Primary Objective: To investigate the effect of treatment with nebulized rhDNase targeted to the peripheral airways compared to rhDNase targeted to the central airways on FEF75 in children with CF who are on maintenance treatment with rhDNase.…
ID
Source
Brief title
Condition
- Respiratory disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint will be the change in FEF75 compared to baseline after one
month of treatment. FEF75 is the most suitable endpoint since it is sensitive
to peripheral airways obstruction.
Secondary outcome
Secondary endpoints will include:
Lung clearance index (LCI) measurements as assessed by multiple breath washout;
Other values obtained in the flow volume curve: MMEF25-75, FEV1, FVC.
Other study parameters, such as use of antibiotics and number of exacerbations
(if applicable)
Background summary
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 which start early in
life[1-3]. 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. RhDNase is an identical copy of the
native human DNase. 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.
Lung damage In CF is thought to begin by mucus impaction predominantly
localized in the peripheral airways. Chronic infection and chronic airway
inflammation lead to structural damage. To prevent this damage from occurring
sputum mobilization using physiotherapy techniques is important in the
treatment of CF pulmonary disease. Daily nebulization of rhDNase facilitates
the mobilisation of mucus from the airways. However, relatively little of the
inhaled drug is deposited in the peripheral airways. Hence this compartment of
the lung is thought to be relatively under treated. Mucus clearance from
peripheral airways can probably be improved by targeting rhDNase selectively to
these airways. Therefore we hypothesize that rhDNase targeted to the peripheral
airways can improve lung function in children with CF.
Study objective
Primary Objective: To investigate the effect of treatment with nebulized
rhDNase targeted to the peripheral airways compared to rhDNase targeted to the
central airways on FEF75 in children with CF who are on maintenance treatment
with rhDNase.
Secondary Objective(s): To investigate the effect of treatment with nebulized
rhDNase targeted to the peripheral airways compared to rhDNase targeted to the
central airways on lung clearance index (LCI), and on spirometry parameters
(MMEF25-75, FEV1 and FVC) in children with CF who are on maintenance treatment
with rhDNase.
Study design
This study will be a multi centre, randomized controlled clinical trial.
Intervention
Nebulization of rhDNase targeted to the peripheral airways, using the Akita
nebulizer.
Study burden and risks
The target population of this study are children rather than adults, because CF
is a genetic disease leading to pulmonary problems starting in early childhood.
Recent studies have suggested that inflammation and infection in the CF lung
develops very early in life, even in asymptomatic infants. This warrants early
treatment of patients with CF. In addition, elevated DNA concentrations have
been found in bronchoalveolar lavage fluid from infants with CF, suggesting a
role for early treatment with rhDNase. Predominantly the peripheral airways are
damaged and filled with sputum in CF. Therefore, additional benefit may be
expected from treatment targeted to these peripheral airways.
Participating in this study may be beneficial for CF patients. A possible
benefit of the nebulization of rhDNase targeted to the peripheral airways could
be an improvement in lung function and/or symptoms on top of the treatment
effect of regular maintenance therapy. For patients randomized to nebulization
targeted to the central airways, no additional benefits over regular
maintenance therapy with rhDNase are to be expected.
The risks associated with participation are small. RhDNase is a registered drug
since 1994 for the treatment of mucous impaction in CF. RhDNase is registered
for use in children over 5 years of age and in adults. Administration of
rhDNase to children for chronic or acute respiratory symptoms is proven to be
safe in multiple studies.
Serious and life threatening side effects have not been described. Side effects
were mild and included pharyngitis, rhinitis and hoarseness, which resolved
spontaneously. A more efficient delivery of rhDNase to the peripheral airways
theoretically could reduce the above mentioned side effects.
Dr. Molenwaterplein 60
3015 GJ Rotterdam
Nederland
Dr. Molenwaterplein 60
3015 GJ Rotterdam
Nederland
Listed location countries
Age
Inclusion criteria
The criteria of inclusion will be the following:
- Age between 6 and 18 years old;
- Diagnosis of CF confirmed by sweat-test and/or DNA analysis and/or electro physiology testing (nasal potential difference measurement);
- Routine treatment with rhDNase once daily, started at least one month before enrolment in the study;
- Stable condition, in this study defined as: condition of patient judged to be stable by the treating physician AND no i.v antibiotics (hospital or at home) in the previous month and constant medication regime during the previous 2 weeks (for example: no additional antibiotics course, no newly started inhaled or systemic corticosteroids etc).
- Ability to perform lung function tests (assessed by trained lung function technician);
- Lung function: FVC > 40% predicted;
- Signed written informed consent.
Exclusion criteria
The following exclusion criteria will be used:
- Inability to follow instructions of the investigator;
- Inability to inhale rhDNase;
- Concomitant medical conditions that effect inhaled treatment (e.g. cleft palate, severe malacia);
- Current respiratory tract infection;
- Pulmonary complications that might put the patient at risk to participate in the study;
- Neuromuscular disease;
- Poor compliance with treatment as assessed by the patient*s paediatrician;
- Active ABPA (allergic bronchopulmonary aspergillosis) defined as an oral course of prednisone for ABPA within the last three months.
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 | EUCTR2007-000935-25-NL |
| ISRCTN | ISRCTN64225851 |
| CCMO | NL15632.078.07 |