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Genomic Research in Alpha-1 Antitrypsin Deficiency

Information source: University of Pittsburgh
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Alpha 1 Antitrypsin Deficiency; AATD

Phase: N/A

Status: Recruiting

Sponsored by: University of Pittsburgh

Official(s) and/or principal investigator(s):
Naftali Kaminski, MD, Principal Investigator, Affiliation: Yale University
Stephen Wisniewski, PhD, Principal Investigator, Affiliation: University of Pittsburgh
Michael Becich, MD, PhD, Principal Investigator, Affiliation: University of Pittsburgh

Overall contact:
Naftali Kaminski, MD, Phone: 203-737-4612, Email: naftali.kaminski@yale.edu

Summary

This project is designed to examine the interaction between the microflora in the lower airway and the concentration of a serum protein called alpha-1 antitrypsin. The hypothesis is that alpha-1 antitrypsin impacts the diversity and content of the lower airway microflora, resulting in a less inflammatory airway. The Specific Aims are: 1. To compare the lower respiratory tract microbiome and virome population diversity and content in age and GOLD stage matched PiZZ individuals not receiving augmentation therapy, PiZZ individuals on augmentation therapy, PiMZ individuals not receiving augmentation therapy, and PiMM individuals with chronic obstructive pulmonary disease (COPD). 2. Determine correlations between bronchoalveolar lavage (BAL) and peripheral blood gene expression patterns and patterns in lung microbial and viral populations across all cohorts. 3. Correlate the presence or absence of computed tomography (CT) bronchiectasis and bronchiolectasis with patterns in the microbiome population diversity and content. 4. To identify and define novel molecular phenotypes of Alpha-1 Antitrypsin Deficiency (AATD) based on computational integration of clinical, transcriptomic, and microbiome data.

Clinical Details

Official title: Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) - Alpha-1 Protocol

Study design: Observational Model: Case-Only, Time Perspective: Cross-Sectional

Primary outcome: Number and diversity of lower respiratory tract (LRT) microbes

Detailed description: Alpha-1 Antitrypsin Deficiency (AATD, Alpha-1) is a genetic condition that predisposes to early onset pulmonary emphysema and airways obstruction, often indistinguishable from usual smoker's chronic obstructive pulmonary disease (COPD). Prominent features of AATD COPD include basilar predominant panacinar emphysema, frequent radiographic bronchiectasis, and a prominent interaction with environmental factors that influence clinical disease phenotypes. Alpha-1 antitrypsin (AAT) is the most abundant serum and lung antiprotease and has a variety of biologic activities that influence lung homeostasis. Prominent among these are roles in neutrophil elastase inhibition, antiprotease activities against cathepsins, involvement in the complement cascade, and interaction with toll receptors. Since the effects of AAT on lung homeostasis remain poorly understood, the Alpha-1 protocol for the Genomic Research in AAT Deficiency and Sarcoidosis (GRADS) grant (hereafter called GRADS Alpha-1 protocol) is designed to investigate the overarching hypothesis that alpha-1 antitrypsin (AAT) impacts the diversity and content of the lower airway microflora, resulting in a less inflammatory airway. Since the risk for bronchiectasis, COPD severity as measured by GOLD stage, and emphysema extent is proportional to the serum AAT concentration, comparison between different genotypes of AAT replete and deficient populations will provide data to determine if the diversity and content of the lower airway microflora influence the risk of COPD in the AATD population. The AATD population is selected because these individuals have a measurable interaction with environmental burdens22,28 and may be key to garnering an understanding of the interplay between this important anti-protease, airways and lower lung inflammation, peripheral blood gene expression, and radiologic and clinical phenotypes of COPD. The GRADS Alpha-1 Study is a prospective cross-sectional cohort study that will enroll approximately 200 participants at seven clinical centers with a total of nine recruitment locations over two years. An ancillary application to SPIROMICS will request data from 50 PiMM subjects, all (estimate 10) PiMZ subjects, and any (estimate 1) PiZZ subjects. The remainder of the participants (N=~139) will be recruited through GRADS Alpha-1 centers. All participants will have two study-related visits (Baseline and Bronchoscopy). During the study visits, clinic staff will conduct physical examinations and tests, collect biological specimens, and administer a series of questionnaires to study participants. Participants could also receive a telephone call to determine the final status of any adverse event, 1 month after study conclusion.

Eligibility

Minimum age: 40 Years. Maximum age: 80 Years. Gender(s): Both.

Criteria:

