Primary objective:To compare the change in small airways obstruction (FEF75%) in patients with CF when inhaling one ampule of inhaled tobramycin with the Akita® compared to standard of treatment (twice daily nebulization of one ampule using standard…
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: change in FEF75 (Z-score and L/s) after 4 weeks of targeted
treatment
Secondary outcome
Secondary endpoints will include:
• Change in FEV1, FVC, FEF25, FEF50, MMEF25-75 (Z-scores and absolute values);
• Change in Lung Clearance Index (LCI) measurements as assessed by multiple
breath washout;
• Change in Pa bacterial CFUs (defined as the log10 value for the number of Pa
CFUs per millilitre of sputum, either expectorated or collected by suction of
the oropharynx);
• Change in the following conditions: Eradication = elimination of Pa;
Persistence = persistence of Pa detected at previous visit; Superinfection =
appearance of a pathogen (other than Pa) not detected at previous visit;
Re-infection = re-appearance of Pa detected at screening and previously
eradicated.
• Change in percentage of trapped air on MRI (% of total lung volume);
• Change in FEV1 before and after nebulisation (safety parameter);
• Systemic bioavailability of inhaled tobramycin, defined by trough level;
• Change in creatinine and blood urea nitrogen (BUN) values as measure of early
renal toxicity;
• Change in hearing function (measured by HFPTA);
• Compliance rate;
• Patient satisfaction (use of device);
• Cystic Fibrosis questionnaire-revised (CFQ-R): respiratory symptoms scale
scores and treatment burden scale scores.
Background summary
Small Airways Disease (SAD) plays an important role in the pathophysiology of
cystic fibrosis (CF). Chronic infection and airway inflammation lead to
structural tissue damage. Obstruction and destruction of small airways lead to
air-trapping, hypoperfusion and bronchiectasis. When Pseudomonas aeruginosa
(Pa) is acquired, even faster deterioration of the airways results. Inhaled
tobramycin is an antibiotic used to treat Pa infections and is shown to be
effective for eradication and for chronic treatment. Unfortunately, small
airways are difficult to reach with standard nebulizer therapy. The newly
introduced smart nebuliser Akita® is more efficient. It improves lung
deposition from 10-15% of the loading dose with standard nebulizer therapy to
70%, with an increased deposition in the small airways. Peripheral targeting
has been shown to reduce small airways obstruction (FEF75%) when delivering
dornase alpha. Furthermore, it can record adherence to therapy electronically.
Since nebulizer therapy is time-consuming and cumbersome, adherence is thought
to be poor. Traditionally inhaled tobramycin is dosed twice daily, but no true
dose finding studies are performed for inhaled tobramycin. For intravenous use,
tobramycin once daily is shown to be as effective as thrice daily, and results
in less toxicity. The bactericide efficacy of aminoglycosides, such as
tobramycin, improves with higher peak levels. Inhalation of the double dose in
a single inhalation presumably leads to higher peak levels, which might result
in the same or even better efficacy of tobramycin therapy and may lead to
better compliance. We hypothesize that once daily inhaled tobramycin with an
efficient nebulizer is more effective in treatment of small airways, and more
effective in suppressing Pa infection compared to standard of treatment.
Study objective
Primary objective:
To compare the change in small airways obstruction (FEF75%) in patients with CF
when inhaling one ampule of inhaled tobramycin with the Akita® compared to
standard of treatment (twice daily nebulization of one ampule using standard
nebulizer equipment)
Secondary objective:
1. To compare changes in lung function parameters (FEV1, FVC, FEF25-75%,
MMEF25-75) and LCI.
2. To compare changes in bacterial CFUs and the following conditions
(eradication, persistence, superinfection and re-infection) of Pseudomonas
aeruginosa in sputum between both treatment arms.
3. To compare the effect on *trapped air* between both treatment arms as
depicted by spirometer controlled expiratory chest Magnetic Resonance Imaging
(MRI).
4. To assess safety of Akita® tobramycin inhalation therapy in CF-patients by
monitoring trough levels of tobramycine, ototoxicity and nephrotoxicity.
Study design
Open label, international, multi centre, randomised controlled cross-over
trial.
Intervention
26 patients will be inhaling tobramycin at home for 2x28 days in a cross-over
setting: one month with the Akita® nebuliser (once daily 300 mg tobramycin) and
the other month with their own nebulizer equipment (twice daily 300 mg
tobramycin).
Study burden and risks
The target population in this study are adults as well as children since the
chronic Pa infection starts in childhood in many patients. Inflammation and
infection in the CF lung is suggested to develop very early in life and
therefore early treatment is necessary. In children and adults with CF a more
effective and efficient nebulizer is likely to improve quality of life.
Participating in this study is likely to be beneficial for CF patients. More
efficient nebulization of tobramycin targeted to the peripheral airways could
reduce small airways obstruction, improve lung function and reduce symptoms on
top of the treatment effect of maintenance therapy.
The risks associated with participation are small. Tobramycin (BRAMITOB®) is a
registered drug since 2007 for treatment of chronic Pa lung infections 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
used off label by many patients for inhalation of tobramycin and dornase alpha,
in both children and adults. However, information on the efficacy of nebulized
tobramycin in combination with the Akita® on SAD is lacking. To date no serious
or life threatening side effects have been described.
Since the Akita® is more efficient compared to conventional nebulizers, dosing
in our study is aimed to keep the daily dose to the patient equal to that of
routinely administered tobramycin. It has been well described that only in the
order of 10% of the inhaled tobramycin is systemically absorbed. Systemic
exposure therefore will be in the order of only 5% of the doses used for
intravenous treatment. In addition we will check through levels to exclude high
through levels. Hence, the risk for toxic effects is expected to be small.
Wytemaweg 80, room Na-1723
Rotterdam 3015CN
NL
Wytemaweg 80, room Na-1723
Rotterdam 3015CN
NL
Listed location countries
Age
Inclusion criteria
• Age >= 12 years
• Clinical diagnosis of CF and a positive sweat test or two CF-related mutations;
• Chronic Pseudomonas aeruginosa colonization requiring maintenance therapy with inhaled tobramycin, defined according to the Leeds criteria (>50% Pseudomonas aeruginosa positive airway cultures over last 12 months);
• Small airways obstruction present on spirometry (defined as follows: dissociation between FVC and FEF75 values (i.e. FEF75 at least 20% (absolute percent predicted) less than FVC);
• Ability to breathe through a mouthpiece and to use the inhaler;
• Ability to perform lung function tests;
• Written informed consent (12-18 years: child and parents; >= 18 years: patient).
Exclusion criteria
• Severe acute exacerbation of pulmonary infection (needing intravenous treatment) within one month prior to start or during the study;
• Known impaired kidney function (estimated creatinine clearance < 60 ml/min);
• Known aminoglycoside hypersensitivity;
• Evidence of impaired auditory function (auditory threshold in either ear above 20 dB at frequencies between 250 and 8000 Hz);
• Start of nephrotoxic or ototoxic drugs, e.g. aminoglycosides, within 1 month prior to start or during the study;
• Use of systemic steroids (at a dose >= equivalent of 10 mg/day of prednisone) in the previous 2 weeks;
• Therapy (e.g. furosemide) or disease which may complicate evaluation of the study protocol, as judged by the investigator;
• Pregnancy or breast feeding;
• 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.
• Use of Tobramycin Inhalation Powder as part of the maintenance therapy;• 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.
• Use of Tobramycin Inhalation Powder as part of the maintenance therapy
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 | EUCTR2014-001401-41-NL |
| CCMO | NL48806.078.14 |