Inosine pranobex is safe and effective for the treatment of subjects with confirmed acute respiratory viral infections: analysis and subgroup analysis from a Phase 4, randomised, placebo-controlled, double-blind study
This was a Phase 4, randomised, placebo-controlled, double-blind, multicentre study that evaluated the efficacy of inosine pranobex in subjects with clinically diagnosed ILI, including subjects with laboratory-confirmed acute respiratory viral infections due to influenza A or B virus, RSV, adenovirus, or parainfluenza virus 1 or 3. The study also evaluated the efficacy of inosine pranobex in subgroups of subjects less than 50 years of age who were without related diseases (such as asthma, bronchitis, chronic bronchitis, and chemical bronchitis) and who were non-obese (BMI 30 kg/m2) or obese (BMI ?30 kg/m2) as well as a subgroup of subjects at least 50 years of age without related ongoing disease. In addition, a subgroup analysis was conducted in subjects less than 50 years of age for time to resolution of all influenza-like symptoms to mild or none.
In the current study, the analysis of the primary endpoint of time to resolution of all influenza-like symptoms showed a faster improvement in subjects treated with inosine pranobex compared with subjects administered placebo, although the difference between treatment groups did not reach the threshold of statistical significance. The results were similar for the secondary efficacy endpoints of time to resolution of respiratory symptoms (cough, sore throat, and nasal obstruction), time to absence of fever, and time to resumption of normal activity. The difference in the occurrence of viral respiratory infection complications between treatment groups was not statistically significant.
Immunosenescence, ie, the age-related decline of the immune system, and obesity play an important role in the efficacy of the immune response to pathogens [18, 19]. Older subjects show a diminished immune response to pathogens, which increases their risk for severe infection and compromises their ability to adequately combat viral infections. This phenomenon was observed with split-virus influenza vaccines; a low response to the vaccine was observed in older adults, whereas the vaccine was effective in younger subjects. This low response resulted in increased susceptibility to influenza and associated complications in older adults compared to younger adults who typically benefit from a higher response [20, 21]. Obesity has also been identified as an independent risk factor for increased susceptibility to influenza virus infection; this susceptibility results from diminished CD4+ and CD8+ T-cell responses and lower influenza vaccine antibody levels [19, 22, 23]. Obesity may also increase the risk of pneumonia or other infections by restricting lung volume [24]. Immunosenescence and obesity can bias efficacy studies because of the impaired response of the immune system to pathogens, as the risk of complications is increased in such individuals.
In the subgroup analysis of the current study, in subjects less than 50 years of age who were without related ongoing disease and in those less than 50 years of age who were non-obese (BMI 30 kg/m2), statistically significant differences in time to resolution of influenza-like symptoms favoured the inosine pranobex group over the placebo group. Statistically significant differences were not observed between the inosine pranobex and placebo groups in subjects at least 50 years of age without related ongoing disease or in subjects less than 50 years of age who were obese (BMI ?30 kg/m2). Thus, the efficacy of inosine pranobex was improved in non-obese subjects compared with obese subjects, probably because the immune system in the former is more capable of defending against pathogens and is not negatively affected by obesity-related complications. Older patients have a decreased immune response to pathogens as a result of immunosenescence; therefore, they may take longer to recover from illnesses such as influenza and anti-influenza drugs may not be as effective. In an additional analysis, in subjects less than 50 years of age, statistically significant differences in time to resolution of influenza-like symptoms to mild or none favoured the inosine pranobex group over the placebo group, thus indicating that the improvement of symptoms was better with inosine pranobex than placebo in this subset of subjects (HR: 1.298; 95 % CI: 1.035, 1.627).
A substantial decrease in the proportion of subjects with all influenza-like symptoms was observed in the inosine pranobex group after 9 days while a decrease to similar proportions occurred only after 11 days for subjects in the placebo group. This difference could be a result of the time necessary for activation of the immune system, as inosine pranobex acts indirectly by stimulating the immune system and does not directly attenuate the symptoms. This result is also consistent with the results observed in a study in healthy volunteers in which inosine pranobex showed immunomodulating properties through an increase in serum levels of interferon-?, IL-2, IL-10, and tumour necrosis factor-? from 7 to 10 days [13].
The approved dose and treatment duration of inosine pranobex (two 500-mg tablets orally 3 times daily) were used in this study, and the administered treatment did not vary according to weight or symptom duration. From the subgroup analysis, the posology of inosine pranobex (3 g/day orally) in this study is most suitable for subjects less than 50 years of age without related ongoing disease and subjects less than 50 years of age who were non-obese (BMI 30 kg/m2). For certain subjects, such as those at least 50 years of age and those who are obese, different dosing strategies could be more appropriate; varying the dosing regimen requires further evaluation.
The use of a placebo-only group in this study was justified because ILI is generally mild and self-limiting and no other treatments are approved for acute respiratory viral infections other than influenza. In addition, the use of influenza-specific antivirals (neuraminidase inhibitors or amantadine) is not a component of routine medical management of ILI in many countries, including the countries in which the study was conducted.
Performing a high-quality efficacy trial for ILI is challenging because of epidemiologic considerations from the influenza outbreak period; the influenza season cannot be predicted in advance and can vary from year to year [25]. Furthermore, the enrolment of subjects with symptoms that have been present for less than 36 h is necessary, as the first 36 h is the period of maximal viral replication and antiviral medication is expected to have the most benefit during this time. The current study was anticipated to be performed in 1 influenza season in the Northern Hemisphere, between 01 October 2014 and 30 April 2015, and enrol the required number of subjects in each group during this timeframe. However, enrolment was challenging, as it could not be commenced because of a low attack rate and was only started after a late alert was issued by national public health authorities in the first week of December 2014 regarding the statistically higher incidence of acute respiratory viral infections. A low density of circulating viruses was present until the end of January 2015, which resulted in the enrolment of subjects until 30 April 2015 in order to maximize the number of completed subjects. Approximately 60 % of the randomised subjects were expected to have a positive laboratory confirmation of acute respiratory tract infection. However, only 137 subjects met the criteria for inclusion in the mITT analysis set, which was 121 subjects fewer than the 258 subjects expected. The effects of the absence of a significant influenza outbreak adversely affected the statistical power, thus reducing the power of the study, which could potentially explain the lack of statistical significance for the primary and secondary efficacy endpoints.
A slightly longer duration of treatment or a different dosing strategy may have influenced the observed efficacy of inosine pranobex, as proof of therapeutic effect requires a high attack rate, ie, a higher number of sick patients during one influenza season. The attack rate is difficult to predict, and studies, which will adjust the sample size calculations to account for the possibility of a below-average flu season or studies with longer duration, e.g., those that include 2 or more influenza seasons to account for lower than predicted attack rates, are necessary to achieve the desired results [25].
In addition, 10.8 % of enrolled subjects in the inosine pranobex group reported a medical history of gastrointestinal disorders and 10.4 % reported hepatobiliary disorders. Pharmacokinetic parameters were not measured in this study, but it is possible that the presence of these disorders at baseline may have affected the absorption, distribution, and metabolism of the study drug and may have influenced the study results, including the efficacy results. Furthermore, age, comorbidities, and the obesity of enrolled subjects, particularly in subjects more than 50 years of age, may also have affected the outcome of the study.
The safety analysis demonstrated that inosine pranobex treatment was well tolerated, and no major differences in safety profiles were observed between treatment groups. Treatment-emergent SAEs were reported in 2 subjects, and none were considered to be related to study drug by the investigators. No subjects died during the study. No significant changes were observed in vital signs and physical examinations in either study group.