Clinical trial NCT02295566: RATNO, Reducing Antibiotic Tolerance Using Nitric Oxide in CF - a Phase 2 Pilot Study
Official title: RATNO (Reducing Antibiotic Tolerance Using NO) Reducing Antibiotic Tolerance Using Low Dose Nitric Oxide in Cystic Fibrosis - a Phase 2 Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cystic Fibrosis
Keywords: Nitric Oxide
Pseudomonas Aeruginosa
Biofilm
Lead sponsor: University Hospital Southampton NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: University of Southampton
First posted: 2014-11-20
Enrollment: 12
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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.

Primary outcomes:
measure: Biovolume of Pseudomonas Aeruginosa (PA) biofilms in sputum
timeFrame: 2 years
Secondary outcomes:
measure: Bacterial density
timeFrame: 2 years
measure: Forced Expiratory Volume in 1 second (FEV1)
timeFrame: 2 years
measure: Nitric Oxide levels in sputum
timeFrame: 2 years
measure: Bacterial species identification
timeFrame: 5 years
measure: Exhaled Nitric Oxide
timeFrame: 2 years
measure: Health related quality of life score (HRQOL)
timeFrame: 2 years
Other outcomes:
Locations:
city: Southampton
country: United Kingdom
facility: University Southampton NHS Foundation Trust
state: Hampshire
Study officials:
affiliation: University Hopsital Southampton NHS Foundation Trust
name: Saul Faust
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital Southampton NHS Foundation Trust
name: Gary Connett, FRCPCH MD
role: STUDY_DIRECTOR
affiliation: Universityh of Southampton
name: Jeremy Webb, PhD
role: STUDY_DIRECTOR
References: