Genomic Research in Sarcoidosis (GRADS Sarc)

• ClinicalTrials.gov Identifier: NCT01831739
• Recruitment Status: Completed
• First Posted: April 15, 2013
• Last Update Posted: January 12, 2016
• Sponsor: University of Pittsburgh
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Naftali Kaminski, Yale University

Study Description

Brief Summary:

This project is designed to address the following hypothesis:

Distinct patterns in lung microbiome are characteristic of sarcoidosis phenotypes and reflected in changes in systemic inflammatory responses as measured by peripheral changes in gene transcription.

The Specific Aims are:

1. To identify peripheral blood mononuclear cell (PBMC) gene expression patterns that characterize distinct sarcoidosis phenotypes.
2. To determine whether patterns in the lung microbiome are associated with sarcoidosis severity and disease phenotypes
3. To correlate mRNA and microRNA expression patterns in sarcoidosis affected organs with changes in microbiome, clinical parameters and PBMC gene expression patterns
4. To integrate clinical, transcriptomic, and microbiome data to identify novel molecular phenotypes in sarcoidosis.

Condition or disease
Sarcoidosis

Detailed Description:

Sarcoidosis is a systemic disease characterized by the formation of granulomatous lesions, especially in the lungs, liver, skin, and lymph nodes, with a heterogeneous set of clinical manifestations and a variable course 1. Despite significant progress in the understanding of the genetic predisposition and role of immunity, it is still a challenge to explain the clinical presentation of sarcoidosis. Standard clinical assessment, imaging, and pulmonary function tests (PFTs) do not allow prediction of disease course and response to therapy. Furthermore, there are no good long-term therapies. Considering that the interactions between potential infections, changes in systemic inflammation, and patterns in lung microbiome and the different and distinct disease phenotypes in sarcoidosis are not well understood, the Sarcoidosis protocol for the Genomic Research in AAT Deficiency and Sarcoidosis (GRADS) grant (hereafter called GRADS Sarcoidosis protocol) is designed to address the following:

Hypothesis

Distinct patterns in lung microbiome are characteristic of sarcoidosis phenotypes and reflected in changes in systemic inflammatory responses as measured by peripheral changes in gene transcription.

Specific Aims

1. To identify peripheral blood mononuclear cell (PBMC) gene expression patterns that characterize distinct sarcoidosis phenotypes.
2. To determine whether patterns in the lung microbiome are associated with sarcoidosis severity and disease phenotypes
3. To correlate mRNA and microRNA expression patterns in sarcoidosis affected organs with changes in microbiome, clinical parameters and PBMC gene expression patterns
4. To integrate clinical, transcriptomic, and microbiome data to identify novel molecular phenotypes in sarcoidosis.

Focusing on accessible PBMCs should enable GRADS researchers to identify markers for disease phenotypes, severity, and outcome. Analysis of lesional transcriptomes (mRNA, microRNA and lincRNA) will add mechanistic insights. High throughput unbiased analysis of the lung microbiome will potentially identify patterns in the lung microbiome that determine disease activity and persistence, as well as response to therapy.

Participants are assigned a provisional clinical phenotype upon obtaining consent at time of enrollment by the respective recruiting center. Clinical phenotypes will be reviewed, confirmed, and monitored to ensure achievement of study objectives. Participants who cannot be assigned a clinical phenotype after the initial study visit will be excluded from additional study participation.

Study Design

• Study Type: Observational
• Actual Enrollment: 368 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) - Sarcoidosis Protocol
• Study Start Date: May 2013
• Actual Primary Completion Date: June 2015
• Actual Study Completion Date: September 2015

