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

Multi-center, Randomized Trial With I.V. Prolastin® to Evaluate Frequency of Exacerbations and Progression of Emphysema by Means of Multi-slice CT Scans in Patients With Congenital Alpha-1-antitrypsin Deficiency.

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.

Study Overview

• Status: Completed
• Conditions: Alpha 1-Antitrypsin Deficiency
• Intervention / Treatment: Drug: Alpha1-Proteinase Inhibitor (Human); Drug: Albumin (Human) 20%, United States Pharmacopeia (USP)

Detailed Description

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®?

• Study Type: Interventional
• Enrollment (Actual): 77
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Hellerup, Denmark, 2900
    • Gentofte Hospital Department of Respiratory Medicine
• Sweden
  • Malmö, Sweden
    • Department of Pulmonary Medicine, Malmö University Hospital
• United Kingdom
  • England
    • Birmingham, England, United Kingdom, B15 2TH
      • Queen Elizabeth Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient with pulmonary emphysema due to severe congenital AAT deficiency of phenotype protease inhibitor Z (PiZ) or other rare genotypes (not MS, MZ or SZ) and AAT serum level < 11 microns (µM) or < 80 mg/dL (status to be confirmed by phenotyping and genotyping)
• Inspiratory capacity (VC - ERV) > 1.2 L and forced expiratory volume at one second (FEV1) < 80% of predicted value post bronchodilator
• FEV1/VC < 70% of predicted value post-bronchodilator or transfer factor of carbon monoxide (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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Group 1; Prolastin	Drug: Alpha1-Proteinase Inhibitor (Human); Weekly infusion of 60 mg/kg body weight for 2 years; Other Names: Prolastin; TAL-05-00007; alpha-1 antitrypsin (AAT); BAY x 5747; BAY 10-5233; NDC 13533-601-30; NDC 13533-601-35
PLACEBO_COMPARATOR: Group 2	Drug: Albumin (Human) 20%, United States Pharmacopeia (USP); Weekly infusion for 2 years. Albumin (Human) 20% will be diluted with 5% glucose to a final concentration of 2.0%.; Other Names: BAY 34-9255; Plasbumin®-20; Plasbumin®-20 (Low Aluminum); TAL-05-00008; TAL-05-00024; NDC 13533-691-20; NDC 13533-691-71; Albumin (Human) 20%; NDC 3533-683-20; NDC 1533-683-71

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The Progression Rate of Emphysema Determined by Change in 15th Percentile of Lung Density Measured by Annual CT Scan of the Whole Lung	24 or 30 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in Lung Density at Each Visit as Measured by Computed Tomography	24 or 30 months
The Frequency of Exacerbations as Determined by Patient Diary.	24 or 30 months
The Deterioration of the Lung Function Will be Assessed by Measurement of the Change in Forced Expiratory Volume at One Second (FEV1) and Transfer Factor of Carbon Monoxide (KCO)	24 or 30 months
Duration and Severity of the Exacerbations	24 or 30 months
Mortality	24 or 30 months
Quality of Life With a Disease Specific Instrument, the St. George's Respiratory Questionnaire	24 or 30 months

Collaborators and Investigators

• Sponsor: Grifols Therapeutics LLC
• Investigators: Principal Investigator: Asger Dirksen, MD PHD, University of Copenhagen

Publications and helpful links

General Publications

• Brand P, Schulte M, Wencker M, Herpich CH, Klein G, Hanna K, Meyer T. Lung deposition of inhaled alpha1-proteinase inhibitor in cystic fibrosis and alpha1-antitrypsin deficiency. Eur Respir J. 2009 Aug;34(2):354-60. doi: 10.1183/09031936.00118408. Epub 2009 Feb 27.
• 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 alpha1-antitrypsin deficiency. Eur Respir J. 2009 Jun;33(6):1345-53. doi: 10.1183/09031936.00159408. Epub 2009 Feb 5.
• 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. doi: 10.1183/09031936.00026409. 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 Aalpha-Val360, a specific marker of neutrophil elastase activity in vivo. Thorax. 2011 Aug;66(8):686-91. doi: 10.1136/thx.2010.154690. 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(1):136. doi: 10.1186/1465-9921-11-136.
• 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(1):75. doi: 10.1186/1465-9921-10-75.

Helpful Links

• FDA Approved Product Labeling Information - Prolastin®
• FDA Approved Product Labeling Information - Plasbumin®-20 (Low Aluminum)

Study record dates

Study Major Dates

• Study Start: December 1, 2003
• Primary Completion (ACTUAL): January 1, 2007
• Study Completion (ACTUAL): January 1, 2007

Study Registration Dates

• First Submitted: September 12, 2005
• First Submitted That Met QC Criteria: December 7, 2005
• First Posted (ESTIMATE): December 9, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): August 21, 2014
• Last Update Submitted That Met QC Criteria: August 5, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: replacement therapy; alpha 1 proteinase inhibitor; alpha1 proteinase inhibitor; congenital emphysema
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Liver Diseases; Genetic Diseases, Inborn; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Subcutaneous Emphysema; Pulmonary Emphysema; Emphysema; Alpha 1-Antitrypsin Deficiency; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Serine Proteinase Inhibitors; Trypsin Inhibitors; Protease Inhibitors; Alpha 1-Antitrypsin
• Other Study ID Numbers: 100533