Safety and Pharmacokinetics of Alpha-1 Proteinase Inhibitor in Subjects With Alpha1-Antitrypsin Deficiency

Study Overview
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Brief Summary
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This is a study to assess the safety and pharmacokinetics of weekly infusions of 120 mg/kg of Prolastin-C (alpha1-proteinase inhibitor [alpha1-PI] [Human]), compared to weekly infusions of 60 mg/kg of Prolastin-C in patients with alpha 1-antitrypsin deficiency (AATD).

Detailed Description
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The question of whether higher doses of alpha1-PI (>60 mg/kg) are able to provide better protection to patients with alpha 1-antitrypsin deficiency is currently unknown. As a first step to address this question, the present study has been undertaken. This is a multi-center, randomized, double-blind, crossover study to assess the safety and pharmacokinetics of weekly infusions of 120 mg/kg of Prolastin-C, compared to weekly infusions of 60 mg/kg of Prolastin-C in patients with alpha 1-antitrypsin deficiency. This study is a crossover design with 2 treatment sequences: Treatment Sequence 1: 60 mg/kg weekly infusion of Prolastin-C for 8 weeks followed by 120 mg/kg weekly infusion of Prolastin-C for 8 weeks (starting at Week 1) (total of 16 treatment weeks) Treatment Sequence 2: 120 mg/kg weekly infusion of Prolastin-C for 8 weeks followed by 60 mg/kg weekly infusion of Prolastin-C for 8 weeks (starting at Week 11) (total of 16 treatment weeks) Approximately 15 subjects are planned to be entered into each treatment sequence. At Weeks 8 to 11 and Weeks 18 to 21, a total of 15 serial blood samples for each subject will be drawn for pharmacokinetic analysis. The expected duration of the study subject's participation will be approximately 25 weeks (which includes a 3-Week Screening Phase, 2-Week Washout Period [between different alpha-1 PI treatment doses], and a 4-Week Follow-up Period). The following safety parameters will be assessed: adverse events, pulmonary exacerbations, vital signs, pulmonary function tests, and clinical laboratory tests.

Official Title
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A Randomized Double-blind Crossover Study to Assess the Safety and Pharmacokinetics of Two Different Doses of Weekly Intravenous Administration of Alpha1-Proteinase Inhibitor (Human) Prolastin®-C in Subjects With Alpha1-Antitrypsin Deficiency

Conditions
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Emphysema, Alpha 1-antitrypsin Deficiency (AATD)

Intervention / Treatment
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* Biological: Prolastin-C, 60 mg/kg
* Biological: Prolastin-C, 120 mg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be between 18 and 70 years of age Have a documented diagnosis of congenital AATD Have a post-bronchodilator Forced Expired Volume in 1 second (FEV1) of ≥30% and <80% and FEV1/forced vital capacity (FVC) <70% If receiving alpha-1 PI augmentation therapy, be willing to discontinue the treatment for the duration of the study Exclusion Criteria: Had a moderate or severe pulmonary exacerbation during the 4 weeks before the study History of lung or liver transplant Any lung surgery during the past 2 years Confirmed liver cirrhosis Elevated liver enzymes Severe concurrent disease Females who are pregnant or breast-feeding or unwilling to practice effective contraception during the study Infection with hepatitis A, B, or C, human immunodeficiency or parvovirus B19 Smoking during the past 6 months Use of systemic steroids within 4 weeks of the study Use of antibiotics for an exacerbation within 4 weeks of the study

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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prolastin-C, 60 mg/kg<br>60 mg/kg weekly infusion of Prolastin-C for 8 weeks. Subjects were infused with 60 mg/kg Prolastin-C by means of one of two possible treatment sequences: 1) 60 mg/kg weekly infusion of Prolastin-C for 8 weeks followed by 120 mg/kg Prolastin-C for 8 weeks, or 2) 120 mg/kg Prolastin-C for 8 weeks followed by 60 mg/kg weekly infusion of Prolastin-C for 8 weeks (total of 16 weeks). | Biological: Prolastin-C, 60 mg/kg<br>* 60 mg/kg weekly infusion of Prolastin-C for 8 weeks<br>* Other names: Alpha-1 MP;|
| Experimental: Prolastin-C, 120 mg/kg<br>120 mg/kg weekly infusion of Prolastin-C for 8 weeks. Subjects were infused with 120 mg/kg Prolastin-C by means of one of two possible treatment sequences: 1) 60 mg/kg weekly infusion of Prolastin-C for 8 weeks followed by 120 mg/kg Prolastin-C for 8 weeks, or 2) 120 mg/kg Prolastin-C for 8 weeks followed by 60 mg/kg weekly infusion of Prolastin-C for 8 weeks (total of 16 weeks). | Biological: Prolastin-C, 120 mg/kg<br>* 120 mg/kg weekly infusion of Prolastin-C for 8 weeks<br>* Other names: Alpha-1 MP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subjects With Treatment-Emergent Adverse Events (TEAEs) | Number of subjects experiencing at least one TEAE. TEAEs were defined as any adverse event (AE) during the study that began on or after the date of first dose of investigational product (i.e., Prolastin-C). | 22 weeks | 
| Subjects With Drug-Related TEAE(s) | Number of subjects with at least one TEAE that was determined by the Investigator to be either possibly related or related to the investigational product (i.e., Prolastin-C). | 22 weeks | 
| Subjects With Treatment-Emergent Serious Adverse Events (SAEs) | Number of subjects who experienced at least one treatment-emergent SAE. | 22 weeks | 
| Subjects Withdrawn Due to an AE(s) | Number of subjects who were withdrawn from the study due to at least one AE. | 22 weeks | 
| Subjects With Treatment-Emergent Pulmonary Exacerbation(s) | Number of subjects with at least one treatment-emergent pulmonary exacerbation | 22 weeks | 
| Subjects With Severe TEAE(s) or Pulmonary Exacerbation(s) | Number of subjects who experienced at least one severe TEAE or pulmonary exacerbation. | 22 weeks | 
| Number of TEAEs | Total number of TEAEs reported. | 22 Weeks | 
| Number of Drug-related TEAEs | Total number of drug-related TEAEs reported | 22 Weeks | 
| Number of Treatment-Emergent Pulmonary Exacerbations | Total number of treatment-emergent pulmonary exacerbations. | 22 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-7days | Area Under the Alpha-1 PI Concentration-Time Curve from Day 0 to Day 7 | Week 8 and Week 18 at the following timepoints: 0 (pre-infusion), completion of first infusion bag, completion of 2nd infusion bag, and 15 min, 30 min, and 1, 2, 4, 8, 24, 48, 120, and 168 hours post-dose | 
| Mean Trough | The average trough concentration at steady-state, calculated as the mean value using the four Trough measurements obtained at Weeks 6, 7, 8 and at 7 days (168 hours) post infusion at Week 8 for the first treatment period or prior to the start of the infusions at Weeks 16, 17, 18, and at 7 days (168 hours) post infusion at Week 18 for the second treatment period. | Single measurment immediately prior to infusion at Weeks 6, 7, 8, 9 and Weeks 16, 17, 18, 19 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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emphysema, alpha 1-antitrypsin, alpha 1-antitrypsin deficiency (AATD), alpha 1-proteinase inhibitor (Alpha-1 PI)