Effect of Intravenous Administration of C1-inhibitor on Inflammation and Coagulation after Bronchial Instillation of House Dust Mite Allergen and Lipopolysaccharide in Allergic Asthma Patients

Several lines of evidence have implicated the complement system in asthma: (1)
allergen-antibody complexes and allergen polysaccharides and proteases can
activate complement; (2) strong anaphylatoxin production has been reported in
the airways of asthma patients; and (3) a functional role for C5a and C3a in
asthma has been established by experimental studies in C3 or C5 deficient mice,
showing that these anaphylatoxins act synergistically in driving inflammation
after allergen challenge in a sensitized host.
C1-inhibitor is a pivotal regulator of the complement system by virtue of its
capacity to inhibit both the classical pathway and the MBL pathway. Moreover,
C1-inhibitor can inhibit other inflammatory cascades, in particular the contact
system and the coagulation system. In addition to these findings, recent animal
data has shown that modulation of both the respiratory and the gut microbiota
could protect against allergic immune responses [4]. However, these findings
have not yet been verified in humans.

The primary objectives are to determine the inhibitory effect of intravenously
administered C1-inhibitor as well as the influence of depletion of the human
microbiota on allergic lung inflammation induced by house dust mite (HDM) plus
lipopolysaccharide (LPS) exposure.

Double-blind, randomized placebo controlled single center intervention study,
with an additional open labeled study arm

40 patients will receive either C1-inhibitor or a placebo intravenously. 20
patients will be pretreated with broad-spectrum antibiotics and receive placebo
treatment. All 60 patients subsequently undergo two bronchoscopies. During the
first bronchoscopy bronchial instillation of HDM and sham will be performed.
After 7 hours subjects undergo a second bronchoscopy during which a
bronchoalveolar lavage (BAL) and epithelial brush will be performed. During the
last patients will be sedated with i.v. midazolam.

The burden associated with this study includes a screening visit, during which
an intake interview, physical examination, routine blood tests and spirometry
will be performed. C1-inhibitor, a registered drug for hereditary angioedema,
will be administered intravenously in subjects. From other clinical trials
using C1-inhibitor and observations in patients with hereditary angioedema
intravenously administration of C1-inhibitor is considered safe and is
associated with limited adverse events. A fecal collection kit will be handed
over to all patients, enabling them to collect a feces sample at home. A
randomly selected subgroup of 20 patients will receive broad spectrum
antibiotics, which will be handed over to the patients during an additional
study visit 9 days prior to the study. This selected group of patients will
receive a second fecal collection kit, to collect a second sample at home.
Antibiotic treatment will be finished 36 hours prior to the study day.

Two bronchoscopies are performed on patients. The first one includes a
bronchoprovocations with HDM and LPS. The second one (after 7 hours) includes a
bronchoalveolar lavage and brushing in order to obtain epithelial cells. In our
previous trials with identical set up, the burden of the bronchoscopies are
considered to be acceptable by patients. Following intrabronchial instillation
of LPS a slight temperature raise can occur. This, however, did not exceed 37.6
'C. Patients were able to be discharged afterwards.
The anticipated risk of this study is therefore low.