Study of the Effect of Aerosolized, Recombinant Alpha 1-Antitrypsin on Epithelial Lining Fluid Analytes in Subjects With Alpha 1-Antitrypsin Deficiency

A Phase 1B/2A Study to Evaluate the Effect of Aerosolized, Recombinant Alpha 1-Antitrypsin on Epithelial Lining Fluid Analytes in Subjects With Alpha 1-Antitrypsin Deficiency

The study was a Phase 1B/2A, uncontrolled, open-label, single-center study in individuals with congenital AAT (alpha 1-antitrypsin) deficiency. A baseline bronchoscopy with bronchoalveolar lavage (BAL) was performed 3 to a maximum of 4 weeks prior to the first administration of study drug. Fifteen eligible subjects were randomized to receive 1 of 3 dosing regimens of rAAT (100 mg daily, 100 mg twice daily, or 200 mg daily) administered via nebulization for 7 consecutive days. A post-treatment nadir BAL was obtained on study Day 8 (12 hours after last dose for subjects who receive drug therapy twice daily and 24 hours after the last dose for subjects who receive study product daily). BALs were conducted in the same lung lobe/segment. Follow-up visits took place on Day 15 and Day 36.

Study Overview

• Status: Completed
• Conditions: Alpha1-antitrypsin Deficiency
• Intervention / Treatment: Drug: Aerosolized, Recombinant Alpha 1-Antitrypsin

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • Shands Hospital at the University of Florida

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed Informed Consent
• Male or female 18 years of age or older
• Documented, endogenous plasma AAT levels < 11 µM (< 80 mg/dL), either obtained from the medical history or, if not documented, plasma AAT measured after 28 day washout of any prior replacement therapy
• Forced expiratory volume at 1 second (FEV1) that is >= 50% of predicted, measured 30 minutes after a short-acting inhaled bronchodilator
• Arterial oxygen percent saturation (SaO2, measured using room air) within the normal limits for the individual study site
• For subjects receiving an inhaled corticosteroid, inhaled or oral β-2 agonist (e.g., albuterol via metered dose inhaler [MDI]) or inhaled anticholinergic bronchodilator (e.g., ipratropium bromide), or oral PDE (phosphodiesterase) inhibitor, treatment on a stable dose for at least 14 days prior to enrollment
• For any female of childbearing potential, a negative urine test for pregnancy within 3 days prior to enrollment 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
• Laboratory results obtained at the screening visit, meeting the following criteria:
• Serum aspartate transaminase (AST) and alanine transaminase (ALT) <= 2 times upper limit of normal range (ULN)
• Serum total bilirubin <= 2 times ULN
• < 2+ proteinuria on urine dipstick
• Serum creatinine <= 1.5 times ULN
• Absolute neutrophil count >= 1500 cells/mm3
• Hemoglobin >= 10.0 g/dL
• Platelet count >= 100,000/mm3

Exclusion Criteria:

• Clinically significant pulmonary impairment, other than emphysema and/or chronic bronchitis
• Moderate to severe bronchiectasis
• Clinically significant cardiac, hemostatic, or neurologic impairment, or other significant medical condition that, in the opinion of the investigator, would affect subject safety or compliance
• Psychiatric or cognitive disturbance or illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect subject safety or compliance
• Acute exacerbation of emphysema within 28 days prior to the screening visit
• Pregnancy or lactation
• Known history of allergy to yeast products
• Medical history precluding the use of epinephrine or other rescue medication for treatment of anaphylaxis
• Prior history of adverse reactions to the local anesthetic, sedative, BAL procedure, or pre-medication employed at the study center
• Use of oral or parenteral glucocorticosteroids, or alpha 1-antitrypsin replacement therapy within 28 days prior to baseline BAL, or any use planned during the study. However, the subject may enroll provided that a) consent is given to undergo a 28-day washout of the replacement or steroid therapy, and b) no study procedures are done until the washout is completed.
• Use of another investigational drug or investigational device within 28 days prior to baseline BAL
• Any upper or lower respiratory infection within 28 days prior to baseline BAL
• Having received a lung or liver transplant

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Alpha 1-antitrypsin levels assessed from epithelial lining fluid (ELF) samples	Baseline (minimum of 3 to a maximum of 4 weeks prior to the first administration of study product).
Alpha 1-antitrypsin levels assessed from epithelial lining fluid (ELF) samples	Day 8 after the first administration of study product

Collaborators and Investigators

• Sponsor: Baxalta now part of Shire
• Collaborators: Arriva Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2004
• Primary Completion (Actual): October 14, 2004
• Study Completion (Actual): October 14, 2004

Study Registration Dates

• First Submitted: September 8, 2005
• First Submitted That Met QC Criteria: September 8, 2005
• First Posted (Estimate): September 12, 2005

Study Record Updates

• Last Update Posted (Actual): May 5, 2021
• Last Update Submitted That Met QC Criteria: April 29, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Liver Diseases; Genetic Diseases, Inborn; Subcutaneous Emphysema; Emphysema; Alpha 1-Antitrypsin Deficiency; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Trypsin Inhibitors; Alpha 1-Antitrypsin; Protein C Inhibitor
• Other Study ID Numbers: 410302