Inclusion Criteria: 1. Age between age 40 and 80 (inclusive) at Baseline Visit 2. Alpha-1 Antitrypsin genotype PiZZ or PiMZ 3. Able to tolerate and willing to undergo study procedures 4. Signed informed consent Exclusion Criteria: 1. History of comorbid condition severe enough to significantly increase risks based on investigator discretion 2. Diagnosis of unstable cardiovascular disease including myocardial infarction in the past 6 weeks, uncontrolled congestive heart failure, or uncontrolled arrhythmia 3. Partial pressure of oxygen in the blood (PaO2) on room air at rest <50 mmHg or saturation level of oxygen in hemoglobin(SaO2) on room air at rest <85% 4. Post bronchodilator Forced Expiratory Volume in One Second (FEV1)<30% predicted 5. Use of anticoagulation (patients on warfarin or clopidogrel will be excluded; patients on aspirin alone can be studied even with concurrent use) 6. 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 7. Active pulmonary infection with tuberculosis 8. History of pulmonary embolism in the past 2 years 9. Non-COPD obstructive disease (various bronchiolitides, sarcoid, LAM, histiocytosis X) or parenchymal lung disease, pulmonary vascular disease, pleural disease, severe kyphoscoliosis, neuromuscular weakness, or other cardiovascular and pulmonary disease, that, in the opinion of the investigator, limit the interpretability of the pulmonary function measures 10. Prior significant difficulties with pulmonary function testing 11. Hypersensitivity to or intolerance of albuterol sulfate or ipratropium bromide or propellants or excipients of the inhalers 12. Hypersensitivity to or intolerance of all drugs required for sedation during conscious sedation bronchoscopy. 13. History of Lung volume reduction surgery, lung resection or bronchoscopic lung volume reduction in any form 14. History of lung or other organ transplant 15. History of large thoracic metal implants (e. g., Automatic Implantable Cardioverter Defibrillators (AICD) and/or pacemaker) that in the opinion of the investigator limit the interpretability of CT scans 16. Currently taking >=10mg a day/20mg every other day of prednisone or equivalent systemic corticosteroid 17. Currently taking any immunosuppressive agent excepting systemic corticosteroids 18. History of lung cancer or any cancer that spread to multiple locations in the body 19. Current illicit substance abuse, excluding marijuana 20. Known HIV/AIDS infection 21. History of or current exposure to chemotherapy or radiation treatments that, in the opinion of the investigator, limits the interpretability of the pulmonary function measures. 22. Has a BMI > 40 kg/m2 at baseline exam 23. Current or planned pregnancy within the study course. 24. Currently institutionalized (e. g., prisons, long-term care facilities) 25. Have a genotype of PiMZ and ever received intravenous or inhaled alpha-1 augmentation therapy (Alpha-1 Proteinase Inhibitor, A1PI) 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 six weeks can be rescreened for the study once the six-week window has passed. 2. Participants who present with current use of acute antibiotics or steroids can be rescreened for the study ≥30 days after discontinuing acute antibiotics/steroids. This does not apply to participants who are on chronic prednisone therapy of <10 mg per day or <20 mg every other day. 3. Participants who present with a myocardial infarction or eye, chest, or abdominal surgery within six weeks can be rescreened after the six week window has passed. Study coordinators should consult with the site principal investigator prior to rescreening these participants. 4. Female participants who present <3 months after giving birth will be asked to reschedule their visit until three months have passed since the birth. 5. Individuals who are PiZZ receiving alpha-1 augmentation therapy (Alpha-1 Proteinase Inhibitor, A1PI) must be off augmentation therapy for >6 months to qualify for stratified enrollment in the PiZZ group not receiving augmentation therapy.

Locations and Contacts

Naftali Kaminski, MD, Phone: 203-737-4612, Email: naftali.kaminski@yale.edu

Arizona Health Sciences Center, Tucson, Arizona 85742, United States; Recruiting
Nancy Casanova, MD, Email: ngcasan@uic.edu
Skip Garcia, MD, Principal Investigator
Kenneth Knox, MD, Sub-Investigator

University of California - San Francisco, San Francisco, California 94143, United States; Recruiting
Joris Ramstein, BA, Phone: 415-476-5896, Email: Joris.Ramstein@ucsf.edu
Laura Koth, MD, Email: laura.koth@ucsf.edu
Laura Koth, MD, Principal Investigator

National Jewish Health, Denver, Colorado 80206, United States; Recruiting
Nabeel Hamzeh, MD, Phone: 303-398-1867, Email: hamzehn@njhealth.org
Briana Barkes, Email: barkesb@njhealth.org
Lisa Maier, MD, Principal Investigator
Nabeel Hamzeh, MD, Sub-Investigator

Yale University, New Haven, Connecticut 06510, United States; Recruiting
Erica Herzog, MD, PhD, Phone: 203-785-3207, Email: erica.lyndrup@yale.edu
Donna Carrano, RN, Email: donna.carrano@yale.edu
Erica Herzog, MD, PhD, Principal Investigator

Johns Hopkins University, Baltimore, Maryland 21224, United States; Recruiting
Edward Chen, MD, Phone: 410-550-8663, Email: chenedwa@jhmi.edu
Linda Breslin, Email: sarcoidosisresearch@jhmi.edu
David Moller, MD, Principal Investigator
Edward Chen, MD, Sub-Investigator

University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States; Recruiting
Ayannah Fitzgerald, BAS/BSN, Phone: 215-662-6041
Ronald Collman, MD, Email: collmanr@mail.med.upenn.edu
Milton Rossman, MD, Principal Investigator
Ronald Collman, MD, Principal Investigator

University of Pittsburgh, Pittsburgh, Pennsylvania 15213, United States; Recruiting
Stephen Bruno, BA, Phone: 412-605-1550, Email: brunos@upmc.edu
Kevin Gibson, MD, Phone: 412-624-7225, Email: gibsonkf@upmc.edu
Kevin Gibson, MD, Principal Investigator

Medical University of South Carolina, Charleston, South Carolina 29425, United States; Recruiting
Charlie Strange, MD, Phone: 843-792-6474, Email: strangec@musc.edu
Deirdre Walker, Email: waldei@musc.edu
Charlie Strange, MD, Principal Investigator

Vanderbilt University, Nashville, Tennessee 37240, United States; Recruiting
Wonder Drake, MD, Phone: 615-322-2035, Email: wonder.drake@vanderbilt.edu
Wonder Drake, MD, Principal Investigator

Additional Information

Study Website

Starting date: May 2013
Last updated: January 10, 2014

Page last updated: August 23, 2015

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