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

Background

The common cold is caused by a variety of respiratory viruses, such as human rhinoviruses (HRV), coronaviruses, human enteroviruses (HEV), respiratory syncytial virus (RSV), parainfluenza viruses, or influenza viruses.[1] Rhinoviruses are the most common cause of respiratory tract infections in individuals of all ages. In adults, rhinoviruses cause approximately 50 % of common colds and up to 90 % of colds during the autumn epidemic season. Common colds are frequent illnesses in both children and adults; on average, adults report 2.5 episodes per year.[2] It has been estimated that the total economic impact of non–influenza-related viral upper respiratory tract infections approaches $40 billion annually,[2] and such infections can result in serious and even life-threatening sequelae in patients with underlying illnesses such as asthma, COPD or immune compromise. With the exception of influenza and RSV, there are no vaccinations or anti-viral medicinal products available for treatment of infection with the viruses that cause the common cold.

Iota-carrageenan (I-C)—a sulfated polysaccharide found in some species of red seaweed (Chondrus crispus) — has demonstrated antiviral activity against respiratory viruses in cell culture and in animal models.[3,4] The I-C polymer seems to bind directly to viruses, preventing viral attachment to host cells. In vitro and in vivo studies have demonstrated the effectiveness of I-C against several viruses such as HRV[4] and influenza A.[3] In vitro tests have established that I-C does not penetrate freshly excised bovine nasal mucosa, and therefore is not absorbed systemically (data on file, Marinomed Biotechnology GmbH). Carrageenan is generally recognized as safe (GRAS) for use in food and topical applications. Because the primary site of infection and replication of most cold-causing viruses is the nasal mucosa, it was speculated that early and targeted treatment of the nasal mucosa with I-C may block viral entry at the level of the respiratory mucosa, and interfere locally with the propagation of viral replication.

Therefore, a nasal spray containing 0.5 % saline and 0.12 % iota-carrageenan (I-C nasal spray) has been developed and registered as a medical device. This product has recently been licensed to Boehringer Ingelheim, the sponsor of the current study. Between 2008 and 2011, three randomized clinical trials (two in adults and one in children) were conducted comparing I-C nasal spray with saline solution (placebo). In all 3 trials, there were indications of efficacy, including significantly reduced cold symptoms;[5] positive effects on symptoms in patients in whom less co-medication or no co-medication was used;[6] significantly reduced viral loads;[5–7] and faster reduction of common cold symptoms.[6,7] Treatments were safe and well tolerated.[5–7]

The ICICC trial (ICICC: Iota-Carrageenan In Common Cold) was designed as a controlled evaluation of the safety and efficacy of I-C in the treatment of patients with early common cold symptoms. The effects of treatment on cold symptoms and the duration of the cold and on viral load were assessed.

Methods

Trial Design and Patient Population. The ICICC trial was conducted at the Common Cold Center, Cardiff, Wales, UK. It was a randomized, placebo-controlled, double-blind, two-arm parallel group trial, with the aim of investigating the efficacy of I-C nasal spray in comparison with placebo nasal spray for the treatment of early common cold in adults (≥18 years). The trial was registered under the clinicaltrials.gov accession number NCT01944631.

Volunteer patients were recruited by poster advertisements around the Cardiff University campus and by e-mail to the students and staff of Cardiff University. Based on the results of a previous trial,[5] it was calculated that a sample size of 93 in each group would have 90 % power to detect the expected difference in means between the TSS2–4 scores of the groups (see below for definition of TSS2–4); it was therefore planned to include a total of 200 patients eligible for randomization. To be eligible for participation, patients were to have had common cold symptoms for ≤48 h before trial entry, based on self-reporting during the screening interviews. Patients were to rate eight common cold symptoms (headache, muscle ache, chilliness, sore throat, blocked nose, runny nose, cough, and sneezing) on a 0 to 3 rating scale[8] (0 = no symptoms, 3 = maximum severity) and were to have a total symptom score (the sum of these eight common cold symptoms at baseline) of ≤9. Patients were also to have a score of ≥1 for at least one of the following symptoms: sore throat, runny nose, or blocked nose which reflects the standard cold study design according to Jackson.

