Alpha 1 Antitrypsin DeficiencyGRADS Alpha-1NCT01832220
Genomic Research in Alpha-1 Antitrypsin Deficiency
An observational study of Alpha 1 Antitrypsin Deficiency and AATD, run by University of Pittsburgh at 9 sites in United States.
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. Read more about this study
- Who is it for?
- Ages 40 to 80 years
- Conditions the study is for
- Alpha 1 Antitrypsin Deficiency, AATD
- How many people
- 140 participants
- Where
- 9 sitesUnited States
- Study dates
- May 2013to Sep 2015
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
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.
Who may be able to join
- 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
Who cannot join
- 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
Show all 31Show fewer
- 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
- Currently taking >=10mg a day/20mg every other day of prednisone or equivalent systemic corticosteroid
- Currently taking any immunosuppressive agent excepting systemic corticosteroids
- History of lung cancer or any cancer that spread to multiple locations in the body
- Current illicit substance abuse, excluding marijuana
- Known HIV/AIDS infection
- 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.
- Has a BMI > 40 kg/m2 at baseline exam
- Current or planned pregnancy within the study course.
- Currently institutionalized (e.g., prisons, long-term care facilities)
- Have a genotype of PiMZ and ever received intravenous or inhaled alpha-1 augmentation therapy (Alpha-1 Proteinase Inhibitor, A1PI)
- 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 six weeks can be rescreened for the study once the six-week window has passed.
- 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.
- 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.
- Female participants who present <3 months after giving birth will be asked to reschedule their visit until three months have passed since the birth.
- 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.
Trial locations and contacts
9 sites in 1 country.
9 sites in 1 country
United States9 sites
Johns Hopkins University
Baltimore, Maryland, 21224
Medical University of South Carolina
Charleston, South Carolina, 29425
National Jewish Health
Denver, Colorado, 80206
Vanderbilt University
Nashville, Tennessee, 37240
Yale University
New Haven, Connecticut, 06510
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
University of Pittsburgh
Pittsburgh, Pennsylvania, 15213
University of California - San Francisco
San Francisco, California, 94143
Arizona Health Sciences Center
Tucson, Arizona, 85742
About this study
Official title: Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) - Alpha-1 Protocol
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:
- 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).
- Determine correlations between bronchoalveolar lavage (BAL) and peripheral blood gene expression patterns and patterns in lung microbial and viral populations across all cohorts.
- Correlate the presence or absence of computed tomography (CT) bronchiectasis and bronchiolectasis with patterns in the microbiome population diversity and content.
- To identify and define novel molecular phenotypes of Alpha-1 Antitrypsin Deficiency (AATD) based on computational integration of clinical, transcriptomic, and microbiome data.
Read the 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.
- Conditions
- Alpha 1 Antitrypsin Deficiency, AATD
- Keywords
- Genomics, Microbiome, Microflora, Virome, Alpha-1
- Medical subject headings
- alpha 1-Antitrypsin Deficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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. |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Single time point split into 2 visits over 1 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Apr 2013 (estimated)
- Study startMay 2013
- Primary completionJun 2015
- Study completionSep 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Alpha 1 Antitrypsin DeficiencyStudies of the same condition, open and under way.
- More trials run by University of PittsburghThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case only
- Time perspective
- Cross-sectional
- Enrolment
- 140 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pittsburgh
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Principal investigator, Naftali Kaminski, Yale University
- Investigators
- Naftali Kaminski, MD, Principal investigator, Yale UniversityStephen Wisniewski, PhD, Principal investigator, University of PittsburghMichael Becich, MD, PhD, Principal investigator, University of Pittsburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01832220
- Sponsor's protocol ID
- 13010343
- Other IDs
- U01HL112707
- Acronym
- GRADS Alpha-1
- Status last verified
- Jan 2016
- First submitted
- 8 Apr 2013
- Last updated
- 12 Jan 2016
- Results posted
- No
- Data monitoring committee
- Yes
Publications
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.
PubMed 26153726
Study at a glance
From the registry record, last updated by the sponsor on 12 Jan 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) - Alpha-1 Protocol
- ClinicalTrials.gov ID
- NCT01832220
- Acronym / sponsor ID
- GRADS Alpha-1 / 13010343
- Conditions
- Alpha 1 Antitrypsin Deficiency, AATD
- Keywords
- Genomics, Microbiome, Microflora, Virome, Alpha-1
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 140 participants (actual)
- Lead sponsor
- University of PittsburghUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- May 2013
- Primary completion
- Jun 2015 (actual)
- Study completion
- Sep 2015 (actual)
- First posted
- 16 Apr 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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).
- Determine correlations between bronchoalveolar lavage (BAL) and peripheral blood gene expression patterns and patterns in lung microbial and viral populations across all cohorts.
- Correlate the presence or absence of computed tomography (CT) bronchiectasis and bronchiolectasis with patterns in the microbiome population diversity and content.
- To identify and define novel molecular phenotypes of Alpha-1 Antitrypsin Deficiency (AATD) based on computational integration of clinical, transcriptomic, and microbiome data.
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.
Study design
- Observational model
- Case only
- Time perspective
- Cross-sectional
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| 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. |
Who may qualify
- Ages
- 40 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- 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.
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (31 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Number and diversity of lower respiratory tract (LRT) microbes
Time frame: Single time point split into 2 visits over 1 month
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.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Jan 2016.
- Derived from this study: PubMed 26153726Strange 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Naftali Kaminski, MD principal investigator
Yale University
Stephen Wisniewski, PhD principal investigator
University of Pittsburgh
Michael Becich, MD, PhD principal investigator
University of Pittsburgh
9 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Alpha 1 Antitrypsin Deficiency and AATD, run by University of Pittsburgh at 9 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Jan 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number and diversity of lower respiratory tract (LRT) microbes (time frame: Single time point split into 2 visits over 1 month). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01832220, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Jan 2016.