Phase II Investigation of the Efficacy of Antimycobacterial Therapy in Chronic Pulmonary Sarcoidosis

Abstract

BackgroundA Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort.Research QuestionThe objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis.Study Design and MethodsIn a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George’s Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses.ResultsThe intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (–8.0 for placebo vs –1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (–2.3 vs –7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24).InterpretationDespite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis. A Phase I, single-center investigation found that 8 weeks of antimycobacterial therapy improved sarcoidosis FVC. Safety and efficacy assessments have not been performed in a multicenter cohort. The objective of this study was to determine the safety and efficacy of antimycobacterial therapy on the physiological and immunologic end points of sarcoidosis. In a double-blind, placebo-controlled, multicenter investigation, patients with pulmonary sarcoidosis were randomly assigned to receive 16 weeks of concomitant levofloxacin, ethambutol, azithromycin, and rifabutin (CLEAR) or matching placebo to investigate the effect on FVC. The primary outcome was a comparison of change in percentage of predicted FVC among patients randomized to receive CLEAR or placebo in addition to their baseline immunosuppressive regimen. Secondary outcomes included 6-min walk distance (6MWD), St. George’s Respiratory Questionnaire (SGRQ) score, adverse events, and decrease in mycobacterial early secreted antigenic target of 6 kDa (ESAT-6) immune responses. The intention-to-treat analysis revealed no significant differences in change in FVC among the 49 patients randomized to receive CLEAR (1.1% decrease) compared with the 48 randomized to receive placebo (0.02% increase) (P = .64). Physiological parameters such as the change in 6MWD were likewise similar (P = .91); change in SGRQ favored placebo (–8.0 for placebo vs –1.5 for CLEAR; P = .028). The per-protocol analysis revealed no significant change in FVC at 16 weeks between CLEAR and placebo. There was no significant change in 6MWD (36.4 m vs 6.3 m; P = .24) or SGRQ (–2.3 vs –7.0; P = .14). A decline in ESAT-6 immune responses at 16 weeks was noted among CLEAR-treated patients (P = .0003) but not patients receiving placebo (P = .24). Despite a significant decline in ESAT-6 immune responses, a 16-week CLEAR regimen provided no physiological benefit in FVC or 6MWD among patients with sarcoidosis. Sarcoidosis is an idiopathic, granulomatous disease with limited therapeutic options.1Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999.Am J Respir Crit Care Med. 1999; 160: 736-755Crossref PubMed Scopus (2186) Google Scholar,2Grunewald J. Grutters J.C. Arkema E.V. Saketkoo L.A. Moller D.R. Muller-Quernheim J. Sarcoidosis.Nat Rev Dis Primers. 2019; 5: 45Crossref PubMed Scopus (164) Google Scholar Current guidelines recommend various forms of immunosuppression as a mainstay of treatment, although these agents carry significant toxicities and have suboptimal efficacy. Corticosteroids have been proposed as the drug of choice for the treatment of pulmonary sarcoidosis, but toxicities are common. In addition, although antimalarial, cytotoxic, and biologic agents exhibit efficacy, relapse following tapering or discontinuation of these agents, as well as their side effect profiles, underscore the necessity for safer, more effective options.3Gottlieb J.E. Israel H.L. Steiner R.M. Triolo J. Patrick H. Outcome in sarcoidosis. The relationship of relapse to corticosteroid therapy.Chest. 1997; 111: 623-631Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar,4Vorselaars A.D. Verwoerd A. van Moorsel C.H. Keijsers R.G. Rijkers G.T. Grutters J.C. Prediction of relapse after discontinuation of infliximab therapy in severe sarcoidosis.Eur Respir J. 2014; 43: 602-609Crossref PubMed Scopus (94) Google Scholar Although no definitive agent has been identified in sarcoidosis granulomas, independent laboratories have reported the presence of mycobacterial proteins and DNA in sarcoidosis lesions.5Mitchell D.N. Mycobacteria and sarcoidosis.Lancet. 1996; 348: 768-769Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 6Oswald-Richter K.A. Beachboard D.C. Seeley E.H. et al.Dual analysis for mycobacteria and propionibacteria in sarcoidosis BAL.J Clin Immunol. 2012; 32: 1129-1140Crossref PubMed Scopus (63) Google Scholar, 7Song Z. Marzilli L. Greenlee B.M. et al.Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis.J Exp Med. 2005; 201: 755-767Crossref PubMed Scopus (290) Google Scholar In addition, several investigators have described immune responses against secreted mycobacterial virulence factors in patients with sarcoidosis.7Song Z. Marzilli L. Greenlee B.M. et al.Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis.J Exp Med. 2005; 201: 755-767Crossref PubMed Scopus (290) Google Scholar, 8Chen E.S. Wahlstrom J. Song Z. et al.T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis.J Immunol. 2008; 181: 8784-8796Crossref PubMed Scopus (139) Google Scholar, 9Ahmadzai H. Cameron B. Chui J.J. Lloyd A. Wakefield D. Thomas P.S. Peripheral blood responses to specific antigens and CD28 in sarcoidosis.Respir Med. 2012; 106: 701-709Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Immune responses against these mycobacterial antigens disappear with spontaneous clinical resolution of pulmonary sarcoidosis,8Chen E.S. Wahlstrom J. Song Z. et al.T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis.J Immunol. 2008; 181: 8784-8796Crossref PubMed Scopus (139) Google Scholar as well as following administration of antimycobacterial therapy to patients with this disease.10Drake W.P. Richmond B.W. Oswald-Richter K. et al.Effects of broad-spectrum antimycobacterial therapy on chronic pulmonary sarcoidosis.Sarcoidosis Vasc Diffuse Lung Dis. 2013; 30: 201-211PubMed Google Scholar The clinical utility of antimycobacterial therapy was suggested by an 8-week, single-blind randomized trial of concomitant Levaquin, azithromycin, ethambutol, and rifabutin (CLEAR) in cutaneous sarcoidosis; an open-label trial similarly reported improved FVC, 6-min walk distance (6MWD), and early secreted antigenic target of 6 kDa (ESAT-6) responses in pulmonary sarcoidosis.10Drake W.P. Richmond B.W. Oswald-Richter K. et al.Effects of broad-spectrum antimycobacterial therapy on chronic pulmonary sarcoidosis.Sarcoidosis Vasc Diffuse Lung Dis. 2013; 30: 201-211PubMed Google Scholar,11Drake W.P. Oswald-Richter K. Richmond B.W. et al.Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study.JAMA Dermatol. 2013; 149: 1040-1049Crossref PubMed Scopus (61) Google Scholar Histologic evidence of granulomatous resolution following administration of the CLEAR regimen among patients with cutaneous sarcoidosis was also noted.11Drake W.P. Oswald-Richter K. Richmond B.W. et al.Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study.JAMA Dermatol. 2013; 149: 1040-1049Crossref PubMed Scopus (61) Google Scholar A case report of resolution of ocular sarcoidosis with the same regimen has also been reported.12Richmond B.W. Richter K. King L.E. Drake W.P. Resolution of chronic ocular sarcoidosis with antimycobacterial therapy.Case Rep Intern Med. 2014; 1: 5042PubMed Google Scholar We designed a Phase IIB study to further define the safety and efficacy of the CLEAR regimen in sarcoidosis patients with progressive pulmonary disease. This randomized, double-blind, placebo-controlled investigation compared a regimen of antimycobacterial therapy consisting of CLEAR vs a four-drug placebo regimen for 16 weeks. Each patient received 8 weeks of four drugs (induction phase), followed by 8 weeks of two drugs (consolidation phase). The primary end point was the absolute change in percentage of predicted FVC comparing baseline FVC vs FVC following completion of 16 weeks of therapy. The secondary end points included change in 6MWD, St. George’s Respiratory Questionnaire (SGRQ) score, adverse events of grades 1 to 5, and in ESAT-6-specific immune responses. The study protocol was approved by the Vanderbilt University Medical Center Institutional Review Board by Health Sciences Committee 1 (#121532) and was registered at ClinicalTrials.gov.13National Institutes of Health Clinical Center. Phase II investigation of antimycobacterial therapy on progressive, pulmonary sarcoidosis. NCT02024555. ClinicalTrials.gov. National Institutes of Health; 2013. Updated July 9, 2020. https://clinicaltrials.gov/ct2/show/NCT02024555.Google Scholar This study was conducted in accordance with the amended Declaration of Helsinki, and written informed consent was obtained from all patients. The Data and Safety Monitoring Board for this study reviewed data throughout the study and performed the single planned interim analysis for safety and efficacy after 50 randomized patients had completed their 16-week regimen. Patient were randomized to receive either an oral antibiotic regimen consisting of 8 weeks of daily levofloxacin 500 mg, ethambutol (1,200 mg for ≥ 50 kg; 800 mg for < 50 kg) once daily, azithromycin 250 mg, and rifabutin 300 mg vs a daily identical-appearing four-drug placebo regimen. For the last 8 weeks of the study, participants were given two of the four drugs based on their individual tolerance and toxicity during the first 8 weeks. The placebo regimen was administered in the same format. The levofloxacin, ethambutol, and