Trial of Antimycobacterial Therapy in Sarcoidosis

Study Overview
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Brief Summary
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Growing research from independent laboratories provide an association between mycobacteria and sarcoidosis. More recent immunologic and molecular studies demonstrate immune responses to mycobacteria virulence factors. The purpose of this study is to assess if administration of anti-mycobacterial drug therapy will aid in resolution of cutaneous sarcoidosis lesions.

Detailed Description
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Independent molecular and immunologic investigations strengthen the association between mycobacterial antigens and sarcoidosis pathogenesis. Molecular analysis of sarcoidosis granulomas reveals the presence of Mycobacterium tuberculosis complex (MTB) DNA and proteins that are significantly absent from granulomatous controls. Mycobacterial DNA has been detected in cutaneous sarcoidosis lesions, in addition to systemic immune responses against mycobacterial antigens. Due to the association between sarcoidosis and mycobacterial antigens, we postulated that broad spectrum antimycobacterial therapy could lead to restoration of T cell function and clinical improvement of chronic cutaneous sarcoidosis lesions. We investigated the safety and efficacy of Concomitant Levofloxacin, Ethambutol, Azithromycin, and Rifampin (CLEAR) therapy among chronic cutaneous sarcoidosis subjects, with change in lesion diameter from baseline to completion of 8 weeks of therapy as the primary endpoint; we assessed for decreases in granuloma burden, if granulomas were evident upon histologic examination. Change in modified Sarcoidosis Activity Severity Index (SASI) was the secondary endpoint.

Official Title
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Phase I/II Study of the Effects of Antibiotics on Sarcoidosis Pathogenesis

Conditions
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Sarcoidosis

Intervention / Treatment
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* Drug: Antibiotic Regimen
* Drug: Placebo Regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with sarcoidosis as defined by the ATS/ERS/WASOG statement on sarcoidosis as defined by the clinical presentation consistent with sarcoidosis, biopsy finding granulomas, and no alternative for the cause of the granulomas, such as tuberculosis Patients must have chronic cutaneous skin lesions with or without taking chronic therapy (corticosteroids, methotrexate (max 10mg/week), azathioprine, hydroxychloroquine, cyclophosphamide, minocycline, doxycycline and chloroquine), in which the dose has not been altered in the 2 months prior to starting the study. Subject has a diagnosis of cutaneous sarcoidosis for greater than 6 months with a Sarcoidosis Activity and Severity Index assessment score of at least 4. Diagnosis can be made by either: Skin lesions characteristic of sarcoidosis and a biopsy showing granulomas with no evidence of mycobacteria, fungus, or malignancy. A biopsy that does not show granulomas, but the patient has characteristic skin lesions and history of clinical features suggesting sarcoidosis (previous biopsy revealing noncaseating granuloma, bilateral hilar adenopathy, erythema nodosum, uveitis, raised ACE level, BAL lymphocytosis (CD4:CD8>3.5), panda/lambda sign on gallium scan) Accepted clinical variants include, but are not necessarily limited to the following: lupus pernio nodular subcutaneous annular angiolupoid plaque papular lichenoid psoriasiform For purposes of this study moderate to severe cutaneous sarcoidosis is defined as the presence of sarcoidal skin lesions with any of the following features: At least 5 easily visible facial lesions, or Disease which involves > 3% BSA, or Disease which confers functional impairment (e.g. nasal or visual field obstruction), or Disease which confers significant symptoms of itching and/or pain. If female, subject is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), or is using one of the following methods of birth control for the duration of the study and 90 days after study completion: condoms, sponge, foams, jellies, diaphragm, or intrauterine device contraceptives (oral or parenteral) for three months prior to study drug administration a vasectomized sole partner Females of childbearing potential must have a negative serum pregnancy test at screening visit. Exclusion Criteria: No consent/inability to obtain consent. Age less than 18 years of age. Inability to obtain biopsy or draw blood. CPK, ALT or AST >5 times upper limit of normal (ULN) Pregnancy or breast feeding. Current use of medications metabolized by rifampin (See Appendix). Allergy to macrolides, quinolones or rifamycins. Visual Impairment as defined by differentiating colors. Family or personal history of long QT syndromes. Patients receiving another interventional investigational drug within the 30 days prior to dosing Use of any investigational medication within the past 28 days prior to study enrollment. Subject has been hospitalized for infection or received IV antibiotics within the previous 2 months prior to baseline. Subject has a history of tuberculosis at anytime or close contact with a person with active tuberculosis within the previous 6 months, or persistent or active infections requiring hospitalization or treatment with IV antibiotics, IV antiretrovirals, or IV antifungals within 30 days of baseline, OR oral antibiotics, antivirals, or antifungals for purpose of treating infection, within 14 days of baseline. Evidence of other active skin diseases or skin infections during screening that may interfere with evaluation of sarcoidosis. Subject has an active infection requiring systemic antibiotics at time of screening Subject has a history of listeriosis, treated or untreated tuberculosis, exposure to individuals with tuberculosis. Subject has a variant of sarcoidosis that is not amenable to study evaluation, in the absence of chronic indurated lesions, such as: Acute, benign sarcoid associated with erythema nodosum Acute iritis Ichthyosiform sarcoidosis Hypo- or hyperpigmented macular sarcoidosis Ulcerative sarcoidosis Erythroderma Alopecia Patients otherwise unsuitable for participation in the opinion of the investigator

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Antibiotic Regimen<br>The Antibiotic Regimen consists of Levaquin 750 mg loading on day 1, then 500 mg po QD and Ethambutol 15-25 mg/kg for a maximum of 1200mg QD and Azithromycin 500mg on day 1, then 250 mg po QD and Rifampin 5-10 mg/kg for a maximum of 300mg po QD. All four drugs are given concomitantly. | Drug: Antibiotic Regimen<br>* Levaquin 750 mg loading on day 1, then 500 mg po QD Ethambutol 15-25 mg/kg for a maximum of 1200mg QD Azithromycin 500mg on day 1, then 250 mg po QD Rifampin 5-10 mg/kg for a maximum of 300mg po QD All four drugs are given concomitanly<br>* Other names: Rifampin=Rifadin;|
| Placebo Comparator: Placebo Regimen<br>The placebo regimen consists of Lactose tablets, one for each antibiotic with equivalent pills | Drug: Placebo Regimen<br>* lactose control tablets; one for each antibiotic with equivalent pills<br>* Other names: Lactose control tablets;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Lesion Size at the Completion of Antibiotic Therapy, Measured on a Continuous Scale; Change Will be Determined by Change in Diameter of the Lesions |  | Baseline to 8 weeks | 
| Granuloma Burden | Number of patients with a decrease in Granuloma Burden (only in those patients having granulomas present at baseline biopsy) | Baseline to 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Modified Sarcoidosis Activity and Severity Index (SASI) at Completion of Therapy. | Characterization of lesion severity was conducted using Modified Sarcoidosis Activity and Severity Index (SASI), measuring erythema, induration and desquamation. The modification was that the same scale was applied to any part of the body, instead of the face alone. The scale range is 0 (no problem) to 72 (very severe). | Baseline to 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sarcoidosis, mycobacteria, cutaneous lesions