Alpha 1 Antitrypsin DeficiencyPhase 2NCT01669421
Effect of Double Dose of Alpha 1-antitrypsin Augmentation Therapy on Lung Inflammation.
A Phase 2 study testing Alpha-1 Antitrypsin (human) in people with Alpha 1 Antitrypsin Deficiency, run by Michael Campos, MD at 1 site in United States.
Trial summary
The current treatment of individuals with alpha-1 antitrypsin deficiency (AATD) who develop lung disease (COPD) is the administration of intravenous purified alpha-1 antitrypsin (augmentation therapy) at a fixed dose of 60 mg/kg per week. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Alpha 1 Antitrypsin Deficiency
- What is being tested?
- Alpha-1 Antitrypsin (human)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteUnited States
- Study dates
- Jul 2012to May 2016
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Males or Females aged between 18 and 75 years.
- Diagnosis of AATD, based on documentation of "at-risk" genotypes such as Pi ZZ, SZ or Znull OR documentation of a pre-therapy AAT level < 11 µM.
- Evidence of COPD (emphysema or airflow obstruction) with FEV1 < 80%
- Receiving standard dose of augmentation therapy (with any commercial formulation) for at least 1 month at the dose of 60 mg/kg/week.
- At least ONE of the following criteria of disease severity:
- 2 or more acute exacerbations or 1 hospitalization due to respiratory symptoms in the past 12 months. Definition of exacerbations: the use of antibiotics and a course of steroids to treat a flare of pulmonary symptoms, regardless if the subject required emergency room care or hospital admission. The diagnosis of the acute exacerbation will be obtained by direct history obtained from the patient and confirmed by the PI. Attempts should be made to have documentation from the patient's treating physicians, although not required for study entry.
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- St. George Respiratory Questionnaire (SGRQ) total score ≥ 60.
- Chronic bronchitis: daily or almost daily sputum expectoration at least 3 months of the year for at least 2 consecutive years. The diagnosis of chronic bronchitis will be obtained by direct history obtained from the patient and confirmed by the PI. Attempts should be made to have documentation from the patient's treating physicians, although not required for study entry.
- Documented FEV1 decline of at least ≥ 60 ml/year for 2 consecutive years while receiving augmentation therapy
Who cannot join
- Patients unsuitable to have a bronchoscopy due to poor clinical condition as judged by the PI. In general we will exclude subjects with hypoxemia, coagulopathy or FEV1 below 40% predicted.
- Note: Subjects with FEV1 values below 40% predicted may be included and reassessed after optimization of therapy. Final determination to include the patient if deemed suitable for the procedure will be determined by the PI before first planned bronchoscopy (regardless of FEV1 value).
- Patients participating in other clinical trials.
- Use of chronic antibiotics or oral steroids
- Continues to smoke
- Inability to sign informed consent
- Pregnancy or willing to become pregnant
- Known IgA deficiency (we will include only patients already receiving augmentation therapy so it will be unlikely to encounter this exclusion criteria)
Trial locations and contacts
1 site in 1 country.
United States1 site
Division of Pulmonary and Critical Care, Human Reseach, U of Miami
Miami, Florida, 33136
About this study
Official title: Effect of a Higher Dose of Alpha-1 Antitrypsin Augmentation Therapy on Lung Inflammation in Subjects With Alpha-1 Antitrypsin Deficiency.
The current treatment of individuals with alpha-1 antitrypsin deficiency (AATD) who develop lung disease (COPD) is the administration of intravenous purified alpha-1 antitrypsin (augmentation therapy) at a fixed dose of 60 mg/kg per week. This dose aims at increasing the deficient AAT serum levels just above a predetermined "safety threshold" of 11 uM. However, normal levels of AAT are between 25-50 uM.
AAT has shown not only to inhibit lung proteases such as neutrophil elastase, but also to modulate inflammation. Given that many subjects with AATD who receive augmentation therapy still have significant lung disease and inflammation, this study will evaluate whether doubling the dose to 120 mg/kg/week has an effect in decreasing lung inflammation.
Read more
Only the dosing of 60 mg/kg /week has received FDA approval. FDA has granted an IND number to this study to test the higher dose of 120 mg/kg/week.
The study will evaluate systemic (serum) and pulmonary (bronchoscopy samples)markers of inflammation in 3 phases: standard dose (4 weeks), double dose (4 weeks) and standard dose (4 weeks).
