Phase II Investigation of Antimycobacterial Therapy on Progressive, Pulmonary Sarcoidosis

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

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.

Study Overview

• Status: Completed
• Conditions: Sarcoidosis; Antimycobacterial Therapy
• Intervention / Treatment: Drug: Azithromycin; Drug: Levofloxacin; Drug: Rifampin; Drug: Ethambutol; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 97
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Columbus, Ohio, United States, 43221
      • Ohio State University
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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.

2. 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.

3. Possess evidence of parenchymal or nodal disease on chest radiograph.

Exclusion Criteria:

1. Inability to obtain consent
2. Age less than 18 years
3. 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
4. FVC predicted value is < 45%.
5. End-stage fibrotic pulmonary disease.
6. Significant underlying liver disease.
7. Allergy or intolerance to any of the antibiotics within the CLEAR regimen.
8. Allergy or intolerance to albuterol
9. Poor venous access for obtaining blood samples
10. 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.
11. Significant disorder, other than sarcoidosis, that would complicate the treatment evaluation, (such as respiratory, cardiac, neurologic, musculoskeletal or seizure disorders)
12. Use of an investigational drug within 30 days prior to screening or within 5 half-lives of the agent, whichever is longer.
13. Currently receiving >40mg prednisone.
14. ALT or AST >5 times upper limit of normal (ULN)
15. Leukopenia, as defined by WBC <3.0 cells/mm3 or absolute neutrophil count <1000
16. Breast feeding.
17. 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.
18. If patient is on immunomodulators, they must be on regimen for ≥ 3-month period and on a stable dose for > 4 weeks.
19. Family or personal history of long QT interval
20. Most recent nuclear medicine scan or echocardiogram (if done), demonstrating cardiac ejection fraction <35%
21. 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.
22. 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.
23. On medications that interact with the antibiotics of the CLEAR regimen
24. History of or receiving treatment for pulmonary hypertension. Receiving biologic medication within the 6 months prior to screening visit

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin; Levofloxacin 500mg po QD; Ethambutol 1200mg po QD; Azithromycin 250 mg po QD; Rifampin 600mg po QD or Rifabutin 300mg po QD	Drug: Azithromycin; Other Names: Z-pack; Drug: Levofloxacin; Other Names: Levaquin; Drug: Rifampin; Other Names: Rifadin, Rimactane; Drug: Ethambutol
Placebo Comparator: Placebo; 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; This will serve as a placebo to the antibiotics used in antimycobacterial therapy.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Vanderbilt University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Wonder Drake, MD, Vanderbilt University School of Medicine

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (Actual): April 1, 2019
• Study Completion (Actual): April 1, 2019

Study Registration Dates

• First Submitted: December 26, 2013
• First Submitted That Met QC Criteria: December 26, 2013
• First Posted (Estimate): December 31, 2013

Study Record Updates

• Last Update Posted (Actual): July 9, 2020
• Last Update Submitted That Met QC Criteria: July 7, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Lung Diseases; Lung Diseases, Interstitial; Sarcoidosis, Pulmonary; Sarcoidosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Cytochrome P-450 CYP1A2 Inhibitors; Anti-Infective Agents, Urinary; Renal Agents; Rifampin; Azithromycin; Levofloxacin; Ofloxacin; Ethambutol
• Other Study ID Numbers: R01HL117074 (U.S. NIH Grant/Contract); R01HL117074-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No