azithromycin were paid for at full cost through the Vanderbilt Investigational Drug Pharmacy. Rifabutin was donated by the Pfizer Global Medical Grant Program (#53232269). Adults aged ≥ 18 years with the diagnosis of sarcoidosis as defined by the 1999 American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and Other Granulomatous Disorders statement on sarcoidosis were eligible for enrollment.1Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999.Am J Respir Crit Care Med. 1999; 160: 736-755Crossref PubMed Scopus (2186) Google Scholar Participants were also selected based on demonstration of pulmonary disease progression according to at least one of the following three criteria: (1) decline of absolute percentage of predicted FVC or diffusing capacity for carbon monoxide of at least on progression in on or decline in score, as by the to participants were for immune responses to ESAT-6 or evidence of as defined by of responses to either of were the was participants were to have evidence of or disease on were with the CLEAR trial all was for the primary end change from baseline of FVC data from participants with chronic pulmonary sarcoidosis with et therapy in patients with chronic sarcoidosis and pulmonary J Respir Crit Care Med. PubMed Scopus Google Scholar obtained the of for the primary end A of completed participants was to have to a in change of FVC predicted from The were as to < 18 participants of not to one of the following of for the of the study and following study a or are not effective A at was the was of predicted < pulmonary or to of the the CLEAR or to for blood of with a with the 6 to the or a sarcoidosis, that the treatment or of an drug to or of the is receiving mg of or more the of as defined by a < or absolute < as defined by the to or of from from the patient is on on a regimen for or and on a for or of or < has or or treatment with or agents to and are not to significant in the or or to or following in the of the patient safety or or to the study drug according to in the of the patient safety with the of the CLEAR of or receiving treatment for pulmonary biologic the 6 to were assigned to receive the CLEAR or placebo regimen by a according to and of ≥ mg or were and to by a at Vanderbilt University Medical Center not with the were to all of trial drug to for completion for the per-protocol analysis was defined as administration of at least of the 16 weeks. participants were and for adverse adverse events were and reported according to a adverse events was reviewed and by the and clinical The of adverse events was according to the for The events were as an adverse that was not to a trial an adverse of 1 or that was to a trial drug an adverse of or that was to a trial drug to to trial drug discontinuation to a trial or a that was to a trial Each adverse in or was defined as a adverse was reported and reviewed by the as well as the Data Safety Monitoring The provided safety for of the This trial was approved by the Vanderbilt University Program and by the at the for the and of the data and and for the of the trial to the This randomized Phase II clinical trial was conducted to determine CLEAR a significant P < in the 6MWD, and immune responses against patients were randomized to treatment from 5, to of 49 patients were randomized to receive CLEAR and 48 to receive placebo. Data were and for analysis on The primary end point was baseline to 16-week change in FVC as We defined the 16-week FVC predicted as the to 16 weeks from a of to weeks from The primary comparison between the CLEAR and placebo was conducted on an intention-to-treat among patients with baseline and 16-week outcomes = and P were with matching with as H. et vs treatment for a trial protocol for the randomized clinical 2019; PubMed Scopus Google et therapy in outcomes of the 2019; Full Text Full Text PDF PubMed Scopus Google Scholar The data were according to for in Scholar the change the by for for secondary end points were compared by the of the between data The for data was to baseline and 16-week change treatment at 8 and 16 weeks. were for a per-protocol of patients = of ESAT-6 and adverse events was not based on The ESAT-6 analysis was the comparison and was conducted by a comparing baseline with 16-week their cohort. The of an and an adverse events not was compared between treatment by the or We patients from through of were and randomized to treatment The for from study were as (1) significant a of a drug between one of the CLEAR with a that the patient was patient to pulmonary for with study and on a The and clinical of all study participants according to their are in the baseline were well treatment of the = 50 was and the were = with American = A was in the placebo and in the CLEAR Although not