Read the detailed description
This is a pilot study to test the effect of double dose augmentation therapy with Zemaira (CSL Behring) on lung inflammation, compared with standard doses of 60 mg/kg/week.
Our hypothesis is that some patients with AATD receiving augmentation therapy at the standard dose of 60 mg/kg/week continue to have a significant lung inflammation that may lead to detrimental clinical consequences. This inflammation can be further reduced with higher AAT dosing.
The study will enroll 20 subjects with AATD and COPD already receiving augmentation therapy with any brand at standard doses for at least a month. For inclusion and exclusion criteria see below.
Protocol:
The study will take place over approximately 12 weeks: a month receiving Zemaira at standard dose (60 mg/kg/week), a month at double dose (120 mg/kg/week) and a month at standard dose (60 mg/kg/week). The infusions at standard doses will be done at home and infusions with higher doses will be provided at the study site.
the study involves scheduled blood draws for clinical labs and serum for research samples. At the end of each phase a bronchoscopy will be performed (3 in total) to obtain research samples (lung lavage, brushings and endobronchial biopsies).
The first bronchoscopy after receiving 4 weeks of standard augmentation therapy will assess the "residual" inflammation that may be present despite augmentation therapy. The second bronchoscopy after double dose augmentation therapy phase will be to assess changes (decreases) in inflammatory markers. The third bronchoscopy after resuming standard dosing is to assess if inflammation returned to baseline levels (required for proof of concept).
There will be approximately 9 visits to the study clinic. This study does not include placebo (no active drug) treatment. Besides blood draws and bronchoscopy, the study will include questionnaires and lung function testing.
- Conditions
- Alpha 1 Antitrypsin Deficiency
- Being tested
- Alpha-1 Antitrypsin (human)
- Keywords
- 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.
Alpha-1 Antitrypsin (human)Drug
Also called Zemaira, Alpha-1 proteinase inhibitor (human)
Comparison of Zemaira (Alpha 1 Antitrypsin Human) 120 mg/kg/weekly for four weeks versus 2 phases with same drug administered at standard doses of 60 mg/kg/weekly for four weeks each
| Study group | Role | What they receive |
|---|---|---|
| Alpha-1 Antitrypsin (human) standard dose baseline | Experimental | Alpha-1 Antitrypsin (human) 60 mg per kg per week for 4 weeks. Study week 4 Receives: Drug: Alpha-1 Antitrypsin (human) |
| Alpha-1 Antitrypsin (human) Double dose | Experimental | Alpha-1 Antitrypsin (human) 120 mg/kg per week for 4 weeks. Study week 8 Receives: Drug: Alpha-1 Antitrypsin (human) |
| Alpha-1 Antitrypsin (human) standard dose | Experimental | 4 weeks on A1PI at 60 mg/kg per week after the other 2 phases. Collected@ study week 12 Receives: Drug: Alpha-1 Antitrypsin (human) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Changes in Inflammatory Biomarkers in Bronchoalveolar Lavage Fluid
Assess the variations in the levels of several cytokines and inflammatory biomarkers in BAL after changing A1PI dosing.
Measures were done using the bead technology.
Measured: Between baseline (week 4), double dose A1PI (week 8) and again standard dose (week 12)
Secondary outcomes (2)
Change in Inflammatory Biomarkers in Serum Samples
Assess the variations in the levels of cytokines and inflammatory biomarkers using the bead technology.
Measured: Between baseline (week 4), double dose A1PI (week 8) and again standard dose (week 12)
Number of Adverse Events Reported
Measured: From Week 1 to week 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Aug 2012 (estimated)
- Study startJul 2012
- Primary completionMay 2016
- Study completionMay 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Alpha 1 Antitrypsin DeficiencyStudies of the same condition, open and under way.
- 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
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- Michael Campos, MD
- Sponsor type
- University, hospital or other
- Collaborators
- CSL Behring
- Responsible party
- Sponsor-investigator, Michael Campos, MD, University of Miami
- Investigators
- Michael A Campos, MD, Principal investigator, University of Miami
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01669421
- Sponsor's protocol ID
- 20100844
- Status last verified
- Apr 2019
- First submitted
- 14 Aug 2012
- Last updated
- 8 May 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Tonelli AR, Brantly ML. Augmentation therapy in alpha-1 antitrypsin deficiency: advances and controversies. Ther Adv Respir Dis. 2010 Oct;4(5):289-312. doi: 10.1177/1753465810373911. Epub 2010 Jul 22.
