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Bronchiectasis Alpha-1 Augmentation Trial- Modulating Airway Neutrophil Function (BATMAN)

Primary Purpose

Bronchiectasis Adult

Status
Recruiting
Phase
Phase 4
Locations
United Kingdom
Study Type
Interventional
Intervention
Alpha 1-Proteinase Inhibitor 180mg/kg
Alpha 1-Proteinase Inhibitor 120mg/kg
Sodium chloride
Sponsored by
University of Dundee
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bronchiectasis Adult

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age >18 years
  • Bronchiectasis on high resolution computerised tomography (CT) scan affecting 1 or more lobes
  • Sputum neutrophil elastase activity greater than or equal to 7 µg/ml on neutrophil elastase assay at the screening visit*
  • Daily sputum production as determined by the researcher from the patient's self-report
  • Able to provide a sputum sample at the screening and randomization visits either spontaneously
  • Ability to give informed consent
  • Able to perform all trial procedures with minimal assistance
  • Willing to have pregnancy testing, if appropriate

Exclusion Criteria:

  • Severe alpha-1 antitrypsin deficiency (<57 mg/dl in serum) regardless of genotype#
  • Immunoglobulin A (IgA) deficient patients with antibodies against IgA
  • History of anaphylaxis or other severe systemic reaction to Alpha1-Proteinase Inhibitor
  • Primary diagnosis of Chronic Obstructive Pulmonary Disease (COPD) in the opinion of the investigator
  • Primary Diagnosis of asthma in the opinion of the investigator
  • Active allergic bronchopulmonary aspergillosis, NTM, immunodeficiency or another aetiology of bronchiectasis requiring a specific treatment
  • Treatment with antibiotic therapy for an exacerbation of bronchiectasis (other than long term oral or inhaled antibiotics at stable dose) in the 4 weeks prior to randomization
  • Cystic fibrosis
  • Unstable cardiac disease in the opinion of the investigator
  • Congestive cardiac failure and in the opinion of the investigator should not receive iv infusions.
  • Traction bronchiectasis due to interstitial lung disease
  • Current smoker
  • Pregnant or breast feeding

Sites / Locations

  • NHS TaysideRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Active Comparator

Placebo Comparator

Placebo Comparator

Arm Label

Alpha1-Proteinase Inhibitor 180mg/kg

Alpha1-Proteinase Inhibitor 120mg/kg

Placebo 1

Placebo 2

Arm Description

Alpha1-Proteinase Inhibitor 180mg/kg, intravenous infusion, 50mg/ml

Alpha1-Proteinase Inhibitor 180mg/kg, intravenous infusion, 50mg/ml

Sodium chloride 0.9% volume to match that of Alpha1-Proteinase Inhibitor 180mg/kg, intravenous infusion.

Sodium chloride 0.9% volume to match that of Alpha1-Proteinase Inhibitor 120mg/kg, intravenous infusion.

Outcomes

Primary Outcome Measures

To determine the effect of intravenous alpha-1 proteinase inhibitor on sputum neutrophil elastase activity
Change from baseline in sputum neutrophil elastase activity measured in units/ml

Secondary Outcome Measures

To determine the effect of intravenous alpha-1 proteinase inhibitor on neutrophil function
Change from baseline in alpha-1 antitrypsin levels by immunoassay
To determine the effect of intravenous alpha-1 proteinase inhibitor on neutrophil function
Sputum neutrophil extracellular traps measured using immunoassay
To determine the effect of intravenous alpha-1 proteinase inhibitor on neutrophil function
Activity of cathepsin G and proteinase-3 in sputum
To determine the effect of intravenous alpha-1 proteinase inhibitor on neutrophil function
Sputum neutrophil cell counts
To determine the effect of intravenous alpha-1 proteinase inhibitor on neutrophil function
Sputum neutrophil migration
To determine the effect of intravenous alpha-1 proteinase inhibitor on neutrophil function
Sputum neutrophil degranulation
To determine the effect of intravenous alpha-1 proteinase inhibitor on neutrophil function
Sputum neutrophil phagocytosis
To determine clinical benefits of alpha-1 proteinase inhibitor
Spirometry: forced expiratory volume in 1 minute (FEV1)
To determine clinical benefits of alpha-1 proteinase inhibitor
Spirometry: forced vital capacity (FVC)
To determine clinical benefits of alpha-1 proteinase inhibitor
Spirometry: forced expiratory flow 25-75% (FEV25-75)
To determine clinical benefits of alpha-1 proteinase inhibitor
Spirometry: forced expiratory volume in 1 minute/forced vital capacity (FEV1/FVC)
To determine clinical benefits of alpha-1 proteinase inhibitor
Spirometry: forced expiratory volume in 1 minute (FEV1); forced vital capacity (FVC); forced expiratory flow 25-75% (FEV25-75); forced expiratory volume in 1 minute/forced vital capacity (FEV1/FVC)
To determine safety and tolerability of intravenous alpha-1 proteinase inhibitor administration
Adverse events, serious adverse events and trial treatment withdrawals will be recorded and a comparison made between the 4 treatment groups