a planned analysis of of (P = with treatment (P = on as with their (P = no by to = = = or end points FVC 6-min walk = 48 for CLEAR and placebo SGRQ = 48 and = for CLEAR and placebo SGRQ = 48 and = for CLEAR and placebo SGRQ = 48 and = for CLEAR and placebo SGRQ = 48 and = for CLEAR and placebo on on a on a biologic on a or biologic on of or biologic = concomitant Levaquin, ethambutol, azithromycin, and = ESAT-6 = early secreted antigenic target of 6 = 48 for CLEAR and placebo = 48 and = for CLEAR and placebo in a CLEAR = concomitant Levaquin, ethambutol, azithromycin, and = ESAT-6 = early secreted antigenic target of 6 The clinical data were intention-to-treat and were from the intention-to-treat In the per-protocol in the and in the placebo of the patients were of to weeks of the regimen = = in clinical immunosuppressive regimen on study drugs = = of during study = = and found to receiving with antimycobacterial such as at the of = = The were included in the per-protocol In the intention-to-treat were no significant differences in the primary end point from baseline to 16 in predicted between the CLEAR and placebo vs placebo P = patients during the to and of to the of FVC was weeks and to primary end point was between treatment with a of weeks for placebo and weeks for CLEAR II patients. were and of physiological such as 6MWD m; m; P = revealed no significant differences A change in the SGRQ an in of The and significant differences in of the placebo CLEAR P = = and FVC 6-min walk SGRQ SGRQ SGRQ SGRQ FVC 6-min walk SGRQ SGRQ SGRQ SGRQ of baseline to 16-week differences in P are from CLEAR = concomitant Levaquin, ethambutol, azithromycin, and SGRQ = St. George’s Respiratory in a of baseline to 16-week differences in P are from CLEAR = concomitant Levaquin, ethambutol, azithromycin, and SGRQ = St. George’s Respiratory In the per-protocol were following of patients to data analysis to factors in the of baseline vs 16 end points of the patients revealed that were no differences in the primary end point change from baseline in predicted between CLEAR-treated patients compared with patients receiving placebo vs placebo P = of physiological and end points revealed no significant for were no significant differences in the 6MWD of patients randomized to the CLEAR or placebo regimen (36.4 m vs 6.3 m; P = The SGRQ also revealed no significant differences in the between the P = .14). CLEAR-treated patients had in and compared with patients receiving placebo. Although was no significant baseline in ESAT-6-specific between the two P = was a significant in the following 16 weeks of therapy. There was no significant change in randomized to receive placebo P = a significant decline in the ESAT-6 among the patients randomized to the CLEAR regimen P = .0003) for baseline and 16-week were were included in this participants were for adverse A of adverse events were noted in adverse in or was defined as an The of was similar for CLEAR = and placebo = (P = of the four in the CLEAR were to to study was to in the placebo cohort. There were no in this the by from = Medical = severe adverse in a = Medical = severe adverse In this randomized, double-blind, placebo-controlled trial of CLEAR no benefit from the study on pulmonary for the intention-to-treat and per-protocol secondary end such as 6MWD and no significant from and SGRQ was at the end of the CLEAR regimen. There was a significant decline in immune responses against ESAT-6 among the CLEAR-treated but no change was among randomized to receive placebo Although mycobacteria have been proposed to agents for sarcoidosis, the study no evidence to that The are from a randomized trial in CLEAR therapy was for cutaneous sarcoidosis, and also from an report of CLEAR W.P. Richmond B.W. Oswald-Richter K. et al.Effects of broad-spectrum antimycobacterial therapy on chronic pulmonary sarcoidosis.Sarcoidosis Vasc Diffuse Lung Dis. 2013; 30: 201-211PubMed Google Scholar,11Drake W.P. Oswald-Richter K. Richmond B.W. et al.Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study.JAMA Dermatol. 