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 )

Tracking Information

• First Submitted Date: October 19, 2005
• First Posted Date: October 20, 2005
• Results First Submitted Date: February 15, 2011
• Results First Posted Date: July 20, 2011
• Last Update Posted Date: May 13, 2021
• Actual Study Start Date: December 20, 2005
• Actual Primary Completion Date: June 5, 2006 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 18, 2011)

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.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: April 17, 2021)

• 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
• 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)
• 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
• 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
• 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.
• Maximum Plasma Concentration (Cmax) [ Time Frame: Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion ]
  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 ]
  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 ]
  Computed from Cmax (mg/ml) divided by dose per kg body weight (mg/kg).
• 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

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Pharmacokinetic Study of ARALAST (Human Alpha1- PI)
• 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double; Primary Purpose: Treatment
• Condition: Alpha 1-Antitrypsin Deficiency

Intervention

• 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.
• 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.

Study Arms

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

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 18, 2011): 25
• Original Enrollment (submitted: October 19, 2005): 24
• Actual Study Completion Date: June 5, 2006
• Actual Primary Completion Date: June 5, 2006 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, New Zealand

Administrative Information

• NCT Number: NCT00242385
• Other Study ID Numbers: 460501
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Takeda ( Baxalta now part of Shire )
• Original Responsible Party: Not Provided
• Current Study Sponsor: Baxalta now part of Shire
• Original Study Sponsor: Baxter BioScience
• Collaborators: Baxter Healthcare, Ltd. (New Zealand), Baxter Healthcare Pty. Ltd. (Australia)

Investigators

• Study Director: Study Director; Takeda

• PRS Account: Takeda
• Verification Date: April 2021