Inclusion criteria constructed similarly to the previous 3 clinical trials conducted with I-C. Patients with high symptom scores (≥9) were excluded in order to recruit only patients in the early stages of a cold and exclude subjects with later infections. This strategy was designed to start treatment early to optimize the chance to improve the clinical course of a cold. This early intervention strategy may have been partially responsible for lowering the power of the study, since the proportion of patients in the trial who did not develop full-blown colds was relatively high (reflected by only about 24 % rhinovirus-positive patients; see Results and Discussion).

Trial Treatment and Outcome Measures. Patients were instructed to self-administer 1 puff (0.14 mL) of trial medication to each nostril 4 times per day. Trial medication was either I-C nasal spray (1.20 g iota-carrageenan/L in 0.5 % NaCl) or placebo (0.5 % NaCl). Both patients and investigators were blinded to treatment allocation. Treatment was to be mandatory for 4 days, and depending on patient preference, could be continued for up to 6 additional days, resulting in a maximum treatment duration of 10 days.

Patients were to record their symptoms once per day in the evening of Days 1–10 in a symptom diary, using the 0–3 rating scale for each of the eight cold symptoms (see above). The primary endpoint of the trial was the mean total symptom score (TSS) of those documented eight single cold symptoms calculated as the averaged daily sum over Days 2–4 (TSS2–4). Secondary endpoints included the mean of the daily sum of three systemic common cold symptoms (headache, muscle ache, and chilliness) over Days 2–4 (SSS2–4); the mean of the daily sum of 5 single local common cold symptoms (sore throat, blocked nose, runny nose, cough, and sneezing) over Days 2–4 (LSS2–4); area under the curve (AUC) of daily symptom scores over the 10-day period (AUC-TSS1–10) calculated as the sum of the eight single cold symptoms over Days 1–10; duration of the cold (as determined by patients' answer in the diary to the question "Do you still have a cold?" at the end of each treatment day); and the patients' assessment of efficacy as evaluated at the end of trial visit, at which patients answered the question "How effective was the treatment in relieving your common cold symptoms?" using a 0–4 scale (0 = poor, 1 = fair, 2 = good, 3 = very good, or 4 = excellent). Further pre-specified endpoints included TSS at each study day (Days 1–10) and viral load (change from baseline) on Day 3 or 4 for various virus types. After trial data were unblinded, three exploratory analyses were performed: assessment of TSS2–4 excluding a patient with aberrantly high symptom scores (TSS2–4, ex 1pt); the mean of the TSS over Days 1–4 (TSS1–4); and change in TSS1–4 relative to baseline (TSS1–4, rel) to adjust for the potential impact of baseline TSS (TSS0) on TSS1–4 (TSS0 scores ranged from 3.00–9.00 in the I-C group and from 2.00–9.00 in the placebo group). To calculate TSS1–4, rel, TSS0 was subtracted from TSS1–4 and the result was divided by TSS0. In addition, TSS2–4 scores were calculated for the virus positive subset and the HRV/HEV positive subset (see Analysis sets below for definition). Safety was assessed on the basis of incidence of treatment-emergent adverse events (AEs) and overall tolerability was assessed by the patients themselves and recorded by the investigator at the final visit.

Viral Assessment. Respiratory viruses and viral load were determined from nasopharyngeal lavage samples obtained at baseline and on either Day 3 or 4.[9] Viral presence was to be determined for all patients using both qualitative and quantitative tests for respiratory viruses. Real-time polymerase chain reaction (RT-PCR) was used for qualitative determinations of the presence of influenza A and B, picornaviruses, HRV/HEV, human bocavirus, human metapneumovirus, coronaviruses 229E, HKU1, NL63, and OC43, adenovirus, human parechovirus, respiratory syncytial virus, and parainfluenza virus types 1–4. Quantitative viral loads for HRV and HEV were determined using the panenterhino/Ge/08 assay.[10,11] Quantitative viral loads for influenza A and B and coronaviruses 229E, HKU1, NL63, and OC43 were assessed according to Garbino et al..[12,13] The panenterhino/Ge/08 assay provided quantifiable HRV and HEV viral load results; however, in some patients, virus was detectable but viral loads were below the level of quantification of the test. Such patients were considered to be virus-positive, but non-quantifiable (that is, a qualitative positive result). The total number of virus-positive patients was obtained by summing up the number of patients who had a positive result on any qualitative assay, or who had a detectable quantitative (quantifiable or non-quantifiable) result on the panenterhino/Ge/08 assay.

