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Clinical trials performed in Europe with Cyclamen Europaeum
PFAAR, O.
Department of Otorhinolaryngology,
Heidelberg-Mannheim University.
Germany
New Treatment Approaches to Rhinosinusitis: Less is more.
Crete. Greece. 15-19 June 2008
Keywords New Treatment approaches to Rhinosinusitis - PDF
ABSTRACT
A considerable body of documented and published evidence is now available on the safety and efficacy of the treatment of Rhinosinusitis with cyclamen extract. However, there are no randomised, controlled, multicentre, double-blind, parallel-group studies that compare this treatment with placebo. Performance of a study such as CYC-E-03 that meets these requirements (where all the subjects received a basal treatment with antibiotics) has shown that in the group treated with cyclamen (even though the groups were small), there is a positive trend towards a reduction in symptoms, both overall and of individual nasal symptoms. Increased secretion is also observed. More over, statistically significant differences were observed in the rate of obstruction/oedema of the middle meatus.
Rhinosinusitis is a highly prevalent disease with a growing incidence. The US National Health Survey 2001 showed that up to 14.7% of the population suffer from chronic inflammatory diseases of the nasal/paranasal sinuses. And according to the National Ambulatory Medical Care Survey 2002, rhinosinusitis is the fifth most common diagnosis for which antibiotics are prescribed. Given its social and health impact, in recent years numerous guidelines have been published in an attempt to improve the diagnosis and treatment of this disorder (such as the EP3OS guidelines).
According to the EP3OS position paper, published by the European Academy of Allergology and Clinical Immunology (EAACI) and accepted by the European Rhinologic Society (ERS), rhinosinusitis is defined as an inflammation of the nasal and paranasal sinuses that is accompanied by a number of characteristic symptoms, such as obstruction, secretion, facial pain and loss of the sense of smell. It is a disease that is basically diagnosed from its clinical signs and symptoms; nasal endoscopy and sinonasal CT are the tests used to confirm the diagnosis.
The EP3OS provide a complete scheme for managing and treating the Rhinosinusitis in its different steps and with the different available tools. Regarding the pharmacological part of the treatments, for adults acute rhinosinusitis there’s a scheme based on the Medicine Based on Evidence which assess the different drug products from the level of evidence available on studies and proposes a grade of recommendation. Currently there are four groups of drugs with a grade of recommendation “ A” (based on the highest levels of evidence: Ia and Ib): Oral antibiotics (level Ia, in severe cases or after 5 days), topical corticosteroid (Ib), topical steroid and oral antibiotic combined (Ib) and oral corticosteroid (Ib, reduces pain in severe disease).
EVIDENCE FOR CYCLAMEN EXTRACT
In recent years, there has been a growing body of evidence that consistently confirms the efficacy and safety of cyclamen extract in the treatment of rhinosinusitis. For example, Bezshapochny et al. have shown that administration of this product to 28 patients with acute mucopurulent rhinosinusitis is associated with significant benefits: after three days of treatment, the nasal congestion, headache and facial pressure have disappeared in most of the patients (21 out of 28). Khechinashvili et al. show that the use of cyclamen extract in 50 patients (12 with acute exacerbations of chronic bronchitis) is associated with an efficacy in excess of 90% in relieving most of the symptoms after 4-5 days of treatment (nasal congestion, nasal secretion, headache and facial pressure). In a study performed by Zaritskaya et al. on 35 patients (including 11 children aged 8-15 years), after 8 days of treatment, most of the patients show a reduction or complete disappearance of the signs and symptoms of the disease. Lastly, Kryukov et al. have performed a study in patients with acute exacerbations of chronic rhinosinusitis or acute rhinosinusitis (n=120), giving Sinuforte® once a day (n=60) or standard therapy (n=60) for 7 days. The study shows that Sinuforte® and conventional therapy are associated with similar levels of efficacy, which are particularly high in this population with acute rhinosinusitis or with acute exacerbations of exudative-purulent chronic rhinosinusitis.
Focussing on the cyclamen extract’s mechanism of action, Dr. Pfaar pointed out that “it induces stimulation of the trigeminal nerve by means of a physical action, which causes activation of the nasal and paranasal mucosa. This in turn leads to a reflex secretion, drainage of the sinuses and expulsion of the mucus. In addition, the drug has an osmotic effect that favours cell secretion and reduced oedema in the nasal mucosa.”
MULTICENTRE RANDOMISED STUDY (KRYUKOV)
Turning in greater depth to one of the more recent studies published on the cyclamen extract, the speaker described the features and results of a multicentre randomised trial performed by Kryukov et al. The study was designed to determine the efficacy and safety of treatment with cyclamen extract in patients with (mild or moderate) acute rhinosinusitis and exudative-purulent chronic rhinosinusitis, comparing the results with those obtained with administration of a standard therapy.
