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

Alpha 1-Antitrypsin Deficiency Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00263887
• Other study ID #: 100533
• Status: Completed
• Phase: Phase 2
• First received: September 12, 2005
• Last updated: August 5, 2014
• Start date: December 2003
• Est. completion date: January 2007

Study information

• Verified date: August 2014
• Source: Grifols Therapeutics Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: Danish Medicines AgencySweden: Medical Products AgencyUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

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®?

Recruitment information / eligibility

• Status: Completed
• Enrollment: 77
• Est. completion date: January 2007
• Est. primary completion date: January 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Alpha 1-Antitrypsin Deficiency
• Emphysema

Intervention

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

Locations

Country	Name	City	State
Denmark	Gentofte Hospital Department of Respiratory Medicine	Hellerup
Sweden	Department of Pulmonary Medicine, Malmö University Hospital	Malmö
United Kingdom	Queen Elizabeth Hospital	Birmingham	England

Sponsors (1)

Lead Sponsor	Collaborator
Grifols Therapeutics Inc.

Countries where clinical trial is conducted

Denmark,  Sweden,  United Kingdom, 

References & Publications (3)

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 20 — View 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: 10.1183/09031936.0 — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	Change in Lung Density at Each Visit as Measured by Computed Tomography		24 or 30 months	No
Secondary	The Frequency of Exacerbations as Determined by Patient Diary.		24 or 30 months	Yes
Secondary	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	Yes
Secondary	Duration and Severity of the Exacerbations		24 or 30 months	Yes
Secondary	Mortality		24 or 30 months	Yes
Secondary	Quality of Life With a Disease Specific Instrument, the St. George's Respiratory Questionnaire		24 or 30 months	Yes

External Links

•   FDA Approved Product Labeling Information - Plasbumin®-20 (Low Aluminum)
•   FDA Approved Product Labeling Information - Prolastin®
•   FDA Enforcement, Report Index (Class I, Class II Recall, Market Alerts and Medical Product Safety Alerts)