Cystic Fibrosis
Conditions
Keywords
Nitric Oxide, Pseudomonas Aeruginosa, Biofilm
Brief summary
The lungs of most patients with cystic fibrosis (CF) become chronically infected with bacteria called Pseudomonas aeruginosa during childhood. This infection is now known to consist of free-living bacteria (known as planktonic bacteria) and bacteria in colonies on body surfaces known as biofilms. The bacteria in biofilms are more resistant and tolerant to antibiotics. Current CF treatment of exacerbations aims to eradicate or control pseudomonal infection using aggressive antibiotic regimes. Despite this treatment many patients develop chronic infection which is never cleared. Chronic infection causes damage to the lungs. Patients colonised with Pseudomonas are more unwell and die at a younger age. Our laboratory has established that low dose nitric oxide (NO) can disrupt pseudomonal biofilms in the laboratory. This pilot study will discover whether non-toxic levels of NO administered to participants during an episode of acute infection (exacerbation) will disrupt bacteria from biofilms and increase the effectiveness of antibiotic therapy. This protocol describes a participant-blind randomised controlled pilot study of treatment with nitric oxide gas during an acute infective exacerbation (also known simply as an acute exacerbation). Patients with CF aged 12 or above will be asked to take part. They will be randomised to receive 7 days either of inhaled nitric oxide gas or placebo alongside standard therapy during an exacerbation. Sputum samples will be obtained before, during and after the treatment period for microbiological analysis. The primary endpoint will be the microbiological effect on bacterial biofilms before and after NO adjunctive therapy. Secondary microbiological endpoints will include the between group differences in pseudomonal colony forming units (CFUs), biofilm NO levels and detailed characterisation of biofilms before and after treatment. Secondary clinical endpoints will include lung function and well-established indicators quality of life. The aim of this randomised pilot study is as proof of concept and to guide the design of a large multi-centre trial to definitively evaluate the effectiveness of NO or NO donors as adjunctive therapy in CF.
Detailed description
Not required
Interventions
DRUGNitric Oxide
Not required
DRUGControl
Not required
Sponsors
University of Southampton
University Hospital Southampton NHS Foundation Trust
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adolescents and young adults with cystic fibrosis aged 12 or above * Colonised with Pseudomonas aeruginosa (confirmed on sputum sample)
Exclusion criteria
* Colonisation with Burkholderia cepacia * Known hypersensitivity to the antibiotics used in the study * Other known contraindications to the antibiotics to be used in the study including known aminoglycoside related hearing/renal damage * Patients requiring non-invasive ventilation (NIV) * Patients who have a pneumothorax * Patients who are admitted for specific treatment of nontuberculous mycobacteria (NTM) * Patients who cannot tolerate nasal cannula e.g. those who cannot breathe through their nose * Patients who have nasal polyposis that is causing significant blockage of the nasal passages * Adolescents who are not Gillick competent (and therefore not able to give their own assent in addition to parental consent) * Patients not likely to survive the time period of the study washout period (4 months from enrolment) * Treatment with an investigational drug or device within the last 3 months prior to enrolment * Patients who are pregnant (a pregnancy test will be carried out for females of 11 years and above as is standard practice for clinical trials) * Immediate families of investigators or site personnel directly affiliated with the study. Immediate family is defined as child or sibling, whether biological or legally adopted.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Biovolume of Pseudomonas Aeruginosa (PA) biofilms in sputum | 2 years | Assessment of PA biofilms using FISH and image analysis, colony forming units and quantitative polymerase chain reaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Forced Expiratory Volume in 1 second (FEV1) | 2 years | To assess the effect of NO on lung function measured by FEV1 |
| Nitric Oxide levels in sputum | 2 years | To estimate the NO levels in sputum in each group. |
| Bacterial density | 2 years | To estimate the effect of adjunctive low dose inhaled nitric oxide given with standard antibiotic therapy on the whole community of bacteria within the CF lung by determination of CFU counts on non-selective agar. |
| Exhaled Nitric Oxide | 2 years | To assess the effect of low dose inhaled nitric oxide on exhaled nitric oxide levels |
| Health related quality of life score (HRQOL) | 2 years | To assess the effect of low dose inhaled nitric oxide on HRQOL using the Cystic Fibrosis Questionnaire - United Kingdom (CFQ-UK). |
| Bacterial species identification | 5 years | To determine the characteristics in the wider microbial community within the CF lung using molecular methods during an exacerbation and to compare these characteristics between the two groups. |
Countries
United Kingdom
Outcome results
None listed