Efficacy and Safety of Alpha1-Proteinase Inhibitor (Human), Modified Process (Alpha-1 MP) in Subjects With Pulmonary Emphysema Due to Alpha1 Antitrypsin Deficiency (AATD)

Study Overview
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Brief Summary
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This is a multi-center, randomized, placebo-controlled, double blind clinical study to assess the efficacy and safety of two separate dose regimens of Alpha-1 MP versus placebo for 156 weeks (i.e., 3 years) using computed tomography (CT) of the lungs as the main measure of efficacy. The two Alpha-1 MP doses to be tested are 60 mg/kg and 120 mg/kg administered weekly by IV infusion for 156 weeks. The study consists of an optional pre-screening phase, Screening Phase, a 156-week Treatment Phase, and an End of Study Visit at Week 160.

Official Title
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A Randomized, Double-Blind, Placebo Controlled Study to Assess the Efficacy and Safety of Two Dose Regimens (60 mg/kg and 120 mg/kg) of Weekly Intravenous Alpha1 Proteinase Inhibitor (Human) in Subjects With Pulmonary Emphysema Due to Alpha1 Antitrypsin Deficiency

Conditions
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Pulmonary Emphysema in Alpha-1 PI Deficiency

Intervention / Treatment
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* Biological: Alpha-1 MP
* Other: 0.9% Sodium Chloride for Injection, USP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a documented total alpha1-PI serum level < 11 µM. Have a diagnosis of congenital AATD with an allelic combination of ZZ, SZ, Z(null), (null)(null), S(null), or at-risk alleles. At the Screening (Week -3) Visit, have a post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥ 30% and < 80% of predicted and FEV1/forced vital capacity (FVC) < 70% (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II or III). Have a carbon monoxide diffusing capacity (DLCO) ≤ 60% of predicted (corrected for HgB) within the past 2 years OR evidence of pulmonary emphysema on CT scan within the past 2 years per the Investigator's judgment. Have clinical evidence of pulmonary emphysema per the Investigator's judgment. Exclusion Criteria: Has received alpha1-PI augmentation therapy for more than 1 month within the six months prior to the Screening Visit. Has received alpha1-PI augmentation therapy within one month of the Screening Visit. Has had a chronic obstructive pulmonary disease (COPD) exacerbation within the 5 weeks prior to the Screening Visit or during the Screening Phase. Unable to physically (e.g., unable to fit inside the CT scanner) or mentally (e.g., claustrophobic) undergo a CT scan. History of lung or liver transplant. Any lung surgery during the past 2 years (excluding lung biopsy). On the waiting list for lung surgery, including lung transplant. Smoking during the past 12 months or a positive urine cotinine test at screening that is due to smoking. Maybe on Nicotine replacement, including vapor cigarettes. History of anaphylaxis or severe systemic response to any plasma-derived alpha1-PI preparation or other blood product(s). Use of systemic steroids above a stable dose equivalent to 5 mg/day prednisone (i.e., 10 mg every 2 days) within the 5 weeks prior to the Screening Visit (inhaled steroids are not considered systemic steroids) or during the Screening Phase. Use of systemic or aerosolized antibiotics for a COPD exacerbation within the 5 weeks prior to the Screening Visit or during the Screening Phase. Known selective or severe Immunoglobulin A (IgA) deficiency.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alpha-1 MP 60 mg/kg<br>Alpha-1 MP 60 mg/kg administered weekly by IV infusion for 156 weeks | Biological: Alpha-1 MP<br> <br> * Other names: Prolastin-C;|
| Experimental: Alpha-1 MP 120 mg/kg<br>Alpha-1 MP 120 mg/kg administered weekly by IV infusion for 156 weeks | Biological: Alpha-1 MP<br> <br> * Other names: Prolastin-C;|
| Placebo Comparator: Placebo<br>0.9% Sodium Chloride for Injection, USP, administered weekly by IV infusion for 156 weeks | Other: 0.9% Sodium Chloride for Injection, USP<br> <br> * Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Whole lung PD15 (15th percentile point) | Whole lung PD15 measured by CT scan | Week -3 (baseline measure), Week 52, Week 104, Week 130, Week 156 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AEs) | Monitoring of AEs | Week -3 through Week 160 | 
| Serious Adverse Events (SAEs) | Monitoring of SAEs | Week -3 through Week 160 | 
| Discontinuations from the study due to AEs | Monitoring of discontinuations due to AEs | Week -3 through Week 160 | 
| Severe COPD Exacerbations | Severe COPD exacerbations as defined by American Thoracic Society/European Respiratory Society (ATS/ERS) criteria (i.e., COPD exacerbations requiring hospitalization) | Week -3 through Week 160 | 
| Change from Baseline in PD15 of the basal lung region | PD15 of the basal lung region measure by CT scan | Week -3 (baseline measure), Week 52, Week 104, Week 130, Week 156 | 
| Change from baseline in carbon monoxide diffusing capacity (DLco) | DLco performed according to American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines | Weeks 26, 52, 78, 104, 130 and 156 | 
| Changes from baseline in forced expiratory volume in 1 second (FEV1) | FEV1 performed according to ATS/ERS guidelines | Weeks 26, 52, 78, 104, 130 and 156 | 
| Change from baseline in Saint George's Respiratory Questionnaire: Minimum value = 0, maximum value = 100, higher scores indicate worse condition | Health-related quality of life assessment tool | Weeks 26, 52, 78, 104, 130 and 156 | 
| Change from baseline in the EuroQoL (Quality of Life)- 5 Dimension- 5 Level (EQ-5D-5L): Minimum value (for each one of the 5 levels) = 1, maximum value (for each one of the 5 levels) = 5, higher scores indicate worse condition | Heath-related quality of life assessment tool | Weeks 26, 52, 78, 104, 130 and 156 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Emphysema, Alpha-1 Antitrypsin Deficiency, AATD, Alpha-1 PI Deficiency, Alpha-1 Proteinase Inhibitor