Genomic Research in Alpha-1 Antitrypsin Deficiency

NCT01832220 | Completed DMC

• 2 other identifiers: 13010343U01HL112707
• Study Type: observational
• Target: 140
• Locations: 1 country
• Sites: 9

Brief 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. 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. 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. 3.Correlate the presence or absence of computed tomography (CT) bronchiectasis and bronchiolectasis with patterns in the microbiome population diversity and content.
4. 4.To identify and define novel molecular phenotypes of Alpha-1 Antitrypsin Deficiency (AATD) based on computational integration of clinical, transcriptomic, and microbiome data.

Conditions

Alpha 1 Antitrypsin Deficiency; AATD

Keywords

Genomics; Microbiome; Microflora; Virome; Alpha-1

Outcome Measures

Primary Outcomes (1)

• Number and diversity of lower respiratory tract (LRT) microbes

  Presenting characteristics (e.g., sex) will be compared among those with and without augmentation therapy using the appropriate test for continuous (e.g., t-test, Wilcoxon) or discrete (e.g., chi-square) data. Paired t-test will be used to compare the diversity, as measured by the number of microbes, and McNemar's test will be used to compare the lower respiratory tract (LRT) microbiome and virome, assessed by the presence or absence of specific organisms (e.g., viral, gram negative bacteria). Conditional logistic regression will be used to determine if there is an independent association with the use of augmentation therapy after controlling for presenting characteristics that differed between the two populations. The primary analysis will determine if the PiZZ individuals on augmentation therapy have a difference in the number and diversity of LRT microbes identified than matched PiZZ individuals who are not on augmentation therapy.

  Single time point split into 2 visits over 1 month

Study Arms (4)

PiZZ not on therapy

Individuals with the PiZZ genotype not on augmentation therapy.

PiZZ on therapy

Individuals with the PiZZ genotype on augmentation therapy.

PiMZ not on therapy

Individuals with the PiMZ genotype not on augmentation therapy.

PiMM with COPD

Individuals with the PiMM genotype and COPD.

Eligibility Criteria

• Age: 40 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

The GRADS Alpha-1 Study will enroll approximately 200 participants 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=\~150) will be recruited through nine GRADS clinical sites. Potential participants are invited to participate through the Alpha-1 Foundation Research Registry by email, telephone, mailings, or website per Registry protocols and procedures. Additionally, participants are recruited at the clinical centers by invitations to participate through flyers, websites and mailings and by physician referrals. Other recruitment protocols approved by the local institutional review board for human research are allowed.

You may qualify if:

• Age between age 40 and 80 (inclusive) at Baseline Visit
• Alpha-1 Antitrypsin genotype PiZZ or PiMZ
• Able to tolerate and willing to undergo study procedures
• Signed informed consent

You may not qualify if:

• History of comorbid condition severe enough to significantly increase risks based on investigator discretion
• Diagnosis of unstable cardiovascular disease including myocardial infarction in the past 6 weeks, uncontrolled congestive heart failure, or uncontrolled arrhythmia
• 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%
• Post bronchodilator Forced Expiratory Volume in One Second (FEV1)\<30% predicted
• 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
• Active pulmonary infection with tuberculosis
• History of pulmonary embolism in the past 2 years
• 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
• Prior significant difficulties with pulmonary function testing
• Hypersensitivity to or intolerance of albuterol sulfate or ipratropium bromide or propellants or excipients of the inhalers
• Hypersensitivity to or intolerance of all drugs required for sedation during conscious sedation bronchoscopy.
• History of Lung volume reduction surgery, lung resection or bronchoscopic lung volume reduction in any form
• History of lung or other organ transplant
• 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

Sponsors & Collaborators

• University of Pittsburgh: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (9)

Arizona Health Sciences Center

Tucson, Arizona, 85742, United States

Location

University of California - San Francisco

San Francisco, California, 94143, United States

Location

National Jewish Health

Denver, Colorado, 80206, United States

Location

Yale University

New Haven, Connecticut, 06510, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21224, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Vanderbilt University

Nashville, Tennessee, 37240, United States

Location

Related Publications (1)

• Strange C, Senior RM, Sciurba F, O'Neal S, Morris A, Wisniewski SR, Bowler R, Hochheiser HS, Becich MJ, Zhang Y, Leader JK, Methe BA, Kaminski N, Sandhaus RA; GRADS Alpha-1 Study Group. Rationale and Design of the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis Study. Alpha-1 Protocol. Ann Am Thorac Soc. 2015 Oct;12(10):1551-60. doi: 10.1513/AnnalsATS.201503-143OC.

  PMID: 26153726 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Serum, plasma, urine, stool, BAL fluid.

MeSH Terms

Conditions

alpha 1-Antitrypsin Deficiency

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Subcutaneous Emphysema; Emphysema; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Naftali Kaminski, MD

  Yale University

  PRINCIPAL INVESTIGATOR

• Stephen Wisniewski, PhD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

• Michael Becich, MD, PhD

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Boehringer-Ingelheim Professor of Internal Medicine and Chief of Pulmonary, Critical Care and Sleep Medicine

Study Record Dates

• First Submitted: April 8, 2013
• First Posted: April 16, 2013
• Study Start: May 1, 2013
• Primary Completion: June 1, 2015
• Study Completion: September 1, 2015
• Last Updated: January 12, 2016

Record last verified: 2016-01

Locations

US (9)