In total, 120 patients aged 18-60 years were recruited for this trial. Half of the patients received single-agent therapy once a day with Sinuforte® (lyophilised powder for intranasal administration), while the other half received a conventional treatment for rhinosinusitis (daily punctures of the maxillary sinuses, amoxicillin-clavulanic acid 1.0 g b.i.d., otrivine spray t.i.d. in both nostrils and antihistamine therapy [Telfast® once daily]).
To determine the primary efficacy endpoints, the visual analogue scale (VAS, from 0 to 10) for pain, nasal obstruction and secretion has been used. Fibroendoscopy, X-ray examinations and mucociliary clearance provided the secondary endpoints.
The group treated with cyclamen extract experienced a marked improvement in pain, ventilation and secretion during the first days of treatment, which became virtually undetectable after 7 days. A similar trend (although less marked) was seen in the group receiving standard therapy.
It is concluded from this pilot study that topical administration of cyclamen europaeum is effective in patients with mild-moderate acute rhinosinusitis or exudative-purulent chronic rhinosinusitis, and no significant differences were observed with respect to the efficacy obtained with conventional therapy.
DOUBLE-BLIND, CONTROLLED STUDY
On the basis of these encouraging results, it was considered necessary to perform a multicentre, controlled, double-blind, parallel-group trial in 9 ORL centres in Germany. This was the study CYC-E-03, the first randomised, placebo-controlled trial with cyclamen extract. The primary objective was to compare the efficacy of cyclamen extract with placebo in about 100 patients receiving antibiotic therapy for moderate-severe rhinosinusitis.
Patients with moderate-severe acute rhinosinusitis (according to the EP3OS 2005 criteria, that is, two or more of the following characteristic symptoms for more than 10 days but less than 12 weeks: nasal congestion, anterior/posterior nasal secretion, facial pain/pressure and/or impaired or lost sense of smell) were included in the study. The symptoms’ severity was also assessed applying the EP3OS criteria (by assessment on the VAS of the question: how troublesome are your rhinosinusitis symptoms?).
As basal treatment, all of the patients received amoxicillin 500 mg every 8 hours for 8 days.
Group 1 (with 48 patients in the intention-to-treat analysis) also received a single daily intranasal spray of cyclamen extract (one spray of aerosol in each nostril) for 14 days (at night), while the control group (n=51) received a placebo aerosol (with the same external features as the study product) for 14 days (at night).
A greater tendency towards an improvement was seen in all of the symptoms assessed in the cyclamen extract group in both visit 2 (after 7 days of treatment) and in visit 3 (after 14 days), being particularly marked as regards nasal symptoms. There were no statistically significant differences, no doubt due to the limited number of patients remaining in the final analysis; in fact, in the per protocol analysis, only 40 patients in the cyclamen extract group and 42 patients in the control group could be assessed.
With the secondary efficacy endpoints, the changes induced in the endoscopic signs (mucopurulent secretion in the middle meatus and oedema of the mucosa with obstruction, mainly in the middle meatus), overall treatment assessment (by the investigators and the patients), daily symptom assessment (using diaries), assessment of the quality of sleep, need for additional treatment to control the disease and occurrence of adverse events were taken into account.
Efficacy Analysis
99 patients were randomized (cyclamen:48, Placebo:51). Study groups were homogeneous on demographic and clinical baseline data. The analysis shows statistically significant differences between means of facial pain (-1.2 with CI 95% from -2.3 to -0.1; p=0,036). Cure of endoscopic signs was higher (p=0,043) in cyclamen (48,7%) than placebo (30,9%). Both patient (p=0,0327) and investigator (p=0,0324) satisfaction were in favor of cyclamen. No serious or unexpected adverse events were reported.
In summary, study CYC-E-03, the first randomised, double-blind trial comparing cyclamen extract with placebo in patients with moderate-severe, non-viral, acute rhinosinusitis treated with antibiotics, shows interesting results, in spite of the limited number of patients, with some significant results. As regards symptom severity, a positive trend towards a greater reduction in the overall symptom score, especially in facial pain is seen in the patients receiving cyclamen extract. As noteworthy endoscopic findings, administration of cyclamen extract induces a positive trend towards a greater amount of secretion, recording statistically significant differences compared with the placebo group in the rate of cure. As Dr. Pfaar concluded, “in order to obtain clearer and more significant results, we need a prospective controlled study in which a greater number of patients is included.”
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