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, CPB Purpose of protocol (Precis): 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-alpha;, INF-gamma;, 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). 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) Imaging (Standard chest x-ray and computerized tomography, and high resolution computerized tomography with semi-quantitative and quantitative scoring) Progress achieved: Fifty three subjects have been enrolled and randomized.Forty four subjects have completed the 1 year treatment phase of the study. Accrual Ceiling: 96 Total number of subjects enrolled: 53 Total of subjects randomized to study agent: 53 Total number of subjects completed 1 year of study agent: 46 Total of currently active participants: 3 Number of patients still on study agent 1 Number of patients still in the follow-up phase 2 Total number of withdrawals: 6 Reasons to continue the protocol: Sarcoidosis is a multi-system granulomatous inflammatory disease of unknown etiology. 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. Despite over 25 clinical trials to date, there is still no FDA approved therapy for sarcoidosis. In recent years, from 1988 to 2007, the age-adjusted sarcoidosis mortality has increased significantly, 50.5% in women and 30.1% in men, (Swigris, et. al., Am J Respir Crit Care Med 2011;183(11):1524-30), highlighting the need for more effective therapies. Presently in the USA there are four open treatment trials for pulmonary sarcoidosis listed in Clinicaltrials.gov;three of which have clinical endpoints. This protocol is one of the three, and points to the fact that there are few clinical trials in pulmonary sarcoidosis and more are still needed. This protocol has been powered for 20% attrition, which indicates that 78 subjects are required to complete the 12-month treatment phase. Thus far, we have observed 11.3% attrition, reflecting a satisfactory tolerability and subject retention profile. Consequently, we believe that there is merit in continuing. Because we have active subjects, on-going collection of their data will be important in evaluating the primary and secondary endpoints of this study. Study Findings to Date: An interim analysis was previously performed on the available data from 49 of 50 randomized subjects. The analysis was completed in accordance with protocol;it demonstrated no significant difference between the treatment groups. The study has remained double blinded. There have been no serious adverse events attributable to the study agent. Of the serious adverse events, most were considered to be unrelated or unlikely. Of note, the screening process has enabled the investigational team to clinically phenotype and collect biological specimens on the majority of candidate subjects. As a byproduct, we have approximately seven active translational research collaborations with intramural investigators, including Alan Sher, PhD, Bruno Andrade, MD, Eva Mezey, PhD, Thomas Waldmann, MD, and Stewart Levine, MD. 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.
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