Phase II Investigation of Antimycobacterial Therapy on Progressive, Pulmonary Sarcoidosis

Study Overview
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Brief Summary
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The primary purpose of this study is to investigate the efficacy and safety of oral antimycobacterial therapy in patients with confirmed progressive pulmonary sarcoidosis. We suspect that the CLEAR regimen will improve the absolute FVC percent predicted in chronic pulmonary sarcoidosis participants.

Detailed Description
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Primary Objective: To assess the efficacy and safety of oral CLEAR therapy in patients with confirmed progressive pulmonary sarcoidosis. Hypothesis: The CLEAR regimen will improve the absolute FVC percent predicted in chronic pulmonary sarcoidosis participants by augmenting T cell responses through the normalization of p56Lck expression and IL-2 production.

Official Title
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Investigation of the Efficacy of Antimycobacterial Therapy on Pulmonary Sarcoidosis Phase II Randomized, Double-blind, Placebo-controlled Trial

Conditions
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Sarcoidosis; Antimycobacterial Therapy

Intervention / Treatment
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* Drug: Levofloxacin
* Drug: Ethambutol
* Drug: Azithromycin
* Drug: Rifampin
* Drug: Placebo


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, as well as biopsy demonstrating granulomas, and no alternative for the cause of the granulomas, such as tuberculosis for at least one year prior to randomization. Evidence of disease progression as defined by at least one of the following three criteria: Decline of absolute percent predicted of FVC (FVC ≥45% or higher of predicted value) or DLCO of at least 5% on serial measurements (DLCO range >35%, if measured); Radiographic progression in chest imaging on side by side comparison; Change in dyspnea score, as measured by Transition Dyspnea Index (TDI); Positive peripheral immune responses to ESAT-6 as a biomarker of response to CLEAR regimen. Possess evidence of parenchymal or nodal disease on chest radiograph. Exclusion Criteria: Inability to obtain consent Age less than 18 years Female participants of childbearing potential not willing to use 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, non-hormonal intrauterine device, a vasectomized sole partner or abstinence. Note: Oral contraceptive pills are not effective birth control when taking rifamycin. A negative urine pregnancy test at screening visit if female of childbearing potential FVC predicted value is < 45%. End-stage fibrotic pulmonary disease. Significant underlying liver disease. Allergy or intolerance to any of the antibiotics within the CLEAR regimen. Allergy or intolerance to albuterol Poor venous access for obtaining blood samples History of active tuberculosis, close contact with a person with active tuberculosis within the 6 months prior to the screening visit or has a positive PPD. Significant disorder, other than sarcoidosis, that would complicate the treatment evaluation, (such as respiratory, cardiac, neurologic, musculoskeletal or seizure disorders) Use of an investigational drug within 30 days prior to screening or within 5 half-lives of the agent, whichever is longer. Currently receiving >40mg prednisone. ALT or AST >5 times upper limit of normal (ULN) Leukopenia, as defined by WBC <3.0 cells/mm3 or absolute neutrophil count <1000 Breast feeding. Color perception impairment as defined by the inability to differentiate colors per personal history or history of optic neuritis from any cause, including from sarcoidosis. If patient is on immunomodulators, they must be on regimen for ≥ 3-month period and on a stable dose for > 4 weeks. Family or personal history of long QT interval Most recent nuclear medicine scan or echocardiogram (if done), demonstrating cardiac ejection fraction <35% Participant has persistent or active infection(s) requiring hospitalization or treatment with antibiotics, antiretrovirals, or antifungals within 30 days prior to baseline. Minocycline and doxycycline are not considered antibiotics when used to treat sarcoidosis. Any significant finding in the patient's medical history or physical or psychiatric exam prior to or after randomization that, in the opinion of the investigator, would affect patient safety or compliance or ability to deliver the study drug according to protocol. On medications that interact with the antibiotics of the CLEAR regimen History of or receiving treatment for pulmonary hypertension. Receiving biologic medication within the 6 months prior to screening visit