Full Information

First Posted
June 29, 2022
Last Updated
April 13, 2023
Sponsor
University of Dundee
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1. Study Identification

Unique Protocol Identification Number
NCT05582798
Brief Title
Bronchiectasis Alpha-1 Augmentation Trial- Modulating Airway Neutrophil Function
Acronym
BATMAN
Official Title
A Proof of Concept Trial of Alpha-1 Antitrypsin Augmentation Therapy in Patients With Bronchiectasis
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
November 1, 2022 (Actual)
Primary Completion Date
October 2024 (Anticipated)
Study Completion Date
October 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Dundee

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No

5. Study Description

Brief Summary
Double-blind, randomized, cross-over trial involving 20 participants with bronchiectasis. This trial will make an important contribution to therapeutic development in bronchiectasis by determining whether alpha-1 antitrypsin (AAT) therapy results in reduced airway inflammation and improves neutrophil function. Patients will be randomly assigned to receive Prolastin-C 120mg/kg (n=10 patients) by weekly intravenous infusions, Prolastin-C 180mg/kg (n=10 patients) by weekly intravenous infusions or placebo (0.9% saline) for a period of 4 weeks, followed by a 3-5 week washout period and a further 4 weeks during which patients will cross-over to receive the alternative therapy.
Detailed Description
Bronchiectasis is a debilitating chronic disease associated with a vicious cycle of lung inflammation, infection and failure of mucociliary clearance. It affects up to 566/100,000 patients in Europe and the prevalence is increasing. Excess neutrophil proteinase activity is central to the pathogenesis of bronchiectasis. Neutrophil elastase is released from activated neutrophils recruited to the bronchiectasis lung and exacerbates inflammation through multiple mechanisms. These include stimulating goblet cell hyperplasia and mucus production, altering of ciliary beat frequency, preventing neutrophil phagocytosis of pathogens through cleavage of phagocytic receptors and preventing apoptotic cell clearance through the cleavage of phosphatidylserine. Neutrophil elastase activity in the bronchiectasis lung is increased because the concentration of elastase released from neutrophils exceeds the inhibitory capacity of the natural anti-proteinase defences of the lung. Of these, alpha-1 proteinase inhibitor accounts for approximately 90% of the inhibitory capacity. The adverse effects of excess proteinase activity are observed in genetic alpha-1 antitrypsin deficiency (A1ATD) where patients develop progressive emphysema, lung function decline, and bronchiectasis. The majority of bronchiectasis patients do not have genetic A1ATD but do have functional alpha-1 antitrypsin deficiency because elastase activity exceeds the available alpha-1 antitrypsin in the lung. There are currently no licensed treatments that directly target excessive neutrophil elastase activity in bronchiectasis. The investigators hypothesize that augmentation of alpha-1 proteinase inhibitor could have beneficial effects in patients with bronchiectasis who have elevated sputum neutrophil elastase activity. Currently, licensed alpha-1 antitrypsin augmentation therapy is given by intravenous infusions on a weekly basis to patients with genetic A1ATD. Inhaled alpha-1 proteinase inhibitor has been used previously in trials in cystic fibrosis. While inhaled alpha1 proteinase inhibitor may have a role in the future in bronchiectasis, the investigators are proposing to conduct a trial of intravenous administration as a proof-of-concept due to the known safety profile of the licensed product and due to increasing evidence that neutrophils in bronchiectasis are dysfunctional in the systematic circulation, with an activated phenotype and evidence of systematic elastin degradation measured by serum desmosine. The investigators propose a proof-of-concept trial which will gather important data to determine the feasibility and scientific value of a future efficacy trial of alpha-1 proteinase inhibitor augmentation in bronchiectasis. There is an urgent unmet need for new therapies in bronchiectasis, a point that has been made by physicians, patients and regulators. There are currently no licensed therapies and off-label treatments have limited effectiveness leaving a high disease burden. European registry data shows that approximately 50% of patients experience two or more exacerbations per year and 1/3 experience at least one admission to hospital for severe exacerbations each year. Patients with elevated neutrophil elastase activity in sputum experience more rapid decline in lung function, more exacerbations and worse quality of life, yet there are no treatments which directly target lung inflammation in bronchiectasis. This trial will make an important contribution to therapeutic development in bronchiectasis by determining whether alpha-1 antitrypsin (AAT) therapy results in reduced airway inflammation and improves neutrophil function. This in turn will inform future therapeutic development in bronchiectasis including determining the potential for a future definitive efficacy and safety trial in bronchiectasis patients. This is the "treatable trait" that the investigators aim to target with AAT administration and this approach of treatment guided by a point-of-care biomarker will be a further innovative aspect of the trial. This is a double-blind, randomized, cross-over trial involving 20 participants with bronchiectasis. The trial will consist of a screening period of up to 35 days followed by a total trial duration of up to 13 weeks. Patients will be randomly assigned to receive Prolastin-C 120mg/kg (n=10 patients) by weekly intravenous infusions, Prolastin-C 180mg/kg (n=10 patients) by weekly intravenous infusions or placebo (0.9% saline) for a period of 4 weeks, followed by a 3-5 week washout period and a further 4 weeks during which patients will cross-over to receive the alternative therapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bronchiectasis Adult

