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

Respiratory Research. 2015;16(121)

Conclusions

Although the ICICC study failed to reach statistically significant outcomes for the primary and secondary endpoints, strong trends favouring treatment effect of I-C were observed. The primary and secondary endpoints consistently tended to be improved in the I-C spray group compared to the placebo group, with clinically relevant effect sizes, even though the population included patients with low baseline scores. Several rational and important exploratory analyses led to statistically significant and clinically relevant outcome differences. Unfortunately, the relatively low numbers of subjects with demonstrated viral infection limited study conclusions. Nonetheless, the outcome of the ICICC study is supported by previous evidence of I-C's in vitro antiviral activity and symptom and viral reduction in prior cold studies. The ICICC trial's outcome supports I-C spray as representing a potentially useful treatment option for the common cold. Trial results show it to be safe, well-tolerated, and minimally invasive, as well as suggesting efficacy.

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Trial registration
NCT01944631 (clinicaltrials.gov)

Acknowledgements
We acknowledge Dr. Jill Holbrook who provided medical writing services on behalf of BI Pharma GmbH & Co. KG. We thank the staff at the Common Cold Centre: Dr. Moutaz Jawad, Dr. Eugene Wong, Miss Suhair Jawad, Mr. Ben Pope and Miss Edyta Zwolska. We acknowledge Prof Laurent Kaiser, University Hospitals of Geneva, Division of Infectious Diseases, Division of Laboratory Medicine - Laboratory of Virology, Geneva, Switzerland and his staff, Dr. Caroline Tapparel, Aline Mamin and Yves Thomas, for performing the virus analysis.

Table 1. Demographic characteristics – treated set
	I-C	Placebo	Total
Number of patients, N (%)	100 (100.0)	100 (100.0)	200 (100.0)
Sex, N (%)
Male	40 (40.0)	38 (38.0)	78 (39.0)
Female	60 (60.0)	62 (62.0)	122 (61.0)
Race, N (%)
Asian	8 (8.0)	2 (2.0)	10 (5.0)
Black or African American	2 (2.0)	1 (1.0)	3 (1.5)
Hawaiian or Pacific Islander	0	1 (1.0)	1 (0.5)
White	90 (90.0)	96 (96.0)	186 (93.0)
Age, mean (SD) [years]	20.01 (2.37)	19.93 (1.90)	19.97 (2.14)
BMI, mean (SD) [kg/m ²]	23.98 (3.67)	23.66 (3.89)	23.82 (3.78)
Smoking history, N (%)
Never smoked	80 (80.0)	83 (83.0)	163 (81.5)
Ex-smoker	7 (7.0)	4 (4.0)	11 (5.5)
Current smoker	13 (13.0)	13 (13.0)	26 (13.0)
Alcohol history, N (%)
Does not drink	5 (5.0)	4 (4.0)	9 (4.5)
No significant drinking	95 (95.0)	96 (96.0)	191 (95.5)

BMI body mass index, SD standard deviation

Table 2. Total symptom scores over Days 2 to 4 (TSS _2–4), ANCOVA-adjusted means, FAS
	N	Adjusted^a mean (SE)	I-C vs. placebo
	N	Adjusted^a mean (SE)	Adjusted^a mean (SE) difference^b	95 % CI	p-value*
TSS₀ ^c
I-C	98	6.75 (0.17)
Placebo	97	6.79 (0.18)
TSS_2–4
I-C	98	5.78 (0.25)	−0.61 (0.36)	(-1.32, 0.10)	0.0895
Placebo	97	6.39 (0.25)

CI confidence interval, SE standard error
*For ANCOVA-adjusted comparison of placebo with I-C
^aThe means were adjusted for TSS₀
^bA negative treatment difference favored I-C
^cTSS₀ values are unadjusted means

Table 3. Secondary symptom score endpoints SSS _2–4, LSS _2–4, and AUC-TSS _1–10, ANCOVA-adjusted means, FAS
	N	Adjusted^a mean (SE)	I-C vs. placebo
	N	Adjusted^a mean (SE)	Adjusted^a mean (SE) difference^b	95 % CI	p-value*
SSS_2–4
I-C	98	1.12 (0.10)	−0.18 (0.15)	(-0.46, 0.11)	0.2310
Placebo	97	1.30 (0.10)
LSS_2–4
I-C	98	4.66 (0.22)	−0.44 (0.30)	(-1.04, 0.16)	0.1465
Placebo	97	5.10 (0.22)
AUC-TSS_1–10
I-C	98	41.94 (2.19)	0.73 (3.10)	(-5.39, 6.85)	0.8148
Placebo	97	41.21 (2.20)

