The characteristics of the studies are tabulated in Table 3. Overall, 413 patients were treated with STW 5 in randomized controlled studies, about 5,795 patients in prospective non-interventional studies, and more than 40,000 children in retrospective database surveillances.
Comparative clinical studies
Four clinical studies evaluated STW 5 versus placebo and one study tested the non-inferiority of STW 5 to the prokinetic drug cisapride. A panel of gastroenterological experts participated in planning the studies and developed the primary efficacy criterion, the gastrointestinal symptom score (GIS). This score is a summary score consisting of ten gastrointestinal symptoms, which are evaluated on five-point Likert scales. The GIS was validated and is sensitive, responsive, and specific for functional dyspepsia . All studies had a similar design.
Von Arnim et al. [11, 27] performed a randomized, double-blind, placebo-controlled study, which included 315 patients with functional dyspepsia diagnosed according to the Rome II criteria. After a washout of 7 days, the patients were randomized to an 8 weeks treatment period with either STW 5 3 × 20 drops/day or placebo. Patients were followed up for 6 months. The primary endpoint was the change of the GIS over the treatment period. The GIS improved in both groups (see Fig. 2). After 4 and 8 weeks of treatment, the improvement was significantly higher in the STW 5 group compared to placebo and the difference between the two groups was clinically relevant. Investigators’ and patients’ global assessments confirmed the significant superiority of STW 5. On average, patients treated with STW 5 remained recurrence-free longer than patients who had received placebo. Though in the very good and good categories of tolerability assessments by patients, there was a slight imbalance in favor of placebo, the overall tolerability of STW 5 and placebo were comparable (see Fig. 3). No clinically relevant changes of laboratory or vital parameters and no serious adverse events occurred. The proportion of patients with documented adverse events was practically identical in both treatment groups. Five patients reported seven adverse events, in which a causal relationship to STW 5 could not be excluded (abdominal pain, pruritus, sore throat, alopecia, hypersensitivity, hypertension, gastrointestinal pain).
The other three studies in patients with functional dyspepsia comparing STW 5 to placebo showed basically similar results, i.e. a statistically significant and clinically relevant superiority of STW 5 versus placebo as determined by the GIS and an almost identical proportion of patients with adverse events in both treatment groups. Adverse events at least possibly related to STW 5 reported in these studies were esophagitis, bronchitis, diarrhea, nausea, stomatitis, and abdominal pain [12–14].
One of the studies examined gastric emptying as secondary parameter with the help of the 13C octanoic acid breath test for the assessment of the gastric half-emptying time . The findings from this study suggested that the clinical effects of STW 5 were not simply mediated by accelerating gastric emptying, but by more complex processes, reflecting the multi-faceted pharmacological profile of the drug.
The studies of STW 5 versus placebo with patients suffering from functional dyspepsia were sufficiently comparable in design to be submitted to several meta-analyses [17–19]. These meta-analyses detected a significant efficacy of STW 5. The latest and largest included 637 patients and found a standardized mean difference of − 1.1, indicating a large and clinically relevant effect (p = 0.0005), although there was statistically significant heterogeneity between studies .
One clinical trial compared STW 5 to the prokinetic drug cisapride 3 × 20 mg/day . To ensure double-blind conditions, this study used a double dummy design. One-hundred eighty-six patients with functional dyspepsia of the dysmotility type were enrolled and received STW 5, cisapride, or a research compound for 4 weeks after a 1-week washout phase. Patients were followed up for 6 months. Like in the placebo-controlled studies, the primary endpoint was the change of the GIS during the treatment period. During treatment, the GIS decreased significantly in both groups: from comparable baseline scores of 14.3–14.5 points, the GIS decreased to 2.3 points in the STW 5 group and to 3.5 in the cisapride group, showing a numerical superiority of STW 5 and a statistically confirmed non-inferiority to cisapride (see Fig. 4). Patients, who were symptom-free after treatment, were evaluated for recurrence during the 6-month follow-up period. There were no significant differences between the groups in this parameter. A further secondary endpoint, the efficacy assessments by investigators and patients, again showed comparable results for STW 5 and cisapride. The tolerability of STW 5 was assessed as being very good or good by more than 93 % of investigators and patients; in the cisapride group, this proportion was between 81 and 91 %. More patients reported adverse events in the cisapride group (33 %) compared to the STW 5 group (21 %). Two adverse events in the STW 5 group were classified as having a probable causal relation relationship to the study medication (abdominal cramps; dizziness and nausea), whereas in the cisapride group one such adverse event was reported (diarrhea).
