Efficacy and tolerability of Citrus/Cydonia comp.® 1% solution for injection in patients with grass pollen seasonal allergic rhinitis: A randomised, double-blind, placebo-controlled clinical trial

Considering the high prevalence of allergic rhinitis and the fact that a
significant number of sufferers with severe symptoms are resistant to treatment
with usual pharmacotherapy (antihistamines and topical nasal corticosteroids)
(Wilson et al., 2005), there still is a space and need for the development of
new treatment concepts.
Citrus/Cydonia comp. is an anthroposophic medicine, which contains lemon juice
(Citrus limon, succus) and a aqueous extract from quince (Cydonia oblonga,
fructus rec., 1:2.1). For over eighty years now, Citrus/Cydonia comp. is being
prescribed as a subcutaneous injection or as a nasal spray for patients who
suffer from seasonal allergic rhinitis. In several European countries,
Citrus/Cydonia comp. is commercially available under the trade name *Gencydo®*
for the prophylaxis and treatment of allergic diseases, specifically those
affecting the respiratory tract such as hay fever.
A survey on clinical experiences, carried out among a group of 39 general
practitioners in the Netherlands, indicates that the subcutaneous treatment
with Citrus/Cydonia comp. ampoules is profoundly effective (Bruin et al.,
2001). Firstly, a permanent effect from the treatment with Citrus/Cydonia comp.
tends to be experienced, which indicates that the patients in question are
claiming to lastingly suffer less from hay fever or even that they are free
from complaints. Secondly, the effect is occurring within a period of two
weeks, up to three months, after the actual treatment. Thirdly, the effect is
optimal after a treatment of several years. In a therapeutic causality report,
positive effects with Citrus/Cydonia comp. were observed in a group of 13
patients suffering from grass pollen mediated hay fever (Baars et al., 2005).
In most patients, Citrus/Cydonia comp. injections were given before the onset
of and during the grass pollen season and symptom severity did not increase
during the pollen season. Furthermore, 69% of the patients reported an
improvement of symptoms. In addition, a prospective, observational study on the
effect of Citrus/Cydonia comp. nasal spray on hay fever symptoms reported
positive results without side effects in 140 patients (Rother and Oexle, 2008).
Recently, the immunological pathways underlying the positive effects of
Citrus/Cydonia comp. in patients with seasonal allergic rhinitis were studied
(Baars and Savelkoul, 2008). Therefore, peripheral blood mononuclear cells
(PMBCs) were isolated from a healthy and an allergic donor and the effect of
Citrus/Cydonia comp. on differentiation capacity and Th1 (e.g. IFN-*) and Th2
(e.g. IL-5) cells was examined. Citrus/Cydonia comp. showed a selective effect
on the differentiation of T-cells by producing relatively more IL-10 than
IL-12. Furthermore, it also had an effect on the induction of regulatory (IL-10
producing) T-cell subsets. It was therefore concluded that Citrus/Cydonia comp.
can potentially restore the disturbed immune state of allergic rhinitis
patients by modulation of the Th1-Th2 balance. This immunotherapeutic potency
and the positive results from the observed clinical cases, form the rational to
further evaluate the effects of Citrus/Cydonia comp. in seasonal allergic
rhinitis.
Recently it was demonstrated in a comparative study of two different routes of
administration of Citrus/Cydonia comp. 1%, that subcutaneous injections
resulted in larger clinical effects on nasal and non-nasal allergic rhinitis
symptom severity in patients suffering seasonal allergic rhinitis compared to
the nasal administration. The subcutaneous route was also more effective in the
differentiation and induction of (regulatory) T-cells and the balancing of the
Th1 and Th2 pathways (Baars et al., 2009).

Based on the considerations laid down above, Citrus/Cydonia comp. may be an
effective and safe treatment for seasonal allergic rhinitis. Due to its
selective effect on immunological pathways, Citrus/Cydonia comp. might restore
the disturbed immune state of rhinitis patients by modulation of the Th1-Th2
balance.

1. Clinically relevant reduction of symptom severity by use of Citrus/Cydonia
comp. subcutaneous injections

2. To examine the safety of treatment

3. To examine treatment effects on immunological parameters

4. To develop and validate an immunological model

Randomised, double-blind, placebo-controlled comparative clinical trial with
two parallel treatment groups and one epidemiological comparison group of
healthy volunteers

After a 2-week run in period the patients will be randomised to a 6 weeks
treatment period.

Either:
6 weeks of subcutaneous injection of Citrus/Cydonia comp.® 1% solution twice a
week
or:
6 weeks of subcutaneous injection of 0.9% saline solution (placebo) twice a
week

Patients:
In the 2 weeks before onset of the study, participants cannot use regular hay
fever medication which will result in an increase of hay fever symptoms. (For
treatment with cromoglycates it is a period of 4 weeks). They can use rescue
medication (antihistaminicum) according protocol guidelines during the 8 weeks
of the study.

All participating patients will receive 2 times a week a subcutaneous
injection during 6 weeks
There are no known side effects of the subcutaneous administration of Citrus/
Cydonia comp. or placebo injection other than local and small pain symptoms
that last for only a short amount of time.

All participating patients will complete an online qeustionnaire once a day (2
minutes) during 8 weeks
Next to this there is an intake visit, where medical history is discussed and a
short physical examination is (bloodpressure, heart/ lungs/ ENT) is
accomplished. If not available a bloodsample (RAST) will be taken (total visit:
about 1 hour), during 2 following visits bloodsample are taken and there will
be one telephone call by the investigator.
The risks are the common small risks of venous blood samples.

All participating healthy subjects have an intake visit, where medical history
is discussed and a short physical examination is (bloodpressure, heart/ lungs/
ENT) is accomplished. If not available a bloodsample (RAST) will be taken
(total visit: about 1 hour), during 2 following visits a bloodsample is taken.
The risks are the common small risks of venous blood samples.