PubMed 20650978Stockley RA, Bayley DL, Unsal I, Dowson LJ. The effect of augmentation therapy on bronchial inflammation in alpha1-antitrypsin deficiency. Am J Respir Crit Care Med. 2002 Jun 1;165(11):1494-8. doi: 10.1164/rccm.2109013.
PubMed 12045122Petrache I, Hajjar J, Campos M. Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency. Biologics. 2009;3:193-204. doi: 10.2147/btt.2009.3088. Epub 2009 Jul 13.
PubMed 19707408Campos MA, Geraghty P, Holt G, Mendes E, Newby PR, Ma S, Luna-Diaz LV, Turino GM, Stockley RA. The Biological Effects of Double-Dose Alpha-1 Antitrypsin Augmentation Therapy. A Pilot Clinical Trial. Am J Respir Crit Care Med. 2019 Aug 1;200(3):318-326. doi: 10.1164/rccm.201901-0010OC.
PubMed 30965011
Study at a glance
From the registry record, last updated by the sponsor on 8 May 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of a Higher Dose of Alpha-1 Antitrypsin Augmentation Therapy on Lung Inflammation in Subjects With Alpha-1 Antitrypsin Deficiency.
- ClinicalTrials.gov ID
- NCT01669421
- Acronym / sponsor ID
- 20100844
- Conditions
- Alpha 1 Antitrypsin Deficiency
- Keywords
- Alpha 1
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- Michael Campos, MDUniversity, hospital or other
- Collaborators
- CSL Behring
- Study start
- Jul 2012
- Primary completion
- May 2016 (actual)
- Study completion
- May 2016 (actual)
- First posted
- 21 Aug 2012 (estimated)
- Results
- Posted 8 May 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The current treatment of individuals with alpha-1 antitrypsin deficiency (AATD) who develop lung disease (COPD) is the administration of intravenous purified alpha-1 antitrypsin (augmentation therapy) at a fixed dose of 60 mg/kg per week. This dose aims at increasing the deficient AAT serum levels just above a predetermined "safety threshold" of 11 uM. However, normal levels of AAT are between 25-50 uM.
AAT has shown not only to inhibit lung proteases such as neutrophil elastase, but also to modulate inflammation. Given that many subjects with AATD who receive augmentation therapy still have significant lung disease and inflammation, this study will evaluate whether doubling the dose to 120 mg/kg/week has an effect in decreasing lung inflammation.
Only the dosing of 60 mg/kg /week has received FDA approval. FDA has granted an IND number to this study to test the higher dose of 120 mg/kg/week.
The study will evaluate systemic (serum) and pulmonary (bronchoscopy samples)markers of inflammation in 3 phases: standard dose (4 weeks), double dose (4 weeks) and standard dose (4 weeks).
Detailed description
This is a pilot study to test the effect of double dose augmentation therapy with Zemaira (CSL Behring) on lung inflammation, compared with standard doses of 60 mg/kg/week.
Our hypothesis is that some patients with AATD receiving augmentation therapy at the standard dose of 60 mg/kg/week continue to have a significant lung inflammation that may lead to detrimental clinical consequences. This inflammation can be further reduced with higher AAT dosing.
The study will enroll 20 subjects with AATD and COPD already receiving augmentation therapy with any brand at standard doses for at least a month. For inclusion and exclusion criteria see below.
Protocol:
The study will take place over approximately 12 weeks: a month receiving Zemaira at standard dose (60 mg/kg/week), a month at double dose (120 mg/kg/week) and a month at standard dose (60 mg/kg/week). The infusions at standard doses will be done at home and infusions with higher doses will be provided at the study site.
the study involves scheduled blood draws for clinical labs and serum for research samples. At the end of each phase a bronchoscopy will be performed (3 in total) to obtain research samples (lung lavage, brushings and endobronchial biopsies).
The first bronchoscopy after receiving 4 weeks of standard augmentation therapy will assess the "residual" inflammation that may be present despite augmentation therapy. The second bronchoscopy after double dose augmentation therapy phase will be to assess changes (decreases) in inflammatory markers. The third bronchoscopy after resuming standard dosing is to assess if inflammation returned to baseline levels (required for proof of concept).
