Pharmacokinetic Study of ARALAST (Human Alpha1- PI)

Phase 1

Completed

Conditions: Alpha 1-Antitrypsin Deficiency

Registration Number: NCT00242385

Lead Sponsor: Baxalta now part of Shire

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 25

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Mean Residence Time (MRT)	Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion	Computed as total area under the moment curve (AUMC) divided by total AUC
Time to Maximum α1-PI Concentration Post-infusion (Tmax)	Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion	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.
Incremental Recovery	Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion	Computed from Cmax (mg/ml) divided by dose per kg body weight (mg/kg).
Systemic Clearance (CL)	Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion	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)
Apparent Volume of Distribution at Steady State	Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion	Computed as weight-adjusted CL \* MRT
Adverse Events (AEs)	Throughout study period (7 months)	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
Total Area Under the Curve Per Dose	Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion	Total area under the α1-PI concentration vs. time curve from pharmacokinetic day 0 to time infinity (AUC 0-infinity) per dose
Terminal Half-life	Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion	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.
Maximum Plasma Concentration (Cmax)	Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion	Maximum α1-PI concentration following infusion