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

April 17, 2021 updated by: Baxalta now part of Shire

The Effect of Augmentation Therapy With ARALAST Fraction IV-1 (ARALAST) Alpha1-Proteinase Inhibitor (α1-PI) on the Level of α1-PI and Other Analytes in the Bronchoalveolar (BAL) Epithelial Lining Fluid (ELF)

The purpose of this study is to evaluate the effects of weekly augmentation therapy with ARALAST Fraction IV-1 (Fr IV-1) on epithelial lining fluid (ELF) alpha 1-proteinase inhibitor levels and other ELF analytes and to assess the safety of the treatment. Eligible subjects with a diagnosis of severe congenital alpha 1-antitrypsin deficiency will receive 8 consecutive weekly treatments with 60 mg/kg/week of functional ARALAST Fr IV-1 administered intravenously. The efficacy and safety assessments will include two bronchoscopies with bronchoalveolar lavage on study initiation and on study termination and multiple imaging and laboratory safety assessments. Each subject will participate for a minimum of 12 weeks.

Study Overview

Status

Completed

Study Type

Interventional

Enrollment (Actual)

21

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • South Australia
      • Adelaide, South Australia, Australia
    • Victoria
      • Melbourne, Victoria, Australia
    • Western Australia
      • Nedlands, Western Australia, Australia
      • Hamilton, New Zealand
    • Auckland
      • Otahuhu, Auckland, New Zealand

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Signed and dated informed consent.
  • Male or female 18 years of age or older.
  • Documented, endogenous serum α1-PI level < 40 mg/dL measured at screening (unless otherwise approved by the Sponsor) after a minimum of 28-day washout of any prior replacement therapy (if applicable).
  • Phenotype Pi Z (which includes Pi*Z/Z, Pi*Z/Null, or Pi*Malton/Z), or Pi*Null/Null.
  • Pulmonary functions at screening meeting the following criteria:

    1. Forced expiratory volume at 1 second (FEV1) >= 50% of predicted value; or
    2. FEV1 > 35% of predicted value and diffusing capacity for carbon monoxide > 45% of predicated value, with no supplemental oxygen therapy and < 3 pulmonary exacerbations or bronchitis requiring antibiotics/corticosteroids within the past 12 months).
  • For any female of childbearing potential, a negative urine test for pregnancy within 7 days prior to the first bronchoalveolar lavage (BAL) visit and agreement to employ adequate birth control measures for the duration of the study.
  • No clinically significant abnormalities detected on a 12-lead electrocardiogram (ECG) performed at the screening visit (ECG previously obtained within the past 12 months may be used, if available).
  • Laboratory results obtained at the screening visit, meeting the following criteria:

    1. Serum alanine aminotransferase (ALT) <= 2 times upper limit of normal (ULN)
    2. Serum aspartate aminotransferase (AST) <= 2 times ULN
    3. Serum total bilirubin <= 2 times ULN
    4. Proteinuria < +2 on dipstick analysis
    5. Serum creatinine <= 1.5 times ULN
    6. Absolute neutrophil count (ANC) >= 1500 cells/mm3
    7. Hemoglobin (Hgb) >= 10.0 g/dL
    8. Platelet count >= 105/mm3
  • If the subject is treated with respiratory medications, such as inhaled bronchodilators or inhaled corticosteroids, or other chronic medications for the treatment of the subjects´s other medical condition(s), the subject's medication doses were unchanged for at least 14 days prior to the baseline BAL visit.

Exclusion Criteria:

  • Clinically significant pulmonary impairment, other than chronic pulmonary disease (COPD).
  • The subject has received any alpha 1 proteinase inhibitor (α1-PI) augmentation therapy (e.g., Prolastin, Zemaira, Aralast, or an investigational α1-PI, by any route including intravenous and inhaled) within 28 days prior to screening.
  • The subject has received an investigational drug or device within 1 month prior to screening, or the subject is currently receiving an investigational drug or device. If the subject receives another investigational drug or device after enrollment, the subjects is to be withdrawn from the trial.
  • Presence of clinical symptoms of any lower respiratory tract infection or acute pulmonary exacerbation within 14 days prior to screening.
  • The subject has a known selective Immunoglobulin A (IgA) deficiency (IgA level less than 15 mg/dL) and/or antibody against IgA.
  • The subject is pregnant or lactating, or intends to become pregnant during the course of the study.
  • The subject is not a suitable candidate for a BAL procedure.
  • Moderate or severe bronchiectasis (total daily sputum production > 10 mL).
  • 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.
  • Prior history of adverse reaction to local anaesthetics, sedatives, pain control drugs, and other medication employed at the study center for perioperative care associated with the BAL procedure.
  • Long-term use of oral or parenteral glucocorticosteroid within 28 days prior to screening.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Bronchoalveolar Lavage (BAL) Epithelial Lining Fluid (ELF) Alpha1-Proteinase Inhibitor (α1-PI) Level
Time Frame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Median change BAL ELF antigenic α1-PI level the from baseline to post-treatment
BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
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
Time Frame: During 8 consecutive weeks of treatment
During 8 consecutive weeks of treatment
Number of Changes in the Rate of Infusion
Time Frame: During 8 consecutive weeks of treatment
Number of decreases in the rate or discontinuations of infusion at 0.2 mL/kg/min
During 8 consecutive weeks of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Ratio of Post- to Pre-treatment BAL ELF Antineutrophil Elastase Capacity (ANEC) Levels
Time Frame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Median ratio of post- to pre-treatment BAL ELF ANEC levels
BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Change in in the Ratio of BAL ELF α1-PI to Human Neutrophil Elastase (HNE) Complex Concentration
Time Frame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Median change in the ratio of BAL ELF α1-PI to HNE complex concentration from baseline to post-treatment
BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Change in the α1-PI Plasma Level
Time Frame: Blood samples were collected at baseline and after 8 consecutive weeks of treatment
Mean change in the plasma level of α1-PI from baseline to post-treatment
Blood samples were collected at baseline and after 8 consecutive weeks of treatment
Change in the Plasma Antineutrophil Elastase Capacity (ANEC) Level
Time Frame: Blood samples were collected at baseline and after 8 consecutive weeks of treatment
Mean change in the plasma ANEC level from baseline to post-treatment
Blood samples were collected at baseline and after 8 consecutive weeks of treatment
Clinically Significant Changes in Vital Signs From Pre- to Post-Infusion
Time Frame: During 8 consecutive weeks of infusion
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
During 8 consecutive weeks of infusion

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in the BAL ELF Free Neutrophil Elastase Level
Time Frame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Median change in the BAL ELF Free Neutrophil Elastase Level from baseline to post-treatment
BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
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)
Median ratio of post- to pre-treatment BAL ELF Total Neutrophil Elastase Level
BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Ratio of Post- to Pre-treatment BAL ELF Interleukin 8 (IL-8) Level
Time Frame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Median ratio of post- to pre-treatment BAL ELF IL-8 Level
BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Change in the BAL ELF Tumor Necrosis Factor-alpha (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)
Median change in the BAL ELF TNF-α from baseline to post-treatment
BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 27, 2006

Primary Completion (Actual)

December 14, 2007

Study Completion (Actual)

December 14, 2007

Study Registration Dates

First Submitted

November 3, 2006

First Submitted That Met QC Criteria

November 3, 2006

First Posted (Estimate)

November 6, 2006

Study Record Updates

Last Update Posted (Actual)

May 13, 2021

Last Update Submitted That Met QC Criteria

April 17, 2021

Last Verified

April 1, 2021

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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