This study is designed to assess the safety and efficacy of aztreonam for inhalation solution/aztreonam 75 mg powder and solvent for nebuliser solution (AZLI) in subjects with non-CF bronchiectasis and gram-negative endobronchial infection.
ID
Source
Brief title
Condition
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the change in the Respiratory Symptoms score on the
QOL-B from baseline to the end of placebo-controlled Course 1 (i.e., change
from Day 0 [Visit 2] to Day 28 [Visit 4]).
Secondary outcome
The secondary endpoints are:
- Change in the Physical Functioning score on the QOL-B from baseline to the
end of placebo-controlled Course 1 (i.e., change from Day 0 [Visit 2] to Day 28
[Visit 4])
- Change in the Respiratory Symptoms score on the QOL-B at the end of
placebo-controlled Course 2 (Day 84 [Visit 6]) compared to baseline (Day 0
[Visit 2])
- Change in the Physical Functioning score on the QOL-B at the end of
placebo-controlled Course 2 compared to baseline
- Time to Protocol-Defined Exacerbation (PDE) prior to open-label AZLI
treatment
Background summary
Bronchiectasis is a disease of the lungs named for its most prominent
morphologic feature: irreversibly dilated central and medium-sized airways. A
common pathophysiologic feature of bronchiectasis is a chronic cycle of
transmural infection and inflammation. The airway becomes compromised by
intrinsic defect or extrinsic insult, leading to tissue injury due either to
the infectious organism directly, or mediated by the host response. The tissue
injury causes further airway compromise and worsening infection, ultimately
leading to more inflammation and lung damage. Regardless of the specific
etiology, this *vicious cycle* is thought to underlie both the characteristic
pathologic changes of bronchiectasis and its clinical sequelae.
There is strong evidence for the benefit of long-term antibiotic treatment in
patients with bronchiectasis based on meta-analysis of existing clinical
trials; in some cases, these trials show significant symptomatic and functional
improvement, presumably as a result of the significant bacterial killing
observed. However, the existing options for antibiotic maintenance therapy in
patients with bronchiectasis are limited, and none has been approved
specifically for this indication. Scheduled therapy with IV antibiotics is
expensive, impractical, and often prone to significant risk of toxicity and
development of resistance. Certain oral agents have potential for use as
maintenance therapy, but their long-term safety and effectiveness in non-CF
bronchiectasis are either unknown or highly suspect due to concerns about
development of resistance.
AZLI is a novel formulation of aztreonam, which has been used extensively as
parenteral therapy for infections caused by a wide range of gram-negative
bacteria. In clinical trials, AZLI has been delivered using the eFlow®
nebulizer system. The eFlow nebulizer system is a single-subject, multi-use
nebulizer that uses a vibrating perforated membrane to generate an aerosol. The
eFlow is an investigational device in the US and is CE marked in Europe. The
eFlow is approved under the trade name Altera® in the US and the EU.
Based on the observed efficacy and safety of AZLI in an adult CF population,
and the significant overlap in pulmonary pathophysiology for patients with CF
and non-CF bronchiectasis, AZLI represents a potential treatment option for
patients with bronchiectasis and gram-negative endobronchial infection. Results
from the clinical experience with AZLI in subjects with bronchiectasis
(GS-US-219-0102) also support this concept.
Study objective
This study is designed to assess the safety and efficacy of aztreonam for
inhalation solution/aztreonam 75 mg powder and solvent for nebuliser solution
(AZLI) in subjects with non-CF bronchiectasis and gram-negative endobronchial
infection.
Study design
This is a Phase 3, double-blind, multicenter, randomized, placebocontrolled
study in subjects with bronchiectasis and gram-negative endobronchial
infection. The study consists of 10 scheduled visits with a total study
duration of 30 weeks.
Enrolled subjects will be randomized with a 1:1 allocation to receive blinded
AZLI or placebo, and will remain on the same treatment arm until the open-label
portion of the study. Subjects who experience worsening respiratory signs
and/or symptoms after
Visit 2 may be treated with nonstudy antibiotics at the investigator*s
discretion without discontinuation from the study.
