To determine if maintenance therapy with AZN will provide significant improvements in PCD lung disease, compared to placebo: reduction in respiratory system exacerbations and improvement in lung function, ventilation inhomogeneity, improvement in…
ID
Source
Brief title
Condition
- Hearing disorders
- Respiratory tract infections
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the efficacy of 6 months of maintenance treatment with AZN on
respiratory system exacerbations in subjects with PCD, 7-40 years of age.
An exacerbation is defined as:
1. Respiratory symptoms leading to start of systemic antibiotic treatment,
irrespective of results of bacterial culture.
2. A decline in FEV1predicted of *10% relative to the avarage of FEV1 %
predicted at Visit 1 and Visit 2, whether or not antibiotics are prescribed
Secondary outcome
Difference in FEV1 % predicted, FVC % predicted and FEF25-75 % predicted
between treatments in the pre- to post-intervention period.
Difference in RV % predicted, RV/TLC % predicted and Raw % predicted between
treatments in the pre- to post-intervention period.
Difference in Lung Clearance Index (LCI), Sacin and Scond between treatments in
the pre- to post-intervention period.
Difference in Respiratory symptoms, Sinus symptoms and Ear & Hearing symptoms
on the QOL-PCD between treatments in the pre- to post-intervention period.
Difference in hearing threshold between treatments in the pre- to
post-intervention period.
Difference in tympanometry between treatments in the pre- to post-intervention
period.
Difference in inflammatory markers between treatments in the pre- to
post-intervention period.
Difference in sputum microbiology between treatments in the pre- to
post-intervention period.
Adverse Events (AE) and Serious Adverse Events (SAE).
Background summary
Primary ciliary dyskinesia (PCD) is a rare, congenital disease manifesting in
the neonatal period or in early childhood and progressing throughout adulthood.
Organelles termed cilia, which line the respiratory epithelium, are either
immotile or dyskinetic and cannot generate coordinated ciliary beating
necessary to expel mucus. As a result, excessive mucus may form plaques and
plugs in the airways that can serve as a nidus for infection. Recurrent lower
respiratory tract infections progress to chronic infection that ultimately
leads to bronchiectasis. PCD causes progressive loss of lung function and in
severe cases can result in chronic respiratory failure with lung
transplantation as the final therapeutic avenue. No orphan drugs are currently
available for the treatment of PCD, and for those therapeutics currently used
in the management of PCD, there have been no randomized controlled clinical
trials (RCTs) to determine their efficacy and safety. *Best* treatments are
anecdotal and largely derived from treatments for patients with other chronic
respiratory disorders, notably cystic fibrosis (CF) and asthma, and therefore
based on distinct pathophysiology of these diseases. Maintenance therapy with
azithromycine in cystic fibrosis has been shown to be safe and efective in
reducing the number of exacerbations and maintaining lungfunction.
Consequently, many lung physicians and pediatric lung physicians already use
azithromycine maintenance therapy in many chronic respiratory disorders,
including PCD. However, the effectiveness and safety has never been studied in
PCD.
Study objective
To determine if maintenance therapy with AZN will provide significant
improvements in PCD lung disease, compared to placebo: reduction in respiratory
system exacerbations and improvement in lung function, ventilation
inhomogeneity, improvement in respiratory symptoms and hearing impairment.
Study design
Multicentre, double blind, randomized, placebo controlled parallel group study.
Intervention
Oral tablets of AZN 250/500 mg according to body weight (of placebo administered three times a week (Monday-Wednesday-Friday) for 6
months
Study burden and risks
As part of the trial the patients will have to take azitromycine or placebo
during a period of 6 months. Antibiotics may have side-effects, predominantly
gastro-intestinal complaints. As the dosage is generally lower than the
therapeutic dosage, we expect this to occur less frequently than normal.
Participation in the trial will result in about two visits more than usual for
a PCD patient during a period of 7 months. Due to a few more procedures than
during a routine visit each visit will last about 1-1* hours longer than a
standard routine visit (Visit 2 and Visit 5 are about 45 minutes longer than
Visit 1, 3 and 4). Interview, physical examination, sampling of sputum for
microbiological analysis and spirometry are part of the routine clinical
practice performed at the regular visits for PCD patients. QOL-PCD
questionnaire, N2 MBW, urine pregnancy test, body plethysmography, audiometry,
tympanometry and blood samples are extra procedures performed due to
participation in the trial (audiometry, tympanometry and blood samples will
only be performed at Visit 2 and Visit 5).
The individual subject receiving AZN in the trial may benefit of receiving the
trial drug in possibly having fewer respiratory system exacerbations and
improvement in lung function, health related quality of life and hearing
impairment during the treatment period, according to the hypothesis.
De Boelelaan 1117
Amsterdam 1081 HV
NL
De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
A confirmed diagnosis of PCD: Characteristic clinical symptoms and high speed video microscopic recordings of abnormal ciliary beat pattern and/or frequency;
and either abnormally low nasal NO production, and/or abnormal ciliary ultra-structure demonstrated by transmission electron microscopy analysis or high resolution immunofluorescence (not incl. isolated IDA) and/or an unequivocal genetic mutation recognized to cause PCD.
Age * 7 years and * 50 years at inclusion;
Ability to swallow tablets;
At least 30 days treatment with antibiotics prescribed against respiratory tract infections/pulmonary exacerbations in the previous 2 years;
No AZN treatment within 1 month prior to screening (visit 1);
No current therapy with systemic, inhaled maintenance antibiotics
FEV1 % predicted > 40 % at screening (Visit 1)
Ability to perform spirometry and Multiple Breath Washout (MBW);
Personally provide, or have a legal guardian provide written informed consent to participate in the trial, according to local regulations.
Exclusion criteria
Known infection with Nontuberculous Mycobacteria (NTM) (found in sputum in the past 6 months prior to screening (Visit 1), Achromobacter xylosoxidans, Burkholderia cepacia or chronic infection with Pseudomonas aeruginosa;
Be currently participating in, or have participated in another investigative drug trial within four weeks prior of screening (Visit 1);
A history of allergic reaction to macrolide antibiotics incl. ketolide antibiotics, peanut, or to any of the excipients of *Azithromycine CF 250 mg* or to any of the ingredients of the placebo.
Liver disease with Alanine transaminase (ALT) twice or more the upper limits of normal or history of portal hypertension ;
Known kidney disease with serum creatinine > 150 µmol/l and/or Glomerular Filtration Rate (GFR) < 50 ml/min;
Known congenital or documented acquired prolonged QT-interval, cardiac arrhythmia, clinical relevant bradycardia, severe heart failure, or electrolyte disturbances.
Known myasthenia gravis.
Current treatment with ciclosporin, coumarin-like oral anticoagulants (e.g. warfarin), digoxin, ergotamine derivatives (e.g. methylergometrine), nelfinavir, rifabutin and active substances known to prolong QT interval such as amiodarone and other class *A and class *** antiarrhythmics, cisapride, terfenadin, antipsychotic agents such as pimozide, antidepressants such as citalopram and fluoroquinolones such as moxifloxacin and levofloxacin;;* Be pregnant or breastfeeding; plan to become pregnant whilst in the trial; or be female of childbearing potential (at the discretion of the investigator) using an unreliable form of contraception;
* Requirement of home oxygen (not incl. supplemental oxygen for use only when exercising, mountaineering or travelling by air) or assisted ventilation;
or;
* Have any concomitant medical, psychiatric, or social condition that, in the Investigator*s opinion, would put the subject at significant risk, may confound the results or may significantly interfere with the subject*s participation in the trial.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-004664-58-NL |
| CCMO | NL48965.029.14 |