MOCSLID-CCC

描述(由申请人提供)： 硬皮病(SSC)是一种破坏性的全身性疾病，肺部受累主要是由SSC相关性间质性肺疾病(SSC-ILD)引起的，已成为导致总死亡的主要原因。开发有效的治疗方法将直接影响SSc-ILD的生活质量和寿命。最初的硬皮病肺研究(SLS I)是第一个随机对照试验，证明SSC-ILD对口服环磷酰胺(CyC)一年的治疗有效，改善了肺功能、呼吸困难、皮肤病和与健康相关的生活质量(HRQOL)。然而，在完成一年的治疗后，环磷酰胺的有益效果在第二年结束时减弱。此外，环磷酰胺与显著的急性毒性有关，长期治疗受到继发性恶性肿瘤风险的限制。霉酚酸酯(MMF)是一种被批准用于器官移植的免疫抑制药物，在几项非对照的初步研究中，已经对SSc-ILD患者进行了长达2年的治疗。据报道，MMF是有效和安全的。我们假设，给予MMF两年的能力将导致SSC-ILD的更好和更持续的改善，而不是用一年的环磷酰胺，而且毒性更小。为了验证这一假设，我们提出了一项为期5年的多中心(12个临床中心加上一个数据协调中心)、平行分组、双盲、随机对照临床试验，对150名活动期SSC-ILD患者进行比较，比较口服MMF(耐受性最高1.5g，bid)2年和口服CyC(2 mg/kg/d，1年，然后安慰剂MMF 2年，维持失明)治疗1年。提出了三个具体目标：1)确定在24个月周期的第2年内，以用力肺活量为主要结果和总体毒性而言，MMF是否比CyC更有效；2)比较MMF和CyC在总肺活量、单次一氧化碳弥散量、呼吸困难(Mahler Transform Dyspnea Index)、多项HRQOL(SGRQ、SF-36)、功能能力(硬皮病健康评估问卷)和皮肤厚度(改良Rodnam皮肤评分)方面的疗效；3)通过收集和创新分析一段时间以来从研究参与者那里连续收集的血液样本和皮肤活检，对总体治疗效果的综合结果指标进行前瞻性验证，以及对MMF或CyC治疗的临床效用(患者确定的价值指标)进行评估，来促进我们对SSC-ILD生物学和治疗反应的理解。(摘要结束)

DESCRIPTION (provided by applicant): Scleroderma (SSc) is a devastating systemic disease in which lung involvement, largely from SSc-related interstitial lung disease (SSc-ILD), has emerged as the leading cause of overall mortality. Developing effective treatments for SSc-ILD will directly impact on both the quality and longevity of life. The original Scleroderma Lung Study (SLS I) was the first randomized controlled trial to demonstrate that SSc-ILD responds to a one year treatment with oral cyclophosphamide (CYC) with improvements in pulmonary function, dyspnea, skin disease, and health-related quality of life (HRQoL). However, the beneficial effects of CYC wane by the end of the 2nd yr, after completing one yr of therapy. Moreover, CYC was associated with significant acute toxicity, and longer therapy is limited by the risk for secondary malignancies. Mycophenolate mofetil (MMF), an immunosuppressive drug approved for organ transplantation, has been administered for up to 2 yrs to patients with SSc-ILD in several uncontrolled pilot studies. MMF was reported to be effective and safe. We hypothesize that the ability to administer MMF for two yrs will result in a better and more sustained improvement in SSc-ILD than can be achieved with one yr of CYC, and with less toxicity. To test this hypothesis, we propose a 5-yr, multi-center (12 clinical centers plus a Data Coordinating Center), parallel-group, double-blind, randomized controlled clinical trial comparing a 2-yr treatment with oral MMF (up to 1.5 g bid, as tolerated) with a 1-yr treatment with oral CYC (2 mg/kg/d for 1 yr followed by placebo MMF for a second yr to maintain the blind) in 150 patients with active SSc-ILD. Three SPECIFIC AIMS are proposed: 1) to determine whether MMF is more effective than CYC over the 2nd yr of a 24-mo period with respect to forced vital capacity as the PRIMARY OUTCOME and overall toxicity; 2) to compare MMF and CYC on the course of total lung capacity, single breath diffusing capacity for carbon monoxide, breathlessness (Mahler Transition Dyspnea Index), several HRQoL measures (SGRQ, SF-36), functional ability (Scleroderma Health Assessment Questionnaire) and skin thickness (modified Rodnam skin scores) as SECONDARY OUTCOMES; and 3) to advance our understanding of the biology and response to treatment of SSc-ILD through the collection and innovative analysis of blood samples and skin biopsies collected serially over time from study participants, the prospective validation of a combined outcome measure of overall treatment effect, and the assessment of the clinical utility (a patient-determined value measure) of treatments with MMF or CYC. (End of Abstract)