[Ergoferon liquid dosage form--efficacious and safe treatment for childhood acute respiratory infections. Interim outcomes of a multi-center, randomized, double-blind, placebo-controlled clinical trial].

The pediatric dosage form of Egroferon--a drug indicated for the treatment of influenza and acute respiratory infections (ARIs)--is developed taking in account the broad range of pathogens (most of which are viruses), and age-dependent features of immune system reactions (absence of specific immunity and immunological memory, relative "immaturity" of immune reactions, reduced interferon production by immunocompetent cells, etc.). Ergoferon interferes with the non-specific mechanisms of antiviral defence that ensure eliciting of an immune response, regardless of the virus type (the interferon system and CD4+cells), and influences virus-induced histamine release and histamine-mediated inflammatory reactions. Used over four years in clinical practice, the drug has shown a high efficacy and safety profile for the treatment of influenza and ARIs in adult patients. The purpose of the multi-center, randomized, double-blind, placebo-controlled study was to evaluate the clinical efficacy and safety of a new ergoferon liquid dosage form in the treatment of ARIs in children. The publication contains the results of the fist study stage completed as per the study plan and data from the interim analysis. METHODS. The screening involved a total of 162 subjects, aged 3 to 17 years (average, 8.2 ± 3.9 years), that had presented to 13 research centers based in Russia with common signs and symptoms of ARI (body temperature ≥ 38.0 degrees C, as measured with a digital infrared temporal artery thermometer; symptom severity score ≥ 4) during seasonal morbidity. Ergoferon was administered in 82 subjects receiving the therapeutic regimen of the drug for 5 days; 80 children received placebo. The subjects were monitored for 6 days. Treatment efficacy was assessed on the basis of morning, evening and total daily ARI symptom scores, including scoring estimates of fever, general symptoms and symptoms affecting the nose, throat and chest. Along with this, calculations were performed to obtain the Total Index (TI) of ARI; illness severity was evaluated using a mathematical "area under the curve" model. RESULTS. Starting from Day 2, the percentage of convalescents was observed to increase--from 6% (morning) and 14% (evening) to 20% and 29% on Day 3, respectively, and 58% and 61% on Day 4. The results suggested a substantially higher efficacy of Ergoferon as compared to placebo treatment (the Cochran-Mantel-Haenszel χ2 test: χ2 = 21.7; p < 0.0001). Ergoferon had a marked effect on fever and other signs of intoxication. In Ergoferon group, the percentage of non-fever subjects, with the endpoint defined at ≤ 37.2 degrees C, was 43% on Day 2, as estimated in the morning and the evening (vs 25% and 19% in the placebo group, respectively; χ2 = 10.6; p = 0.012), and 83% in the morning and 84% in the evening on Day 3 (vs 60% and 54% in the placebo group, respectively; χ2 = 16.7; p = 0.001). The Generalized Linear Model (GENMOD) procedure confirmed the significance of differences between the Ergoferon and placebo groups according to the following parameters: 1) Ergoferon was significantly more effective in reducing body temperature (to lower values) than the placebo; 2) Ergoferon had an earlier effect on fever (main marker of viremia), as compared to placebo; 3) The significant Ergoferon's superiority over placebo was also evident by the morning and evening measurements throughout the five-day therapy. The TI was observed to significantly decrease starting from Day 2 of Ergoferon administration: from 13.0 ± 4.5 to 7.9 ± 4.8 on Day 2 and 4.5 ± 2.9 on Day 3 (based on the patient's diary data); from 14.3 ± 4.2 to 4.9 ± 3.0 on Day 3 (based on the doctor's assessment). The severity of ARI-related intoxication signs was reduced most significantly, in particular as indicated by the results of doctor's objective examination on Day 3 (GENMOD: factor "Treatment"--χ2 = 147.8; p < 0.0001; factor "Day of administration"--X>=6.1; p = 0.013; Tukey-Kramer post hoc analysis: z = -3.09; p = 0.024). The average fever duration in ergoferon-treated subjects was 1.9 ± 0.8 days (p < 0.0001). The overall duration of ARI was much shorter in Ergoferon group than in the group of placebo (p = 0.021). The "area under the curve" measure of TI in Ergoferon group was significantly lower as compared to Placebo group, both according to the patient's diary records (21.9 ± 10.9 TI x Days vs 28.0 ± 13.0 TI x Days; p < 0.002) and the doctor's examination (12.4 ± 4.7 vs 14.2 ± 5.2 TI x Days; p = 0.023). Ergoferon treatment was associated with a lower frequency of using antipyretics (χ2 = 4.1; p = 0.043), particularly on the first day of illness. The monitoring of adverse events as well as the haematology, biochemistry and urinalysis findings were indicative of Ergoferon's safety. No signs of drug incompatibility were observed as a result of ergoferon administration in combination with antipyretics, decongestants, expectorants, inhaled corticosteroids, cromoglicic acid derivatives, leukotriene receptor antagonists, short-acting beta2 agonists and topical anti-septics. There were also no cases of bacterial complications, worsening of illness severity, or acute exacerbations of coexisting allergy or chronic ENT pathology. The children demonstrated good drug tolerance and 100% treatment compliance. CONCLUSIONS. Ergoferon liquid dosage form is an efficacious and safe treatment for ARIs in children. The study results demonstrated the drug's efficacy against the major syndromes associated and caused by viremia--fever and general intoxication. The early onset of the drug's effect was shown to result in a shorter time to convalescence and reduced ARI severity, particularly during the initial days of illness.