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

Results

Approximately 800 patients were evaluated with respect to symptomatology and duration of symptoms (prescreening); of these, 201 were formally enrolled and screened. Of the enrolled patients, one was not randomized, and 200 were randomized and treated (I-C, N = 100; placebo, N = 100). Overall, 97.0 % of the 200 entered patients completed trial treatment, and 3.0 % prematurely discontinued treatment with trial medication. The proportion of patients discontinuing treatment was similar for the treatment groups (I-C: 2 of 100 patients, 2.0 %; placebo: 4 of 100 patients, 4.0 %). The most frequent reason for trial discontinuation was being lost to follow-up (I-C: 1 patient; placebo: 3 patients). Of the 200 treated patients, 98 in the I-C group and 97 in the placebo group provided data for the primary endpoint and were included in the FAS (Fig. 1).

Figure 1.

Disposition of trial patients. 1Placebo (PBO), 2Full analysis set, 3One patient with extreme outlier TSS baseline scores was excluded from some exploratory analyses, 4Virus positive patients were those with a positive qualitative test at baseline and/or a detectable quantitative (quantifiable or non-quantifiable) result on a quantitative test at baseline, 5Defined as a detectable quantitative (quantifiable or non-quantifiable) result on panentorhino/Ge/08 assay, 6Quantifiable result on panenterhino/Ge/08 assay

Including the 200 patients who were treated, baseline demographic characteristics were comparable between the I-C and placebo groups (Table 1).

Primary Endpoint

The primary endpoint of TSS2–4 was lower for the I-C group (5.78, 95 % CI: 5.28–6.28) than for the placebo group (6.39, 95 % CI: 5.89–6.89), but the difference was not statistically significant (−0.61, 95 % CI: −1.32–0.10; p-value 0.0895; Table 2).

Secondary and Other Endpoints

For the secondary endpoints SSS2–4, LSS2–4, and AUC-TSS1–10, there were no statistically significant differences between I-C and placebo ( Table 3 ).

Mean duration of time to 'no cold' was equivalent between the groups, at 7.5 days for I-C and 7.4 days for placebo. The patients' overall assessment of efficacy was similar for I-C and placebo (OR = 1.11, 95 % CI: 0.67–1.84, p = 0.6954). For both I-C and placebo, the most frequent patient assessment was 'good' (I-C: 33.7 %; placebo: 36.1 %) and the second most frequent assessment was 'fair' (I-C: 28.6 %; placebo: 33.0 %).

For TSS at each study day (Days 1–10), the mean daily TSS values were highest for both groups during the four mandatory treatment days. The TSS peaked at Day 2 in the placebo group whereas the TSS in the I-C group decreased steadily without reaching a maximum on Day 2 (Fig. 2). TSS values were lower for the I-C group than for the placebo group on Days 1–4 (mandatory treatment days); the largest differences were observed on Days 1 and 2 of treatment. After Day 4, the TSS values were lower for the placebo group than for the I-C group.

Figure 2.

Adjusted mean TSS values with standard error for each day of the trial (data at baseline are displayed as unadjusted mean values)

Exploratory Analyses of Efficacy

After unblinding, three previously unplanned analyses were performed to provide a better understanding of the primary endpoint. The data for a patient with a TSS2–4 of 16.7 (treated in the I-C group) was removed for an exploratory analysis, because his on-treatment symptom scores were well out of range when compared with the adjusted mean values of 6.39 for placebo and 5.77 for I-C patients (Table 2), suggesting that the patient may have misunderstood the process of symptom reporting. This aberrantly high symptom score was evident over the entire treatment period of 10 days. Furthermore, no respiratory viruses were detectable in his nasopharyngeal samples. Excluding the data for this patient resulted in an adjusted mean TSS2–4 that was statistically significantly lower for the I-C group (TSS2–4, ex 1 pt) compared with the placebo group (p = 0.0364; Table 4).

Because I-C binds to viruses and prevents their entry into cells,[4,5] an immediate effect on symptom scores could also reasonably be expected; in addition, the TSS for the placebo group was increasing from pre-treatment (baseline) to Day 2, indicating progression of the cold. Therefore, a sensitivity analysis was performed using the mean daily TSS over the mandatory treatment Days 1–4 (TSS1–4). For the adjusted mean TSS1–4, there was a statistically significant difference in favour of I-C (p = 0.0495; Table 4).

Finally, in order to adjust for the baseline severity of the cold, the TSS1–4 was analysed relative to baseline (TSS1–4, rel), yielding a statistically significant difference in favour of I-C (p = 0.0421; Table 4).

An exploratory analysis in the subset of 107 patients who tested positive for any virus at baseline yielded a trend in favor of I-C; average adjusted TSS2–4 scores were 0.80 points lower for the I-C group compared with placebo (p = 0.0986; Table 4). In the subset of 55 patients who were positive for rhinovirus/enterovirus at baseline, average adjusted TSS2–4 values were 0.36 points lower than placebo (p = 0.5820; Table 4).

Virologic Analyses

Including data from both qualitative and quantitative assays, the proportion of patients testing positive for virus at baseline was 54.1 % (53 of 98 patients) in the I-C group and 55.7 % (54 of 97 patients) in the placebo group (Table 5). In qualitative assays, the most frequent viruses identified were picornaviruses (I-C: 26.5 % of patients, placebo: 26.8 %) and coronaviruses (I-C: 22.4 %, placebo: 19.6 %; Table 5). Between baseline and Day 3 or 4, 7 of the 53 virus-positive patients in the I-C group converted to virus-negative (13.2 %), as did 8 of 54 patients in the placebo group (14.8 %). Conversely, 4 of the 44 patients in the I-C group (9.1 %) and 5 of the 43 patients in the placebo group (11.6 %) who were virus-negative at baseline converted to virus-positive by Day 3 or 4.

As a post-hoc analysis, the quantitative data for viral types identified in at least 2 patients in each treatment group at baseline were analysed (coronavirus NL63, coronavirus OC43, and quantified panenterhino/Ge/08 assay). For the viruses quantified with the panenterhino/Ge/08 assay, there was a more substantial reduction in virus load in the I-C group (90.2 % compared with 72.0 % for placebo), although this did not reach statistical significance (Table 6). For the coronaviruses, decreases in mean virus quantity from baseline to Visit 2 was similar between the placebo and I-C groups (reduction of 94 % or greater).

Safety and Tolerability

During this trial, there were no serious AEs or deaths. Twelve patients (6.0 %) reported an AE; the frequency was similar between treatment groups, at 5 of 100 patients (5.0 %) in the I-C group and 7 of 100 patients (7.0 %) in the placebo group. AEs of severe intensity were reported for 3 of 100 patients (3.0 %) in the I-C group (one patient with both headache and migraine, one patient with toothache, and one patient with malaise) and for 5 of 100 patients (5.0 %) in the placebo group (one patient each with headache, migraine, nausea, sore throat, and fatigue). One patient in the placebo group discontinued treatment due to an AE (moderate epistaxis). The patients' assessment of tolerability was similar between treatment groups, with the majority rating the tolerability of the nasal spray as excellent, very good, or good (I-C: 87 patients, 88.8 %; placebo: 91 patients, 93.8 %). Only 1 patient in the I-C group (1.0 %) and 2 patients in the placebo group (2.0 %) assessed the tolerability of treatment as poor. Both treatments were therefore considered to be safe and well-tolerated.

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