MOCSLID-CCC

描述（由申请人提供）： 硬皮病（SSc）是一种毁灭性的全身性疾病，其中肺部受累（主要来自SSc相关间质性肺病（SSc-ILD））已成为总体死亡率的主要原因。开发有效的SSc-ILD治疗方法将直接影响生活质量和寿命。最初的硬皮病肺研究（SLS I）是第一项证明SSc-ILD对口服环磷酰胺（CYC）治疗1年有反应的随机对照试验，可改善肺功能、呼吸困难、皮肤病和健康相关生活质量（HRQoL）。然而，CYC的有益效果在完成一年治疗后的第二年结束时减弱。此外，CYC与显著的急性毒性相关，并且较长的治疗受到继发性恶性肿瘤风险的限制。吗替麦考酚酯（MMF）是一种获批用于器官移植的免疫抑制药物，在几项非对照初探性研究中已对SSc-ILD患者给药长达2年。据报告，MMF有效且安全。我们假设，与使用1年CYC相比，使用2年MMF可使SSc-ILD获得更好、更持久的改善，且毒性更低。为了检验这一假设，我们提出了一个5年，多中心，（12个临床中心加一个数据协调中心）、平行组、双盲、随机对照临床试验，比较口服MMF的2年治疗（每日2次最多1.5 g，在150例活动性SSc-ILD患者中接受为期1年的口服CYC治疗（2 mg/kg/d，持续1年，随后安慰剂MMF持续第2年，以维持盲态）。提出了三个具体目的：1）确定在24个月期间的第2年，在用力肺活量（作为主要结局）和总体毒性方面，MMF是否比CYC更有效; 2）比较霉酚酸酯和环磷酰胺对肺总量、一氧化碳弥散量、呼吸困难的影响（Mahler过渡期呼吸困难指数），几项HRQoL指标（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）作为次要结局;和3）通过对研究参与者随时间连续采集的血液样本和皮肤活检进行采集和创新分析，促进我们对SSc-ILD生物学和治疗反应的理解，对总体治疗效果的联合结局指标进行前瞻性验证，并评估MMF或CYC治疗的临床效用（患者确定的价值指标）。(End摘要）

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)