There will be approximately 9 visits to the study clinic. This study does not include placebo (no active drug) treatment. Besides blood draws and bronchoscopy, the study will include questionnaires and lung function testing.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Alpha-1 Antitrypsin (human) standard dose baseline | Experimental | Drug: Alpha-1 Antitrypsin (human)Alpha-1 Antitrypsin (human) 60 mg per kg per week for 4 weeks. Study week 4 |
| Alpha-1 Antitrypsin (human) Double dose | Experimental | Drug: Alpha-1 Antitrypsin (human)Alpha-1 Antitrypsin (human) 120 mg/kg per week for 4 weeks. Study week 8 |
| Alpha-1 Antitrypsin (human) standard dose | Experimental | Drug: Alpha-1 Antitrypsin (human)4 weeks on A1PI at 60 mg/kg per week after the other 2 phases. Collected@ study week 12 |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Males or Females aged between 18 and 75 years.
- Diagnosis of AATD, based on documentation of "at-risk" genotypes such as Pi ZZ, SZ or Znull OR documentation of a pre-therapy AAT level < 11 µM.
- Evidence of COPD (emphysema or airflow obstruction) with FEV1 < 80%
- Receiving standard dose of augmentation therapy (with any commercial formulation) for at least 1 month at the dose of 60 mg/kg/week.
- At least ONE of the following criteria of disease severity:
Key exclusion criteria (8 listed)
- Patients unsuitable to have a bronchoscopy due to poor clinical condition as judged by the PI. In general we will exclude subjects with hypoxemia, coagulopathy or FEV1 below 40% predicted.
- Note: Subjects with FEV1 values below 40% predicted may be included and reassessed after optimization of therapy. Final determination to include the patient if deemed suitable for the procedure will be determined by the PI before first planned bronchoscopy (regardless of FEV1 value).
- Patients participating in other clinical trials.
- Use of chronic antibiotics or oral steroids
- Continues to smoke
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Alpha-1 Antitrypsin (human)Also: Zemaira, Alpha-1 proteinase inhibitor (human)Comparison of Zemaira (Alpha 1 Antitrypsin Human) 120 mg/kg/weekly for four weeks versus 2 phases with same drug administered at standard doses of 60 mg/kg/weekly for four weeks each | Drug | Alpha-1 Antitrypsin (human) Double dose, Alpha-1 Antitrypsin (human) standard dose, Alpha-1 Antitrypsin (human) standard dose baseline |
Primary outcome
Changes in Inflammatory Biomarkers in Bronchoalveolar Lavage Fluid
Time frame: Between baseline (week 4), double dose A1PI (week 8) and again standard dose (week 12)
Assess the variations in the levels of several cytokines and inflammatory biomarkers in BAL after changing A1PI dosing. Measures were done using the bead technology.
2 secondary outcomes
Change in Inflammatory Biomarkers in Serum Samples
Time frame: Between baseline (week 4), double dose A1PI (week 8) and again standard dose (week 12)
Number of Adverse Events Reported
Time frame: From Week 1 to week 12
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 May 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 20650978Tonelli AR, Brantly ML. Augmentation therapy in alpha-1 antitrypsin deficiency: advances and controversies. Ther Adv Respir Dis. 2010 Oct;4(5):289-312. doi: 10.1177/1753465810373911. Epub 2010 Jul 22.
- Background: PubMed 12045122Stockley RA, Bayley DL, Unsal I, Dowson LJ. The effect of augmentation therapy on bronchial inflammation in alpha1-antitrypsin deficiency. Am J Respir Crit Care Med. 2002 Jun 1;165(11):1494-8. doi: 10.1164/rccm.2109013.
- Background: PubMed 19707408Petrache I, Hajjar J, Campos M. Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency. Biologics. 2009;3:193-204. doi: 10.2147/btt.2009.3088. Epub 2009 Jul 13.
- Derived from this study: PubMed 30965011Campos MA, Geraghty P, Holt G, Mendes E, Newby PR, Ma S, Luna-Diaz LV, Turino GM, Stockley RA. The Biological Effects of Double-Dose Alpha-1 Antitrypsin Augmentation Therapy. A Pilot Clinical Trial. Am J Respir Crit Care Med. 2019 Aug 1;200(3):318-326. doi: 10.1164/rccm.201901-0010OC.
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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.
Michael A Campos, MD principal investigator
University of Miami
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Alpha-1 Antitrypsin (human) in people with Alpha 1 Antitrypsin Deficiency, run by Michael Campos, MD at 1 site 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 9 inclusion and 8 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 8 May 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 8 May 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Changes in Inflammatory Biomarkers in Bronchoalveolar Lavage Fluid (time frame: Between baseline (week 4), double dose A1PI (week 8) and again standard dose (week 12)). 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 NCT01669421, which also lists 4 linked publications.
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 8 May 2019.