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

Primary Purpose

Alpha 1-Antitrypsin Deficiency

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Alpha1-Proteinase Inhibitor (Human)
Albumin (Human) 20%, United States Pharmacopeia (USP)
Sponsored by
Grifols Therapeutics LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Alpha 1-Antitrypsin Deficiency focused on measuring alpha 1 proteinase inhibitor, alpha1 proteinase inhibitor, congenital emphysema, replacement therapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Gentofte Hospital Department of Respiratory Medicine
  • Department of Pulmonary Medicine, Malmö University Hospital
  • Queen Elizabeth Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Group 1

Group 2

Arm Description

Prolastin

Outcomes

Primary Outcome Measures

The Progression Rate of Emphysema Determined by Change in 15th Percentile of Lung Density Measured by Annual CT Scan of the Whole Lung

Secondary Outcome Measures

Change in Lung Density at Each Visit as Measured by Computed Tomography
The Frequency of Exacerbations as Determined by Patient Diary.
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)
Duration and Severity of the Exacerbations
Mortality
Quality of Life With a Disease Specific Instrument, the St. George's Respiratory Questionnaire

Full Information

First Posted
September 12, 2005
Last Updated
August 5, 2014
Sponsor
Grifols Therapeutics LLC
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1. Study Identification

Unique Protocol Identification Number
NCT00263887
Brief Title
Alpha-1-Antitrypsin (AAT) To Treat Emphysema In AAT-Deficient Patients (EXACTLE)
Official Title
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.
Study Type
Interventional

2. Study Status

Record Verification Date
August 2014
Overall Recruitment Status
Completed
Study Start Date
December 2003 (undefined)
Primary Completion Date
January 2007 (Actual)
Study Completion Date
January 2007 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Grifols Therapeutics LLC

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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®?

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Alpha 1-Antitrypsin Deficiency
Keywords
alpha 1 proteinase inhibitor, alpha1 proteinase inhibitor, congenital emphysema, replacement therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
77 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group 1
Arm Type
Experimental
Arm Description
Prolastin
Arm Title
Group 2
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Alpha1-Proteinase Inhibitor (Human)
Other Intervention Name(s)
Prolastin, alpha-1 antitrypsin (AAT), BAY x 5747, BAY 10-5233, TAL-05-00007, NDC 13533-601-30, NDC 13533-601-35
Intervention Description
Weekly infusion of 60 mg/kg body weight for 2 years
Intervention Type
Drug
Intervention Name(s)
Albumin (Human) 20%, United States Pharmacopeia (USP)
Other Intervention Name(s)
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
Intervention Description
Weekly infusion for 2 years. Albumin (Human) 20% will be diluted with 5% glucose to a final concentration of 2.0%.
Primary Outcome Measure Information:
Title
The Progression Rate of Emphysema Determined by Change in 15th Percentile of Lung Density Measured by Annual CT Scan of the Whole Lung
Time Frame
24 or 30 months
Secondary Outcome Measure Information:
Title
Change in Lung Density at Each Visit as Measured by Computed Tomography
Time Frame
24 or 30 months
Title
The Frequency of Exacerbations as Determined by Patient Diary.
Time Frame
24 or 30 months
Title
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)
Time Frame
24 or 30 months
Title
Duration and Severity of the Exacerbations
Time Frame
24 or 30 months
Title
Mortality
Time Frame
24 or 30 months
Title
Quality of Life With a Disease Specific Instrument, the St. George's Respiratory Questionnaire
Time Frame
24 or 30 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Asger Dirksen, MD PHD
Organizational Affiliation
University of Copenhagen
Official's Role
Principal Investigator
Facility Information:
Facility Name
Gentofte Hospital Department of Respiratory Medicine
City
Hellerup
ZIP/Postal Code
2900
Country
Denmark
Facility Name
Department of Pulmonary Medicine, Malmö University Hospital
City
Malmö
Country
Sweden
Facility Name
Queen Elizabeth Hospital
City
Birmingham
State/Province
England
ZIP/Postal Code
B15 2TH
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
19251783
Citation
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.
Results Reference
result
PubMed Identifier
19196813
Citation
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.
Results Reference
result
PubMed Identifier
19483042
Citation
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.
Results Reference
result
PubMed Identifier
23226015
Citation
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.
Results Reference
derived
PubMed Identifier
21617168
Citation
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.
Results Reference
derived
PubMed Identifier
20920370
Citation
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.
Results Reference
derived
PubMed Identifier
19678952
Citation
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.
Results Reference
derived
Links:
URL
http://www.talecris-pi.info/inserts/Prolastin.pdf
Description
FDA Approved Product Labeling Information - Prolastin®
URL
http://www.talecris-pi.info/inserts/plasbumin20la.pdf
Description
FDA Approved Product Labeling Information - Plasbumin®-20 (Low Aluminum)

Learn more about this trial

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

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