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Efficacy and Safety Study of Augmentation Therapy With ARALAST Fraction IV-1 (Human Alpha 1 - Proteinase Inhibitor)

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ClinicalTrials.gov Identifier: NCT00396006
Recruitment Status : Completed
First Posted : November 6, 2006
Results First Posted : January 4, 2011
Last Update Posted : November 24, 2017
Sponsor:
Information provided by:
Shire

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Alpha 1-Antitrypsin Deficiency
Intervention Biological: Alpha1-Proteinase Inhibitor
Enrollment 21
Recruitment Details Participants were recruited at 5 hospital sites in New Zealand and Australia. The period studied was 1 year and 2 months.
Pre-assignment Details 21 participants enrolled: 4 were screen failures (i.e., did not meet inclusion/exclusion criteria), 3 were discontinued due to unevaluable baseline bronchoalveolar lavage (BAL) samples, and 1 subject withdrew consent prior to receiving investigational product.
Arm/Group Title Participants Treated With ARALAST Fraction IV-1 (Fr. IV-1)
Hide Arm/Group Description Weekly infusions of ARALAST Fr. IV-1 were administered to participants at a dosage of 60 mg/kg
Period Title: Overall Study
Started 13
Completed 13
Not Completed 0
Arm/Group Title Participants Treated With ARALAST Fr. IV-1
Hide Arm/Group Description [Not Specified]
Overall Number of Baseline Participants 13
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants
<=18 years
0
   0.0%
Between 18 and 65 years
10
  76.9%
>=65 years
3
  23.1%
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 13 participants
59.6
(36.0 to 76.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 13 participants
Female
6
  46.2%
Male
7
  53.8%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 13 participants
Australia 8
New Zealand 5
1.Primary Outcome
Title Change in Bronchoalveolar Lavage (BAL) Epithelial Lining Fluid (ELF) Alpha1-Proteinase Inhibitor (α1-PI) Level
Hide Description Median change BAL ELF antigenic α1-PI level the from baseline to post-treatment
Time Frame BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Per protocol
Arm/Group Title Per Protocol
Hide Arm/Group Description:
Treated participants with no major protocol violations, evaluable pre- and post-treatment BAL procedures, and 8 consecutive weekly treatments.
Overall Number of Participants Analyzed 10
Median (Full Range)
Unit of Measure: μM
0.28
(-0.24 to 4.90)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Per Protocol
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0195
Comments [Not Specified]
Method Wilcoxon signed rank test
Comments [Not Specified]
2.Primary Outcome
Title The Number of Adverse Events (AEs) Related to the Infusion of ARALAST Fr. IV 1 Administered at a Rate of 0.2 mL/kg/Min
Hide Description [Not Specified]
Time Frame During 8 consecutive weeks of treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intent to treat
Arm/Group Title Intent to Treat
Hide Arm/Group Description:
Treated participants with relevant assessments, e.g. if pre- and post-treatment BAL procedures were required to assess the parameter, then the participant had both evaluable BAL procedures.
Overall Number of Participants Analyzed 13
Measure Type: Number
Unit of Measure: adverse events
0
3.Primary Outcome
Title Number of Changes in the Rate of Infusion
Hide Description Number of decreases in the rate or discontinuations of infusion at 0.2 mL/kg/min
Time Frame During 8 consecutive weeks of treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Intent to Treat
Hide Arm/Group Description:
Treated participants with relevant assessments, e.g. if pre- and post-treatment BAL procedures were required to assess the parameter, then the participant had both evaluable BAL procedures.
Overall Number of Participants Analyzed 13
Measure Type: Number
Unit of Measure: infusions
0
4.Secondary Outcome
Title Ratio of Post- to Pre-treatment BAL ELF Antineutrophil Elastase Capacity (ANEC) Levels
Hide Description Median ratio of post- to pre-treatment BAL ELF ANEC levels
Time Frame BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Per protocol
Arm/Group Title Per Protocol
Hide Arm/Group Description:
Treated participants with no major protocol violations, evaluable pre- and post-treatment BAL procedures, and 8 consecutive weekly treatments.
