在事后分析中，在定义的次要结局（包括皮肤评分、呼吸困难和全肺HRCT评分）中也观察到治疗内（而非治疗间）改善。在为期2年的研究过程中，使用MMF治疗SSc-ILD 2年或使用CYC治疗SSc-ILD 1年均导致肺功能、呼吸困难、肺部成像和皮肤病的预定指标显著改善。虽然MMF的耐受性更好，毒性更低，但其在24个月时的疗效高于CYC的假设尚未得到证实。这些结果支持CYC和MMF对进行性SSc-ILD的潜在临床影响，以及由于其更好的耐受性和毒性特征，目前首选MMF。国家心脏、肺和血液研究所/国立卫生研究院，药物供应由Hoffmann-La Roche/Genentech提供。
Twelve months of oral cyclophosphamide (CYC) has been shown to alter the progression of scleroderma-related interstitial lung disease (SSc-ILD) when compared to placebo. However, toxicity was a concern and without continued treatment the efficacy disappeared by 24 months. We hypothesized that a two-year course of mycophenolate mofetil (MMF) would be safer, better tolerated and produce longer lasting improvements than CYC. Patients with SSc-ILD meeting defined dyspnea, pulmonary function and high-resolution computed tomography (HRCT) criteria were randomized in a double-blind, two-arm trial at 14 medical centers. MMF (target dose 1500 mg twice daily) was administered for 24 months in one arm and oral CYC (target dose 2·0 mg/kg/day) administered for 12 months followed by placebo for 12 months in the other arm. The primary endpoint, change in forced vital capacity as a percent of the predicted normal value (FVC %) over the course of 24 months, was assessed in a modified intention-to-treat analysis using an inferential joint model combining a mixed effects model for longitudinal outcomes and a survival model to handle non-ignorable missing data. The study was registered with ClinicalTrials.gov, number NCT00883129, and is closed. Between November, 2009, and January, 2013, 142 patients were randomized. 126 patients (63 MMF; 63 CYC) with acceptable baseline HRCT studies and at least one outcome measure were included in the analysis. The adjusted FVC % (primary endpoint) improved from baseline to 24 months by 2.17 in the MMF arm (95% CI, 0.53–3.84) and 2·86 in the CYC arm (95% confidence interval 1·19–4·58) with no significant between-treatment difference (p=0·24), indicating that the trial was negative for the primary endpoint. However, in a post-hoc analysis of the primary endpoint, within-treatment improvements from baseline to 24 months were noted in both the CYC and MMF arms. A greater number of patients on CYC than on MMF prematurely withdrew from study drug (32 vs 20) and failed treatment (2 vs 0), and the time to stopping treatment was significantly shorter in the CYC arm (p=0·019). Sixteen deaths occurred (11 CYC; 5 MMF) with most due to progressive ILD. Leukopenia (30 vs 4 patients) and thrombocytopenia (4 vs 0 patients) occurred more often in patients treated with CYC. In post-hoc analyses, within- (but not between-) treatment improvements were also noted in defined secondary outcomes including skin score, dyspnea and whole-lung HRCT scores. Treatment of SSc-ILD with MMF for two years or CYC for one year both resulted in significant improvements in pre-specified measures of lung function, dyspnea, lung imaging, and skin disease over the 2-year course of the study. While MMF was better tolerated and associated with less toxicity, the hypothesis that it would have greater efficacy at 24 months than CYC was not confirmed. These findings support the potential clinical impact of both CYC and MMF for progressive SSc-ILD, as well as the current preference for MMF due to its better tolerability and toxicity profile. National Heart, Lung and Blood Institute/National Institutes of Health with drug supply provided by Hoffmann-La Roche/Genentech.