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin<br>Levofloxacin 500mg po QD; Ethambutol 1200mg po QD; Azithromycin 250 mg po QD; Rifampin 600mg po QD or Rifabutin 300mg po QD | Drug: Levofloxacin<br> <br> * Other names: Levaquin;Drug: Ethambutol<br> <br> Drug: Azithromycin<br> <br> * Other names: Z-pack;Drug: Rifampin<br> <br> * Other names: Rifadin, Rimactane;|
| Placebo Comparator: Placebo<br>Riboflavin will be used for rifampin; encapsulated microcrystalline cellulose will be used to replace the levofloxacin, ethambutol and azithromycin. The pill count will be the same as the comparator regimen. | Drug: Placebo<br>* This will serve as a placebo to the antibiotics used in antimycobacterial therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Percent Predicted Absolute Forced Vital Capacity (FVC) in Participants With Pulmonary Sarcoidosis, Comparing Baseline With Performance After Completion of 16 Weeks of Therapy. | Change in percent predicted absolute forced vital capacity (FVC) in participants with pulmonary sarcoidosis, comparing baseline with performance after completion of 16 weeks of therapy. This will involve comparing sarcoidosis and placebo after 16 weeks of therapy. | Baseline to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Radiographic Improvement in Sarcoidosis Lung Disease by Frontal Chest X-ray . | Radiographic improvement in sarcoidosis lung disease by frontal chest x-ray . Local investigators will score chest x-rays. | Baseline and 16 weeks | 
| Six Minute Walk, Distance in Meters | The 6-min walk test (6 MWT) is a submaximal exercise test that entails measurement of distance walked over a span of 6 minutes. | Baseline, 4, 8, and 16 and 24 weeks | 
| Change in Oxygen Saturation | measured using pulse oximetry | Baseline, 4, 8, and 16 and 24 weeks | 
| Change in Level of Dyspnea | Outcome measure if a composite | Baseline, 4, 8 and 16 weeks | 
| Change in the Saint George's Respiratory Questionnaire (SGRQ) | The SGRQ is a 50-item questionnaire developed to measure health status (quality of life) in patients with diseases of airways obstruction. Scores range from 0 to 100, with higher scores indicating more limitations. A minimum change in score of 4 units was established as clinically relevant after patient and clinician testing. | Baseline and 16 weeks | 
| Fatigue Assessment Scale (FAS). | The FAS is a 10-item general fatigue questionnaire to assess fatigue. Total scores can range from 10, indicating the lowest level of fatigue, to 50, denoting the highest. | Baseline, 4, 8, 16 and 24 weeks | 
| Change in the King's Sarcoidosis Questionnaire (KSQ) for the Assessment of Health Status; | The KSQ is a free, online questionnaire to be filled out by sarcoidosis patients. The questionnaire takes around 10 minutes and is split into 5 sections; general health status, lungs, medication, skin and eyes. There are 29 questions in total, however some questions may not be answered (depending on the type of sarcoidosis affected). Each question asks patients to rate how they feel about many different aspects of their life, for instance how much pain they are in or how difficult they find everyday tasks. Information provided is confidential. Results are given as a number between 1-100 with higher numbers indicating better health. | Baseline and 16 weeks | 
| Adverse Events | Safety profile of regimen as evidenced by the number of adverse events | 24 weeks | 
| FEV1% | FEV1% was measure pre and post 6 minute walk test | Baseline, 4, 8, and 16 and 24 weeks | 
| Failure of Standard Therapy | We will assess how many subjects in either arm need escalation of their standard regimen (ie increase in prednisone) during the 16 weeks. | Baseline to 16 weeks | 
| Abnormal Lab Values | Safety profile of regimen as evidenced by the number of abnormal lab values classified as Adverse Events | baseline to 16 weeks |