A Study to Evaluate Safety, Tolerability and Pharmacokinetics of Two Different Doses of Alpha1-Proteinase Inhibitor Subcutaneous (Human) 15% in Participants With Alpha1-Antitrypsin Deficiency

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of 72 milligrams per kilogram (mg/kg) and 180 mg/kg Alpha-1 15%, administered as a single-dose subcutaneous (SC) infusion and subsequently as weekly SC infusions over 8 weeks in participants with Alpha1-Antitrypsin Deficiency (AATD).

Official Title
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A Multi-Center, Single-Dose and Repeat-Dose Over Eight Weeks, Sequential Cohort Study to Evaluate Safety and Tolerability as Well as Pharmacokinetics of Two Different Doses of Alpha1-Proteinase Inhibitor Subcutaneous (Human) 15% Administered Subcutaneously in Subjects With Alpha1-Antitrypsin Deficiency

Conditions
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Alpha1-Antitrypsin Deficiency

Intervention / Treatment
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* Biological: Alpha-1 15%
* Biological: Liquid Alpha1-Proteinase Inhibitor (Human)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a diagnosis of congenital Alpha1-antitrypsin deficiency (AATD) with an allelic combination of ZZ, SZ, Z(null), (null)(null), S(null), or at-risk alleles (subjects with at-risk alleles must be individually evaluated for eligibility by the Medical Monitor). Have a documented pre-Alpha1-Proteinase Inhibitor (PI) augmentation therapy serum alpha-1 antitrypsin (AAT) level <11 micrometer (μM) (80 milligrams per decilitre (mg/dL) if measured by radial immunodiffusion or 50 mg/dL if measured by nephelometry). Subjects may be naïve to Alpha1-PI augmentation therapy or may be currently receiving Alpha1-PI augmentation therapy or received Alpha1-PI augmentation therapy within the past. If the subject is currently receiving Alpha1-PI augmentation therapy of any kind, he/she must be willing to discontinue that treatment for at least 25 days prior to the Week 1 (Baseline) Visit and remain off any kind of Alpha1-PI treatment, other than the IPs for this study, while participating in the study. At the Screening Visit, have a post-bronchodilator forced expiratory volume (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). Exclusion Criteria: Have had a moderate or severe Chronic obstructive pulmonary disease (COPD) exacerbation during the 4 weeks before the Week 1 (Baseline) Visit. Have history of lung or liver transplant. Have any lung surgery during the past 2 years (excluding lung biopsy). Have severe concomitant disease (example, congestive heart failure, clinically significant pulmonary fibrosis, malignant disease [except for skin cancers other than melanoma], history of acute hypersensitivity pneumonitis reaction, or current chronic hypersensitivity pneumonitis). Females who are pregnant, breastfeeding or, if of child-bearing potential, unwilling to practice a highly effective method of contraception (oral, injectable, or implanted hormonal methods of contraception, placement of an intrauterine device (IUD) or intrauterine system (IUS), condom or occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or true abstinence) throughout the study. Have smoked during the past 6 months or a positive urine cotinine test at the Screening Visit that is due to smoking. Participate in another Investigational product (IP) study within one month prior to the Week 1 (Baseline) Visit. Have history of anaphylaxis or severe systemic response to any plasma-derived Alpha1-PI preparation or other blood product(s). Use systemic steroids above a stable dose equivalent to 5 mg/day prednisone (i.e., 10 mg every 2 days) within the 4 weeks prior to the Week 1 (Baseline) Visit. It is recommended to maintain the same dose throughout the study. Use systemic or aerosolized antibiotics for a chronic COPD exacerbation within the 4 weeks prior to the Week 1 (Baseline) Visit. Have known selective or severe Immunoglobulin A (IgA) deficiency.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Treatment Period 1 (Alpha-1 15%, 72 mg/kg)<br>Participants will receive Alpha-1 15% 72 mg/kg, single weekly subcutaneous (SC) infusion in treatment-period 1 (Single-Dose) at Week 1. | Biological: Alpha-1 15%<br>* Alpha1-Proteinase Inhibitor (Human), 15%, Subcutaneous infusion<br>|
