A randomized, double blind placebo-controlled pilot study was conducted in two study centers, the St. Anna Children’s Hospital and a private pediatric clinic in Vienna, Austria.
Total Symptom Score (TSS)
The TSS used was based on the evaluation of eight leading clinical features including the systemic symptoms headache, muscle ache, chilliness (systemic symptom score, SSS), and the local symptoms including sore throat, blocked nose, runny nose, cough, and sneezing (local symptom score, LSS), according to a published scoring system . Severity was rated on a four-point scale with zero indicating the absence of symptoms, and scores of 1 to 3 representing mild, moderate and severe symptoms, respectively.
Previously healthy, immunocompetent children and adolescents between 1 and 18 years of age with symptoms of acute rhinitis prevailing for less than 48 hours, and a total symptom score (TSS) ≤9, were enrolled in the study between January 2009 and January 2010. This low symptom score of 9 was chosen as inclusion criterion because a higher TSS would have led to the use of more co-medications, potentially biasing the effect of Carrageenan. Immunocompetence was evaluated clinically, including a history of less than 5 bacterial infections per year without a stay on intensive care units and without a history of any chronic disease. URTI was defined by the presence of appropriate symptoms according to a scale described above. Suspected bacterial infections, recent use of antimicrobial drugs, and intranasal treatment at first presentation were exclusion criteria. However, additional medication could be prescribed in case of fever, bacterial otitis, wheezing, persistent coughing or pneumonia upon decision of the physician. In line with the Austrian legal requirements, written informed consent was obtained from children above 14 years of age and from their legal guardians in all instances.
At enrolment into the study (first visit), medical history was recorded, physical examination was performed, and samples for molecular virus testing were obtained by a standardized aspiration of nasal secretions. The samples were frozen and stored at −80°C until use. Patients were assigned to receive a nasal spray containing either iota-carrageenan (0.12% / 0.5% sodium chloride) or placebo (0.9% sodium chloride) in a randomized and blinded manner (allocation ratio 1:1), using simple (unrestricted) randomisation. The concentration of iota-carrageenan and sodium chloride for the study medication was chosen identically compared to the previously performed pilot study , using the optimal galenic composition. The nasal spray containers were sequentially numbered. The random allocation sequence was generated by an independent statistician, the participants were enrolled by a study nurse and the investigating pediatricians assigned participants to the interventions. The children and/or their legal guardians received a standardized diary for the recording of symptoms and additional medication. A single puff (0.14 ml) of the spray per nostril was to be administered three times per day for a total of seven days. The patients and parents were requested to record symptoms permitting assessment of the TSS during the first week of treatment. Over the following two weeks (days 8 to 21), recording of the presence or absence of any symptoms was requested for determination of disease duration. Follow-up examination of the patients and collection of nasal secretion samples for molecular virus testing were performed three to five days into treatment (second visit). Final examination and collection of symptom diaries for the evaluation were carried out on the third visit after day 21. Molecular screening and quantitative assessment of viral load were performed for respiratory viruses including rhinovirus (RV), respiratory syncytial virus (RSV), human metapneumovirus (MPV), influenza A (InfA) virus, influenza B (InfB) virus, parainfluenzavirus (PIV1, PIV2, PIV3), and coronaviruses (CoV) by methods described previously [17, 18] (for more detailed description of virus analysis see Additional file 1).
The study has been approved by the local IRB Committee named Ethikkommission St. Anna Kinderspital (project approval number 190109). In line with the Austrian legal requirements, written informed consent was obtained from children above 14 years of age and from their legal guardians in all instances. The study was performed in compliance with the ICH E6 Note for Guidance on Good Clinical Practices (CPMP/ICH/135/95)5, the principles of the Declaration of Helsinki, local drug regulations, and standard operating procedures of the investigator, sponsor and CROs involved. The study protocol and attached documentation were approved by the responsible Ethics Committee.
Comparison between the verum and placebo groups was done by means of Mann–Whitney U-tests for continuous variables and by means of Chi square tests for ordinal or nominal variables. The viral load was compared using Student’s T-test after logarithmic transformation of the data. For comparison of time to disease clearance, the Log Rank (Mantel Cox) test was used. Calculation of the required sample size was based on previous results obtained in adult patients , which indicated that data from 70 individuals would be sufficient to obtain significant results on the primary endpoint, the mean of TSS on days 2 to 7 at the 5% significance level and 80 percent power. It was decided to recruit at least 200 patients in order to be able to analyze an ITT (intention to treat) population of at least 150 patients, with further analysis of per protocol (PP) patients.