Ninety children were enrolled in the study, 74 from the university-based clinic and 16 from private practice sites. Subjects had a median age of 1.5 years. The majority was male (57%) and white non-Hispanic (44%) or Hispanic (39%). Despite randomization, there were notable differences among treatment groups in the frequency of potentially confounding factors, especially gender, presence of siblings in the home, frequency of AOM prior to study entry, and daycare attendance (Table ).
Subject characteristics according to assigned treatment group
Six subjects (7%) withdrew or were lost to follow-up within 3 months of enrollment (1–2 in each group). Only 19% of subjects attended all 5 scheduled osteopathic visits, but 64% had 3 or more treatment visits (see CONSORT diagram [21
]: Additional file 1
). The percentage of subjects that came for follow-up examinations was 69% at 3 months and 62% at 6 months. Medical record information on the occurrence of AOM during at least 3 months of follow-up was available for 84 subjects (93%). The length of follow-up ranged from 2 to 278 days (median 183).
Of 84 children followed for 3 months or more, 44 (52%) had one or more episodes of AOM as defined above. The cumulative incidence of AOM varied from 39% to 80% among the treatment groups (P = 0.04) (Figure ). The highest rate of AOM was among children receiving echinacea alone.
Cumulative incidence of AOM according to assigned treatment group. The P value is for at least one group being significantly different from the others.
The pattern of variation in incidence rates among the treatment groups did not suggest any plausible effect modification between echinacea treatment and OMT on the risk of AOM (Figure ). In addition, a likelihood ratio test for interaction between the two treatments using Cox regression was not significant (P = 0.40). Therefore, the independent effects of echinacea and OMT were assessed separately.
The use of echinacea was associated with an increased risk of AOM of borderline statistical significance. Sixty-five percent of children assigned to echinacea experienced AOM compared to 41% of children taking placebo (RR 1.59, 95% CI 1.04, 2.42). The Kaplan-Meier analysis using all 90 subjects yielded nearly identical results (Figure ).
Kaplan-Meier estimates of the probability of AOM according to treatment with echinacea or placebo.
OMT was not significantly associated with the risk of AOM. Forty-four percent of children receiving OMT experienced AOM compared to 61% of children undergoing sham treatment (RR 0.72, 95% CI 0.48, 1.10). Restriction of the analysis to 56 children who had 3 or more osteopathic treatment visits did not change the findings (RR 0.70, 95% CI 0.41, 1.19). Results of Kaplan-Meier analysis using all 90 children were similar (Figure ).
Kaplan-Meier estimates of the probability of AOM according to treatment with osteopathic manipulative treatment (OMT) or sham.
We estimated the effects of echinacea and OMT on the risk of AOM after adjustment for confounding factors using Cox regression in all 90 subjects (Table ). The adjusted relative risk of AOM for echinacea treatment was 1.73 (95% CI 0.94, 3.18). The adjusted relative risk for OMT was 0.84 (95% CI 0.44, 1.61). Four variables (younger age, male gender, Hispanic ethnicity, and presence of one or more siblings at home) were independently associated with the risk of AOM and were included in the regression model.
Cox regression estimates of the effect of echinacea and osteopathic manipulative treatment on the risk of AOM after adjustment for other factors
There was no significant difference in the median number of episodes of AOM during the study period between treatment and placebo groups for either echinacea or OMT. Comparisons were made using the Mann-Whitney nonparametric test.
One subject withdrew from the study following an adverse effect (vomiting after taking the echinacea placebo). One additional subject reported adverse effects (vomiting and non-urticarial rash two days after starting echinacea for a viral upper respiratory illness) but did not withdraw. Neither adverse effect was considered to have been caused by the study medication. As reported in monthly telephone interviews and at the 3- and 6-month visits, there was no statistically significant difference in reporting of any side effects between placebo and treatment groups for either echinacea or OMT.
Parents were unable to distinguish whether their child was receiving echinacea treatment or placebo. However, when asked about OMT after 3 months, parents of children assigned to OMT were significantly more likely to believe their child was receiving actual OMT than parents of children assigned to sham (Figure ). Even so, only 20% of parents of children assigned to sham treatments believed their child to be receiving placebo. Interestingly, the ability to distinguish OMT from sham treatment disappeared entirely by 6 months.
Parents' beliefs about osteopathic treatment assignment after 3 months in study (n = 54).