Official Title: “Supplementary Oral Azithromycin in Treatment of Intermittent Pseudomonas Aeruginosa Colonization in CF-Patients With Inhaled Colistin and Oral Ciprofloxacin; Postponing Next Isolate of Pseudomonas and Prevention of Chronic Infection. A Prospective, Double-Blinded, Placebo-Controlled Scandinavian Multi-Centre Study.”

In patients with Cystic Fibrosis, recurrent airway infection caused by Pseudomonas aeruginosa ultimately leads to chronic airway infection. The purpose of this study is to determine whether supplementary low-dose azithromycin to standard inhaled colistin and oral ciprofloxacin in the treatment of intermittent pseudomonas airway-infection can postpone the next episode of intermittent pseudomonas airway-infection and prevent development of chronic airway-infection.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver), Placebo Control, Parallel Assignment, Efficacy Study

Study Primary Completion Date: May 2013

Cystic Fibrosis is the most common genetic, inherited, deadly disease in caucasians. The disease is characterized by recurrent airway-infections caused by Pseudomonas aeruginosa, ultimately leading to chronic airway-infection, which is the main cause of the increased morbidity and mortality seen in this disease.

P. aeruginosa has the ability to change to mucoid phenotype - producing alginate and growing in biofilm, which protects the microorganisms from antibiotics and leukocytes. The change in phenotype is seen as chronic infection is established and eradication becomes impossible.

Treatment with long-term, low-dose azithromycin in chronically infected CF-patients can improve the clinical condition of the patients. The exact mechanism for this is not known, but is possibly a combination of anti-inflammatory effects and the ability of azithromycin to inhibit alginate-production. Inhibition of biofilm-formation leaves the bacteria more susceptible to the actions of antibiotics and leukocytes.

Prior to establishment of chronic infection, recurrent, intermittent colonization of the airways with non-mucoid P. aeruginosa is seen. Intermittent infections can be treated using a combination of antibiotics, thereby postponing the next episode of airway-infection with P.

aeruginosa.

The purpose of this study is to clarify wether supplementary azithromycin in the treatment of intermittent pseudomonas-infection in CF-patients can lead to further postponement of next pseudomonas-colonization and maybe prevent development of chronic infection. This is done in a randomised, double-blinded, placebo-controlled multicentre study.

2 treatments will be compared:

1. Inhaled colistin and oral ciprofloxacin in combination with oral azithromycin

2. Inhaled colistin and oral ciprofloxacin in combination with oral placebo.

The treatment will be given for 3 weeks, and the primary end-point is the time until next colonization with P. aeruginosa in the airways of the patients, comparing the 2 treatment-groups.

Intervention(s) in this Clinical Trial

• Drug: Study medication, azithromycin or placebo
  • Granulate for syrup in the group under 8 years, 40 mg/ml. Dose: 5 mg/kg/day in one daily dose.
• Drug: Azithromycin or placebo tablets
  • Tablets of 250 mg, azithromycin or placebo. Dosage: 1 tablet every other day for participants with a weight less than 40 kg´s. 1 tablet every day for participants weighing 40 kg´s or more.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: A
  • Stratification group: Age under 8 years, no CF siblings at home.
• Experimental: B
  • Stratification group: Age >/= 8 years, no CF siblings at home.
• Experimental: C
  • Stratification group: Age >/= 8 years, CF siblings at home.

Primary Measures

• Time to next airway-colonization (re-colonization) with Pseudomonas aeruginosa
  • Time Frame: months to years
    Safety Issue?: No

Secondary Measures

• Clinical condition of the patients (height, weight and lung function)
  • Time Frame: months to years
    Safety Issue?: Yes
• Bacteriological examination of Pseudomonas aeruginosa (phenotype, resistance)
  • Time Frame: months to years
    Safety Issue?: No
• Genotyping of Pseudomonas aeruginosa using Pulsed Field Gel Electrophoresis (re-infection caused by identical or new strain)
  • Time Frame: months to years
    Safety Issue?: No
• Specific, precipitating pseudomonas-antibodies (establishment of chronic infection)
  • Time Frame: Months to years
    Safety Issue?: No

Inclusion Criteria:

• Diagnosis of Cystic Fibrosis based on genotype and/or positive sweat-test
• Written informed consent based on written and spoken information
• No chronic airway-infections with Gram-negative bacteria
• Fertile, sexually active women must use contraception (p-pills, IUD or other methods with a similar Pearl-index) when participating in the study

Exclusion Criteria:

• P. aeruginosa in airway secretions obtained less than 3 months prior to inclusion
• Chronic infection of the airways caused by Gram-negative bacteria (Burkholderia species, Achromobacter xylosoxidans, Pandorea apista or Stenotrophomonas maltophilia)
• Chronic infection of the airways caused by P. aeruginosa (chronic infection is defined by continuing growth of the microorganism for 6 months and/or an increase in specific, precipitating antibodies to a level of at least 2)
• Previous infection with a strain of P. aeruginosa resistant to ciprofloxacin or colistin
• Previous participation in a pseudomonas-vaccination-study
• Patients younger than 1 year
• Pregnant or lactating women, or sexually active women unwilling to use safe contraception (p-pills, IUD or method with similar Pearl-index) when participating in the study
• Severe insufficiency of the liver or kidneys as judged by the local investigator

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 1 Year

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Rigshospitalet, Denmark

Overall Clinical Trial Officials and Contacts

Niels Hoiby, Prof.M.D.DSc Principal Investigator Department of Clinical Microbiology, Rigshospitalet  

Overall Contact: Christine R Hansen, M.D. +45 35 45 47 60 christine.hansen@rh.hosp.dk

Information obtained from ClinicalTrials.gov on October 07, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00411736

Study ID Number: AZI/SCAND/01

ClinicalTrials.gov Identifier: NCT00411736

Health Authority: Denmark: Danish Dataprotection Agency