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

Study Overview
=================
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®?

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.

Conditions
-----------------
Alpha 1-Antitrypsin Deficiency

Intervention / Treatment
-----------------
* Drug: Alpha1-Proteinase Inhibitor (Human)
* Drug: Albumin (Human) 20%, United States Pharmacopeia (USP)


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Prolastin | Drug: Alpha1-Proteinase Inhibitor (Human)<br>* Weekly infusion of 60 mg/kg body weight for 2 years<br>* Other names: NDC 13533-601-35;|
| Placebo Comparator: Group 2<br> | Drug: Albumin (Human) 20%, United States Pharmacopeia (USP)<br>* Weekly infusion for 2 years. Albumin (Human) 20% will be diluted with 5% glucose to a final concentration of 2.0%.<br>* Other names: NDC 13533-691-71;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
alpha 1 proteinase inhibitor, alpha1 proteinase inhibitor, congenital emphysema, replacement therapy