Sarcoidosis; Antimycobacterial Therapy
Conditions
Brief summary
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
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.
Interventions
DRUGLevofloxacin
DRUGEthambutol
DRUGAzithromycin
DRUGRifampin
DRUGPlacebo
This will serve as a placebo to the antibiotics used in antimycobacterial therapy.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Vanderbilt University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Baseline to 16 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Six Minute Walk, Distance in Meters | Baseline, 4, 8, and 16 and 24 weeks | The 6-min walk test (6 MWT) is a submaximal exercise test that entails measurement of distance walked over a span of 6 minutes. |
| Change in Oxygen Saturation | Baseline, 4, 8, and 16 and 24 weeks | measured using pulse oximetry |
| Change in Level of Dyspnea | Baseline, 4, 8 and 16 weeks | Outcome measure if a composite |
| Change in the Saint George's Respiratory Questionnaire (SGRQ) | Baseline and 16 weeks | 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. |
| Fatigue Assessment Scale (FAS). | Baseline, 4, 8, 16 and 24 weeks | 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. |
| Radiographic Improvement in Sarcoidosis Lung Disease by Frontal Chest X-ray . | Baseline and 16 weeks | Radiographic improvement in sarcoidosis lung disease by frontal chest x-ray . Local investigators will score chest x-rays. |
| Adverse Events | 24 weeks | Safety profile of regimen as evidenced by the number of adverse events |
| FEV1% | Baseline, 4, 8, and 16 and 24 weeks | FEV1% was measure pre and post 6 minute walk test |
| Failure of Standard Therapy | Baseline to 16 weeks | We will assess how many subjects in either arm need escalation of their standard regimen (ie increase in prednisone) during the 16 weeks. |
| Abnormal Lab Values | baseline to 16 weeks | Safety profile of regimen as evidenced by the number of abnormal lab values classified as Adverse Events |
| Change in the King's Sarcoidosis Questionnaire (KSQ) for the Assessment of Health Status; | Baseline and 16 weeks | 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. |
Countries
United States
Participant flow
Pre-assignment details
446 participants were screened but only 97 participants met inclusion/exclusion and were randomized.
Participants by arm
| Arm | Count |
|---|---|
| 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
Levofloxacin
Ethambutol
Azithromycin
Rifampin | 49 |
| 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.
Placebo: This will serve as a placebo to the antibiotics used in antimycobacterial therapy. | 48 |
| Total | 97 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo | Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin |
|---|---|---|---|
| 6 minute walk test | 416.33 meters STANDARD_DEVIATION 123.55 | 416.49 meters STANDARD_DEVIATION 105.16 | 416.25 meters STANDARD_DEVIATION 140.69 |
| Age, Continuous | 54.5 years STANDARD_DEVIATION 10 | 54.5 years STANDARD_DEVIATION 10.4 | 54.5 years STANDARD_DEVIATION 9.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 94 Participants | 46 Participants | 48 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Heart Rate | 77.91 beats per minute STANDARD_DEVIATION 13.33 | 76.19 beats per minute STANDARD_DEVIATION 11.66 | 79.59 beats per minute STANDARD_DEVIATION 17.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 28 Participants | 13 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 68 Participants | 34 Participants | 34 Participants |
| Region of Enrollment United States | 97 participants | 48 participants | 49 participants |
| Sex: Female, Male Female | 47 Participants | 27 Participants | 20 Participants |
| Sex: Female, Male Male | 50 Participants | 21 Participants | 29 Participants |
| Weight | 95.19 kilograms STANDARD_DEVIATION 23.24 | 97.54 kilograms STANDARD_DEVIATION 21.99 | 92.78 kilograms STANDARD_DEVIATION 24.45 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 49 | 0 / 48 |
| other Total, other adverse events | 24 / 49 | 16 / 48 |
| serious Total, serious adverse events | 4 / 49 | 3 / 48 |
Outcome results
Primary
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.
Time frame: Baseline to 16 weeks
Population: Only 43 participants in each arm completed this measure
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | 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. | 0.35 percentage predicted absolute FVC | Standard Deviation 6.76 |
| Placebo | 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. | 0.17 percentage predicted absolute FVC | Standard Deviation 7.2 |
Secondary
Abnormal Lab Values
Safety profile of regimen as evidenced by the number of abnormal lab values classified as Adverse Events
Time frame: baseline to 16 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Abnormal Lab Values | low WBC count | 5 participants |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Abnormal Lab Values | elevated glucose | 3 participants |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Abnormal Lab Values | low glucose | 1 participants |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Abnormal Lab Values | low platelet count | 1 participants |
| Placebo | Abnormal Lab Values | low platelet count | 0 participants |
| Placebo | Abnormal Lab Values | low WBC count | 0 participants |
| Placebo | Abnormal Lab Values | low glucose | 1 participants |
| Placebo | Abnormal Lab Values | elevated glucose | 2 participants |
Secondary
Adverse Events
Safety profile of regimen as evidenced by the number of adverse events
Time frame: 24 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Adverse Events | Serious Adverse Events | 4 number of events |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Adverse Events | Non-Serious Adverse Events | 24 number of events |
| Placebo | Adverse Events | Serious Adverse Events | 3 number of events |
| Placebo | Adverse Events | Non-Serious Adverse Events | 16 number of events |
Secondary
Change in Level of Dyspnea
Outcome measure if a composite
Time frame: Baseline, 4, 8 and 16 weeks
Population: this measure was not administered
Secondary
Change in Oxygen Saturation
measured using pulse oximetry
Time frame: Baseline, 4, 8, and 16 and 24 weeks
Population: not all participants completed the measure and it was not recorded at week 24
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Change in Oxygen Saturation | Baseline to week 4 | 0.39 percentage of oxygen saturation | Standard Deviation 3.33 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Change in Oxygen Saturation | Baseline to week 8 | -0.12 percentage of oxygen saturation | Standard Deviation 2.95 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Change in Oxygen Saturation | Baseline to week 16 | 2.54 percentage of oxygen saturation | Standard Deviation 14.8 |
| Placebo | Change in Oxygen Saturation | Baseline to week 4 | -0.85 percentage of oxygen saturation | Standard Deviation 1.95 |
| Placebo | Change in Oxygen Saturation | Baseline to week 8 | -0.43 percentage of oxygen saturation | Standard Deviation 3.31 |
| Placebo | Change in Oxygen Saturation | Baseline to week 16 | -0.46 percentage of oxygen saturation | Standard Deviation 3.79 |
Secondary
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.
