Effect of Double Dose of Alpha 1-antitrypsin Augmentation Therapy on Lung Inflammation.
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|ClinicalTrials.gov Identifier: NCT01669421|
Recruitment Status : Completed
First Posted : August 21, 2012
Last Update Posted : June 1, 2016
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).
|Condition or disease||Intervention/treatment||Phase|
|Alpha 1 Antitrypsin Deficiency||Drug: Alpha-1 Antitrypsin (human)||Phase 2|
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.
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, lung function testing and urine sample testings.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||10 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Effect of a Higher Dose of Alpha-1 Antitrypsin Augmentation Therapy on Lung Inflammation in Subjects With Alpha-1 Antitrypsin Deficiency.|
|Study Start Date :||July 2012|
|Actual Primary Completion Date :||May 2016|
|Actual Study Completion Date :||May 2016|
U.S. FDA Resources
Experimental: Alpha-1 Antitrypsin (human)
Alpha-1 Antitrypsin (human) 120 mg per kg per week for 4 weeks
Drug: Alpha-1 Antitrypsin (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
- CHANGES IN CYTOKINE PROFILE IN BRONCHOALVEOLAR LAVAGE [ Time Frame: at 4, 8 and 12 weeks ]- Inflammatory markers: multiple cytokine panels using bead technology (Luminex) for: IL-1, IL-2, IL8, IL6, GM-CSF, TNF alpha, MCP-1, VEGF, RANTES. In addition, LTB4 will be measured by ELISA.
- CHANGES IN SERUM INFLAMMATORY MARKERS [ Time Frame: At 4, 8 and 12 weeks ]We will measure C-reactive protein and multiple cytokine panels using bead technology (Luminex)for: IL-1, IL-2, IL8, IL6, GM-CSF, TNF alpha, MCP-1, VEGF, RANTES.
- EFFECT OF DOUBLE DOSE ZEMAIRA ON ELASTIN DEGRADATION [ Time Frame: Weeks 4, 8 and 12 ]Desmosine and isodesmosine levels in plasma and BAL
- EFFECT OF DOUBLE DOSE ZEMAIRA ON NEUTROPHIL APOPTOSIS AND MIGRATION [ Time Frame: Weeks 4, 8 and 12 ]Neutrophil apoptosis and migration assays in PMN obtained at the end of each phase.
- CHANGES IN NEUTROPHILIC LUNG INFILTRATION [ Time Frame: 4, 8, 12 weeks ]Neutrophil % in BAL and endobronchial biopsies
- NUMBER OF ADVERSE EVENTS REPORTED [ Time Frame: throughout the study ]Collected by weekly questionnaires
- CHANGES IN METABOLIC AND COAGULATION PROFILES [ Time Frame: throughout the study ]Serial measures of CBC, chemistry panel and coagulation panels
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01669421
|United States, Florida|
|Division of Pulmonary and Critical Care, Human Reseach, U of Miami|
|Miami, Florida, United States, 33136|
|Principal Investigator:||Michael A Campos, MD||University of Miami|