Effect of Double Dose of Alpha 1-antitrypsin Augmentation Therapy on Lung Inflammation.
Condition: Alpha 1 Antitrypsin Deficiency
MeSH terms: Pneumonia; Alpha 1-Antitrypsin Deficiency; Inflammation
Study type: Interventional
Phase: Phase 2

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. 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.
    

Intervention name(s): Alpha-1 Antitrypsin (human)
Intervention type(s): Drug
Intervention description(s): 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
Other intervention name(s): Zemaira; Alpha-1 proteinase inhibitor (human)
Intervention MeSH terms: Protease Inhibitors; Alpha 1-Antitrypsin; Protein C Inhibitor
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Alpha 1