Translational Studies in Sarcoidosis

临床方案（NHLBI 06-H-0072）：阿托伐他汀作为II期和III期肺结节病的疾病调节剂：一项随机、双盲、安慰剂对照试验。一些生物标本也将根据NHLBI临床方案96-H-100收集/储存。

Clinical Protocol (NHLBI 06-H-0072): Atorvastatin as a disease-modifying agent in Stage II and Stage III Pulmonary Sarcoidosis: A randomized, double-blinded, placebo-controlled trial. Some Biospecimens will also be collected/stored under the NHLBI Clinical Protocol 96-H-100. PI: Joseph Fontana, Staff Physician, PVMB Purpose of protocol (Prcis): Sarcoidosis is a multi-system granulomatous inflammatory disease. Pulmonary involvement is most common. Patients typically experience fatigue, weakness and dyspnea. Respiratory muscle weakness, which may be secondary to granulomatous inflammation, is associated with dyspnea and decreased quality of life (QOL). The disease can remit spontaneously or become chronic, with exacerbations and remissions. In some patients, it can progress to pulmonary fibrosis and death. Granulomatous inflammation is characterized primarily by accumulation of monocytes, macrophages and activated T-lymphocytes, with increased production of key inflammatory mediators, TNF-, INF-, IL-2, and IL-12, characteristic of a Th1-polarized response (T-helper lymphocyte-1 response). Corticosteroids are the current mainstay of treatment, but their long-term benefits are not certain. Because steroids often produce undesirable side effects, investigations to identify alternative therapies are warranted. There is sufficient evidence to test the proof of concept that pathways targeted by statins will have a therapeutic effect in sarcoidosis, since, in pre-clinical studies, statins blunt Th1-mediated inflammatory responses. Objectives: The objective of this protocol is to conduct a randomized, double-blind placebo-controlled, trial which aims to determine if atorvastatin administration results in less steroid use and longer steroid-free intervals in patients with pulmonary sarcoidosis who require prednisone treatment. The primary endpoint is the duration of the steroid-sparing period. Secondary clinical and physiological endpoints are intended to analyze possible anti-inflammatory and beneficial effects of the drugs. Since there is no gold standard outcome measure in sarcoidosis, four categories of secondary endpoints will be used to characterize the effects of the therapeutic agent on the clinical course of the disease: imaging (high resolution chest CT); quality of life assessments (SF-36 and SGRQ), anti-inflammatory effects (biomarkers and relapse rates), and functional effects (CPET, PFTs). Finally, we will study the utility of exhaled nitric oxide in monitoring disease activity. Basic Design: Subjects, 18-70 years old, with stage II or III pulmonary sarcoidosis, diagnosed by a compatible clinical history and supported by a lung, lymph node, or tissue biopsy, will be enrolled in the study, if they require prednisone therapy. The subjects will be randomly assigned to two groups; as prednisone is tapered in both groups, one group will receive placebo, and the other, atorvastatin (80 mg/day). The study drug will be administered for twelve months, during which time patients will be periodically evaluated as to their clinical status and prednisone requirements. Pill counts and patient diaries will be used to determine the amount of prednisone use during the study period. Endpoints The primary endpoint is to determine if atorvastatin administration results in longer steroid-sparing intervals in patients with pulmonary sarcoidosis who require prednisone. The secondary endpoints include: Clinical (Total prednisone usage, remission and relapse rates (flares), quality of life indicators (SF-36, SGRQ), dyspnea scales (AMA and BDI/TDI), and an exploratory parameter, the therapeutic index.) Physiologic (Pulmonary function tests, cardiopulmonary exercise tests, and the six-minute walk test) Immunologic (Serum markers: serum angiotensin converting enzyme, tumor necrosis factor alpha II receptor, serum soluble IL-2 receptor, and C-reactive protein; bronchoalveolar lavage fluid inflammatory markers, cell counts, and cytokines; exhaled nitric oxide and carbon monoxide) Imaging (Standard chest x-ray and computerized tomography, and high resolution computerized tomography with semi-quantitative and quantitative scoring) Progress achieved: Since the last continuing review (September 2009) 4 subjects have been enrolled and randomized, bringing the accrual to 41. Three new candidates were recently screened (September and October) and are scheduled for enrollment. We are in the process of scheduling 10 highly eligible candidates for clinical evaluation. Reasons to continue the protocol: Sarcoidosis is a multi-system granulomatous inflammatory disease of unknown etiology. Pulmonary involvement is the most common manifestation. Patients typically experience cough, dyspnea, and fatigue. Disease progression can impair the quality of life and lead to end-stage pulmonary fibrosis and death. Corticosteroids are the current mainstay of treatment, but their long-term benefits are not certain, and their use is associated with a decrease in quality of life. Because steroids produce undesirable side effects, investigations to identify alternative therapies are warranted. While alternative therapies are available, none are FDA-approved. Most alternative therapies are not benign, and there are no long-term data supporting their use in pulmonary sarcoidosis. Given the limited options, none of which are ideal, (that is, highly effective agents with mild side-effect/toxicity profiles), patients, at their own risk, sometimes forego treatment altogether, to avoid the untoward effects of steroids or the alternative agents. Rigorous clinical trials are needed to determine whether anti-inflammatory agents can provide steroid-sparing benefits and improve therapeutic outcomes. Because we have a number of active subjects, on-going collection of their data will be important in evaluating the primary and secondary endpoints of this study. We therefore believe that there is merit in continuing the study as planned. Accrual data: Recruitment Parameters n Telephone Screening Questionnaires 913 Clinical Exams/Screens Completed 127 Accepted 44 Enrolled 41 Study Findings to Date: Forty-one subjects have been enrolled, randomized, and started on study agent. Because the study is double-blinded, we cannot compare differences in treatment arms. For the purpose of this report we are defining evaluable subjects, as those participants who have at least 6 months of data. Pulmonary sarcoidosis flares and prednisone usage are secondary endpoints, and thus far, we have observed the following: 18/34 evaluable subjects ( 53%) have flared; 5 of the 18 flared subjects had a second flare event. With each flare, there is a substantial increase in prednisone usage. Total number of subjects enrolled: 41 Total of subjects randomized to study agent: 41 Total number of subjects completed 1 year of study agent: 31 Total of currently active participants: 14 Number of patients still on study agent 6 Number of patients still in the follow-up phase 8 Total number of withdrawals: 4 Subject Accrual Table: 06-H-0072 American Indian or Alaskan Native Asian or Pacific Islander Black, not of Hispanic Origin Hispanic White, not of Hispanic Origin Other or Unknown Total Male 0 0 7 0 9 0 16 Female 0 0 11 1 13 0 25 Total 0 0 18 0 23 0 41 Subjects withdrawn from protocol: 4 State the current risk/benefit analysis of the study. This research involves greater than minimal risk to subjects with the prospect of direct benefit and is likely to yield generalizeable knowledge about the disease.