Impact of Chemokine Receptor 5 (CCR5) Inhibition on Sarcoidosis Immunophenotypes (GRADS)

An Interventional Study of the Effect of CCR5 Inhibition With Maraviroc on Immune Cells in the the Lung and in Peripheral Blood of Patients With Sarcoidosis

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.

Study Overview

• Status: Terminated
• Conditions: Sarcoidosis
• Intervention / Treatment: Drug: all subjects will receive maraviroc 300mg orally twice a day for 6 weeks; Procedure: Bronchoscopy with bronchoalveolar lavage; Procedure: venipunctures; Procedure: Skin biopsy

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Dorothy P. and Richard P. Simmons center for Interstitial lung Disease at the University of Pittsburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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.

Drug: all subjects will receive maraviroc 300mg orally twice a day for 6 weeks; Other Names: maraviroc; selzentry; Procedure: 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.; Procedure: 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.; Procedure: Skin biopsy; For subjects with sarcoidosis skin lesions, an optional skin biopsy specimen may be collected for research studies.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mononuclear Cell (MNC) Activation and T-cell Differentiation	MNC activation and T-cell differentiation before and after CCR5 inhibition.	6 weeks
Chemokine Receptor 5 (CCR5) Expression Among These Immune Effector Cells	CCR5 expression among these immune effector cells before and after CCR5 inhibition.	6 weeks

Collaborators and Investigators

• Sponsor: Kevin F. Gibson
• Collaborators: University of Pittsburgh
• Investigators: Principal Investigator: Kevin F Gibson, MD, DorothyP. and Richard P. SImmons Center for Interstitial Lung Disease at the University of Pittsburgh

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (Actual): May 1, 2015
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: April 30, 2014
• First Submitted That Met QC Criteria: May 7, 2014
• First Posted (Estimate): May 9, 2014

Study Record Updates

• Last Update Posted (Actual): February 14, 2018
• Last Update Submitted That Met QC Criteria: January 17, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: sarcoidosis; CCR5 inhibition; maraviroc
• Additional Relevant MeSH Terms: Lymphoproliferative Disorders; Lymphatic Diseases; Sarcoidosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Chelating Agents; Sequestering Agents; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; CCR5 Receptor Antagonists; Maraviroc; Dimercaprol
• Other Study ID Numbers: U01HL112711 (U.S. NIH Grant/Contract)