| Experimental: Cohort 1: Single-Dose Data Evaluation Period (Liquid Alpha 1-Proteinase Inhibitor 60 mg/kg)<br>Following treatment period 1, participants in Cohort 1 will enter 21 days of washout/serial pharmacokinetic (PK) phase and then the single-dose data evaluation period. During the single-dose data evaluation phase, Liquid Alpha1- Proteinase Inhibitor (PI) 60 mg/kg, weekly intravenous (IV) Infusions will be administered from intravenous-dose Week 1 (single-dose Week 5) for up to Week 78, with the last IV dose given 1 week prior to the first repeat Alpha-1 15% SC dose. | Biological: Liquid Alpha1-Proteinase Inhibitor (Human)<br>* Intravenous infusion<br>* Other names: Prolastin®-C Liquid;|
| Experimental: Cohort 1: Treatment Period 2 (Alpha-1 15%, 72 mg/kg)<br>Following treatment period 1 and single-dose data evaluation period, participants in Cohort 1 will enter treatment period 2 (Repeat-Dose) and will receive Alpha-1 15% 72 mg/kg, for 8 weekly SC infusions. | Biological: Alpha-1 15%<br>* Alpha1-Proteinase Inhibitor (Human), 15%, Subcutaneous infusion<br>|
| Experimental: Cohort 2: Treatment Period 1 (Alpha-1 15%, 180 mg/kg)<br>Participants will receive Alpha-1 15% 180 mg/kg, single weekly SC infusion in treatment-period 1 (Single-Dose) at Week 1. | Biological: Alpha-1 15%<br>* Alpha1-Proteinase Inhibitor (Human), 15%, Subcutaneous infusion<br>|
| Experimental: Cohort 2: Single-Dose Data Evaluation Period (Liquid Alpha1-Proteinase Inhibitor 120 mg/kg)<br>Following treatment period 1, participants in Cohort 2 will enter 21 days of washout/serial pharmacokinetic (PK) phase and then the single-dose data evaluation phase. During the single-dose data evaluation phase, Liquid Alpha1-PI 120 mg/kg, weekly IV Infusions will be administered from intravenous-dose Week 1 (single-dose Week 5) for up to Week 78, with the last IV dose given 1 week prior to the first repeat Alpha-1 15% SC dose. | Biological: Liquid Alpha1-Proteinase Inhibitor (Human)<br>* Intravenous infusion<br>* Other names: Prolastin®-C Liquid;|
| Experimental: Cohort 2: Treatment Period 2 (Alpha-1 15%, 180 mg/kg)<br>Following treatment period 1 and single-dose data evaluation phase, participants in Cohort 2 will enter treatment period 2 (Repeat-Dose) and will receive Alpha-1 15% 180 mg/kg, for 8 weekly SC infusions. | Biological: Alpha-1 15%<br>* Alpha1-Proteinase Inhibitor (Human), 15%, Subcutaneous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) |  | Up to 668 days | 
| Number of Participants With Suspected Adverse Drug Reactions (ADRs) |  | Up to 668 days | 
| Number of Participants With Infusion Site Reactions |  | Up to 668 days | 
| Number of Participants With Serious Adverse Events (SAEs) |  | Up to 668 days | 
| Number of Participants With AEs and SAEs Leading to Discontinuation |  | Up to 668 days | 
| Number of Participants With Chronic Obstructive Pulmonary Disease (COPD) Exacerbations |  | Up to 668 days | 
| Number of Participants With Clinically Significant Abnormalities in Vital Signs (Heart Rate, Blood Pressure, Respiratory Rate, and Temperature) |  | Up to 668 days | 
| Change from Baseline in Forced Expiratory Volume in 1 Second (FEV1) |  | Up to 668 days | 
| Change from Baseline in Forced Vital Capacity (FVC) |  | Up to 668 days | 
| Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters (Chemistry, Hematology, Urinalysis) |  | Up to 668 days | 
| Immunogenicity: Number of Participants With Alpha1-PI Antibodies |  | Treatment Period 1- Single-Dose Week 1; Treatment Period 2- Repeat-Dose Weeks 1 and 9 | 

 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, Emphysema, Pathologic Processes, Pulmonary Disease, Chronic Obstructive, Lung Diseases, Obstructive, Lung Diseases, Respiratory Tract Diseases, Liver Diseases, Digestive System Diseases, Genetic Diseases, Inborn, Subcutaneous Emphysema, Alpha1-Antitrypsin, Trypsin Inhibitors, Serine Proteinase Inhibitors, Protease Inhibitors, Enzyme Inhibition, Molecular Mechanisms of Pharmacological Action