Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial.
Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial.
复制标题
DOI：
10.1001/jama.2013.283815
复制
发表时间：
2013-12-25
影响因子：
120.7
通讯作者：
Dyck, Peter J.
中科院分区：
文献类型：
--
作者：
Berk, John L.;Suhr, Ole B.;Obici, Laura;Sekijima, Yoshiki;Zeldenrust, Steven R.;Yamashita, Taro;Heneghan, Michael A.;Gorevic, Peter D.;Litchy, William J.;Wiesman, Janice F.;Nordh, Erik;Corato, Manuel;Lozza, Alessandro;Cortese, Andrea;Robinson-Papp, Jessica;Colton, Theodore;Rybin, Denis V.;Bisbee, Alice B.;Ando, Yukio;Ikeda, Shu-ichi;Seldin, David C.;Merlini, Giampaolo;Skinner, Martha;Kelly, Jeffery W.;Dyck, Peter J.
家族性淀粉样多发性神经病（ATTR-FAP）是一种由甲状腺素运载蛋白变异体聚集引起的致死性遗传性疾病，可导致进行性周围神经缺损和残疾。二氟尼柳，一种非甾体抗炎药，在体外稳定甲状腺素运载蛋白四聚体并防止淀粉样纤维形成。确定二氟尼柳对ATTR-FAP患者多发性神经病进展的影响。我们从2006年至2012年在瑞典（Umea）、意大利（Pavia）、日本（松本和熊本）、英国（伦敦）和美国（波士顿、纽约、罗切斯特、明尼苏达州）的淀粉样蛋白中心进行了一项由制药商发起的国际、随机、双盲、安慰剂对照研究。130例临床可检测到周围或自主神经病变的ATTRFAP患者随机分配至二氟尼柳250 mg或安慰剂组，每日两次，持续2年。主要终点是治疗之间多发性神经病进展的差异，通过神经病损伤评分加7项神经测试（NIS+7）测量，范围为0分（无神经功能缺损）至270分（未检测到周围神经功能）。次要结局包括生活质量问卷（SF-36）和改良体重指数（mBMI）。130例随机化患者（66例安慰剂组，64例二氟尼柳）在2年内接受了连续NIS+7评价。由于损耗，我们采用了基于可能性的建模和基线至2年数据的多重插补（MI）分析。根据MI，安慰剂组NIS+7增加25.0分（95% CI，18.4至31.6），二氟尼柳组增加8.7分（95% CI，3.3至14.1），差异为16.3分（95% CI，8.1至24.5，p=0.001）。安慰剂组平均SF-36身体评分下降4.9分（95% CI，-7.6至2.2），二氟尼柳组上升1.5分（95% CI，-0.8至3.7）（p=0.003）。安慰剂组SF-36精神评分下降1.1（95% CI，-4.3至2.0），而二氟尼柳组增加3.7（95% CI，1.0至6.4）（p=0.022）。通过应答者分析，29.7%的二氟尼柳和9.4%的安慰剂在2年时表现出神经系统稳定性（< 2分NIS+7增加）（p=0.007）。在ATTR-FAP患者中，与安慰剂相比，使用二氟尼柳2年可降低神经功能缺损的进展率并保持生活质量。虽然需要更长期的随访研究，但这些发现表明这种治疗对ATTR-FAP有益。
Familial amyloid polyneuropathy (ATTR-FAP), a lethal genetic disease caused by aggregation of variant transthyretin, induces progressive peripheral nerve deficits and disability. Diflunisal, a non-steroidal anti-inflammatory agent, stabilizes transthyretin tetramers and prevents amyloid fibril formation in vitro. To determine the effect of diflunisal on polyneuropathy progression in patients with ATTR-FAP. We conducted an investigator-initiated international, randomized, double-blind, placebo-controlled study at amyloid centers in Sweden (Umea), Italy (Pavia), Japan (Matsumoto and Kumamoto), England (London), and the United States (Boston, New York, Rochester, MN) from 2006 through 2012. 130 ATTRFAP patients with clinically detectable peripheral or autonomic neuropathy were randomly assigned to diflunisal 250 mg or placebo twice daily for 2 years. The primary endpoint, the difference in polyneuropathy progression between treatments, was measured by the Neuropathy Impairment Score plus 7 nerve tests (NIS+7) which ranges from 0 (no neurologic deficits) to 270 points (no detectable peripheral nerve function). Secondary outcomes included a quality of life questionnaire (Short Form-36 (SF-36)) and modified body mass index (mBMI). One hundred thirty randomized patients (66 placebo, 64 diflunisal) underwent serial NIS+7 evaluations over 2 years. Due to attrition, we employed likelihood based modeling and multiple imputation (MI) analysis of baseline to 2 year data. By MI, NIS+7 increased 25.0 points (95% CI, 18.4 to 31.6) among placebo and 8.7 points (95% CI, 3.3 to 14.1) in the diflunisal group, a difference of 16.3 points (95% CI, 8.1 to 24.5, p=0.001). Mean SF-36 physical scores fell 4.9 points (95% CI, −7.6 to −2.2) among placebo and rose 1.5 points (95% CI, −0.8 to 3.7) in the diflunisal group (p=0.003). SF-36 mental scores declined 1.1 (95% CI, −4.3 to 2.0) among placebo while increasing 3.7 (95% CI, 1.0 to 6.4) in the diflunisal group (p=0.022). By responder analysis, 29.7% of diflunisal and 9.4% of placebo exhibited neurologic stability at 2 years (< 2 points NIS+7 increase) (p=0.007). Among patients with ATTR-FAP, the use of diflunisal compared with placebo for 2 years reduced the rate of progression in neurologic impairment and preserved quality of life. Although longer term follow up studies are needed, these findings suggest benefit of this treatment for ATTR-FAP.
登录
查看更多内容
影响因子：
9.9
作者：
DYCK, PJ;LITCHY, WJ;OBRIEN, PC
通讯作者：
OBRIEN, PC
影响因子：
11.2
作者：
DYCK, PJ;LITCHY, WJ;OBRIEN, PC
通讯作者：
OBRIEN, PC
影响因子：
2.9
作者：
COLON, W;KELLY, JW
通讯作者：
KELLY, JW
影响因子：
158.5
作者：
DYCK, PJ;DAUBE, J;SWANSON, C
通讯作者：
SWANSON, C
影响因子：
--
作者：
Dyck, Peter J.;Overland, Carol J.;Vella, Adrian
通讯作者：
Vella, Adrian