Pharmacokinetic Study of ARALAST (Human Alpha1- PI)

• ClinicalTrials.gov Identifier: NCT00242385
• Recruitment Status: Completed
• First Posted: October 20, 2005
• Results First Posted: July 20, 2011
• Last Update Posted: May 13, 2021
• Sponsor: Baxalta now part of Shire
• Collaborator: Baxter Healthcare, Ltd. (New Zealand), Baxter Healthcare Pty. Ltd. (Australia)
• Information provided by (Responsible Party): Takeda ( Baxalta now part of Shire )

Study Description

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.

Condition or disease	Intervention/treatment	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 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double
• 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
• Actual Study Start Date: December 20, 2005
• Actual Primary Completion Date: June 5, 2006
• Actual Study Completion Date: June 5, 2006

Arms and Interventions

Arm	Intervention/treatment
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.

Outcome Measures

Primary Outcome Measures :

1. Area Under the Curve/Dose [ Time Frame: 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 :

1. Total Area Under the Curve Per Dose [ Time Frame: 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
2. Systemic Clearance (CL) [ Time Frame: 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)
3. Mean Residence Time (MRT) [ Time Frame: 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
4. Apparent Volume of Distribution at Steady State [ Time Frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion ]
   Computed as weight-adjusted CL * MRT
5. Terminal Half-life [ Time Frame: 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.
6. Maximum Plasma Concentration (Cmax) [ Time Frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion ]
   Maximum α1-PI concentration following infusion
7. Time to Maximum α1-PI Concentration Post-infusion (Tmax) [ Time Frame: 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.
8. Incremental Recovery [ Time Frame: 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).
9. Adverse Events (AEs) [ Time Frame: 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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

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

Baxalta now part of Shire

Baxter Healthcare, Ltd. (New Zealand), Baxter Healthcare Pty. Ltd. (Australia)

Investigators

• Study Director: Study Director; Takeda

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Li Z, Franke RM, Morris DN, Yel L. Pharmacokinetics and Biochemical Efficacy of an alpha1-Proteinase Inhibitor (Aralast NP) in alpha1-Antitrypsin Deficiency: a Cross-Product Retrospective Comparability Analysis. Pulm Ther. 2022 Sep;8(3):311-326. doi: 10.1007/s41030-022-00199-4. Epub 2022 Aug 24.

• Responsible Party: Baxalta now part of Shire
• ClinicalTrials.gov Identifier: NCT00242385
• Other Study ID Numbers: 460501
• First Posted: October 20, 2005
• Results First Posted: July 20, 2011
• Last Update Posted: May 13, 2021
• Last Verified: April 2021

Keywords provided by Takeda ( Baxalta now part of Shire ):

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; Protease Inhibitors; Alpha 1-Antitrypsin; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Trypsin Inhibitors; Serine Proteinase Inhibitors