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Pharmacokinetic Study of ARALAST (Human Alpha1- PI)

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ClinicalTrials.gov Identifier: NCT00242385
Recruitment Status : Completed
First Posted : October 20, 2005
Results First Posted : July 20, 2011
Last Update Posted : November 24, 2017
Sponsor:
Collaborator:
Baxter Healthcare Corporation
Information provided by:
Shire

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double;   Primary Purpose: Treatment
Condition Alpha 1-Antitrypsin Deficiency
Interventions Biological: Dose of 60 mg/kg Fraction IV-1 Alpha1-Proteinase Inhibitor
Biological: Dose of 60 mg/kg alpha1-proteinase inhibitor
Enrollment 25
Recruitment Details Enrollment was conducted at seven clinical sites in Australia (4 sites) and New Zealand (3 sites) beginning in December 2005.
Pre-assignment Details All 25 enrolled subjects were assigned to groups.
Arm/Group Title ARALAST Fr. IV-1 Then Aralast ARALAST Then ARALAST Fr. IV-1
Hide Arm/Group Description Subjects were randomized to receive either single dose ARALAST 60 mg/kg or single-dose ARALAST 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. Subjects were randomized to receive either single dose ARALAST 60 mg/kg or single-dose ARALAST 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.
Period Title: Period 1
Started 14 11
Completed 14 11
Not Completed 0 0
Period Title: Period 2
Started 14 11
Completed 14 11
Not Completed 0 0
Arm/Group Title Subjects With Severe Congenital α1-PI Deficiency
Hide Arm/Group Description Subjects were randomized to receive either single dose ARALAST 60 mg/kg or single-dose ARALAST 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.
Overall Number of Baseline Participants 25
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 25 participants
59
(20 to 75)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants
Female
8
  32.0%
Male
17
  68.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 25 participants
Australia 14
New Zealand 11
1.Primary Outcome
Title Area Under the Curve/Dose
Hide Description Area under the plasma alpha1-proteinase inhibitor (α1-PI) concentration versus time curve (AUC) calculated by linear trapezoidal method per dose.
Time Frame Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
Arm/Group Title ARALAST Fr. IV-1 ARALAST
Hide Arm/Group Description:
Single-dose ARALAST Fr. IV-1 60 mg/kg administered at 0.2 mL/kg/min
Single dose ARALAST 60 mg/kg administered at 0.2 mL/kg/min
Overall Number of Participants Analyzed 25 25
Median (Full Range)
Unit of Measure: days*kg/mL
0.0822
(0.0750 to 0.094)
0.0920
(0.0804 to 0.098)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ARALAST Fr. IV-1, ARALAST
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments To establish bioequivalence in AUC 0-35d divided by the dose administered with a type I error of 5% the calculated two-sided 90% confidence interval were to be contained completely in the margins of equivalence defined as 80% to 125%.
Method of Estimation Estimation Parameter Ratio of Geometric Means
Estimated Value 0.928
Confidence Interval (2-Sided) 90%
0.858 to 1.002
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Total Area Under the Curve Per Dose
Hide Description Total area under the α1-PI concentration vs. time curve from pharmacokinetic day 0 to time infinity (AUC 0-infinity) per dose
Time Frame Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
Arm/Group Title ARALAST Fr. IV-1 ARALAST
Hide Arm/Group Description:
Single-dose ARALAST Fr. IV-1 60 mg/kg administered at 0.2 mL/kg/min
Single dose ARALAST 60 mg/kg administered at 0.2 mL/kg/min
Overall Number of Participants Analyzed 25 25
Median (Full Range)
Unit of Measure: days*kg/mL
0.0825
(0.0750 to 0.095)
0.0928
(0.0812 to 0.099)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection ARALAST Fr. IV-1, ARALAST
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments To establish bioequivalence in AUC 0-infinity divided by the dose administered with a type I error of 5% the calculated two-sided 90% confidence interval were to be contained completely in the margins of equivalence defined as 80% to 125%.
