Scandinavian Cystic Fibrosis Azithromycin Study

Cystic Fibrosis Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00411736
• Other study ID #: AZI/SCAND/01
• Status: Completed
• Phase: Phase 4
• First received: December 14, 2006
• Last updated: March 13, 2014
• Start date: May 2008
• Est. completion date: March 2014

Study information

• Verified date: March 2014
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: Danish Dataprotection AgencyDenmark: The Regional Committee on Biomedical Research EthicsDenmark: Danish Medicines AgencyNorway: Norwegian Medicines AgencyNorway:National Committee for Medical and Health Research EthicsSweden: Medical Products AgencySweden: Swedish National Council on Medical Ethics
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: March 2014
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

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.
• 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.

Locations

Country	Name	City	State
Denmark	CF-centre Skejby, Skejby Sygehus, Brendstrupgaardsvej 100	Aarhus N
Denmark	CF-centre Copenhagen, Rigshospitalet, Blegdamsvej 9	Copenhagen
Norway	CF-centre Bergen, Haukeland Universitetssykehus	Bergen
Norway	CF-centre Oslo, Ullevaal Universitetssykehus	Oslo
Sweden	CF-centre Göteborg, Drottning Silvias barn- och ungdomssjukhus	Göteborg
Sweden	CF-centre Lund, Universitetssjukhuset i Lund	Lund
Sweden	CF-centre Stockholm, Karolinska Universitetssjukhuset, Huddinge	Stockholm
Sweden	CF-centre Uppsala, Akademiska Barnsjukhuset	Uppsala

Sponsors (2)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark	Cystic Fibrosis Foundation Therapeutics

Countries where clinical trial is conducted

Denmark,  Norway,  Sweden, 

References & Publications (10)

Döring G, Conway SP, Heijerman HG, Hodson ME, Høiby N, Smyth A, Touw DJ. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur Respir J. 2000 Oct;16(4):749-67. Review. — View Citation

Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet. 2002 Sep 28;360(9338):978-84. — View Citation

Gillis RJ, White KG, Choi KH, Wagner VE, Schweizer HP, Iglewski BH. Molecular basis of azithromycin-resistant Pseudomonas aeruginosa biofilms. Antimicrob Agents Chemother. 2005 Sep;49(9):3858-67. — View Citation

Hansen CR, Pressler T, Koch C, Høiby N. Long-term azitromycin treatment of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection; an observational cohort study. J Cyst Fibros. 2005 Mar;4(1):35-40. — View Citation

Høiby N, Frederiksen B, Pressler T. Eradication of early Pseudomonas aeruginosa infection. J Cyst Fibros. 2005 Aug;4 Suppl 2:49-54. Review. — View Citation

Jaffé A, Francis J, Rosenthal M, Bush A. Long-term azithromycin may improve lung function in children with cystic fibrosis. Lancet. 1998 Feb 7;351(9100):420. — View Citation

Kobayashi H. Biofilm disease: its clinical manifestation and therapeutic possibilities of macrolides. Am J Med. 1995 Dec 29;99(6A):26S-30S. — View Citation

Saiman L, Marshall BC, Mayer-Hamblett N, Burns JL, Quittner AL, Cibene DA, Coquillette S, Fieberg AY, Accurso FJ, Campbell PW 3rd; Macrolide Study Group. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003 Oct 1;290(13):1749-56. — View Citation

Valerius NH, Koch C, Høiby N. Prevention of chronic Pseudomonas aeruginosa colonisation in cystic fibrosis by early treatment. Lancet. 1991 Sep 21;338(8769):725-6. — View Citation

Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax. 2002 Mar;57(3):212-6. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to next airway-colonization (re-colonization) with Pseudomonas aeruginosa		up to 5 years	No
Secondary	Clinical condition of the patients (height, weight and lung function)		up to 5 years	Yes
Secondary	Bacteriological examination of Pseudomonas aeruginosa (phenotype, resistance)		5 years	No
Secondary	Genotyping of Pseudomonas aeruginosa using Pulsed Field Gel Electrophoresis (re-infection caused by identical or new strain)		5 years	No
Secondary	Specific, precipitating pseudomonas-antibodies (establishment of chronic infection)		5 years	No