Pharmacokinetic Study of ARALAST (Human Alpha1- PI) - Full Text View

Sponsor:	Baxter Healthcare Corporation
Information provided by:	Baxter Healthcare Corporation
ClinicalTrials.gov Identifier:	NCT00242385

Purpose

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.

Condition	Intervention	Phase
Alpha 1-Antitrypsin Deficiency	Biological: Dose of 60 mg/kg Fraction IV-1 Alpha1-Proteinase Inhibitor Biological: Dose of 60 mg/kg alpha1-proteinase inhibitor	Phase I

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacokinetics Study Intervention Model: Crossover Assignment Masking: Double-Blind Primary Purpose: Treatment
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

Resource links provided by NLM:

Genetics Home Reference related topics: alpha-1 antitrypsin deficiency

MedlinePlus related topics: Alpha-1 Antitrypsin Deficiency

U.S. FDA Resources

Further study details as provided by Baxter Healthcare Corporation:

Primary Outcome Measures:

Area Under the Curve/Dose [ Time Frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion ] [ Designated as safety issue: No ]
Area under the plasma alpha1-proteinase inhibitor (α1-PI) concentration versus time curve (AUC) calculated by linear trapezoidal method per dose.

Secondary Outcome Measures:

Total Area Under the Curve Per Dose [ Time Frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion ] [ Designated as safety issue: No ]
Total area under the α1-PI concentration vs. time curve from pharmacokinetic day 0 to time infinity (AUC 0-infinity) per dose
Systemic Clearance (CL) [ Time Frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion ] [ Designated as safety issue: No ]
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)
Mean Residence Time (MRT) [ Time Frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion ] [ Designated as safety issue: No ]
Computed as total area under the moment curve (AUMC) divided by total AUC
Apparent Volume of Distribution at Steady State [ Time Frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion ] [ Designated as safety issue: No ]
Computed as weight-adjusted CL * MRT
Terminal Half-life [ Time Frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion ] [ Designated as safety issue: No ]
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) [ Time Frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion ] [ Designated as safety issue: No ]
Maximum α1-PI concentration following infusion
Time to Maximum α1-PI Concentration Post-infusion (Tmax) [ Time Frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion ] [ Designated as safety issue: No ]
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 [ Time Frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion ] [ Designated as safety issue: No ]
Computed from Cmax (mg/ml) divided by dose per kg body weight (mg/kg).
Adverse Events (AEs) [ Time Frame: Throughout study period (7 months) ] [ Designated as safety issue: Yes ]
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

Enrollment:	25
Study Start Date:	December 2005
Study Completion Date:	June 2006

Arms	Assigned Interventions
Experimental: ARALAST Fr. IV-1 60 mg/kg	Biological: Dose of 60 mg/kg Fraction IV-1 Alpha1-Proteinase Inhibitor 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.
Active Comparator: ARALAST 60mg/kg	Biological: Dose of 60 mg/kg alpha1-proteinase inhibitor 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.

Arms

Assigned Interventions

Experimental: ARALAST Fr. IV-1

60 mg/kg

Biological: Dose of 60 mg/kg Fraction IV-1 Alpha1-Proteinase Inhibitor

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.

Active Comparator: ARALAST

60mg/kg

Biological: Dose of 60 mg/kg alpha1-proteinase inhibitor

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00242385

Locations

Australia, South Australia

Adelaide, South Australia, Australia

Woodville, South Australia, Australia
Australia, Victoria

Fitzroy, Victoria, Australia
Australia, Western Australia

Nedlands, Western Australia, Australia
New Zealand

Otahuhu, Auckland, New Zealand

Christchurch, New Zealand

Hamilton, New Zealand

Sponsors and Collaborators

Baxter Healthcare Corporation

Investigators

Principal Investigator:

Jeff Garrett, MD

Middlemore Hospital, Otahuhu, Auckland, New Zealand

More Information

No publications provided

Responsible Party:	David Gelmont, MD, Global Medical Director, Head of Specialty Products TA, BioTherapeutics, Baxter Healthcare Corporation
ClinicalTrials.gov Identifier:	NCT00242385 History of Changes
Other Study ID Numbers:	460501
Study First Received:	October 19, 2005
Results First Received:	February 15, 2011
Last Updated:	July 18, 2011
Health Authority:	United States: Food and Drug Administration; Australia: Human Research Ethics Committee; New Zealand: Health and Disability Ethics Committees

Keywords provided by Baxter Healthcare Corporation:

Severe congenital Alpha1-Proteinase Inhibitor (Alpha1-PI) deficiency

Additional relevant MeSH terms:

Alpha 1-Antitrypsin Deficiency
Liver Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Subcutaneous Emphysema
Emphysema

Pathologic Processes
Alpha 1-Antitrypsin
Protease Inhibitors
Trypsin Inhibitors
Serine Proteinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on February 12, 2012