Method of Estimation Estimation Parameter Ratio of Geometric Means
Estimated Value 0.934
Confidence Interval (2-Sided) 90%
0.855 to 1.021
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Systemic Clearance (CL)
Hide Description 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)
Time Frame Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
Arm/Group Title ARALAST Fr. IV-1 ARALAST
Hide Arm/Group Description:
Single-dose ARALAST Fr. IV-1 60 mg/kg administered at 0.2 mL/kg/min
Single dose ARALAST 60 mg/kg administered at 0.2 mL/kg/min
Overall Number of Participants Analyzed 25 25
Median (Full Range)
Unit of Measure: mL/day
951
(782 to 1115)
856
(782 to 918)
4.Secondary Outcome
Title Mean Residence Time (MRT)
Hide Description Computed as total area under the moment curve (AUMC) divided by total AUC
Time Frame Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
Arm/Group Title ARALAST Fr. IV-1 ARALAST
Hide Arm/Group Description:
Single-dose ARALAST Fr. IV-1 60 mg/kg administered at 0.2 mL/kg/min
Single dose ARALAST 60 mg/kg administered at 0.2 mL/kg/min
Overall Number of Participants Analyzed 25 25
Mean (Standard Deviation)
Unit of Measure: days
6.8  (3.9) 6.9  (2.8)
5.Secondary Outcome
Title Apparent Volume of Distribution at Steady State
Hide Description Computed as weight-adjusted CL * MRT
Time Frame Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
Arm/Group Title ARALAST Fr. IV-1 ARALAST
Hide Arm/Group Description:
Single-dose ARALAST Fr. IV-1 60 mg/kg administered at 0.2 mL/kg/min
Single dose ARALAST 60 mg/kg administered at 0.2 mL/kg/min
Overall Number of Participants Analyzed 25 25
Median (Full Range)
Unit of Measure: mL
5606
(4624 to 6162)
5405
(4454 to 6703)
6.Secondary Outcome
Title Terminal Half-life
Hide Description 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.
Time Frame Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
Arm/Group Title ARALAST Fr. IV-1 ARALAST
Hide Arm/Group Description:
Single-dose ARALAST Fr. IV-1 60 mg/kg administered at 0.2 mL/kg/min
Single dose ARALAST 60 mg/kg administered at 0.2 mL/kg/min
Overall Number of Participants Analyzed 25 25
Median (Full Range)
Unit of Measure: days
4.1
(3.1 to 5.4)
4.2
(4.0 to 5.2)
7.Secondary Outcome
Title Maximum Plasma Concentration (Cmax)
Hide Description Maximum α1-PI concentration following infusion
Time Frame Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
Arm/Group Title ARALAST Fr. IV-1 ARALAST
Hide Arm/Group Description:
Single-dose ARALAST Fr. IV-1 60 mg/kg administered at 0.2 mL/kg/min
Single dose ARALAST 60 mg/kg administered at 0.2 mL/kg/min
Overall Number of Participants Analyzed 25 25
Median (Full Range)
Unit of Measure: mg/mL
1.7
(1.4 to 1.8)
1.7
(1.5 to 1.8)
8.Secondary Outcome
Title Time to Maximum α1-PI Concentration Post-infusion (Tmax)
Hide Description 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.
Time Frame Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
Arm/Group Title ARALAST Fr. IV-1 ARALAST
Hide Arm/Group Description:
Single-dose ARALAST Fr. IV-1 60 mg/kg administered at 0.2 mL/kg/min
Single dose ARALAST 60 mg/kg administered at 0.2 mL/kg/min
Overall Number of Participants Analyzed 25 25
Median (Full Range)
Unit of Measure: days
0.00
(0.00 to 0.00)
0.00
(0.00 to 0.00)
9.Secondary Outcome
Title Incremental Recovery
Hide Description Computed from Cmax (mg/ml) divided by dose per kg body weight (mg/kg).
