Primary objective: To determine the safety of once daily inhalation of the recommended daily dose of tobramycin with the Akita® and the PARI-LC® Plus nebulizer in patients with CF. Systemic absorption can be used as surrogate parameter for safety.…
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
- Bacterial infectious disorders
- Respiratory tract infections
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint: systemic bioavailability of inhaled tobramycin, defined as
serum tobramycin AUC0-24hr.
Secondary outcome
Secondary endpoints include: serum tobramycin peak and trough levels, time to
maximum serum level, adverse events.
Background summary
Small Airways Disease (SAD) plays an important role in the pathophysiology of
cystic fibrosis (CF) lung disease. Chronic infection and airway inflammation
lead to progressive structural tissue damage. Chronic infection with
Pseudomonas aeruginosa (Pa) causes faster progression of CF lung disease.
Inhaled tobramycin has proven to be effective in delaying lung function decline
in chronic Pa infections. However, SAD is not improving with current inhaled
therapy, either with standard jet-nebulizer or with dry powder inhaler. The
newly introduced smart nebuliser Akita® is substantially more efficient to
reach the small airways. Recently, the Akita® has been shown to improve SAD
when delivering dornase alpha. Hence, the use of smart nebulisers like the
Akita® for tobramycin inhalation therapy in CF patients chronically infected
with Pa disease might significantly reduce SAD.
The bactericide efficacy of tobramycin is better with high peak levels. For
intravenous use, tobramycin once daily is as effective as thrice daily and
results in less toxicity. Inhaled tobramycin is dosed twice daily. Whether
dosing once daily is as effective has never been studied. This would
significantly reduce treatment burden.
Before we can investigate whether tobramycine inhalation once daily with the
Akita is as effective or more effective than once or twice daily inhalation
with the standard nebulizer, it is important to investigate tobramycin
pharmacokinetics. No information about tobramycin pharmacokinetics following
once daily inhalation exists. Systemic absorption can be used as surrogate for
safety.
Study objective
Primary objective: To determine the safety of once daily inhalation of the
recommended daily dose of tobramycin with the Akita® and the PARI-LC® Plus
nebulizer in patients with CF. Systemic absorption can be used as surrogate
parameter for safety.
Secondary objectives:
- To assess tolerability of inhalation of a double dose of tobramycin by
registering adverse effects (coughing, bronchospasm).
- To compare pharmacokinetics of the recommended dose of inhaled tobramycin
once daily with either the Akita® or PARI-LC® Plus to pharmacokinetic data from
the literature about standard twice daily tobramycin inhalation with the
PARI-LC® Plus.
Study design
Open label, randomised controlled cross-over trial.
Intervention
Intervention: Ten patients will be inhaling tobramycin twice at the outpatient
clinic department in a cross-over setting: once with the Akita® nebulizer and
the other time with the PARI-LC® Plus nebulizer.
Study burden and risks
The target population in this study are adults. The risks associated with
participation are small. Tobramycin (BRAMITOB®) is a registered drug since 2007
for treatment of chronic PA lung infection in CF-patients 6 years and older.
Inhalation of tobramycin in children with CF is proven to be effective and safe
in multiple studies. The Akita® nebulizer is already in use off label for
inhalation of tobramycin. However, information on the efficacy in improving SAD
is lacking. Serious and life threatening side effects have not been described.
The Akita® set to small airways design may lead to a higher systemic exposure
of tobramycin in patients. Due to the dose reduction, proven to be safe in a
previous study (9), all potential toxic effects are expected to be small and
presumably reversible.
Leyweg 275
Den Haag 2545 CH
NL
Leyweg 275
Den Haag 2545 CH
NL
Listed location countries
Age
Inclusion criteria
* Age * 18 years;
* FEV1 predicted * 30%;
* Clinical diagnosis of CF and a positive sweat test or two CF-related mutations;
* Chronic PA colonization requiring;
* Ability to breathe through a mouthpiece and to use the inhaler;
* Ability to perform lung function tests;
* Written informed consent.
Exclusion criteria
* Severe acute exacerbation of pulmonary infection (needing intravenous treatment);
* Patients receiving intravenous tobramycin treatment;
* Patients who are pregnant, planning to become pregnant or breastfeeding;
* Known impaired kidney function (estimated creatinine clearance < 60 ml/min);
* Known aminoglycoside hypersensitivity;
* Therapy (e.g. furosemide) or disease which may complicate evaluation of the study protocol, as judged by the investigator;
* Participation in another drug-investigating clinical study at the start or within 1 month prior to the start;
* Inability to follow instructions of the investigator.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-004488-30-NL |
| CCMO | NL46747.098.13 |