Effect of Double Dose of Alpha 1-antitrypsin Augmentation Therapy on Lung Inflammation.

• CHANGES IN SERUM INFLAMMATORY MARKERS [ Time Frame: At 4, 8 and 12 weeks ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  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 ] [ Designated as safety issue: No ]
  Neutrophil % in BAL and endobronchial biopsies
• NUMBER OF ADVERSE EVENTS REPORTED [ Time Frame: throughout the study ] [ Designated as safety issue: Yes ]
  Collected by weekly questionnaires
• CHANGES IN METABOLIC AND COAGULATION PROFILES [ Time Frame: throughout the study ] [ Designated as safety issue: Yes ]
  Serial measures of CBC, chemistry panel and coagulation panels

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).

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, lung function testing and urine sample testings.

• Tonelli AR, Brantly ML. Augmentation therapy in alpha-1 antitrypsin deficiency: advances and controversies. Ther Adv Respir Dis. 2010 Oct;4(5):289-312. Epub 2010 Jul 22. Review.
• Stockley 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.
• Petrache 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. Epub 2009 Jul 13.

Inclusion Criteria:

• Males or Females aged between 18 and 75 years.
• Diagnosis of AATD with an "at-risk" genotype (i.e.Pi ZZ, SZ or Znull)
• Evidence of COPD (emphysema or airflow obstruction) with FEV1 < 80%
• Receiving standard dose of augmentation therapy for at least 1 month at the dose of 60 mg/kg/week.
• At least ONE of the following criteria of disease severity:
• 1 or more acute exacerbations 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
• 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.
• Documented FEV1 decline of at least > 60 ml/year for 2 consecutive years while receiving augmentation therapy

Exclusion Criteria at study entry:

• Patients participating in other clinical trials.
• Use of chronic antibiotics or oral steroids
• Continues to smoke
• Contraindications for bronchoscopy
• Inability to sign informed consent
• Pregnancy or willing to become pregnant
• Known IgA deficiency

Criteria to be met before first bronchoscopy:

• FEV1 > 40% predicted
• At least 4 weeks on Zemaira
• No Recent exacerbation (> 4 weeks)
• No recent use of systemic steroids or exacerbations (> 4 weeks)
• Should be on standard COPD treatment as specified below

Medications: Subjects will be receiving standard COPD medications during the trial. These medications will include at least one long-acting bronchodilator and an inhaled steroid. Subjects that are not using these medications will be started on them at least 1 month before starting the study.

Subjects will be recruited from the investigator own pool of patients, and by invitation through patient support groups and Alpha-1 Foundation's Research Registry. We anticipate enrollment of 20 subjects.

Subjects not receiving Zemaira: Subjects with AATD and COPD receiving augmentation therapy with a brand other than Zemaira® (Glassia®, Prolastin®, Aralast®) who are interested in participating in this study, will have to be switched to Zemaira®.

Subjects of childbearing potential: Zemaira has no pregnancy safety recommendations. In general It is unknown if Zemaira can cause harm to the fetus. Because this study uses an IND label, we will not enroll pregnant women or women with childbearing potential not using acceptable birth control methods. Acceptable methods of birth control include:

• birth control pills taken for at least one month before study enrolment.
• Implanted birth control devices such as Implanon®, if received at least one month before
• Intra-uterine devices
• Hysterectomy or surgical sterilization
• Abstinence (no sexual intercourse)
• Double-barrier method including a diaphragm with spermicidal gel or a condom with contraceptive foam We will monitor urine pregnancy tests, at study entry, before and after receiving double dose of augmentation therapy and at the last study visit.