Time Frame Pharmacokinetic evaluation: 30 minutes pre-infusion up to 35 days post-infusion
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Data Set - all study subjects who received at least 1 dose of study product, and provided data suitable for pharmacokinetic analysis
Arm/Group Title ARALAST Fr. IV-1 ARALAST
Hide Arm/Group Description:
Single-dose ARALAST Fr. IV-1 60 mg/kg administered at 0.2 mL/kg/min
Single dose ARALAST 60 mg/kg administered at 0.2 mL/kg/min
Overall Number of Participants Analyzed 25 25
Median (Full Range)
Unit of Measure: (mg/mL) / (mg/kg)
0.0259
(0.0234 to 0.028)
0.0258
(0.0237 to 0.027)
10.Secondary Outcome
Title Adverse Events (AEs)
Hide Description

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

Time Frame Throughout study period (7 months)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Safety Analysis Data Set - all study subjects who had evidence of receiving at least one dose of study medication regardless of any protocol violation.
Arm/Group Title ARALAST Fr. IV-1 ARALAST
Hide Arm/Group Description:
Single-dose ARALAST Fr. IV-1 60 mg/kg administered at 0.2 mL/kg/min
Single dose ARALAST 60 mg/kg administered at 0.2 mL/kg/min
Overall Number of Participants Analyzed 25 25
Measure Type: Number
Unit of Measure: Events
Serious AEs 0 0
Non-Serious AEs - Mild 43 45
Non-Serious AEs - Moderate 16 12
Non-Serious AEs - Severe 2 3
Time Frame Throughout the entire study period (7 months)
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title ARALAST Fr. IV-1 ARALAST
Hide Arm/Group Description Subjects received a single dose of ARALAST Fr. IV-1 60 mg/kg at 0.2 mL/kg/min Subjects received a single dose of ARALAST 60 mg/kg at 0.2 mL/kg/min
All-Cause Mortality
ARALAST Fr. IV-1 ARALAST
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
ARALAST Fr. IV-1 ARALAST
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/25 (0.00%)      0/25 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
ARALAST Fr. IV-1 ARALAST
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   23/25 (92.00%)      19/25 (76.00%)    
Gastrointestinal disorders     
Nausea  2/25 (8.00%)  2 3/25 (12.00%)  3
General disorders     
Vessel puncture site bruise  3/25 (12.00%)  3 2/25 (8.00%)  6
Infections and infestations     
Nasopharyngitis  2/25 (8.00%)  2 1/25 (4.00%)  1
Upper respiratory tract infection  3/25 (12.00%)  3 1/25 (4.00%)  1
Injury, poisoning and procedural complications     
Contusion  0/25 (0.00%)  0 3/25 (12.00%)  4
Musculoskeletal and connective tissue disorders     
Muscle strain  2/25 (8.00%)  2 1/25 (4.00%)  1
Musculoskeletal discomfort  2/25 (8.00%)  4 2/25 (8.00%)  2
Myalgia  1/25 (4.00%)  1 2/25 (8.00%)  2
Nervous system disorders     
Headache  4/25 (16.00%)  5 1/25 (4.00%)  3
Lethargy  1/25 (4.00%)  1 2/25 (8.00%)  2
Respiratory, thoracic and mediastinal disorders     
Cough  3/25 (12.00%)  3 1/25 (4.00%)  2
Dyspnoea  0/25 (0.00%)  0 2/25 (8.00%)  4
Pharyngolaryngeal pain  3/25 (12.00%)  3 2/25 (8.00%)  2
Skin and subcutaneous tissue disorders     
Blister  0/25 (0.00%)  0 2/25 (8.00%)  2
1
Term from vocabulary, MedDRA (Unspecified)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Baxter's agreements with PIs vary per individual PI, but contain common elements. Baxter requires a review of results communications (e.g., for confidential information) ≥60 days prior to submission or communication. Baxter may request an additional delay of up to 60 days (e.g., to allow for intellectual property protection).
Results Point of Contact
Name/Title: David Gelmont, MD, Global Medical Director, Head of Specialty Products TA, BioTherapeutics
Organization: Baxter Healthcare Corporation
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
First Submitted: October 19, 2005
First Posted: October 20, 2005
Results First Submitted: February 15, 2011
Results First Posted: July 20, 2011
Last Update Posted: November 24, 2017