ORAL CYCLOPHOSPHAMIDE VS ORAL PLACEBO IN SSC ALVEOLITIS

口服环磷酰胺与口服安慰剂治疗 SSC 肺泡炎

• 批准号: 6668471
• 负责人: CHARLES READ
• 金额: --
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-10 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6668471
• 关键词: clinical research; clinical trials; cooperative study; cyclophosphamide; diagnostic respiratory lavage; drug screening /evaluation; dyspneas; functional ability; human subject; human therapy evaluation; inflammation; longitudinal human study; lung alveolus; patient oriented research; pulmonary fibrosis /granuloma; quality of life; respiratory airway volume; respiratory disorder chemotherapy; systemic scleroderma

In Systemic Sclerosis (SSc), interstitial pulmonary fibrosis is frequent (80%) and is now the leading cause of death. The mortality rate of patients with a forced vital capacity (FVC) <50% of predicted due to SSc pulmonary fibrosis is 40-45% within 10 years of SSc onset. Present evidence suggests that pulmonary fibrosis, which occurs early in the course of SSc, is usually preceded by inflammation which can be detected by examination of cells obtained by bronchoalveolar lavage (BAL). Uncontrolled series suggest that cyclophosphamide (CYC) may stabilize or improve lung function in SSc patients with active alveolitis. We propose to conduct a five- year, l3-center, parallel-group, double-blind, randomized controlled study of oral CYC (1-2 mg/kg/day) versus placebo to assess the efficacy of CYC in stabilizing or improving the course of FVC (as % predicted) in 163 patients with early SSc (within 5 years of clinical disease onset) who are already dyspneic (at least moderate functional impairment and perceived magnitude of task and effort on the Mahler Baseline Dyspnea Index), have an FVC equal to or <85% of predicted and exhibit active alveolitis defined as equal to or >3.0% neutrophils or equal to or >2.0% eosinophils in BAL fluid. Secondarily, we will assess the impact of CYC on quality of life (SF36), functional activity (SSc Health Assessment Questionnaire), dyspnea (Mahler Transition Dyspnea Index) and diffusing capacity for carbon monoxide (DLCO) in these patients. Patients will be recruited for study during the first 3 years (from 6 mos. to 2 yrs, 9 mos) of the 5-year project period. Randomized participants will be treated with study drug for 1 year and followed at 3-month intervals for 2 years. Overall study coordination and data collection, management and analysis will be centralized at UCLA. Proven methods for analyzing time-oriented data employed by the investigators in previous controlled studies of scleroderma will be used to evaluate whether oral CYC (1-2 mg/kg/day) is better than placebo a) in improving or preventing worsening of FVC (the primary outcome variable) and b) in improving or preventing worsening of quality of life, functional ability, breathlessness and DLCO (secondary outcome variables).

在系统性硬化症（SSc）中，间质性肺纤维化是常见的（80%），现在是死亡的主要原因。在SSc发病后10年内，因SSc肺纤维化导致的强迫肺活量(FVC) <预测值50%的患者死亡率为40-45%。目前的证据表明，肺纤维化发生在SSc病程早期，通常在炎症发生之前，可以通过检查支气管肺泡灌洗（BAL）获得的细胞来检测。非对照研究表明，环磷酰胺（CYC）可以稳定或改善伴有活动性肺泡炎的SSc患者的肺功能。我们建议进行一项为期5年、13个中心、平行组、双盲、随机对照的口服CYC （1- 2mg /kg/天）与安慰剂的研究，以评估CYC在163例早期SSc（临床发病5年内）患者中稳定或改善FVC病程（预期百分比）的疗效，这些患者已经存在呼吸困难（至少中度功能障碍，马勒基线呼吸困难指数中任务和努力的感知程度）。FVC等于或<预测的85%，并表现为活动性肺泡炎，定义为BAL液中中性粒细胞等于或>3.0%或嗜酸性粒细胞等于或>2.0%。其次，我们将评估CYC对这些患者的生活质量（SF36）、功能活动（SSc健康评估问卷）、呼吸困难（马勒过渡呼吸困难指数）和一氧化碳弥散能力（DLCO）的影响。患者将在前3年（从6个月开始）招募进行研究。5年的项目周期中有2年，9年以上。随机受试者将接受研究药物治疗1年，每隔3个月随访2年。整体研究协调和数据收集、管理和分析将集中在加州大学洛杉矶分校。研究者在之前的硬皮病对照研究中采用了经过验证的时间数据分析方法，将用于评估口服CYC （1-2 mg/kg/天）是否优于安慰剂：a)改善或预防FVC恶化（主要结局变量）；b)改善或预防生活质量、功能能力、呼吸困难和DLCO恶化（次要结局变量）。