Overall Number of Participants Analyzed 2
Median (Full Range)
Unit of Measure: μM
1.22
(0.63 to 1.81)
5.Secondary Outcome
Title Change in in the Ratio of BAL ELF α1-PI to Human Neutrophil Elastase (HNE) Complex Concentration
Hide Description Median change in the ratio of BAL ELF α1-PI to HNE complex concentration from baseline to post-treatment
Time Frame BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
No per protocol subject had both pre- and post-treatment analytes available, therefore no analysis could be performed on this outcome measure
Arm/Group Title Per Protocol
Hide Arm/Group Description:
Treated participants with no major protocol violations, evaluable pre- and post-treatment BAL procedures, and 8 consecutive weekly treatments.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
6.Secondary Outcome
Title Change in the α1-PI Plasma Level
Hide Description Mean change in the plasma level of α1-PI from baseline to post-treatment
Time Frame Blood samples were collected at baseline and after 8 consecutive weeks of treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Per protocol
Arm/Group Title Per Protocol
Hide Arm/Group Description:
Treated participants with no major protocol violations, evaluable pre- and post-treatment BAL procedures, and 8 consecutive weekly treatments.
Overall Number of Participants Analyzed 12
Mean (Standard Deviation)
Unit of Measure: μM
10.34  (2.50)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Per Protocol
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method paired t-tests
Comments [Not Specified]
7.Secondary Outcome
Title Change in the Plasma Antineutrophil Elastase Capacity (ANEC) Level
Hide Description Mean change in the plasma ANEC level from baseline to post-treatment
Time Frame Blood samples were collected at baseline and after 8 consecutive weeks of treatment
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Per protocol
Arm/Group Title Per Protocol
Hide Arm/Group Description:
Treated participants with no major protocol violations, evaluable pre- and post-treatment BAL procedures, and 8 consecutive weekly treatments.
Overall Number of Participants Analyzed 12
Mean (Standard Deviation)
Unit of Measure: μM
9.46  (2.31)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Per Protocol
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method paired t-tests
Comments [Not Specified]
8.Secondary Outcome
Title Clinically Significant Changes in Vital Signs From Pre- to Post-Infusion
Hide Description

Clinically significant changes in vital signs from pre- to post-infusion are:

  • Heart rate: 25% increase above pre-infusion value
  • Blood pressure: ≥ 30 mm Hg change from pre-infusion blood pressure (systolic or diastolic)
  • Temperature: an increase in body temperature to >38°C (>100.4°F). If the pre-infusion body temperature was already >38°C (>100.4°F), then any further increase in body temperature by 1.1°C (1.98°F) or more was considered clinically significant.
  • Respiratory rate: 25% increase above pre-infusion value
Time Frame During 8 consecutive weeks of infusion
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Intention to treat
Arm/Group Title Intent to Treat
Hide Arm/Group Description:
Treated participants with relevant assessments, e.g. if pre- and post-treatment BAL procedures were required to assess the parameter, then the participant had both evaluable BAL procedures.
Overall Number of Participants Analyzed 13
Measure Type: Number
Unit of Measure: # Clinically significant events
2
9.Other Pre-specified Outcome
Title Change in the BAL ELF Free Neutrophil Elastase Level
Hide Description Median change in the BAL ELF Free Neutrophil Elastase Level from baseline to post-treatment
Time Frame BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Per protocol population with both pre- and post-treatment analytes available from BAL procedures
Arm/Group Title Per Protocol
Hide Arm/Group Description:
Treated participants with no major protocol violations, evaluable pre- and post-treatment BAL procedures, and 8 consecutive weekly treatments.
Overall Number of Participants Analyzed 3
Median (Full Range)
Unit of Measure: nM
41.17
(3.91 to 41.61)
10.Other Pre-specified Outcome
Title Ratio of Post- to Pre-treatment BAL ELF Total Neutrophil Elastase Level
Hide Description Median ratio of post- to pre-treatment BAL ELF Total Neutrophil Elastase Level
Time Frame BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Per protocol
Arm/Group Title Per Protocol
Hide Arm/Group Description:
Treated participants with no major protocol violations, evaluable pre- and post-treatment BAL procedures, and 8 consecutive weekly treatments.