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Alpha1-Proteinase Inhibitor 180mg/kg
Arm Type
Active Comparator
Arm Description
Alpha1-Proteinase Inhibitor 180mg/kg, intravenous infusion, 50mg/ml
Arm Title
Alpha1-Proteinase Inhibitor 120mg/kg
Arm Type
Active Comparator
Arm Description
Alpha1-Proteinase Inhibitor 180mg/kg, intravenous infusion, 50mg/ml
Arm Title
Placebo 1
Arm Type
Placebo Comparator
Arm Description
Sodium chloride 0.9% volume to match that of Alpha1-Proteinase Inhibitor 180mg/kg, intravenous infusion.
Arm Title
Placebo 2
Arm Type
Placebo Comparator
Arm Description
Sodium chloride 0.9% volume to match that of Alpha1-Proteinase Inhibitor 120mg/kg, intravenous infusion.
Intervention Type
Drug
Intervention Name(s)
Alpha 1-Proteinase Inhibitor 180mg/kg
Other Intervention Name(s)
Prolastin-C Liquid
Intervention Description
alpha1-proteinase inhibitor (human) intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Alpha 1-Proteinase Inhibitor 120mg/kg
Other Intervention Name(s)
Prolastin-C Liquid
Intervention Description
alpha1-proteinase inhibitor (human) intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Sodium chloride
Intervention Description
Sodium chloride 09.% intravenous infusion
Primary Outcome Measure Information:
Title
To determine the effect of intravenous alpha-1 proteinase inhibitor on sputum neutrophil elastase activity
Description
Change from baseline in sputum neutrophil elastase activity measured in units/ml
Time Frame
Baseline and 4 weeks
Secondary Outcome Measure Information:
Title
To determine the effect of intravenous alpha-1 proteinase inhibitor on neutrophil function
Description
Change from baseline in alpha-1 antitrypsin levels by immunoassay
Time Frame
Baseline and 4 weeks
Title
To determine the effect of intravenous alpha-1 proteinase inhibitor on neutrophil function
Description
Sputum neutrophil extracellular traps measured using immunoassay
Time Frame
Baseline and 4 weeks
Title
To determine the effect of intravenous alpha-1 proteinase inhibitor on neutrophil function
Description
Activity of cathepsin G and proteinase-3 in sputum
Time Frame
Baseline and 4 weeks
Title
To determine the effect of intravenous alpha-1 proteinase inhibitor on neutrophil function
Description
Sputum neutrophil cell counts
Time Frame
Baseline and 4 weeks
Title
To determine the effect of intravenous alpha-1 proteinase inhibitor on neutrophil function
Description
Sputum neutrophil migration
Time Frame
Baseline and 4 weeks
Title
To determine the effect of intravenous alpha-1 proteinase inhibitor on neutrophil function
Description
Sputum neutrophil degranulation
Time Frame
Baseline and 4 weeks
Title
To determine the effect of intravenous alpha-1 proteinase inhibitor on neutrophil function
Description
Sputum neutrophil phagocytosis
Time Frame
Baseline and 4 weeks
Title
To determine clinical benefits of alpha-1 proteinase inhibitor
Description
Spirometry: forced expiratory volume in 1 minute (FEV1)
Time Frame
Baseline and 4 weeks
Title
To determine clinical benefits of alpha-1 proteinase inhibitor
Description
Spirometry: forced vital capacity (FVC)
Time Frame
Baseline and 4 weeks
Title
To determine clinical benefits of alpha-1 proteinase inhibitor
Description
Spirometry: forced expiratory flow 25-75% (FEV25-75)
