Clinical trial NCT00396006: Efficacy and Safety Study of Augmentation Therapy With ARALAST Fraction IV-1 (Human Alpha 1 - Proteinase Inhibitor)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Alpha 1-Antitrypsin Deficiency
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2006-11-06
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Change in Bronchoalveolar Lavage (BAL) Epithelial Lining Fluid (ELF) Alpha1-Proteinase Inhibitor (α1-PI) Level
timeFrame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
measure: 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
timeFrame: During 8 consecutive weeks of treatment
measure: Number of Changes in the Rate of Infusion
timeFrame: During 8 consecutive weeks of treatment
Secondary outcomes:
measure: Ratio of Post- to Pre-treatment BAL ELF Antineutrophil Elastase Capacity (ANEC) Levels
timeFrame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
measure: Change in in the Ratio of BAL ELF α1-PI to Human Neutrophil Elastase (HNE) Complex Concentration
timeFrame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
measure: Change in the α1-PI Plasma Level
timeFrame: Blood samples were collected at baseline and after 8 consecutive weeks of treatment
measure: Change in the Plasma Antineutrophil Elastase Capacity (ANEC) Level
timeFrame: Blood samples were collected at baseline and after 8 consecutive weeks of treatment
measure: Clinically Significant Changes in Vital Signs From Pre- to Post-Infusion
timeFrame: During 8 consecutive weeks of infusion
Other outcomes:
measure: Change in the BAL ELF Free Neutrophil Elastase Level
timeFrame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
measure: Ratio of Post- to Pre-treatment BAL ELF Total Neutrophil Elastase Level
timeFrame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
measure: Ratio of Post- to Pre-treatment BAL ELF Interleukin 8 (IL-8) Level
timeFrame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
measure: Change in the BAL ELF Tumor Necrosis Factor-alpha (TNF-α) From Baseline to Post-treatment
timeFrame: BAL procedures were performed at baseline and after 8 consecutive weeks of treatment (minimum of 12 weeks)
Locations:
city: Adelaide
country: Australia
state: South Australia
city: Melbourne
country: Australia
state: Victoria
city: Nedlands
country: Australia
state: Western Australia
city: Otahuhu
country: New Zealand
state: Auckland
city: Hamilton
country: New Zealand
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: 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.