Based on earlier studies it is likely that current rhDNase inhalation in children during exacerbations is relatively inefficient. We hypothesize that the efficacy of rhDNase treatment during exacerbations can be improved by targeting the peripheral…
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Verkorte titel
Aandoening
Cystic Fibrosis.
Respiratory disease in patients with cystic fibrosis (CF) is characterized by an abnormal composition of the epithelial lining fluid. As a result patients develop chronic airway infection and inflammation that starts early in life. The sputum in CF is rich in leukocyte-derived DNA which greatly contributes to abnormal viscoelasticity of the CF sputum. This purulent, infected sputum can obstruct the airways. In addition to this chronic state patients can develop exacerbations often related to viral infections. During these episodes the condition of the patients deteriorates. These episodes are characterized by increased cough, difficulty to expectorate the viscous sputum, loss of appetite, and fatigue. A major challenge in the treatment of CF is to mobilize as much sputum as possible from the lung on a daily basis. For this reason patients are doing physiotherapy. In addition most patients inhale recombinant human DNase (rhDNase) daily to reduce the viscosity of the sputum. RhDNase is an identical copy of the native human rhDNase. RhDNase cleaves extracellular DNA through hydrolyses and reduces the viscoelasticity of CF sputum in vitro. RhDNase has been shown to reduce sputum viscosity, improve pulmonary function, and reduce the number of pulmonary exacerbations in patients with moderate lung disease. Similar effects have been demonstrated in patients with mild disease, making rhDNase currently the only mucolytic in CF with proven efficacy.
RhDNase is administered to patients as a nebulized aerosol. Aerosols are deposited in the airways due to impaction, sedimentation and diffusion. Impaction is the main deposition mechanism in the upper and central airways. The larger the particle and the higher its velocity, the more likely the particle is to impact. Sedimentation is an important deposition mechanism in the smaller airways where air velocity is low. For particles with a diameter smaller than 0.5 ìm, deposition is mostly due to Brownian motion and diffusion. Deposition by Brownian motion and diffusion is the most important mechanism in the bronchioles and alveoli.
The deposition mechanisms and the distribution of particles in the lower airways are dependent on several factors:
1. particle size and size distribution;
2. anatomy and physiology of normal airways;
3. pathologic changes of airway structure;
4. breathing pattern.
Of the four factors discussed above, only two can be influenced for therapy: particle size and breathing pattern. Thus, these are the factors that can be adjusted to improve the deposition pattern of medication in the lung. Predominantly the peripheral airways are damaged and filled with sputum in CF. Since effective sputum mobilization is an important aim in the treatment of an exacerbation, additional benefit may be expected from administering rhDNase targeted to the peripheral airways.
Ondersteuning
Onderzoeksproduct en/of interventie
Uitkomstmaten
Primaire uitkomstmaten
Disease is most prominent in the peripheral airways in CF. Therefore our primary outcome measurement will be focussed on the periphery of the lung, using FEF75 and FEF75-25 (assessed by spirometry). FEF75 and FEF75-25 measured on study day 12 (after 7 days of treatment with Akita) is our primary outcome parameter.
Doel van het onderzoek
Based on earlier studies it is likely that current rhDNase inhalation in children during exacerbations is relatively inefficient. We hypothesize that the efficacy of rhDNase treatment during exacerbations can be improved by targeting the peripheral airways more efficiently in CF.
To obtain an optimal lung deposition of rhDNase in children with CF during an exacerbation, the mean particle size of aerosols should be smaller than commonly used for adults. Furthermore, a slow inhalation maneuver should be performed to enable particles to penetrate deeply into the lung. Administration of rhDNase with a MMAD of 3,0 ìm and a slow, deep inhalation maneuver using the Akita® nebulizer gives a better peripheral lung deposition in patients with CF.
Our hypothesis is that a better peripheral lung deposition will result in:
- A bigger improvement in lung function compared to conventional treatment, especially considering the measurements of the peripheral airways: FEF75, FEF75-25 (FEF = Forced Expiratory Flow rate);
- Reduction of inhomogeneity of ventilation;
- A faster improvement of clinical symptoms.
Onderzoeksopzet
N/A
Onderzoeksproduct en/of interventie
The intervention in this study is the peripheral deposition of rhDNase, using the Akita nebulizer.
All patients use DNase as maintenance therapy, thus this medication is not an intervention.
Publiek
Dr. Molenwaterplein 60
E.M. Bakker
Dr. Molenwaterplein 60
Rotterdam 3015 GJ
The Netherlands
+31 (0)10 4636683
e.bakker@erasmusmc.nl
Wetenschappelijk
Dr. Molenwaterplein 60
E.M. Bakker
Dr. Molenwaterplein 60
Rotterdam 3015 GJ
The Netherlands
+31 (0)10 4636683
e.bakker@erasmusmc.nl
Belangrijkste voorwaarden om deel te mogen nemen (Inclusiecriteria)
The criteria of inclusion will be the following:
1. Age between 6 and 18 years old;
2. Diagnosis of CF confirmed by sweat-test and/or DNA analysis and/or electro physiology testing (nasal potential difference measurement);
3. Admission to hospital because of a pulmonary exacerbation requiring treatment with iv antibiotics.
Criteria for a pulmonary exacerbation will be based on the definition of exacerbation by Rosenfeld et al. and will include at least three of the following:
· Decreased exercise tolerance
· Increased cough
· Increased sputum / chest congestion
· School or work absenteeism
· Decreased appetite
· Increased adventitial sounds on lung examination
· Decrease in FEV1 (% predicted)
4. Enrolment in the study between 1 to 5 days after admission for an exacerbation;
5. Routine treatment with rhDNase once daily, started at least two weeks before enrolment in the study;
6. Ability to perform lung function tests (assessed by trained lung function technician);
7. Lung function: FVC >= 30% predicted;
8. Signed written informed consent.
Belangrijkste redenen om niet deel te kunnen nemen (Exclusiecriteria)
The following exclusion criteria will be used:
1. Inability to follow instructions of the investigator;
2. Inability to inhale rhDNase;
3. Concomitant medical conditions that effect inhaled treatment (e.g. cleft palate, severe malacia);
4. Pulmonary complications that might put the patient at risk to participate in the study;
5. Deterioration primarily related to ABPA (allergic bronchopulmonary aspergillosis).
Opzet
Deelname
Opgevolgd door onderstaande (mogelijk meer actuele) registratie
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Andere (mogelijk minder actuele) registraties in dit register
Geen registraties gevonden.
In overige registers
Register | ID |
---|---|
NTR-new | NL511 |
NTR-old | NTR553 |
Ander register | : MEC-2005-308 |
ISRCTN | ISRCTN50584238 |