Alpha-1-Antitrypsin (AAT) To Treat Emphysema In AAT-Deficient Patients (EXACTLE)

• The frequency of exacerbations as determined by patient diary. [ Time Frame: 24 or 30 month ] [ Designated as safety issue: Yes ]
• The deterioration of the lung function will be assessed by measurement of the change in FEV1 and KCO [ Time Frame: 24 or 30 month ] [ Designated as safety issue: Yes ]
• Duration and severity of the exacerbations [ Time Frame: 24 or 30 month ] [ Designated as safety issue: Yes ]
• Mortality [ Time Frame: 24 or 30 month ] [ Designated as safety issue: Yes ]
• Quality of life with a disease specific instrument, the St George's Respiratory Questionnaire [ Time Frame: 24 or 30 month ] [ Designated as safety issue: Yes ]

• The frequency of exacerbations as determined by patient diary.
• The deterioration of the lung function will be assessed by measurement of the change in FEV1 and KCO
• Duration and severity of the exacerbations as determined by diary cards
• Mortality
• Quality of life with a disease specific instrument, the St George’s Respiratory Questionnaire

The goal of this trial was to explore the utility of evaluating emphysema progression through CT scans measuring lung density during a 2 year period of weekly infusions of either placebo or human alpha-1-antitrypsin (AAT; Prolastin®). Exacerbation data recorded in patient diaries were also collected. All efficacy data were analyzed for potential use in evaluating Prolastin efficacy in this and other clinical trials.

This is a one to one randomized, placebo-controlled, clinical, exploratory study with the aim of collecting information on possible clinical endpoints i.e., the progression of emphysema by lung density measurements with CT scan and frequency of exacerbations that could be used for a subsequent placebo controlled clinical trial. Progression of disease will be investigated in 80 patients with alpha-1-antitrypsin deficiency, who will be treated with human alpha-1-antitrypsin (AAT; Prolastin®) or placebo weekly for two years to analyze the effect of treatment on lung density and exacerbations. Targeted augmentation therapy with weekly infusions of Prolastin® will be a dose of 60 mg/kg body weight (range of 51.72 to 71.43 mg per kg body weight).

Therefore, this study focuses on several questions:

• Is the 15th percentile point calculated by analysis of CT lung histograms a useful endpoint for clinical trials in AAT deficiency?
• Is quantitation of exacerbations in AAT-deficient patients a useful endpoint for clinical trials in AAT deficiency?
• Are there significant differences between the treatments in favor of Prolastin®?

• Drug: Alpha1-Proteinase Inhibitor (Human)
  Weekly infusion of 60 mg/kg body weight for 2 years
  Other Names:

  • Prolastin
  • alpha-1 antitrypsin (AAT)
  • BAY x 5747
  • BAY 10-5233
  • TAL-05-00007
  • NDC 13533-601-30
  • NDC 13533-601-35
• Drug: Albumin (Human) 20%, USP
  Weekly infusion for 2 years. Albumin (Human) 20% will be diluted with 5% glucose to a final concentration of 2.0%.
  Other Names:

  • Plasbumin®-20
  • Plasbumin®-20 (Low Aluminum)
  • Albumin (Human) 20%
  • TAL-05-00008
  • TAL-05-00024
  • BAY 34-9255
  • NDC 3533-683-20
  • NDC 1533-683-71
  • NDC 13533-691-20
  • NDC 13533-691-71

• Experimental: Group 1
  Prolastin
  Intervention: Drug: Alpha1-Proteinase Inhibitor (Human)
• Placebo Comparator: Group 2
  Intervention: Drug: Albumin (Human) 20%, USP

• Brand P, Schulte M, Wencker M, Herpich CH, Klein G, Hanna K, Meyer T. Lung deposition of inhaled {alpha}1-proteinase inhibitor in CF and {alpha}1-antitrypsin deficiency. Eur Respir J. 2009 Feb 27; [Epub ahead of print]
• Dirksen A, Piitulainen E, Parr DG, Deng C, Wencker M, Shaker SB, Stockley RA. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha-1 antitrypsin deficiency. Eur Respir J. 2009 Feb 5; [Epub ahead of print]
• Soriano JB, Miravitlles M. Your racing horses will help you to quit: a lesson for COPD and alpha1-antitrypsin deficiency research. Eur Respir J. 2009 Jun;33(6):1244-6. No abstract available.
• Vijayasaratha K, Stockley RA. Relationship between frequency, length, and treatment outcome of exacerbations to baseline lung function and lung density in alpha-1 antitrypsin-deficient COPD. Int J Chron Obstruct Pulmon Dis. 2012;7:789-96. doi: 10.2147/COPD.S31797. Epub 2012 Nov 27.
• Carter RI, Mumford RA, Treonze KM, Finke PE, Davies P, Si Q, Humes JL, Dirksen A, Piitulainen E, Ahmad A, Stockley RA. The fibrinogen cleavage product A?-Val360, a specific marker of neutrophil elastase activity in vivo. Thorax. 2011 Aug;66(8):686-91. Epub 2011 May 26.
• Stockley RA, Parr DG, Piitulainen E, Stolk J, Stoel BC, Dirksen A. Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry. Respir Res. 2010 Oct 5;11:136.
• Parr DG, Dirksen A, Piitulainen E, Deng C, Wencker M, Stockley RA. Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study of augmentation therapy in alpha 1-antitrypsin deficiency. Respir Res. 2009 Aug 13;10:75.

Inclusion Criteria:

• Patient with pulmonary emphysema due to severe congenital AAT deficiency of phenotype PiZ or other rare genotypes (not MS, MZ or SZ) and AAT serum level < 11 µM or < 80 mg/dL (status to be confirmed by phenotyping and genotyping)
• Inspiratory capacity (VC - ERV) > 1.2 L and FEV1 < 80% of predicted value post bronchodilator
• FEV1/VC < 70% of predicted value post-bronchodilator or KCO < 80% of predicted value post-bronchodilator
• History of at least one exacerbation in the past 2 years
• Written informed consent

Exclusion Criteria:

• FEV1 < 25% of predicted value post-bronchodilator
• Augmentation therapy for more than one month with plasma-derived human alpha 1-antitrypsin (AAT) within the last 2 years
• History of lung transplant
• Any lung surgery within the past 2 years
• On any thoracic surgery waiting list
• Diagnosis of liver cirrhosis
• Severe concomitant disease
• Active pulmonary infection/exacerbations within the last month
• Active smoking during the last 6 months or plasma positive for cotinine
• Body weight < 42 kg or > 92 kg
• Pregnancy or lactation
• Women of child-bearing potential without adequate contraception