RATNO, Reducing Antibiotic Tolerance Using Nitric Oxide in CF - a Phase 2 Pilot Study
- Registration Number
- NCT02295566
- 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 (CFU"s), 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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 12
- Adolescents and young adults with cystic fibrosis aged 12 or above
- Colonised with Pseudomonas aeruginosa (confirmed on sputum sample)
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Control Group Control Air/oxygen mix (according to clinical need) delivered via nasal canulae for 8 hours a night for 7 nights. Nitric Oxide Group Nitric Oxide Inhaled Nitric Oxide delivered via nasal canulae at 10ppm for 8 hours a night for 7 nights.
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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.
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).
Trial Locations
- Locations (1)
University Southampton NHS Foundation Trust
🇬🇧Southampton, Hampshire, United Kingdom