2013; 149: 1040-1049Crossref PubMed Scopus (61) Google Scholar for the of CLEAR therapy is that the the of sarcoidosis is This with the of to mycobacteria from sarcoidosis et of cell from blood not between patients with sarcoidosis and Full Text Full Text PDF PubMed Scopus Google L. for mycobacteria in from patients with pulmonary sarcoidosis. A Vasc Diffuse Lung Dis. Google Scholar Other for the of CLEAR therapy also The were designed to a with sarcoidosis, but the of the data and the for are and have the study to patients with D.R. clinical in sarcoidosis: or study Respir J. 2014; PubMed Scopus (25) Google Scholar in the placebo on therapy not in a 16-week of to treatment the effect is but this study throughout the treatment is also that the treatment was to efficacy of such as to 6 to effect benefit in pulmonary The of in J PubMed Scopus Google Scholar therapy not in improved one study noted that these patients to an FVC but at a patients were not K. Lung decline according to clinical in mycobacterial Full Text Full Text PDF PubMed Scopus Google Scholar FVC an of treatment has been to with and with et for clinical of sarcoidosis.Sarcoidosis Vasc Diffuse Lung Dis. 2012; Google H. and therapy of pulmonary sarcoidosis.Eur Respir J. 2013; PubMed Scopus Google Scholar the of clinical that the end point is not the of the Immune responses against mycobacterial such as ESAT-6 and are in patients with sarcoidosis E.S. Wahlstrom J. Song Z. et al.T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis.J Immunol. 2008; 181: 8784-8796Crossref PubMed Scopus (139) Google K. H. et al.Mycobacterial ESAT-6 and are by sarcoidosis by the American sarcoidosis Clin Immunol. 30: PubMed Scopus Google K.A. Beachboard D.C. et mycobacterial antigens are of the adaptive immune response in pulmonary sarcoidosis.Respir PubMed Scopus Google Scholar investigators found the antimycobacterial responses disappear with clinical resolution of E.S. Wahlstrom J. Song Z. et al.T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis.J Immunol. 2008; 181: 8784-8796Crossref PubMed Scopus (139) Google Scholar Immune responses against ESAT-6 have also been with or as well as mycobacteria B. et specific decline with 2013; PubMed Scopus Google Scholar, and of ESAT-6 and in mycobacteria from of in 2019; PubMed Scopus Google Scholar, J.C. L. K. PubMed Scopus (27) Google these responses decline with effective antimycobacterial Z. J. et of antigen diagnosis of disease and treatment A. PubMed Scopus Google Scholar, et and responses to antigens in patients with are after Immunol. PubMed Scopus Google Scholar, et responses as of treatment response in and Full Text Full Text PDF PubMed Scopus Google Scholar A significant decline in the ESAT-6 immune responses among randomized to receive CLEAR not is and of is that the decrease in ESAT-6 response in the CLEAR is to an effect of one or more in the treatment regimen reported improved immune capacity and and as well as from sarcoidosis following completion of the CLEAR W.P. Oswald-Richter K. Richmond B.W. et al.Oral antimycobacterial therapy in chronic cutaneous sarcoidosis: a randomized, single-masked, placebo-controlled study.JAMA Dermatol. 2013; 149: 1040-1049Crossref PubMed Scopus (61) Google Scholar The in with CLEAR treatment of sarcoidosis in the capacity to pathogenic antigens such as In addition, the of antigens such as ESAT-6 during treatment of mycobacterial of such as this also the of during the treatment of sarcoidosis. The between in a virulence with mycobacterial (ESAT-6) and the of the study that mycobacterial antigens are of of sarcoidosis, as suggested by of mycobacterial antigens in sarcoidosis Z. Marzilli L. Greenlee B.M. et al.Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis.J Exp Med. 2005; 201: 755-767Crossref PubMed Scopus (290) Google Scholar but is not to the or progression of the disease. the study not to the presence of in the that the of CLEAR in in the immune responses by the presence of investigation the of the CLEAR regimen on further is The study have The of was of the patients were from the per-protocol of the of = = were to < weeks of study more to the of 16 weeks of CLEAR therapy on the primary and secondary end to the and toxicities with a four-drug to antimycobacterial therapy is well et to and to as by a study in 2019; PubMed Scopus Google Scholar, A. L. D. to and treatment among patients with a Respir J. 2019; PubMed Scopus Google Scholar, of to treatment for in and a PubMed Scopus Google Scholar such as and from azithromycin and levofloxacin, as well as from have the SGRQ score, to an SGRQ were noted among CLEAR-treated patients these is the to patients with disease for < 1 We not patients 1 of diagnosis was that of drug efficacy from spontaneous resolution in among patients with is more patients are < years of and not have chronic Respiratory in pulmonary 2013; Google Scholar sarcoidosis clinical patients 1 of their for and or have that according to a is a of pulmonary A.D. et of infliximab in sarcoidosis.Eur Respir J. PubMed Scopus Google van et and safety of infliximab in severe sarcoidosis.Respir Med. Full Text Full Text PDF PubMed Scopus Google Scholar was not included in the study the at of study was and the cost of this as an analysis was In a of patients with progressive pulmonary sarcoidosis, the CLEAR therapy not in significant in predicted FVC was with significant in ESAT-6-specific immune responses.

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