Value of Inhaled Treatment With Aztreonam Lysine in Bronchiectasis

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Brief Title

Value of Inhaled Treatment With Aztreonam Lysine in Bronchiectasis

Official Title

A Trial of the Safety, Tolerability and Efficacy of 2 Doses of Cayston (Aztreonam Lysine) Compared to Placebo in Participants With Bronchiectasis

Brief Summary

      A randomised controlled trial of the safety, tolerability and effectiveness of 2 doses of
      Cayston (Aztreonam Lysine) compared to placebo in participants with bronchiectasis.

      Bronchiectasis not due to cystic fibrosis is a chronic inflammatory disease characterised by
      cough, sputum production and frequent respiratory tract infections. There are currently no
      licensed therapies for bronchiectasis approved by regulators in the United States or Europe.
      The disease has a high morbidity, particularly in the presence of chronic P. aeruginosa and
      other chronic Gram-negative infections.

      This trial will test the hypothesis that 12 months treatment with Aztreonam lysine for
      inhalation will be safe and well tolerated, and will result in a significant increase in the
      time to first pulmonary exacerbation in participants with bronchiectasis and a history of
      frequent exacerbations.

      This is a multi-centre randomised double-blind placebo controlled parallel group trial with
      four treatment arms. It will enroll 100 bronchiectasis patients with a history of at least 3
      exacerbations in the previous year and the presence of chronic Gram-negative infection in
      sputum at screening. Patients will be treated following a one month on, one month off
      treatment regimen for 12 months.

      The primary objective is to evaluate the safety and tolerability of Aztrenam lysine in these
      patients by recording adverse events and trial treatment withdrawals.
    

Detailed Description

      Chronic neutrophilic inflammation is a feature of bronchiectasis and the levels of
      neutrophilic inflammation predict the risk of future exacerbations. Neutrophilic inflammation
      is highest in participants with P. aeruginosa and other Gram negative pathogens and
      inflammation can be suppressed by inhaled antibiotic treatment . There is therefore a strong
      rationale for the effectiveness of inhaled antibiotic treatment in bronchiectasis.

      Studies of inhaled antibiotics in bronchiectasis have given mixed results to date. Several
      open label studies in the late 1980's, testing nebulised β-lactams, demonstrated reduced
      sputum purulence, sputum volume and improvements in inflammatory markers. In an early phase
      II double-blind placebo-controlled trial by Barker et al. nebulised tobramycin significantly
      reduced the primary outcome of P. aeruginosa bacterial load but was poorly tolerated by some
      participants. Subsequently a single centre randomised controlled trial of nebulised
      gentamicin for 12 months reported significant benefits but was limited by open label design
      and small sample size. Haworth et al recruited 144 participants with chronic P. aeruginosa
      infection and randomized participants to nebulised colistin or placebo. The trial narrowly
      failed to meet its primary end-point (colistin group 165 days versus placebo 111 days;
      p=0.11). In the secondary end-points, a large improvement in quality of life using the SGRQ
      was noted (mean difference −10.5 points; p=0.006).

      Aztreonam is an inhaled antibiotic licensed for treatment in cystic fibrosis. Two recent
      phase III trials in bronchiectasis randomised 266 (AIR-BX1) and 274 (AIR-BX2) participants to
      Aztreonam 75mg three times daily or placebo over the course of two 28-day treatment cycles
      (with 28 days off treatment between cycles). The primary outcome was the newly developed
      Quality of Life Bronchiectasis (QoL-B) questionnaire. Unfortunately the trial failed to meet
      its primary end-point, with a significant change observed in the QOL-B respiratory symptom
      score in AIR-BX2 but not in AIR-BX1. Treatment related adverse effects were also increased in
      the Aztreonam treated participants.

      Likely explanations for the difficulties encountered in this previous trial include that the
      trial population was quite heterogeneous, with many participants having no history of
      exacerbations and appearing to have relatively mild disease. Many patients did not have a
      history exacerbations in this trial whereas the ERS bronchiectasis guidelines suggest
      limiting inhaled antibiotic use to patients with a history of 3 or more exacerbations per
      year. The characteristics of the included participants included high rates of pulmonary
      non-tuberculous mycobacterial disease and COPD. Nadig and Flume compared the characteristics
      of included participants in this trial to their own population of participants with severe
      bronchiectasis treated with inhaled antibiotics and identified little correlation, suggesting
      that the trials included a skewed population that was not representative of real-life
      clinical practice (Nadig and Flume AJRCCM 2016).

      In addition, no dose finding studies were performed in bronchiectasis. The dose of 75mg three
      times daily was chosen based on efficacy and safety in cystic fibrosis. The rates of adverse
      events appear to be higher in bronchiectasis suggesting that doses selected for CF may not be
      fully appropriate for participants with non-CF bronchiectasis. Whether lower doses may have
      efficacy and better safety has not been investigated.

      There is a need to determine the safety and efficacy of Aztreonam lysine in participants with
      bronchiectasis and a history of frequent exacerbations.