CI confidence interval, SE standard error
*For ANCOVA-adjusted comparison of placebo with I-C
^aThe means were adjusted for baseline SSS, LSS, or TSS
^bA negative treatment difference favored I-C

Table 4. Exploratory analyses of total symptom scores, ANCOVA-adjusted means
	N	Adjusted^a mean (SE)	I-C vs. placebo
	N	Adjusted^a mean (SE)	Adjusted^a mean (SE) difference^b	95 % CI	p-value*
TSS_{2–4, ex 1 pt}
I-C	97	5.67 (0.24)	−0.72 (0.34)	(−1.40, −0.05)	0.0364
Placebo	97	6.39 (0.24)
TSS_1–4
I-C	98	6.02 (0.21)	−0.60 (0.30)	(−1.19, −0.00)	0.0495
Placebo	97	6.62 (0.21)
TSS_{1–4, rel}
I-C	98	−0.08 (0.05)	−0.13 (0.06)	(−0.25, −0.01)	0.0421
Placebo	97	0.05 (0.05)
Subset analyses
TSS_2–4, virus positive patients
I-C	53	5.87 (0.34)	−0.80 (0.48)	(−1.75, 0.15)	0.0986
Placebo	54	6.67 (0.34)
TSS_2–4, HRV/HEV positive patients
I-C	27	6.08 (0.46)	−0.36 (0.65)	(−1.66, 0.94)	0.5820
Placebo	28	6.44 (0.46)

CI confidence interval
*For ANCOVA-adjusted comparison of placebo with I-C
^aThe means were adjusted for baseline TSS
^bA negative treatment difference favours I-C

Table 5. Viruses identified at baseline in trial participants
	I-C	Placebo
Total number of patients tested (N)	98	97
Number of virus positive patients^{a, b} (N, %)	53 (54.1)	54 (55.7)
Influenza Type A	1 (1.0)	2 (2.1)
Picornavirus (including HRV and HEV)	30 (30.6)	28 (29.3)
Positive qualitative picornavirus assay	26 (26.5)	26 (26.8)
Positive qualitative enterovirus assay	2 (2.0)	0 (0.0)
Positive result^c on panenterhino/Ge/08 assay	27 (27.6)	28 (28.9)
Quantifiable result on panenterhino/Ge/08 assay	22 (22.4)	24 (24.7)
Human metapneumovirus	0 (0.0)	1 (1.0)
Coronavirus	23 (22.4)	19 (19.6)
Coronavirus 229E	1 (1.0)	2 (2.0)
Coronavirus HKU1	1 (1.0)	2 (2.1)
Coronavirus NL63	9 (9.2)	4 (4.1)
Coronavirus OC43	12 (12.2)	11 (11.3)
Adenovirus	0 (0.0)	2 (2.1)
Respiratory syncytial virus	0 (0.0)	1 (1.0)
Parainfluenza	5 (5.1)	5 (5.2)
Type 1	3 (3.1)	0 (0.0)
Type 2	1 (1.0)	1 (1.0)
Type 4	1 (1.0)	4 (4.1)

Categories are not exclusive; patients may appear in more than one category
^aEight patients were positive for 2 different viruses
^bNo patient tested positive for influenza B, human bocavirus, human paraecho virus, or parainfluenza 3
^cDetectable (quantifiable or non-quantifiable) result at baseline

Table 6. Change in panenterhino/Ge/08 assay viral load in nasal secretions - patients with quantifiable baseline viral load, ANCOVA-adjusted means
	N	Adjusted^a mean (SE)	I-C vs. placebo
	N	Adjusted^a mean (SE)	Adjusted^a mean (SE) difference^b	95 % CI	p-value*
Baseline [log (copies/mL)]^c
I-C	22	5.840 (0.200)
Placebo	24	6.139 (0.201)
Change from baseline, [log (copies/mL)]
I-C	22	−1.007 (0.191)	−0.453 (0.266)	−0.990, 0.084	0.0958
Placebo	24	−0.554 (0.183)
Reduction from baseline (%)^c,d
I-C	22	90.2
Placebo	24	72.0

CI confidence interval, SE standard error
*For ANCOVA-adjusted comparison of placebo with I-C
^aThe means were adjusted for baseline viral load
^bA negative treatment difference favored I-C
^cBaseline values are unadjusted means
^dCalculated according to Eccles et al. [5]