Sarcoidosis
Conditions
Keywords
sarcoidosis, CCR5 inhibition, maraviroc
Brief summary
The study hypothesizes that inhibition of the receptor CCR5 by maraviroc will diminish inflammation in patients with sarcoidosis. Subjects with active sarcoidosis will first undergo bronchoscopy with bronchoalveolar lavage to recover lung immune cells for baseline analysis. They will then receive the drug maraviroc for 6 weeks duration. They will then undergo a repeat bronchoscopy with bronchoalveolar lavage to recover lung immune cells for analysis following maraviroc treatment.
Detailed description
The investigators hypothesize that inhibition of CCR5 by maraviroc may have a beneficial immunomodulatory effect on the granulomatous inflammation of pulmonary sarcoidosis. The specific aim of this proposal is the investigate the effect of CCR5 inhibition on the trafficking of mononuclear cells to the lung, skin, peripheral blood in subjects with active sarcoidosis exposed to the CCR5 inhibitor, maraviroc. A second aim will be to isolate by cell sorting cluster of differentiation 4 (CD4)+CCR5+ T cells for amplified gene expression profiling before and after CCR5 inhibition, experiments the investigators believe will elucidate genes associated with downstream activation and inhibition of CCR5 receptor function.
Interventions
DRUGall subjects will receive maraviroc 300mg orally twice a day for 6 weeks
Bronchoscopy employs a flexible instrument that is inserted into the trachea and proximal airways after topical anesthesia. Bronchoalveolar lavage involves the instillation of saline solution through the bronchoscope into the airways followed by recovery under suction to collects lung fluid containing cells and proteins.
PROCEDUREvenipunctures
Venipunctures will be performed at study entry, after two weeks, and at the end of the study to collect blood for research studies and safety laboratories.
PROCEDURESkin biopsy
For subjects with sarcoidosis skin lesions, an optional skin biopsy specimen may be collected for research studies.
Sponsors
University of Pittsburgh
Kevin F. Gibson
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically proven sarcoidosis from any site (noncaseating granulomas without other causes). 2. Diagnosis of active sarcoidosis (Sec. 5.5.4.t) clinical stage II by Chest X-ray (CXR). 3. Forced Vital Capacity (FVC) \>45% and Diffusing Capacity for Carbon Monoxide (DLCO) \>50% of predicted values. 4. Evidence of active sarcoidosis (see criteria above) 5. Able and willing to complete all study procedures (e.g., bronchoscopy, post-drug surveillance) 6. Age: 18+ years old (prevalence greatest in young adults; pediatric maraviroc safety not established). 7. Not on immunosuppression for sarcoidosis at the time of recruitment, (e.g., steroids, tumor necrosis factor alpha (TNF-a) blockade) 8. Liver function (transaminases, bilirubin), coagulation (International Normalized Ratio (INR), partial thromboplastin time (PTT), platelet count), blood urea nitrogen (BUN), creatinine, and white blood count (WBC) within normal limits. 9. If female: negative pregnancy test, agreement to use reliable contraception if of childbearing potential 30 days prior and for 30 days after study completion (drug safety during pregnancy not established). 10. Negative HIV and HBsAg tests
Exclusion criteria
1. Diagnosis of infection based upon clinical evaluation and/or microbial testing. 2. The diagnosis of any disease involving the heart, lungs, liver (HVC), kidney, hematologic, endocrine, or Gl systems which, in the judgment of the PI, would pose an undue risk to the subject if they participated in this study. This includes but is not limited to diabetes, uncontrolled hypertension, liver disease (HVC), or history of malignancy. 3. Medications that will either inhibit or induce CYP3A4 (including St John's Wort)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Cell Count and Differentials in Blood and Bronchoalveolar Lavage Fluid Pre- and Post Maraviroc | 6 weeks | General indicators of inflammation following chemokine receptor 5 (CCR5) inhibition in blood and bronchoalveolar lavage |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mononuclear Cell (MNC) Activation and T-cell Differentiation | 6 weeks | MNC activation and T-cell differentiation before and after CCR5 inhibition. |
| Chemokine Receptor 5 (CCR5) Expression Among These Immune Effector Cells | 6 weeks | CCR5 expression among these immune effector cells before and after CCR5 inhibition. |
Countries
United States
Participant flow
Recruitment details
Subjects with sarcoidosis stage II and active disease
Pre-assignment details
Willing to undergo two Bronchoalveolar lavages
Participants by arm
| Arm | Count |
|---|---|
| Sarcoidosis Stage II All subjects with active stage II sarcoidosis with or without skin disease will receive the drug maraviroc 300mg to be taken orally twice a day for 6 weeks duration.
all subjects will receive maraviroc 300mg orally twice a day for 6 weeks
Bronchoscopy with bronchoalveolar lavage: Bronchoscopy employs a flexible instrument that is inserted into the trachea and proximal airways after topical anesthesia. Bronchoalveolar lavage involves the instillation of saline solution through the bronchoscope into the airways followed by recovery under suction to collects lung fluid containing cells and proteins.
venipunctures: Venipunctures will be performed at study entry, after two weeks, and at the end of the study to collect blood for research studies and safety laboratories.
Skin biopsy: For subjects with sarcoidosis skin lesions, an optional skin biopsy specimen may be collected for research studies. | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | Sarcoidosis Stage II |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Age, Continuous | 37 years |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 3 |
| serious Total, serious adverse events | 0 / 3 |
Outcome results
Primary
Total Cell Count and Differentials in Blood and Bronchoalveolar Lavage Fluid Pre- and Post Maraviroc
General indicators of inflammation following chemokine receptor 5 (CCR5) inhibition in blood and bronchoalveolar lavage
Time frame: 6 weeks
Population: Data could not be analyzed
| Arm | Measure | Group | Value |
|---|---|---|---|
| Unknown | Total Cell Count and Differentials in Blood and Bronchoalveolar Lavage Fluid Pre- and Post Maraviroc | total cell count and differential in blood and BAL | — |
| Unknown | Total Cell Count and Differentials in Blood and Bronchoalveolar Lavage Fluid Pre- and Post Maraviroc | Mononuclear cell activation and T cell differentia | — |
Secondary
Chemokine Receptor 5 (CCR5) Expression Among These Immune Effector Cells
CCR5 expression among these immune effector cells before and after CCR5 inhibition.
Time frame: 6 weeks
Population: Study was terminated before data were collected for this outcome measure.
Secondary
Mononuclear Cell (MNC) Activation and T-cell Differentiation
MNC activation and T-cell differentiation before and after CCR5 inhibition.
Time frame: 6 weeks
Population: Study was terminated before data were collected for this outcome measure.