Overall Number of Participants Analyzed 5
Median (Full Range)
Unit of Measure: nM
1.24
(0.47 to 30.97)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Per Protocol
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1875
Comments [Not Specified]
Method Wilcoxon signed rank test
Comments [Not Specified]
11.Other Pre-specified Outcome
Title Ratio of Post- to Pre-treatment BAL ELF Interleukin 8 (IL-8) Level
Hide Description Median ratio of post- to pre-treatment BAL ELF IL-8 Level
Time Frame BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Per protocol
Arm/Group Title Per Protocol
Hide Arm/Group Description:
Treated participants with no major protocol violations, evaluable pre- and post-treatment BAL procedures, and 8 consecutive weekly treatments.
Overall Number of Participants Analyzed 6
Median (Full Range)
Unit of Measure: pg/mL
1.46
(0.48 to 10.38)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Per Protocol
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4375
Comments [Not Specified]
Method Wilcoxon signed rank
Comments [Not Specified]
12.Other Pre-specified Outcome
Title Change in the BAL ELF Tumor Necrosis Factor-alpha (TNF-α) From Baseline to Post-treatment
Hide Description Median change in the BAL ELF TNF-α from baseline to post-treatment
Time Frame BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Per protocol population with both pre- and post-treatment analytes available from BAL procedures
Arm/Group Title Per Protocol
Hide Arm/Group Description:
Treated participants with no major protocol violations, evaluable pre- and post-treatment BAL procedures, and 8 consecutive weekly treatments.
Overall Number of Participants Analyzed 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame 1 year, 2 months
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Intent to Treat
Hide Arm/Group Description Treated participants with relevant assessments, e.g. if pre- and post-treatment BAL procedures were required to assess the parameter, then the participant had both evaluable BAL procedures.
All-Cause Mortality
Intent to Treat
Affected / at Risk (%)
Total   --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Intent to Treat
Affected / at Risk (%) # Events
Total   1/13 (7.69%)    
Investigations   
Hepatitis A antibody positive 1 [1]  1/13 (7.69%)  1
1
Term from vocabulary, MedDRA (Unspecified)
[1]
Not related to investigational product. This participant had received 2 Hepatitis A vaccinations in the year prior to enrollment.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Intent to Treat
Affected / at Risk (%) # Events
Total   7/13 (53.85%)    
General disorders   
Inflammation 1 [1]  1/13 (7.69%)  1
Sluggishness  2/13 (15.38%)  2
Vessel puncture site haematoma 1 [1]  1/13 (7.69%)  1
Infections and infestations   
Bronchitis 1 [1]  1/13 (7.69%)  1
Sinusitis 1 [1]  1/13 (7.69%)  1
Injury, poisoning and procedural complications   
Contusion 1 [1]  1/13 (7.69%)  1
Post procedural complication 1 [1]  2/13 (15.38%)  3
Investigations   
Blood pressure systolic abnormal 1 [1]  1/13 (7.69%)  1
Respiratory rate increased 1 [1]  1/13 (7.69%)  1
Musculoskeletal and connective tissue disorders   
Back pain 1 [1]  1/13 (7.69%)  1
Nervous system disorders   
Migrane  1/13 (7.69%)  1
Respiratory, thoracic and mediastinal disorders   
Chest discomfort 1 [1]  1/13 (7.69%)  1
Rhinorrhoea  1/13 (7.69%)  6
1
Term from vocabulary, MedDRA (Unspecified)
[1]
Not related to study drug
Isoelectric focusing (IEF) analyses that were intended to compare the profile of plasma α1-PI & ELF α1-PI were not carried out due to fact that ELF samples were either missing, insufficient or too dilute for such assays.
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.
The data from the study shall be published (if applicable) by the sponsor. The investigators and the steering committee may be involved if agreed to by the sponsor. Neither the investigator nor any other person within his/her institution has the right to publish separately or individually without permission by the sponsor.
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: NCT00396006     History of Changes
Other Study ID Numbers: 460502
First Submitted: November 3, 2006
First Posted: November 6, 2006
Results First Submitted: December 15, 2010
Results First Posted: January 4, 2011
Last Update Posted: November 24, 2017