Efficacy and tolerability of Citrus/Cydonia comp.® solution for injection in patients with grass pollen seasonal allergic rhinitis:
Randomised, double-blind, placebo-controlled comparative clinical trial with three parallel treatment groups

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.

1. Clinically relevant reduction of symptom severity by use of Citrus/Cydonia
comp. subcutaneous injections 2. To examine the use of rescue medication in the
three groups, 3.safety of treatment

Randomised, double-blind, placebo-controlled comparative clinical trial with
three parallel treatment groups

Due to weather conditions the pollen level can be (too) low. In order to get
the optimal conditions for the study the period of the total time for wash out
and/or treatment will be extended for all subjects.
2-3 weeks wash-out period, depending on the pollen season
6-8 weeks intervention period depending on the pollen season

After a 2-week (3 weeks in case of extended treatment) run in period the
patients will be randomised to a 6 weeks treatment period (8 weeks in case of
extended treatment). Either: 6 weeks (8 weeks in case of extended treatment) of
subcutaneous injection of Citrus/Cydonia comp.® 1% solution twice a week or: 6
weeks (8 weeks in case of extended treatment) of subcutaneous injection of 0.9%
saline solution (placebo) twice a week or 6 weeks (8 weeks in case of extended
treatment) of subcutaneous injection of Citrus/Cydonia comp.® 1-5% solution
twice a week

In the 2 weeks (3 weeks in case of extended treatment) 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 (11 weeks in case of extended treatment) weeks
of the study. All participating patients will receive 2 times a week a
subcutaneous injection during 6 weeks (8 weeks in case of extended treatment).
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 questionnaire once a day (2 minutes) during 8 weeks (11
weeks in case of extended treatment). 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 (total visit: about 1
hour), and there will be one telephone call by the investigator (5 minutes).
In case of extended treatment there will be 1 extra thelephone call at week 5
(5 minutes)