Groups and Cohorts

Group/Cohort
Multi-organ; Non-acute presentation, any Scadding stage, evidence of 5 or more organ systems involved, chronic or uncertain clinical course.
Non-acute, Stage I, untreated; Non-acute presentation, Scadding stage I, no multi-organ involvement, chronic or uncertain clinical course, no cardiac manifestations, untreated for at least 3 months.
Stage II-III, treated; Non-acute presentation, Scadding stages II or III, no multi-organ involvement, chronic or uncertain clinical course, no cardiac manifestations, treated for at least 3 months.
Stage II-III, untreated; Non-acute presentation, Scadding stage II or III, no multi-organ involvement, chronic or uncertain clinical course, no cardiac manifestations, untreated for at least 3 months.
Stage IV treated; Non-acute presentation, Scadding stage IV, no multi-organ involvement, chronic or uncertain clinical course, no cardiac manifestations, treatment current and for at least 3 months.
Stage IV untreated; Non-acute presentation, Scadding stage IV, no multi-organ involvement, chronic or uncertain clinical course, no cardiac manifestations, untreated for at least 3 months.
Acute Sarcoidosis, untreated; Acute presentation, Scadding stages I, II, or III, chronic or uncertain clinical course, no cardiac manifestations, untreated for at least 3 months.
Remitting, untreated; Remitting clinical course, no treatment for at least 3 months.
Cardiac defining therapy; Chronic or uncertain clinical course, no multi-organ involvement, cardiac manifestations defining need for systemic corticosteroid and/or immunomodulatory therapy.

Outcome Measures

Primary Outcome Measures :

1. PBMC Gene Expression [ Time Frame: Baseline, 6 months, 12 months ]
   To identify peripheral blood mononuclear cell (PBMC) gene expression patterns that characterize distinct sarcoidosis phenotypes, samples will be run in batches in block designs (equal numbers of phenotypes) and batches will be analyzed independently to determine reproducibility - a subset of samples will be rerun to assure continuity and established normalization algorithms will be applied 1-3. Normalized human transcript (mRNA and microRNA) levels obtained from PBMC will be related to established phenotypes as well as cross phenotype characteristics using linear models, i.e., ANOVA or linear regression using the LIMMA package (http://bioinf.wehi.edu.au) or BRB ArrayTools (http://linus.nci.nih.gov/BRB-ArrayTools.html).

Biospecimen Retention:   Samples With DNA

Serum, plasma, urine, stool, BAL fluid.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Subjects will be prescreened for predefined clinical phenotypes of sarcoidosis. Those who meet initial criteria and ERS/ATS criteria for a sarcoidosis diagnosis will be recruited and phenotyped by questionnaire, physical exam, research chest CT exam, pulmonary function tests, and blood and urine tests with a total recruitment goal of 400.

A subset of participants who have suspected pulmonary sarcoidosis, but who have not undergone a biopsy, will be recruited so that material may be obtained during their clinically indicated biopsy. If a diagnosis of sarcoidosis is confirmed, they will be enrolled and followed. If an alternative diagnosis is made, they will not undergo any further testing.

Participants who cannot be classified within the clinical phenotypes based on data from the initial visit will not continue in the study. Recruitment of participants with defined clinical phenotypes will be monitored and ongoing recruitment goals adjusted to achieve overall study objectives.

Criteria

Inclusion Criteria:

1. Age between the ages of 18 and 85.

2. Have a diagnosis of sarcoidosis established by consensus criteria (ATS/ERS), confirmed by either biopsy or by manifestations consistent with acute sarcoidosis (Löfgren's syndrome) in absence of other known diagnosis.

   OR Have a suspected diagnosis of sarcoidosis and is scheduled to undergo a biopsy procedure to confirm a diagnosis of sarcoidosis using the same consensus criteria (ATS/ERS).

3. Able to tolerate and willing to undergo study procedures.
4. Be capable of understanding study forms.
5. Provide signed informed consent.

Exclusion Criteria:

1. History of comorbid condition severe enough to significantly increase risks based on investigator discretion.
2. Currently an active smoker.