At Visit 2, subjects will begin the first of two double-blind,
placebo-controlled 28-day treatment courses. Each placebocontrolled course will
be followed by a 28-day off-treatment interval. After completing both
placebo-controlled courses, all subjects will receive a 28-day open-label
course of AZLI, returning to clinic at the end of the 28-day treatment period,
and 4 and 8 weeks after the last dose of study drug.
Intervention
Two 28-day placebo-controlled treatment courses are planned, followed by one
28-day open-label course of AZLI treatment. AZLI/placebo is to be administered
three times daily (TID) for 28 days per course, with a minimum of 4 hours
between doses. Each dose is to be preceded by administration of a short-acting
inhaled bronchodilator. AZLI will be administered via the eFlow® nebulizer
system.
Study burden and risks
There will be 10 scheduled clinic visits. Planned visits include screening
prior to randomization, evaluations at 14-day intervals during the first
placebo-controlled course, and every 28 days subsequently.
Study procedures will include administration of the Quality of Life
Questionnaire - Bronchiectasis (QOL-B) and the 6-Minute Walk Test (6MWT) during
each clinic visit. Spirometry will be performed after bronchodilator
administration at each scheduled visit; in addition, spirometry will be
repeated after in-clinic study drug treatment at Visits 2 and 7. Sputum will be
collected at every visit for microbiology assessments. Adverse events
(including hospitalizations) and concomitant medication use will be assessed at
every visit. Blood will be collected for standard laboratory tests at Visits 1,
2, 4, 6, 8 and 10.
199 East Blaine Street
WA 98102 Seattle
NL
199 East Blaine Street
WA 98102 Seattle
NL
Listed location countries
Age
Inclusion criteria
- Male/Female >= 18 years old
- Bronchiectasis confirmed by documented computed tomography (CT) scan within 5 years prior to Visit 1, or by prior approval of the Medical Monitor without intervening lung resection
- Reported chronic sputum production on most days during the 4 weeks prior to Visit 1
- Positive sputum culture for target gram-negative organism(s) at Visit 1
- Documented history of positive sputum culture (or bronchoscopic culture) for a target gram-negative organism OR documented history of treatment with antibiotics with gram-negative coverage for an exacerbation of bronchiectasis within 5 years prior to Visit 1
- Chest X-Ray (CXR) obtained and interpreted at Visit 1 or between Visits 1 and 2, without significant acute findings (e.g., no new infiltrate) With prior approval of the Medical Monitor, a CXR obtained within 10 days prior to Visit 1 may be acceptable for study entery.
- Forced expiratory volume in one second (FEV1) >=20% predicted approximately 15 minutes post-bronchodilator at Visit 1
Exclusion criteria
- Hospitalization within 14 days prior to Visit 1
- Reported episode of hemoptysis > 30 mL (~2 tablespoons) within 28 days prior to Visit 1, on the day of Visit 1, and from Visit 1 through Visit 2
- Antibiotics to treat respiratory symptoms (excluding chronic, stable treatment with a macrolide) within 14 days prior to Visit 1, on the day of Visit 1, and from Visit 1 through Visit 2
- Change in bronchodilator, inhaled corticosteroid, macrolide, or bronchial hygiene therapies within 28 days prior to visit 1 and through study completion.
- Change in systemic corticosteroid therapy within 28 days prior to Visit 1 and from Visit 2. After Visit 2, systemic corticosteroid therapy (maximum of 14 days per course) will be allowed to treat worsening respiratory signs and/or symptoms.
- Previous treatment with or exposure to Cayston® (AZLI)
- Serious adverse event between Visits 1 and 2
- History of cystic fibrosis (CF)
- Current treatment for nontuberculous mycobacteria (NTM) infection
- Active mycobacterium tuberculosis (MTB) infection within one year prior to Visit 1
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-023959-28-NL |
| ClinicalTrials.gov | NCT01314716 |
| CCMO | NL36935.094.11 |