Pharmacokinetic Study of ARALAST (Human Alpha1- PI)

Study Overview
=================
Brief Summary
-----------------
The primary purpose of this study is to characterize the pharmacokinetic profile of intravenous Aralast Fraction (Fr.) IV-1, a sterile, stable, lyophilized preparation of functionally intact human Alpha1- Proteinase Inhibitor (α1-PI). This pharmacokinetic study will be a randomized controlled clinical trial with a cross-over design. Twenty-four subjects will be enrolled into the study. Overall study duration will be approximately 6-8 months.

Official Title
-----------------
Single-Dose, Double-Blind, Crossover Study to Evaluate the Pharmacokinetic Comparability of ARALAST Fraction IV-1 Alpha1-Proteinase Inhibitor (ARALAST Fr. IV-1) and ARALAST

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

Intervention / Treatment
-----------------
* Biological: Dose of 60 mg/kg Fraction IV-1 Alpha1-Proteinase Inhibitor
* Biological: Dose of 60 mg/kg alpha1-proteinase inhibitor


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The subject or subject´s legally authorized representative has provided written informed consent Subject is 18 years of age or older Subject has a documented, endogenous plasma Alpha1-PI level < 8 Micromolar Subject is of the genotype Pi*Z/Z, Pi*Z/Null, Pi*Null/Null, Pi*Malton/Z, or others, dependent on the approval by the Sponsor If the subject is female or of childbearing potential, the subject has a negative urine test for pregnancy within 7 days prior to first study product administration and agrees to employ adequate birth control measures for the duration of the study Laboratory results obtained at the screening visit, meeting the following criteria: Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) <= 2 times the upper limit of normal (ULN) Serum total bilirubin <= 2 times ULN Proteinuria < +2 on dipstick analysis Serum creatinine <= 1.5 times ULN Absolute neutrophil count (ANC) >= 1500 cells/mm3 Hemoglobin >= 10.0 g/dL Platelet count >= 10^5/mm3 If the subject is treated with any respiratory medications, including inhaled bronchodilators and inhaled or oral corticosteroids, the subjects´ medication doses were unchanged for at least 14 days prior to first study product administration Nonsmoker for a minimum of 3 months prior to first study product administration Exclusion Criteria: The subject has received any Alpha1-PI augmentation therapy (including Aralast and investigational Alpha1-PIs, by any route including intravenous and inhaled) within 42 days prior to first study product administration The subject has received an investigational drug or device within 1 month prior to first study product administration, or the subject is currently receiving an investigational drug The subject has a known selective immunoglobulin A (IgA) deficiency (IgA level < 15 mg/dL) and/or antibody to IgA The subject has a pulmonary exacerbation or had a pulmonary exacerbation in the past 14 days prior to first study product administration The subject is pregnant or lactating, or intends to become pregnant during the course of the study The subject has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject safety or compliance

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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARALAST Fr. IV-1<br>60 mg/kg | Biological: Dose of 60 mg/kg Fraction IV-1 Alpha1-Proteinase Inhibitor<br>* Subjects meeting the eligibility criteria were randomized to receive either single dose ARALAST alpha1-proteinase inhibitor 60 mg/kg or single-dose ARALAST alpha1-proteinase inhibitor Fr. IV-1 60 mg/kg at 0.2 mL/kg/min during the first treatment period with crossover to the alternate study product during the second treatment period, with a minimum of 7 days between the two treatment periods.<br>|
| Active Comparator: ARALAST<br>60mg/kg | Biological: Dose of 60 mg/kg alpha1-proteinase inhibitor<br>* Subjects meeting the eligibility criteria were randomized to receive either single dose ARALAST alpha1-proteinase inhibitor 60 mg/kg or single-dose ARALAST alpha1-proteinase inhibitor Fr. IV-1 60 mg/kg at 0.2 mL/kg/min during the first treatment period with crossover to the alternate study product during the second treatment period, with a minimum of 7 days between the two treatment periods.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Curve/Dose | Area under the plasma alpha1-proteinase inhibitor (α1-PI) concentration versus time curve (AUC) calculated by linear trapezoidal method per dose. | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Area Under the Curve Per Dose | Total area under the α1-PI concentration vs. time curve from pharmacokinetic day 0 to time infinity (AUC 0-infinity) per dose | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | 
| Systemic Clearance (CL) | Computed as dose divided by AUC 0-infinity (AUC 0-infinity was calculated as the sum of AUC from time 0 to the time of last quantifiable concentration plus a tail area correction) | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | 
| Mean Residence Time (MRT) | Computed as total area under the moment curve (AUMC) divided by total AUC | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | 
| Apparent Volume of Distribution at Steady State | Computed as weight-adjusted CL * MRT | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | 
| Terminal Half-life | Computed from the terminal or disposition rate constant obtained from log_e -linear fitting using the least squares deviation to the last five quantifiable concentrations above pre-infusion level. | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | 
| Maximum Plasma Concentration (Cmax) | Maximum α1-PI concentration following infusion | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | 
| Time to Maximum α1-PI Concentration Post-infusion (Tmax) | Time to reach C-max. Tmax is the number of days from infusion to maximum concentration. Samples drawn at the end of infusion are considered to be time zero. | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | 
| Incremental Recovery | Computed from Cmax (mg/ml) divided by dose per kg body weight (mg/kg). | Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion | 
| Adverse Events (AEs) | Investigators assessed severity of AEs (occurring during or after infusions) based on: MILD: Transient discomfort, does not interfere in a significant manner with participant's normal functioning level; Resolves spontaneously or may require minimal therapeutic intervention MODERATE: AE produces limited impairment of function, can require therapeutic intervention; AE produces no sequelae; SEVERE: AE results in marked impairment of function, can lead to temporary inability to resume usual life pattern; AE produces sequelae, which require prolonged therapeutic intervention | Throughout study period (7 months) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Severe congenital Alpha1-Proteinase Inhibitor (Alpha1-PI) deficiency