3. Undergoing bronchoscopy (clinical or research) with any one of the following:

   1. severe pulmonary impairment (<50% predicted FVC, <1 L FEV1; DLco <40% predicted, resting hypoxemia <92% with or without supplemental oxygen)
   2. other co-morbid disease that would preclude bronchoscopy.
   3. hypersensitivity to or intolerance of any of the drugs required for sedation during conscious sedation bronchoscopy.
4. Known systemic autoimmune disease such as rheumatoid arthritis, lupus, scleroderma, Sjögrens, etc.
5. Found to have an alternative interstitial lung disease during evaluation and/or screening.
6. Diagnosis of unstable cardiovascular disease including myocardial infarction in the past 6 weeks, uncontrolled congestive heart failure, or uncontrolled arrhythmia
7. Use of anticoagulation (patients on warfarin or clopidogrel will be excluded, patients on aspirin alone can be studied even with concurrent use)
8. Dementia or other cognitive dysfunction which in the opinion of the investigator would prevent the participant from consenting to the study or completing study procedures
9. Non-Sarcoidosis pulmonary disease (e.g., rheumatoid arthritis, lupus, scleroderma) that, in the opinion of the investigator, limits the interpretability of the analysis of sarcoidosis pulmonary disease
10. Primary biliary cirrhosis or autoimmune hepatitis
11. Crohn's disease
12. Chronic beryllium disease
13. Have an active bacterial or viral infection at time of screening.
14. Have an active or ongoing serious infection, including HIV, HBV and HCV
15. Active tuberculosis or are taking any medication for tuberculosis
16. Have a history of demyelinating diseases, lymphoproliferative diseases, or other malignancies other than presumed cured non-metastatic skin cancer
17. Have evidence of a likely malignancy on chest x-ray
18. Are currently pregnant at time of screening
19. Currently institutionalized (e.g., prisons, long-term care facilities)
20. Hypersensitivity to or intolerance of albuterol sulfate or propellants or excipients of the inhalers
21. History of Lung volume reduction surgery, lung resection or bronchoscopic lung volume reduction in any form.
22. History of lung or other organ transplant
23. Unable to comprehend consent document and/or questionnaires

Conditional Exclusions:

1. Participants who present with an upper respiratory infection or pulmonary exacerbation, either solely participant-identified or that has been clinically treated, in the last four weeks can be rescreened for the study once the four-week window has closed.
2. Participants who present with current use of acute antibiotics or have acute antibiotics within the past four weeks can be rescreened for the study ≥28 days after discontinuing acute antibiotics.
3. Female participants who present <3 months after giving birth will be asked to reschedule their visit until three months have passed since the birth.
4. Former smoker who quit < 3months prior to enrollment

Contacts and Locations

Locations

United States, Arizona

Arizona Health Sciences Center

Tucson, Arizona, United States, 85724

United States, California

University of California - San Francisco

San Francisco, California, United States, 94143

United States, Colorado

National Jewish Health

Denver, Colorado, United States, 80206

United States, Connecticut

Yale University

New Haven, Connecticut, United States, 06510

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21224

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

University of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15213

United States, South Carolina

Medical University of South Caolina

Charleston, South Carolina, United States, 29425

United States, Tennessee

Vanderbilt University

Nashville, Tennessee, United States, 37240

Sponsors and Collaborators

University of Pittsburgh

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Naftali Kaminski, MD; Yale University
• Principal Investigator: Stephen Wisniewski, PhD; University of Pittsburgh
• Principal Investigator: Michael Becich, MD, PhD; University of Pittsburgh

More Information

Additional Information:

Study Website 

• Responsible Party: Naftali Kaminski, -Ingelheim Professor of Internal Medicine and Chief of Pulmonary, Critical Care and Sleep Medicine, Yale University
• ClinicalTrials.gov Identifier: NCT01831739
• Other Study ID Numbers: 13020130; U01HL112707 ( U.S. NIH Grant/Contract )
• First Posted: April 15, 2013
• Last Update Posted: January 12, 2016
• Last Verified: January 2016

Keywords provided by Naftali Kaminski, Yale University:

Genomics; Microbiome; Microflora; Virome

Additional relevant MeSH terms:

Sarcoidosis; Lymphoproliferative Disorders; Lymphatic Diseases