Analysis Sets. Two main analysis sets (the treated set and the full analysis set [FAS]) were evaluated. The treated set included all patients who were documented to have taken at least one dose of trial medication, and was used for safety analyses. The FAS included patients documented to have taken at least one dose of trial medication, for whom a baseline TSS was recorded, and who supplied data for assessment of the primary endpoint. The FAS was used for analysis of the primary and secondary endpoints. Three analysis subsets within the FAS were also defined after unblinding, and included 1) the virus positive subset (those patients whose nasal lavage specimens yielded a least one positive qualitative or a detectable quantitative [quantifiable or non-quantifiable] result at baseline); 2) the HRV/HEV positive subset (those patients whose lavage yielded a least a detectable [quantifiable or non-quantifiable] result on the panenterhino/Ge/08 assay at baseline); and 3) the quantifiable HRV/HEV subset (those patients who had a quantifiable result on the panenterhino/Ge/08 assay at baseline). These subsets were used for analysis of additional exploratory endpoints.

Statistical Methods. The primary endpoint TSS2–4 was analyzed using an analysis of covariance (ANCOVA) adjusting for continuous covariates 'TSS0 ' and 'treatment'. Differences between I-C and placebo treatment groups were assessed based on the adjusted means and the corresponding two-sided 95 % confidence intervals (CIs). The secondary endpoints SSS2–4, LSS2–4, and AUC-TSS1–10 (adjusted for TSS0 and treatment) were analyzed similarly. The three exploratory endpoints TSS2–4, ex 1pt, TSS1–4, and TSS1–4, rel were analyzed in the same way as the primary endpoint, that is, by adjusting for 'TSS0 ' and 'treatment'. For all the above endpoints, missing single symptom scores at baseline and at any post-baseline measurement time were replaced by zero, if at least one of the eight symptom scores was available. Thereafter, missing daily TSS, LSS and SSS data were replaced the last observation carried forward procedure.

The duration of the cold was examined by recording the time to loss of cold, defined by the first "no" response to the question "Do you still have a cold?" in the patient's daily symptom diary. The log rank test stratifying for TSS0 was used to compare treatment groups. The endpoint variable was censored at day 10 if a patient did not recover from his or her cold. To test whether patients' assessment of efficacy differed between the I-C group and the placebo group, an ordinal logistic regression model adjusting for TSS0 was applied to the efficacy score (0–4) provided by patients. Missing entries were assigned the least favorable category.

The analysis of the endpoint variable TSS at each study day (Days 1–10) used a restricted maximum likelihood-based repeated measures approach, using all longitudinal TSS data from Days 1–10. The statistical model included the fixed categorical effects of treatment, day and treatment-by-day interaction and the continuous covariate of TSS0. An unstructured covariance structure was used to model within-patient errors. Missing single symptom scores at baseline and at any post-baseline measurement time were replaced by 0, if at least one of the 8 symptom scores was available. If a patient had a missing TSS at a specific day and all subsequent days until Day 10 and the cold ended on that day (that is, the question "Do you still have a cold" was answered by "no" at that day at latest), the missing TSS values for that and the subsequent days until Day 10 were replaced by 0. For all other cases no imputation of missing TSS values was performed.

The mean change in viral load from baseline was adjusted for the continuous covariates 'baseline viral load' and 'treatment' using an ANCOVA. Differences between I-C and placebo treatment were assessed based on the adjusted means and the corresponding 95 % CIs, which were calculated using a two-sided approach. For quantitative viral load analyses, missing values and values below the limit of quantification (LOQ) were replaced with the LOQ value.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....