Efficacy and Safety of Iota-Carrageenan Nasal Spray Versus Placebo in Early Treatment of the Common Cold in Adults

The ICICC Trial

R. Eccles; B. Winther; S.L. Johnston; P. Robinson; M. Trampisch; S. Koelsch

Disclosures

Respiratory Research. 2015;16(121) 

In This Article

Discussion

This randomized, double-blind, and placebo-controlled ICICC trial was conducted to further evaluate the safety and efficacy of I-C in the treatment of patients with early common cold symptoms, and was conducted at one study site, primarily among university students who were in apparent good health except for early common cold symptoms. The analyses from the ICICC trial support the findings of three previous randomized clinical trials, which examined I-C nasal spray in adults[5,7] and children[6] with acute common cold symptoms: in 35 adult patients, administration of I-C nasal spray significantly reduced cold symptoms and the viral concentration in nasal lavages;[5] in 203 adult patients, cold duration was significantly shorter in virus-positive patients treated with I-C, viral load was significantly reduced, and there was a significantly faster reduction of common cold symptoms after the first 3 days of treatment;[7] and in 153 children, although there was no significant difference between the I-C group and the placebo group for mean total symptom score, exploratory analyses indicated a positive effect on symptoms in patients in whom less co-medication or no co-medication was used.[6] In the ICICC trial, although the primary endpoint TSS2–4 did not demonstrate a statistically significant difference between I-C and placebo, there was a clear trend towards benefit of I-C treatment.

Consistent trends in favor of I-C for secondary endpoints and statistically significant outcomes for exploratory analyses were also observed for the ICICC trial. The finding that nominally greater treatment effects were seen in the ICICC trial among patients who were virus-positive, is supported by a pooled analysis by Koenighofer,[14] which combined the Fazekas and Ludwig trials.[6,7] The pooled analysis examined only those patients who were virus-positive, and showed that nominal response rates were higher in virus-positive patients than in all participants of the Ludwig and Fazekas trials.

There may be several reasons for the unexpectedly low power of the trial, which resulted in trends rather than statistically significant outcomes for the primary endpoint and HRV/HEV viral load reductions. First, the proportion of patients for whom a respiratory virus could be detected was smaller than anticipated; respiratory viruses (all groups/types analysed) were found at baseline in only 54.9 % of patients (54.1 % in the I-C group and 55.7 % in the placebo group). Efforts were made to recruit patients with the earliest onset of a common cold. Thus, self-reported cold symptoms were used for patient inclusion criteria, without the requirement for demonstration of virus positivity to enter treatment. Since the early symptoms of common colds may be rather non-specific for respiratory virus infection, these symptoms may present in other conditions such as vasomotor rhinitis, in which certain nonspecific stimuli including changes in environment (temperature, humidity, or barometric pressure), airborne irritants (odors or fumes), dietary factors (spicy food or alcohol) or emotional factors trigger nasal symptoms. Patients inadvertently included with non-infectious conditions would not be expected to respond clinically to antiviral therapy, and therefore are likely to cause an under-estimation of any true antiviral treatment effect. Consistent with this, the ICICC trial demonstrated that among those patients who had quantifiable virus at baseline, the I-C patients had a greater decrease in viral load than did placebo patients, suggesting an antiviral effect of I-C. In addition, TSS2–4 scores in the patients who were virus-positive at baseline showed strong trend in favor of I-C. However, since this was a subset of the total enrolled population, the virus-positive subset was underpowered for the TSS2–4 score endpoint. In particular, the percentage of patients with HRV/HEV identified at baseline was substantially smaller than anticipated: only 23.6 % had quantifiable virus (22.4 % in the I-C group and 24.7 % in the placebo group). Other studies using both molecular methods and viral culture have demonstrated that human rhinoviruses are the etiologic agent in 50–90 % of common colds.[1,15] The current trial was also conducted primarily in the fall (October until February), which includes the period of greatest HRV infection incidence.[1,15] Because virus shedding tends to be the greatest in the first several days of infection and generally continues for up to 2 weeks, it is unlikely that the low positive rate for HRV/HEV infection was due to missing the window of HRV shedding. More likely, the current study was conducted during a season of low HRV prevalence, resulting in fewer than expected infections among trial patients. In two previous clinical trials conducted with I-C,[6,7] the number of patients with confirmed HRV infection was higher than in the current trial, at 46 %[6] and 30 %[7] (although these values are as well lower than the percentages reported for other studies[1,15]). Therefore, the smaller-than-expected number of patients infected with the HRV/HEV viruses likely limited the ICICC trial's ability to differentiate between the I-C and placebo treatments.

