Peripheral targeting of inhaled rhDNase for chronic obstructive asthma in childhood.

One of the aims of the pharmacological management of asthma is to normalize
pulmonary function. In fact, in many children with asthma treated with ICS and
inhaled b2-agonists, pulmonary function tests return to (nearly) normal
values[4]. However, airflow limitation (airways obstruction) persists in a
proportion of these patients. The pathogenesis of this persistent obstruction
is unclear. Airway wall inflammation and edema, increased bronchomotor tone,
increased sputum volume, increased sputum viscoelasticity and decreased
mucociliary clearance all play an important role in the pathogenesis of airways
obstruction in childhood asthma. Since absolute airway resistance is higher in
childhood than in adulthood, it is likely that mucus retention contributes
substantially to airways obstruction in childhood asthma.
In severe asthma dramatic improvement has been described in a few patients
after inhalation of the mucolytic rhDNase. In addition in pathology studies
extensive mucus plugging has been described in asthma patients. Based on these
findings we think that additional treatment benefit can be obtained when mucus
plugging is targeted as part of asthma treatment in children with asthma and
persistent airways obstruction.
Therefore we would like to investigate the additional effect of rhDNase
treatment in children with asthma and persistent obstructive pulmonary
function.

Primary Objective: To investigate the effect of treatment with nebulized
rhDNase on pulmonary function in children with asthma and persistent
obstructive pulmonary function.
Secondary Objectives: To investigate the effect of treatment with nebulized
rhDNase on lung clearance index (LCI), FENO values and symptom scores in
children with asthma and persistent obstructive pulmonary function.

This study will be a randomized placebo-controlled clinical trial.

All patients will be treated with 3 weeks of placebo or 3 weeks of rhDNase,
followed by a 4-week follow-up period. After the 4 weeks of follow-up, one
study visit to the hospital is scheduled and lung function tests are performed.
Children will be randomized to receive rhDNase or placebo.

The target population of this study are children rather than adults, because
this early and persistent airflow limitation is a typical feature of childhood
asthma. Furthermore, asthma characteristics, mechanisms and severity are
age-specific. Firstly, the presentation of asthma differs between children and
adults. In childhood, asthma is less affected by other pulmonary disorders, or
by loss of elastic recoil of the lung. The clinical picture is more often
characterized by reversible airways obstruction, unlike in adults. Small
improvements in airways obstruction are easier to recognize and, above all,
clinically relevant.
Secondly, baseline airway resistance depends on geometric factors and on airway
mechanics, being much higher in children than in adults. If viscous mucus is
clinically relevant in worsening airway obstruction, it is most likely to occur
in children because of their much smaller airway size, facilitating mucus
impaction in the smallest airways.

Children participating in this study will be treated at home and will come to
the hospital for 4 study visits. At each visit, pulmonary function tests will
be performed (non-invasive). During the two 3-week periods of treatment,
patients will be asked to fill in a symptom diary.
The risks associated with participation are small. RhDNase is a registered drug
since 1994 for the treatment of mucous impaction in CF. In addition DNase has
been extensively used for the treatment of patients with atelectasis due to a
variety of pulmonary diseases like PCD, asthma, RSV brochiolitis or due to
mechanical ventilation. 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, most frequently reported in CF-studies, were mild and included
pharyngitis, rhinitis and hoarseness, which resolved spontaneously.