Of the 146 screened potential participants, 104 met eligibility criteria and of those 59 agreed to participate in the study. A total of 59 participants were enrolled in the trial, and 54 (27 per group) were randomized to study medication (see for participant disposition). Six participants had a large response during the placebo-run-in period and should have been dropped from the study prior to randomization, however they were erroneously randomized to study medication. Because they had been randomized, these participants were allowed to remain in the trial and are included in the intent to treat analysis. Fifty percent of participants were referred from advertisements in parenting or co-op newsletters, 20% from Bastyr University publications or websites, and 30% from other sources.
Participant Flow Diagram For Screening, Enrollment And Completion Of Study
The demographic characteristics of the participants are displayed in . Forty-one percent of participants randomized to Hypericum and 44% of participants randomized to placebo had previously used medications for the treatment of their ADHD symptoms. There were small differences between most demographic characteristics of the two groups. The Hypericum group did, however, have a higher percentage of boys (20 of 27 in the Hypericum group vs. 14 of 27 in the placebo group) and a lower percentage with co-occurring oppositional defiant disorder (9 of 27 in the Hypericum group vs. 15 of 27 in the placebo group). Randomized study participants took a mean of 82.0% of study medication (95% CI 77.5 to 86.4%) during the study, and there was no significant difference in medication adherence between the Hypericum and placebo groups.
Baseline Characteristics Of Study Participants
In the primary intention-to-treat analysis, no significant difference was seen between the two groups in the change in ADHD RS-IV scores from baseline to week 8. The improvement in ADHD RS-IV total score was 5.2 points (95% CI −9.4 to −1.1) in the placebo group, whereas the improvement in ADHD RS-IV total score in the Hypericum group was 4.4 points (95% CI −7.9 to −0.9) (see ). When the inattentive and hyperactive scales were examined for differences, again there was no significant difference in the change in scores between the groups (). Analysis of age and gender-normalized percentile scores revealed no differences between the groups. There was no difference in the proportion of participants who were rated as much or very much improved on the CGI Improvement scale (12 of 27 in the Hypericum group (95% CI 25.5 to 64.7%) and 14 of 27 in the placebo group (95% CI 31.9 to 71.3%), p=0.59).
Mean ADHD-IV Rating Scale Total Score for Each Study Visit, error bars depict the 95% confidence interval around the mean score for each study visit. N= 27 for each group at each time point, with last observation carried forward for missing data.
ADHD Rating Scale-IV Scores Of Study Participants
No statistically significant difference was found in the proportion of participants who experienced one or more of the following: rash, nausea/vomiting, headache, and sunburn during the trial between the two groups (). Participants’ weight was measured at each study visit. Participants in the Hypericum group gained 3.3 pounds (95% CI 2.2 to 4.5 pounds), and those in the placebo group gained 2.3 pounds (95% CI 1.3 to 3.4 pounds) over the eight week trial (p=0.22). No significant difference was seen in the change in height between the groups during the eight-week trial.
Percentage (95% CI) of Participants Experiencing Adverse Events
Additional analyses were conducted to determine if use of Hypericum was associated with improved ADHD RS-IV scores in the participants who completed the study according to protocol. As shown in , three participants, one from the Hypericum group and two from the placebo group, dropped out of the study and were excluded from the per protocol analysis. In addition, four participants were excluded from the Hypericum group (2 for poor compliance and 2 due to a large placebo response during the run-in phase) and 6 placebo participants (2 for poor compliance and 4 with a large placebo run-in response). In the per protocol analyses, no statistically significant differences were seen between the groups in the ADHD RS-IV scores (difference from week 8 to baseline on the total ADHD RS-IV the Hypericum group improved 4.8 points (95% CI −8.7 to −0.9) and placebo group improved 6.1 points (95% CI −11.7 to −0.4), p=0.69) or the proportion of participants who were responders on the CGI Improvement scale (Hypericum group 40.9% (95% CI 20.7 to 63.6%) and placebo 42.1% (95% CI 20.3 to 66.5%), p=0.94).
Medication status was not associated with a statistically significant improvement in total ADHD RS-IV score in the regression analysis that controlled for age, gender, household income, parental rating of ADHD severity, and co-occurring oppositional defiant disorder at baseline (beta coefficient for effect of medication status −0.68, 95% CI −5.54 to 4.18, p=0.78).
In the blinding analysis, parents correctly identified the medication status 52.9% (95% CI 38.5 to 67.1%) of the time (kappa 0.07, p=0.31). Children correctly identified their medication status 43.1% (95% CI 29.3 to 57.8%) of the time (kappa 0.17, p=0.84) and the principal investigator correctly identified the medication status 56.9% (95% CI 42.2 to 70.7%) of the time (kappa 0.14, p=0.16).
In analyses conducted to determine if use of Hypericum had an effect on other behavioral problems, as measured by the CBCL and YSR, there were no significant differences between the Hypericum and placebo groups for the a priori selected scales: internalizing problems, externalizing problems, total problems, DSM-IV affective, DSM-IV anxiety, DSM-IV oppositional, and DSM-IV conduct (). No differences between the Hypericum and placebo groups were found in the subscales of the CPRS: Conners’ ADHD Index difference from week 8 to baseline Hypericum group improved 4.6 points (95% CI −8.5 to −0.8) and placebo group improved 7.8 points (95% CI −12.3 to −3.2), p=0.29; and Conners’ DSM-IV Total ADHD Scale Hypericum group improved 3.7 points (95% CI −7.9 to 0.5) and placebo group improved 6.9 points (95% CI −11.5 to −2.2), p=0.30. Finally, there were no differences in the quality of life of participants in the Hypericum and placebo groups, as measured by the PedsQL. Difference from week 8 to baseline on the parent rated total PedsQL score the Hypericum group improved 1.1 points (95% CI −2.5 to 4.8) and placebo group improved 5.1 points (95% CI 1.1 to 9.2), p=0.13; and in the child rated total PedsQL score the Hypericum group improved 5.0 points (95% CI 1.4 to 8.6 points) and the placebo group improved 6.1 points (95% CI 1.5 to 10.8), p=0.69. Analysis of the subgroup of children who had never previously taken pharmaceutical medication for their ADHD symptoms revealed no significant improvement of ADHD symptoms with the use of Hypericum compared to placebo (difference from week 8 to baseline on the total ADHD RS-IV in Hypericum group improved 6.4 points (95% CI −10.7 to −2.1) and placebo group improved 7.6 points (95% CI −13.0 to −2.1), p=0.71).
Achenbach Measures Of Behavior Completed By Parent (CBCL) And Children Older Than 11 Years Of Age (YSR)