BACKGROUND 背景

        Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis and a leading cause of systemic sclerosis–related death. Nintedanib, a tyrosine kinase inhibitor, has been shown to have antifibrotic and antiinflammatory effects in preclinical models of systemic sclerosis and ILD.

        間質性肺疾病(ILD)是係統性硬化症(SS)的常見表現，是導致SS死亡的主要原因。Nintedanib是一種酪氨酸激酶抑製劑(TKI)，在SS和ILD的臨床前研究中已被證明具有抗纖維化和抗炎作用。

        METHODS 方法

        We conducted a randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of nintedanib in patients with ILD associated with systemic sclerosis. Patients who had systemic sclerosis with an onset of the first non-Raynaud’s symptom within the past 7 years and a high-resolution computed tomographic scan that showed fibrosis affecting at least 10% of the lungs were randomly assigned, in a 1:1 ratio, to receive 150 mg of nintedanib, administered orally twice daily, or placebo.

        我們進行了一項隨機、雙盲、安慰劑對照試驗，來研究nintedanib在SS相關的ILD患者中的療效和安全性。我們將過去7年內首次出現雷諾綜合征以外症狀且HR-CT顯示至少有10%肺野纖維化的患者納入研究，並按照1:1的比例隨機分配口服nintedanib每天兩次，每次150mg或接受安慰劑。

        The primary end point was the annual rate of decline in forced vital capacity (FVC), assessed over a 52-week period. Key secondary end points were absolute changes from baseline in the modified Rodnan skin score and in the total score on the St. George’s Respiratory Questionnaire (SGRQ) at week 52.

        主要終點是52周時間內，評估用力肺活量(FVC)年下降率。次要終點主要是第52周改良的Rodnan皮膚評分和St. George’s呼吸問卷 (SGRQ)的總分與基線相比的絕對變化。

        RESULTS 結果

        A total of 576 patients received at least one dose of nintedanib or placebo; 51.9% had diffuse cutaneous systemic sclerosis, and 48.4% were receiving mycophenolate at baseline. In the primary end-point analysis, the adjusted annual rate of change in FVC was−52.4 ml per year in the nintedanib group and −93.3 ml per year in the placebo group difference, 41.0 ml per year; 95% confidence interval [CI], 2.9 to 79.0; P = 0.04). Sensitivity analyses based on multiple imputation for missing data yielded P values for the primary end point ranging from 0.06 to 0.10.

        本研究共入組576例患者，每例患者至少接受一劑nintedanib或安慰劑治療;51.9%患者有彌漫性皮膚表現，48.4%接受基線嗎替麥考酚酯(MMF)治療。對主要終點進行統計分析發現：nintedanib組和安慰劑組調整後FVC年下降總量分別是-52.4ml、-93.3ml(相差 41.0ml;95%置信區間[CI]，2.9—79.0;P=0.04)。使用多重插補分析缺失病例的影響，發現病例缺失對於主要終點指標FVC的變化並無影響，P值在0.06到0.10之間。

        The change from baseline in the modified Rodnan skin score and the total score on the SGRQ at week 52 did not differ significantly between the trial groups, with differences of −0.21 (95% CI, −0.94 to 0.53; P = 0.58) and 1.69 (95% CI, −0.73 to 4.12 [not adjusted for multiple comparisons]), respectively. Diarrhea, the most common adverse event, was reported in 75.7% of the patients in the nintedanib group and in 31.6% of those in the placebo group.

        在第52周，改良後的Rodnan皮膚評分與SGRQ總得分與基線相比變化無顯著性差異，分別為- 0.21 (95% CI， - 0.94 - 0.53;P = 0.58)和1.69 (95% CI， - 0.73至4.12[未行多重比較來調整])。腹瀉是最常見的不良事件，nintedanib組75.7%的患者出現腹瀉，安慰劑組31.6%的患者出現腹瀉。

        CONCLUSIONS 結論

        Among patients with ILD associated with systemic sclerosis, the annual rate of decline in FVC was lower with nintedanib than with placebo; no clinical benefit of nintedanib was observed for other manifestations of systemic sclerosis. The adverse-event profile of nintedanib observed in this trial was similar to that observed in patients with idiopathic pulmonary fibrosis; gastrointestinal adverse events, including diarrhea, were more common with nintedanib than with placebo.

        SS相關ILD患者中，nintedanib組的FVC年下降率低於安慰劑組;nintedanib對其他SS的臨床表現沒有任何益處。本試驗中nintedanib的不良事件分布與特發性肺纖維化患者相似;包括腹瀉在內的胃腸道不良事件在nintedanib組比安慰劑組更常見。

        原始出處：

        Oliver Distler, et al.Nintedanib for Systemic Sclerosis–Associated Interstitial Lung Disease.NEJM. May 2019.