A second issue that affected the analysis of the trial was the inclusion of one patient treated in the I-C group whose TSS scores were much higher than expected and were much different than those of other trial participants. This patient reported exceptionally high symptom scores over the entire treatment period of 10 days; his AUC-TSS1–10 was more than 3-fold higher than the overall population mean value. Interestingly, no virus was detected from this patient either at baseline or in a follow-up sample. While there is no ready explanation for these aberrant values, it is possible that this patient misinterpreted the symptom scoring methodology. When the primary endpoint TSS2–4 was re-evaluated excluding the data from this patient, the difference between the I-C and placebo patients became statistically significant.

Two other exploratory analyses further support the conclusion that I-C was efficacious. Because I-C may have had an early effect on symptoms, the assessment of on-treatment symptom scores was broadened to include Day 1. The comparison of TSS1–4 between I-C and placebo groups demonstrated a statistically significant effect of I-C, and a statistically significant change in TSS1–4 relative to baseline. Two additional exploratory analyses, although performed on very small samples, did not reach statistical significance, but also support the assertion of I-C efficacy: TSS2–4 scores in PCR-confirmed respiratory virus-positive patients were on average 0.8 points lower in the I-C group compared with placebo, and TSS2–4 scores in patients with PCR-confirmed rhinovirus infection were also on average 0.4 points lower in the I-C group.

The day-by-day TSS scores indicated an advantage for I-C on Days 1 and 2, which appeared to be lost by Days 4–5. It is not clear why the apparent TSS advantage disappeared on the later treatment days; however, the placebo was a saline nasal spray, which may have had some clinical benefit from saline irrigation of the nasal passages.[16–18]

The I-C spray is registered and marketed as medical device in several European countries and is intended to be used in patients with early cold symptoms. Data from several experiments suggest that the mechanism of action may be prevention of binding to attachment sites and/or interference of viral entry. First, in vitro studies have demonstrated activity against a variety of viruses – various strains of HRV and influenza and herpesvirus, denguevirus, and papillomavirus.[3,4,19–21] This non-specificity suggests the absence of a specific direct-acting antiviral (DAA). Secondly, the observed antiviral effects occurred early in the infection cycle, most likely during the stages of attachment and/or entry, and the antiviral effect tended not to be I-C concentration-dependent. It is, therefore, unlikely that carrageenan's effect is that of a DAA targeted to the metabolic or reproductive mechanisms. Since a variety of viruses cause the common cold and since the virus infection cycles typically involve binding and entry with nasal mucosal cells, the antiviral properties of iota carrageenan represents an attractive and promising option for treatment.

Published clinical evidence concerning the frequencies of detectable viruses varies but with modern techniques, viruses (particularly rhinoviruses) have been found in up to 90 % of patients suffering from cold symptoms. It can therefore be expected that in real-life conditions patients/consumers who empirically choose to use the I-C spray have a relatively high likelihood of being infected with rhinovirus or one of a variety of respiratory viruses that manifest with the common cold symptoms. The uncertainty of true infection in such a setting is counter-balanced by the very low intolerance and toxicity rates of the I-C spray and its relative inexpensiveness, thus giving favorable potential benefit-risk and benefit-cost ratios to the empiric use of the I-C spray.

In clinical trials of cough & cold, a substantial proportion of studies demonstrate trends but may not reach statistically significant efficacy outcomes. This observation may be due to the large variability in the disease severity between native infection and patients recruited in the early stages of a cold. When a controlled clinical trial tries to recruit patients at the earliest stages of a common cold - when symptoms are still emerging and are mild - patients may incorrectly believe they are coming down with a cold, prior to full blown cold symptoms. The relatively low frequency of rhinovirus-positive patients in the ICICC study demonstrates that there is often a trade-off when this standard design is used for cold studies. The peculiarities of the outcome of the ICICC study are also useful in that they may trigger a discussion among the scientific community about more suitable study designs to investigate common cold treatments.

Furthermore, the results of the ICICC study are in line with many other common cold studies which showed relatively small effects of treatment on symptom severity or duration. One example is the study by Barrett et al. on Echinacea which showed as well trends in the direction of benefit, amounting to an average half day reduction in the duration of a week-long cold, or an approximate 10 % reduction in overall severity. The authors concluded that "while these results do not allow us to reject the null hypothesis and confidently claim evidence-of-benefit, data are also insufficient to exclude the possibility of a clinically significant effect".[22]

Although not addressed in the ICICC trial, I-C's antiviral properties lead to speculation that its use might decrease cold transmission to patients' family members and other social contacts.

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