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

November 17, 2014 updated by: University Hospital Southampton NHS Foundation Trust

RATNO (Reducing Antibiotic Tolerance Using NO) Reducing Antibiotic Tolerance Using Low Dose Nitric Oxide in Cystic Fibrosis - a Phase 2 Pilot Study

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Not required

Study Type

Interventional

Enrollment (Actual)

12

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • Hampshire
      • Southampton, Hampshire, United Kingdom, SO16 6YD
        • University Southampton NHS Foundation Trust

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

12 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Nitric Oxide Group
Inhaled Nitric Oxide delivered via nasal canulae at 10ppm for 8 hours a night for 7 nights.
Drug: Nitric Oxide
Not required
Placebo Comparator: Control Group
Air/oxygen mix (according to clinical need) delivered via nasal canulae for 8 hours a night for 7 nights.
Drug: Control
Not required
Other Names:
  • Oxygen
  • Air

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Biovolume of Pseudomonas Aeruginosa (PA) biofilms in sputum
Time Frame: 2 years
Assessment of PA biofilms using FISH and image analysis, colony forming units and quantitative polymerase chain reaction.
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Bacterial density
Time Frame: 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.
2 years
Forced Expiratory Volume in 1 second (FEV1)
Time Frame: 2 years
To assess the effect of NO on lung function measured by FEV1
2 years
Nitric Oxide levels in sputum
Time Frame: 2 years
To estimate the NO levels in sputum in each group.
2 years
Bacterial species identification
Time Frame: 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.
5 years
Exhaled Nitric Oxide
Time Frame: 2 years
To assess the effect of low dose inhaled nitric oxide on exhaled nitric oxide levels
2 years
Health related quality of life score (HRQOL)
Time Frame: 2 years
To assess the effect of low dose inhaled nitric oxide on HRQOL using the Cystic Fibrosis Questionnaire - United Kingdom (CFQ-UK).
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital Southampton NHS Foundation Trust

Collaborators

University of Southampton

Investigators

  • Principal Investigator: Saul Faust, University Hopsital Southampton NHS Foundation Trust
  • Study Director: Gary Connett, FRCPCH MD, University Hospital Southampton NHS Foundation Trust
  • Study Director: Jeremy Webb, PhD, Universityh of Southampton

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2011

Primary Completion (Actual)

December 1, 2012

Study Completion (Actual)

July 1, 2013

Study Registration Dates

First Submitted

August 20, 2014

First Submitted That Met QC Criteria

November 17, 2014

First Posted (Estimate)

November 20, 2014

Study Record Updates

Last Update Posted (Estimate)

November 20, 2014

Last Update Submitted That Met QC Criteria

November 17, 2014

Last Verified

November 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RHM CHI0548
  • 2010-023529-39 (EudraCT Number)
  • 11/H0502/7 (Other Identifier: National Research Ethics Service)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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