      The researchers hypothesise that Aztreonam lysine will be safe and well tolerated and will
      reduce the frequency of exacerbations in participants with bronchiectasis and a history of
      frequent exacerbations. This trial will test two different doses of Aztreonam lysine compared
      to placebo. The efficacy and safety of Aztreonam is supported by the evidence for Aztreonam
      in cystic fibrosis where Aztreonam prolonged the time to first exacerbation by 21 days
      compared to placebo and improved quality of life. The AIR-BX studies evaluated Aztreonam for
      inhalation for only 2 treatment cycles. They showed suppression of chronic Gram-negative
      airway bacterial load but were not designed to evaluate the impact of Aztreonam on the
      frequency or time to first exacerbation. No attempt to identify the optimal dose was made.
      The incidence of treatment related adverse effects was increased in AIR-BX1 but was more
      balanced in AIR-BX2, a trial conducted primarily in European bronchiectasis participants. The
      reason for this imbalance is unknown.

      The researchers hypothesise that 12 months treatment with Aztreonam lysine for inhalation
      will be safe and well tolerated, and will result in a significant increase in the time to
      first pulmonary exacerbation in participants with bronchiectasis and a history of frequent
      exacerbations.

      The Vital BE trial will evaluate two doses of aztreonam lysine to determine the optimal dose
      for testing in future phase 3 trials.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

The number of adverse events, serious adverse events and trial treatment withdrawals in order to evaluate the safety and tolerability of Aztreonam lysine

Secondary Outcome

 To determine the effect of Aztreonam Lysine on time to first protocol-defined pulmonary exacerbation

Condition

Bronchiectasis Adult

Intervention

Aztreonam lysine

Study Arms / Comparison Groups

 Aztreonam lysine, 3 doses per day
Description:  3 doses per day of nebulised Aztreonam lysine (75 mg) for 1 month, followed by 1 month off treatment. The month on, month off regimen will be repeated for a total peroid of 12 months.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

100

Start Date

October 19, 2019

Completion Date

October 31, 2020

Primary Completion Date

October 31, 2020

Eligibility Criteria

        Inclusion Criteria:

          -  ≥ 18 years of age

          -  Able to give informed consent

          -  Clinical diagnosis of Bronchiectasis

          -  CT scan of the chest demonstrating bronchiectasis in 1 or more lobes

          -  A history of at least 3 exacerbations in the previous 12 months

          -  Bronchiectasis severity index score >4

          -  Pseudomonas aeruginosa or other Gram-negative respiratory pathogen detected in sputum
             or bronchoalveolar lavage on at least 1 occasion in the previous 12 months.

          -  A sputum sample that is culture positive for P. aeruginosa or other Gram-negative
             respiratory pathogens sent at the screening visit and within 28 days of randomization.
             Pre-specified eligible organisms include Eschericia coli, Haemophilus influenzae,
             Moraxella catarrhalis, Klebsiella pneumoniae, Proteus mirabilis, Serratia marcescens,
             Achromobacter, Enterobacter and Stenotrophomonas maltophilia

        Exclusion Criteria:

          -  Participant has cystic fibrosis

          -  Immunodeficiency requiring replacement immunoglobulin.

          -  Active tuberculosis or nontuberculous mycobacterial infection (defined as currently
             under treatment, or requiring treatment in the opinion of the investigator).

          -  Recent significant haemoptysis (a volume requiring clinical intervention, within the
             previous 4 weeks).

          -  Treatment with inhaled, systemic or nebulized anti-Pseudomonal antibiotics in the 28
             days prior to randomization

          -  Oral macrolides which have been taken for a period of less than 3 months prior to the
             start of the trial.

          -  Treatment of an exacerbation and receiving antibiotic treatment within 4 weeks of
             randomization

          -  Primary diagnosis of COPD associated with >20 pack years smoking history.

          -  History of poorly controlled asthma or a history of bronchospasm with inhaled
             antibiotics.

          -  Pregnant or lactating females.

          -  Participants with FEV1 <30% predicted value at screening.

          -  Previous history of intolerance to Aztreonam or bronchospasm reported with any other
             inhaled anti-bacterial.

          -  Glomerular filtration rate (eGFR) below 30ml/min/1.73m2 or requiring dialysis. This
             will be determined at screening.

          -  Use of any investigational drugs within five times of the elimination half-life after
             the last trial dose or within 30 days, whichever is longer.

          -  Unstable co-morbidities (cardiovascular disease, active malignancy) which in the
             opinion of the investigator would make participation in the trial not in the
             participants best interest.

          -  Long term oxygen therapy

          -  Women of child bearing age or male partners of women of child bearing age and not
             practicing a method of acceptable birth control (see below)
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

James Chalmers, MBChB, MRCP, 01382 386131, [email protected]

Location Countries

United Kingdom

Location Countries

United Kingdom

Administrative Informations


NCT ID

NCT03696290

Organization ID

2016RC27

Secondary IDs

2018-001590-24

Responsible Party

Sponsor

Study Sponsor

University of Dundee

Collaborators

 Gilead Sciences

Study Sponsor

James Chalmers, MBChB, MRCP, Principal Investigator, University of Dundee


Verification Date

July 2020