Abstract
Context: Since the discovery of toll-like receptor 3 (TLR3), no specific tools have been developed to modulate its activity in upper respiratory tract viral infections (URTIs). ContafluTM (antibodies to TLR3 cytoplasmic fragment) is the first specific TLR3 modulator that showed efficacy in a mouse model of influenza. Objective: To evaluate the efficacy of Contaflu in URTI. Methods: A double-blind randomized placebo-controlled trial in adults with self-reported URTI (the ESTUAR trial) was conducted in 2012/2013 in Belgium. Adult outpatients started a 7-day treatment course with oral tablets of Contaflu or placebo within 36 h after onset of at least one of 4 typical symptoms of URTI. Patients were examined twice by their general practitioners, on days 2-3 and 10-14 after start of treatment. The primary endpoint was the overall severity of URTI calculated as the sum of Wisconsin Upper Respiratory Symptom Survey (WURSS-21) scores over the follow-up. Independent Student’s t test was used to compare the disease severity between groups. Results: A total of 243 patients were enrolled by 32 investigators (121 Contaflu, 122 placebo); 92% of cases matched ICD codes J00 or J06. Most patients had very mild (41.8%) or mild (18.2%) URTI symptoms. In the ITT cohort, neither primary nor secondary outcome measures (duration of URTI, day-to-day and overall functional impairments) showed statistically significant differences between groups. The rate of adverse events was similar in both groups. In patients with moderate to severe URTI symptoms, Contaflu tended to reduce the overall disease severity, daily symptoms, and to improve the functional state. Due to the small size of the corresponding subgroups, Contaflu efficacy on daily scores was statistically significant (p < 0.05) only 1, 2, and 5 days after start of treatment. Conclusion: Contaflu was ineffective in mild URTI and showed efficacy in moderate to severe URTI cases.
Highlights
Influenza and influenza-like illness (ILI) are among the major causes of morbidity and loss of productivity across the globe
We found that severity trajectory in the present study differed considerably from the data obtained in Wisconsin Upper Respiratory Symptom Survey (WURSS) validation study ([18], Figure 1): in particular, median summed score for ESTUAR on Day 2 was 30.5, while in WURSS validation study it was about 50
Adverse Events (AEs) Overall, 198 adverse events (AEs) were reported by 91 patients (37.4%) in the intention to treat (ITT) cohort: 88 AEs were reported by 46 placebo patients and 110 AEs were reported by 45 Contaflu-TAO1 patients
Summary
Influenza and influenza-like illness (ILI) are among the major causes of morbidity and loss of productivity across the globe. Over the last two decades considerable progress has been made in understanding the mechanisms underlying ILI severity, in particular, the role of pattern recognition receptors [4]-[6]. None of these important discoveries have translated so far into emergence of new effective and safe treatments for influenza or ILI [7] [8]. This problem is especially important bearing in mind that over the first 5 days after influenza virus invasion, innate response plays the leading role in antiviral protection [9]. Impaired regulation of body response to the infection (excessive production of inflammatory factors and insufficient efficacy of protective factors) is responsible for severe forms of influenza [9]
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