Enrollment opened in January 2004 and ended in August 2008. Of the 3,321 screened, 719 were enrolled and randomized (). Retention was high. Two people were lost to follow-up, and four withdrew before primary outcome data could be gathered. Reasons for withdrawal were: too sick or too busy to fill out questionnaires, and/or desire to take non-protocol medications. Approximately 98% of intended data were collected. The largest data gap was with nasal wash, where 33 people either refused the second nasal wash or failed to return within time limits (24 to 72 hours after first wash). Following Little’s MCAR test, there were no discernible patterns of missingness in the 0.27% of missing WURSS items. Imputation of WURSS-21 items and calculation of global severity and duration values were done prior to unblinding, using methods outlined above.
Participants were 64% female and 88% white, with 84% reporting at least some college education. Age ranged from 12 to 80 years, with mean 33.7 and standard deviation 14.4. Some 12.8% were current smokers. Baseline measures appeared similar across the four groups (). There were 522 enrolled in Madison and 197 in Verona. Comparing mean age (33.3 vs 34.9; p=0.20), gender (63.4% vs 66.0% female; p=0.52), and those with at least some college education (84.6% vs 82.3%; p=0.47), no significant between-site differences were found.
Baseline characteristics of participants
Average area-under-the-curve global severity and illness duration were lower in the blinded and open-label echinacea groups than in either the blinded placebo or no pill groups (). Mean global severity was 236 and 258 for blinded and unblinded echinacea, respectively, 264 for blinded placebo, and 286 for those without pills. Primary efficacy analysis contrasting global severity in the blinded echinacea and placebo groups yields a mean difference of 28 points (95% CI = −69 to 13). Statistical testing yields T=1.34 and p = 0.089. Because of skewness, the Mann-Whitney U test contrasting median severities of 206 for blinded placebo to 193 for blinded echinacea may be more appropriate, and yields z = 0.97 and p= 0.17. Mean illness duration for the blinded and unblinded echinacea groups was 6.34 and 6.76 days, respectively, compared to 6.87 days for blinded placebo and 7.03 for no pills. Efficacy analysis contrasting illness duration for blinded echinacea vs. blinded placebo yields a mean difference of 0.53 days (95% CI = −1.25 to 0.19), a T-value of 1.97, and p = 0.075. Contrasting the two blinded groups using a general linear model to control for potential confounders also failed to find statistically significant differences (p=0.42 for area-under-the-curve severity; p=0.74 for duration.) Distribution of both global severity was skewed, hence Box Cox transformation was used for that model. Reported p-values are based on one-sided testing and do not adjust for multiple testing.
Primary outcomes: Global severity and duration of illness
Because echinacea is thought to work through immune stimulation with early dosing important, we did a subgroup analysis on the 351 people who were enrolled within 24 hours of their first symptom (). Compared to either the no pill or blinded placebo groups, illness duration and global severity were lower for both echinacea groups. Nevertheless, none of these between group comparisons in this secondary analysis were statistically significant. Results and conclusions did not change significantly after applying a general linear model, controlling for covariates mentioned above.
Analysis of secondary outcomes did not demonstrate effects clearly attributable to echinacea (). Nasal neutrophil count and IL-8 in nasal wash tended to rise faster in the two echinacea groups than in either control group, but these differences were not statistically significant. Self-reported health measures including physical and mental health (SF-8), stress (PSS-4), optimism (LOT), and social support (Ryff PR) did not appear to be influenced by random assignment to echinacea.
Secondary outcomes (day 3 assessments)
Frequency of potential adverse effects was similar (statistically indistinguishable) in the four groups (). The only possible exception was headache, where 62% of those in the no pill group reported having had a headache at some time during their illness, compared to less than 50% in the three pill groups. Responses to open-ended questions asking about possible side effects during monitoring did not show any patterns of side effects attributable to echinacea.
Adherence to dosing regimen was assessed by asking participants “Did you take all your pills as directed?”, and by counting pills in returned pill bottles. Of the 545 people allocated pills, 518 (95%) reported taking pills as directed. Of the 524 bottles returned, 486 (93%) were empty, 27 (5%) had 4 or fewer pills, and 11 (2%) had 5 or more pills left in the bottles There was no indication that those receiving echinacea took their pills differently than those receiving placebo. See .
Test of blinding
Blinding appeared to be intact. Of the 363 receiving blinded pills, 141 (39%) guessed their assignment correctly, 110 (30%) guessed incorrectly, and 107 (29%) refused to guess (). Of 179 assigned blinded placebo, 72 (40%) correctly guessed their assignment, compared to 69 (38%) receiving blinded echinacea. Including only those who were willing to guess pill assignment, a Fisher’s exact test of proportional difference yielded p-value 0.053 (95% CI −0.002, 0.246). While this does not allow us to reject the null and conclude blind-breaking, it does leave open the possibility that a few people were able to correctly ascertain to which group they had been assigned.
Laboratories of the manufacturer (MediHerb, Australia) and the natural products analysis company Chromadex (Clearwater, FL) conducted independent phytochemical assays at successive time points from 2004 to 2007. Both companies used high performance liquid chromatography with reference standards of known purified ingredients. shows the lowest and highest results from MediHerb’s four lab assays and Chromadex’s three assays. Phytochemical concentrations appeared stable over time, with no trends towards lower concentration in later years (data not shown).
Phytochemical composition of echinacea tablets