Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) - Sarcoidosis Protocol
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 368
- 试验地点
- 9
- 主要终点
- PBMC Gene Expression
研究概览
简要总结
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:
- To identify peripheral blood mononuclear cell (PBMC) gene expression patterns that characterize distinct sarcoidosis phenotypes.
- To determine whether patterns in the lung microbiome are associated with sarcoidosis severity and disease phenotypes
- To correlate mRNA and microRNA expression patterns in sarcoidosis affected organs with changes in microbiome, clinical parameters and PBMC gene expression patterns
- To integrate clinical, transcriptomic, and microbiome data to identify novel molecular phenotypes in sarcoidosis.
详细描述
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
- To identify peripheral blood mononuclear cell (PBMC) gene expression patterns that characterize distinct sarcoidosis phenotypes.
- To determine whether patterns in the lung microbiome are associated with sarcoidosis severity and disease phenotypes
- To correlate mRNA and microRNA expression patterns in sarcoidosis affected organs with changes in microbiome, clinical parameters and PBMC gene expression patterns
- To integrate clinical, transcriptomic, and microbiome data to identify novel molecular phenotypes in sarcoidosis.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age between the ages of 18 and
- •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).
- •Able to tolerate and willing to undergo study procedures.
- •Be capable of understanding study forms.
- •Provide signed informed consent.
排除标准
- •History of comorbid condition severe enough to significantly increase risks based on investigator discretion.
- •Currently an active smoker.
- •Undergoing bronchoscopy (clinical or research) with any one of the following:
- •severe pulmonary impairment (<50% predicted FVC, <1 L FEV1; DLco <40% predicted, resting hypoxemia <92% with or without supplemental oxygen)
- •other co-morbid disease that would preclude bronchoscopy.
- •hypersensitivity to or intolerance of any of the drugs required for sedation during conscious sedation bronchoscopy.
- •Known systemic autoimmune disease such as rheumatoid arthritis, lupus, scleroderma, Sjögrens, etc.
- •Found to have an alternative interstitial lung disease during evaluation and/or screening.
- •Diagnosis of unstable cardiovascular disease including myocardial infarction in the past 6 weeks, uncontrolled congestive heart failure, or uncontrolled arrhythmia
- •Use of anticoagulation (patients on warfarin or clopidogrel will be excluded, patients on aspirin alone can be studied even with concurrent use)
- •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
- •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
- •Primary biliary cirrhosis or autoimmune hepatitis
- •Crohn's disease
- •Chronic beryllium disease
- •Have an active bacterial or viral infection at time of screening.
- •Have an active or ongoing serious infection, including HIV, HBV and HCV
- •Active tuberculosis or are taking any medication for tuberculosis
- •Have a history of demyelinating diseases, lymphoproliferative diseases, or other malignancies other than presumed cured non-metastatic skin cancer
- •Have evidence of a likely malignancy on chest x-ray
- •Are currently pregnant at time of screening
- •Currently institutionalized (e.g., prisons, long-term care facilities)
- •Hypersensitivity to or intolerance of albuterol sulfate or propellants or excipients of the inhalers
- •History of Lung volume reduction surgery, lung resection or bronchoscopic lung volume reduction in any form.
- •History of lung or other organ transplant
- •Unable to comprehend consent document and/or questionnaires
- •Conditional Exclusions:
- •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.
- •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.
- •Female participants who present <3 months after giving birth will be asked to reschedule their visit until three months have passed since the birth.
- •Former smoker who quit < 3months prior to enrollment
结局指标
主要结局
PBMC Gene Expression
时间窗: 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).
次要结局
未报告次要终点
研究者
Naftali Kaminski
-Ingelheim Professor of Internal Medicine and Chief of Pulmonary, Critical Care and Sleep Medicine
Yale University