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
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