Time Frame
Baseline and 4 weeks
Title
To determine clinical benefits of alpha-1 proteinase inhibitor
Description
Spirometry: forced expiratory volume in 1 minute/forced vital capacity (FEV1/FVC)
Time Frame
Baseline and 4 weeks
Title
To determine clinical benefits of alpha-1 proteinase inhibitor
Description
Spirometry: forced expiratory volume in 1 minute (FEV1); forced vital capacity (FVC); forced expiratory flow 25-75% (FEV25-75); forced expiratory volume in 1 minute/forced vital capacity (FEV1/FVC)
Time Frame
Baseline and 4 weeks
Title
To determine safety and tolerability of intravenous alpha-1 proteinase inhibitor administration
Description
Adverse events, serious adverse events and trial treatment withdrawals will be recorded and a comparison made between the 4 treatment groups
Time Frame
4 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age >18 years Bronchiectasis on high resolution computerised tomography (CT) scan affecting 1 or more lobes Sputum neutrophil elastase activity greater than or equal to 7 µg/ml on neutrophil elastase assay at the screening visit* Daily sputum production as determined by the researcher from the patient's self-report Able to provide a sputum sample at the screening and randomization visits either spontaneously Ability to give informed consent Able to perform all trial procedures with minimal assistance Willing to have pregnancy testing, if appropriate Exclusion Criteria: Severe alpha-1 antitrypsin deficiency (<57 mg/dl in serum) regardless of genotype# Immunoglobulin A (IgA) deficient patients with antibodies against IgA History of anaphylaxis or other severe systemic reaction to Alpha1-Proteinase Inhibitor Primary diagnosis of Chronic Obstructive Pulmonary Disease (COPD) in the opinion of the investigator Primary Diagnosis of asthma in the opinion of the investigator Active allergic bronchopulmonary aspergillosis, NTM, immunodeficiency or another aetiology of bronchiectasis requiring a specific treatment Treatment with antibiotic therapy for an exacerbation of bronchiectasis (other than long term oral or inhaled antibiotics at stable dose) in the 4 weeks prior to randomization Cystic fibrosis Unstable cardiac disease in the opinion of the investigator Congestive cardiac failure and in the opinion of the investigator should not receive iv infusions. Traction bronchiectasis due to interstitial lung disease Current smoker Pregnant or breast feeding
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
James Chalmers
Phone
01382 383642
Email
j.chalmers@dundee.ac.uk
First Name & Middle Initial & Last Name or Official Title & Degree
Merete Long, PhD
Phone
01382 660111
Email
MLong001@dundee.ac.uk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
James Chalmers
Organizational Affiliation
University of Dundee
Official's Role
Principal Investigator
Facility Information:
Facility Name
NHS Tayside
City
Dundee
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
James Chalmers
Phone
01382 383642
Email
j.chalmers@dundee.ac.uk

12. IPD Sharing Statement

Plan to Share IPD
No

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Bronchiectasis Alpha-1 Augmentation Trial- Modulating Airway Neutrophil Function

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