RATNO, Reducing Antibiotic Tolerance Using Nitric Oxide in CF - a Phase 2 Pilot Study

NCT02295566 | Completed Phase 2 DMC

• 3 other identifiers: RHM CHI05482010-023529-3911/H0502/7
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

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.

Conditions

Cystic Fibrosis

Keywords

Nitric Oxide; Pseudomonas Aeruginosa; Biofilm

Outcome Measures

Primary Outcomes (1)

• Biovolume of Pseudomonas Aeruginosa (PA) biofilms in sputum

  Assessment of PA biofilms using FISH and image analysis, colony forming units and quantitative polymerase chain reaction.

  2 years

Secondary Outcomes (6)

• Bacterial density

  2 years

• Forced Expiratory Volume in 1 second (FEV1)

  2 years

• Nitric Oxide levels in sputum

  2 years

• Bacterial species identification

  5 years

• Exhaled Nitric Oxide

  2 years

Study Arms (2)

Nitric Oxide Group

ACTIVE COMPARATOR

Inhaled Nitric Oxide delivered via nasal canulae at 10ppm for 8 hours a night for 7 nights.

Drug: Nitric Oxide

Control Group

PLACEBO COMPARATOR

Air/oxygen mix (according to clinical need) delivered via nasal canulae for 8 hours a night for 7 nights.

Drug: Control

Interventions

Nitric Oxide DRUG

Not required

Nitric Oxide Group

Control DRUG

Not required

Also known as: Air, Oxygen

Control Group

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Adolescents and young adults with cystic fibrosis aged 12 or above
• Colonised with Pseudomonas aeruginosa (confirmed on sputum sample)

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Hospital Southampton NHS Foundation Trust: lead
• University of Southampton: collaborator

Study Sites (1)

University Southampton NHS Foundation Trust

Southampton, Hampshire, SO16 6YD, United Kingdom

Location

Related Links

• Published results

MeSH Terms

Conditions

Cystic Fibrosis; Pseudomonas Infections

Interventions

Nitric Oxide; Air; Oxygen

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Reactive Nitrogen Species; Free Radicals; Inorganic Chemicals; Nitrogen Oxides; Nitrogen Compounds; Oxides; Oxygen Compounds; Organic Chemicals; Atmosphere; Environment; Ecological and Environmental Phenomena; Biological Phenomena; Meteorological Concepts; Environment and Public Health; Chalcogens; Elements; Gases

Study Officials

• Saul Faust

  University Hopsital Southampton NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

• Gary Connett, FRCPCH MD

  University Hospital Southampton NHS Foundation Trust

  STUDY DIRECTOR

• Jeremy Webb, PhD

  Universityh of Southampton

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 20, 2014
• First Posted: November 20, 2014
• Study Start: May 1, 2011
• Primary Completion: December 1, 2012
• Study Completion: July 1, 2013
• Last Updated: May 30, 2024

Record last verified: 2014-11

Locations

GB (1)