Time frame: Baseline and 16 weeks
Population: KSQ was not administered to participants.
Secondary
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.
Time frame: Baseline and 16 weeks
Population: questionnaire was only administered at baseline and 16 weeks and not all participants completed the questionnaire at week 16
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Change in the Saint George's Respiratory Questionnaire (SGRQ) | -2.23 score on a scale | Standard Error 11.9 |
| Placebo | Change in the Saint George's Respiratory Questionnaire (SGRQ) | -6.30 score on a scale | Standard Error 9 |
Secondary
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.
Time frame: Baseline to 16 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Failure of Standard Therapy | 3 Participants |
| Placebo | Failure of Standard Therapy | 2 Participants |
Secondary
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.
Time frame: Baseline, 4, 8, 16 and 24 weeks
Population: The FAS was not administered to participants.
Secondary
FEV1%
FEV1% was measure pre and post 6 minute walk test
Time frame: Baseline, 4, 8, and 16 and 24 weeks
Population: Week 24 assessment was optional. Not all participants completed all measurements
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | FEV1% | 24 weeks post | 73.09 Percentage of predicted FEV1 | Standard Error 18.333 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | FEV1% | 16 weeks post | 71.39 Percentage of predicted FEV1 | Standard Error 18.33 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | FEV1% | 24 weeks pre | 72.22 Percentage of predicted FEV1 | Standard Error 17.73 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | FEV1% | Baseline pre | 69.11 Percentage of predicted FEV1 | Standard Error 17.23 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | FEV1% | Baseline post | 69.97 Percentage of predicted FEV1 | Standard Error 17.01 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | FEV1% | 4 weeks pre | 71.57 Percentage of predicted FEV1 | Standard Error 17.31 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | FEV1% | 4 weeks post | 71.96 Percentage of predicted FEV1 | Standard Error 16.46 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | FEV1% | 8 weeks pre | 69.30 Percentage of predicted FEV1 | Standard Error 17.22 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | FEV1% | 8 weeks post | 70.36 Percentage of predicted FEV1 | Standard Error 17.62 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | FEV1% | 16 weeks pre | 69.88 Percentage of predicted FEV1 | Standard Error 16.5 |
| Placebo | FEV1% | 8 weeks pre | 73.71 Percentage of predicted FEV1 | Standard Error 19.01 |
| Placebo | FEV1% | 24 weeks post | 66.27 Percentage of predicted FEV1 | Standard Error 19.78 |
| Placebo | FEV1% | 4 weeks pre | 69.56 Percentage of predicted FEV1 | Standard Error 20.52 |
| Placebo | FEV1% | 16 weeks post | 70.41 Percentage of predicted FEV1 | Standard Error 20.03 |
| Placebo | FEV1% | 16 weeks pre | 68.27 Percentage of predicted FEV1 | Standard Error 20.17 |
| Placebo | FEV1% | 24 weeks pre | 63.27 Percentage of predicted FEV1 | Standard Error 20.17 |
| Placebo | FEV1% | 4 weeks post | 73.81 Percentage of predicted FEV1 | Standard Error 18.91 |
| Placebo | FEV1% | Baseline pre | 67.45 Percentage of predicted FEV1 | Standard Error 17.85 |
| Placebo | FEV1% | 8 weeks post | 74.3 Percentage of predicted FEV1 | Standard Error 19.05 |
| Placebo | FEV1% | Baseline post | 73.81 Percentage of predicted FEV1 | Standard Error 18.91 |
Secondary
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.
Time frame: Baseline and 16 weeks
Population: The outcome was not completed due to lack of funds for radiology services.
Secondary
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.
Time frame: Baseline, 4, 8, and 16 and 24 weeks
Population: Week 24 assessment was optional. Not all participants completed the 6 minute walk test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Six Minute Walk, Distance in Meters | Week 4 | 432.65 meters | Standard Error 155.5 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Six Minute Walk, Distance in Meters | Week 16 | 440.37 meters | Standard Error 137.08 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Six Minute Walk, Distance in Meters | Week 8 | 451.59 meters | Standard Error 146.12 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Six Minute Walk, Distance in Meters | Week 24 | 444.68 meters | Standard Error 165.09 |
| Concomitant Levaquin, Ethambutol, Azithromycin and Rifampin | Six Minute Walk, Distance in Meters | Baseline | 416.25 meters | Standard Error 140.69 |
| Placebo | Six Minute Walk, Distance in Meters | Week 24 | 425.18 meters | Standard Error 104.95 |
| Placebo | Six Minute Walk, Distance in Meters | Baseline | 416.41 meters | Standard Error 105.15 |
| Placebo | Six Minute Walk, Distance in Meters | Week 4 | 428.35 meters | Standard Error 92.36 |
| Placebo | Six Minute Walk, Distance in Meters | Week 8 | 420.21 meters | Standard Error 93.9 |
| Placebo | Six Minute Walk, Distance in Meters | Week 16 | 430.85 meters | Standard Error 111.96 |