Genomic Research in Alpha-1 Antitrypsin Deficiency

AATD Clinical Trial

— GRADS Alpha-1  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01832220
• Other study ID #: 13010343
• Secondary ID: U01HL112707
• Status: Completed
• Phase: N/A
• First received: April 8, 2013
• Last updated: January 11, 2016
• Start date: May 2013
• Est. completion date: September 2015

Study information

• Verified date: January 2016
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal GovernmentUnited States: Institutional Review BoardUnited States: Observational Safety Monitoring Board
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 140
• Est. completion date: September 2015
• Est. primary completion date: June 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years to 80 Years

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• AATD
• Alpha 1 Antitrypsin Deficiency
• Alpha 1-Antitrypsin Deficiency

Locations

Country	Name	City	State
United States	Johns Hopkins University	Baltimore	Maryland
United States	Medical University of South Carolina	Charleston	South Carolina
United States	National Jewish Health	Denver	Colorado
United States	Vanderbilt University	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	University of California - San Francisco	San Francisco	California
United States	Arizona Health Sciences Center	Tucson	Arizona

Sponsors (2)

Lead Sponsor	Collaborator
University of Pittsburgh	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No

External Links

•   Study Website