Azithromycin in Patients With CF, Infected With Burkholderia Cepacia Complex

Unity Health Toronto

Status and phase

Unknown

Phase 2

Conditions

Cystic Fibrosis

Treatments

Drug: Azithromycin

Drug: Placebo

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT00298922

TULLIS04A0

AZ 0003

Details and patient eligibility

About

Pulmonary infection with Burkholderia cepacia complex (BCC) in patients with CF is often associated with a more rapid decline in lung function. Because of the resistance of BCC to many antibiotics, treatment options are often limited. New therapies to improve outcomes for patients infected with BCC are needed.

However, because of the unpredictable nature of this pulmonary infection in CF, patients with BCC infection have been excluded from many CF therapeutic trials.

Recent published trials in the United States, Australia, and the United Kingdom have all demonstrated clinical benefits from prolonged administration of azithromycin in CF. In these trials, the vast majority of patients were chronically infected with Pseudomonas aeruginosa.

Patients with BCC were excluded from the US and UK trials, and only four patients with BCC infection were enrolled in the Australian trial. Thus, the effectiveness of azithromycin in CF patients infected with BCC is largely unknown and deserves further study.

The two main ways by which azithromycin is thought to help with the chronic lung infections seen in CF are by [a] reducing inflammation and [b] direct effects on the bacteria, in particular P. aeruginosa. BCC pulmonary infection in CF is often associated with a large inflammatory response similar to or more severe than P. aeruginosa infection. If azithromycin works mainly by an anti-inflammatory mechanism, it should also be helpful in CF patients infected with BCC.

Alternatively, azithromycin could have a direct effect on BCC as seen with P. aeruginosa as the two bacteria have many similarities.

Full description

STUDY DESIGN

Overview
This is a single center, randomized, double-blinded, placebo-controlled 24 week trial of azithromycin in adults with CF chronically infected with BCC. The investigational therapy will be added to usual therapy in patients who are clinically stable at the time of enrollment. After 168 days, the study drug will be discontinued and participants will be evaluated at 196 days off of study drug for 28 days. At that visit, participants will be invited to continue in an open label observational study of azithromycin for 168 additional days. Thus, the duration of the study will be 52 weeks (364 days).
Day 0- Day 168 on Study Drug (24 weeks)
Day 169- Day 196 off Study Drug (4 weeks)
Day 197 - Day 364 on OPEN label Azithromycin (24 weeks)
Measuring primary and secondary endpoints
Primary efficacy endpoint
Primary efficacy endpoint will be the quantitative changes in lung function as measured by FEV1 in % predicted from baseline to completion of the 24 week treatment period. (refer to Appendix C for ATS guidelines).
Primary safety endpoints
Primary safety endpoints collected over the 24 week treatment period will be:
- Adverse events such as gastrointestinal complaints, ototoxicity, tinnitus, hepatitis or leukopenia as determined by:
  
  (i) open ended questioning of study subjects at study visits (ii) laboratory tests for elevated liver function tests or hematologic abnormalities,
- Changes in lung microbiology as determined by:[86] (i) Emergent B. cenocepacia (genomovar III) (ii) Emergent non-B. cenocepacia genomovars (iii) Emergent NTM[87] (iv) Emergent azithromycin resistant NTM (v) Emergent Aspergillus species (vi) Emergent MDRO - (S. maltophilia, A. xylosoxidans, or methicillin-resistant S. aureus) (vii) Emergent P. aeruginosa (viii) Emergent azithromycin resistant S. aureus
Secondary efficacy endpoints
Secondary efficacy endpoints will be:
Quantitative changes in lung function as measured by change in relative percent change in FEV1 and FVC from baseline to completion of the 24 week treatment period.
Quantitative change in FEV1 and FVC in liters in CF study subjects treated with azithromycin compared with those CF study subjects treated with placebo. FEV1 and FVC in liters will be measured according to ATS criteria
The number of days until first administration of intravenous antibiotics and/or the use of oral tetracycline derivatives minocycline / doxycycline for seven or more days during the 24 week period.
The number of pulmonary exacerbations as defined by need for treatment with intravenous or oral tetracycline derivative antibiotics for an increase in pulmonary symptoms during the 24 week period.
The proportion of patients requiring intravenous antibiotics during the 24 week period.
The number of days of treatment with intravenous antibiotics given during the 24 week period.
The proportion of patients hospitalized.
The number of hospital days as calculated by calendar days during the 24 week period.
The proportion of patients requiring oral antibiotics during the 24 week period.
The number of days of treatment with oral non-tetracycline derivative antibiotics given during the 24 week period.
Changes in body weight from baseline to completion of the 24 week treatment period.
Change in level of inflammation as measured by the change in serum CRP and ESR from baseline to the end of the 24 week treatment period.

Enrollment

45 estimated patients

Sex

All

Ages

19+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Informed consent and verbal assent as appropriate has been provided by the subject
Ability to comply with medication use, study visits and study procedures as judged by the site Investigator
Diagnosis of CF as defined by two or more clinical features of CF and a documented sweat chloride > 60 mEq/L by quantitative pilocarpine iontophoresis test or a genotype showing two well characterized disease causing mutations
> 18 years of age
Body weight > 40 kg
BCC present in a sputum/throat culture > 1 year prior to screening and at screening
FEV1 % predicted > 30% as calculated by the Knudsen reference equations
Room air oximetry > 88% at rest
Post-menarche females must be surgically sterile or using an effective form of contraception
Predicted to live > 1 year and clinically stable at that time of enrollment as judged by the investigator.

Exclusion criteria

History of chronic macrolide use, defined as regular macrolide antibiotic use within a three month period prior to enrollment in the study.
AST or ALT > 2.5 times the upper limit of normal performed at the local laboratories on two occasions prior to randomization.
Investigational drug use within 30 days of screening
History of alcohol, illicit drug or medication abuse within 1 year of screening
Use of intravenous antibiotics or oral antibiotics within 14 days of screening.
Use of low dose oral antibiotics (e.g. macrolides, tetracycline, sulfa) for acne or other conditions within 30 days of screening
Use of systemic corticosteroids (> 20 mg of prednisone per day) within 30 days of screening
Initiation of TOBI®, high dose ibuprofen, or rhDNase within 60 days of screening
History of lung transplantation or currently on lung transplant list
History of allergy to a macrolide antibiotic
AFB smear positive at screening suggesting current NTM infection.
Positive serum pregnancy test at screening (to be performed on all post-menarche females)
Absolute neutrophil count < 1000 performed at the local laboratories on two occasions prior to randomization
Creatinine > 1.5 times normal performed at the local laboratories on two occasions prior to randomization.
Chest x-ray changes or physical findings at screening that would compromise the safety of the patient or the quality of the study data
Other major organ dysfunction