One randomized, double-blind, and placebo-controlled clinical study analyzed the efficacy and safety of STW 5 in IBS . As one primary efficacy endpoint, the study used an abdominal symptom score developed by a gastroenterological expert panel, which included eight IBS-specific symptoms evaluated on four-point Likert scale. Two-hundred and eight patients underwent a 1-week washout phase and were then randomized to STW 5, two research compounds, or placebo for 4 weeks. STW 5 reduced the IBS symptom score by 1.5 points more than placebo, a clinically relevant superiority that was also statistically significant (p < 0.0004). The co-primary endpoint abdominal pain, evaluated on four-point Likert scales for the four abdominal quadrants, showed comparable results and again a statistically significant superiority of STW 5 versus placebo. The tolerability as assessed by investigators was generally ‘very good’ or ‘good’ (STW 5: 98 %; placebo: 89 %), with no essential differences to patients’ assessments. There was one adverse drug reaction in the STW 5 group (constipation). No serious adverse events were reported and blood chemistry before and after treatment showed no clinically relevant variations.
Two non-interventional studies with a comparable design enrolled patients with functional dyspepsia (n = 2267) or IBS (n = 2548) [20, 21]. In both studies, patients received STW 5 for up to 4 weeks. In functional dyspepsia, 27 % of patients discontinued therapy after 1 week for freedom of symptoms. The GIS sum score decreased on average by 78 %. In IBS, the single symptoms of the abdominal sum score decreased by 65–80 % each. Approximately 80 % of physicians and patients assessed the effectiveness of STW 5 as very good or good. There were no adverse drug reactions to or interactions with STW 5 documented in these studies.
A retrospective cohort study analyzed 961 patients, who had received STW 5 or metoclopramide in the recommended dose for functional dyspepsia . The primary endpoint of this analysis was the improvement of GIS, outcome parameters included the number of symptom-reef patients after therapy and the duration of inability to work. There were significantly more symptom-free patients after therapy with STW 5 compared to metoclopramide (72 versus 63 %; p < 0.05). Furthermore, the duration of inability to work was significantly shorter under STW 5 than under metoclopramide (median 1 day versus 3 days; p < 0.001). There were no adverse drug reactions to STW 5, but five patients receiving metoclopramide reported vertigo and dizziness. In line with these results, 90 % of physicians rated the tolerability of STW 5 as very good, compared to 71 % for metoclopramide.
Studies in children
Two retrospective database surveillance studies collected data on the use of STW 5 in children up to 12 years of age with gastrointestinal complaints including functional dyspepsia and irritable bowel disease. The studies documented 40,961 and 2,350 patients, respectively, and both studies used a four-point Likert scale for an assessment of efficacy [23, 24]. The physicians judged effectiveness to be very good or good in 88 and 96 % of patients, respectively. Both studies did not detect adverse drug reactions to or interactions with STW 5.
A more recent non-interventional study included 980 children (age 3–14 years) with functional gastrointestinal disorders preferably diagnosed by the Rome III criteria and eligible to treatment with STW 5 . Patients were followed for approximately 1 week. The GIS, extended by four lower abdominal symptoms, served as primary endpoint for clinical effectiveness. Most patients were treated for IBS (43 %) or functional dyspepsia syndrome (26 %). The symptom score decreased by 76 % during the treatment period. The decrease in symptoms was similar for the different age groups, genders, and indications. Patients with a shorter duration of complaints had a lower score at study end (p < 0.0001). The global treatment effect was assessed as good or very good by 87–89 % of patients/parents and physicians. Physicians rated the global tolerability as very good or good for 95 % of the patients. Adverse events assessed as probably or possibly related to STW 5 were nausea, abdominal pain, increased gastrointestinal complaints, and vomiting. One patient experienced skin rash following the concomitant application of penicillin. These events were non-serious.
The safety profile of STW 5 was extensively evaluated in pre-clinical and in controlled and non-interventional or retrospective clinical studies. Pre-clinical evaluations included acute, subchronic, and chronic toxicity, with a specific focus on hepatotoxicity, reproductive toxicity, fertility, embryo- and fetotoxicity, mutagenicity, and cytotoxicity and showed no indications of safety signals relevant for human use [10, 28].
Table 4 shows the number of adverse events observed in the controlled and non-interventional or retrospective clinical studies reviewed above, in which the investigators considered a causal relationship to STW 5 as at least possible (i.e. the adverse events classified as adverse drug reactions). The incidence was 0.04 % and the adverse drug reactions documented were (in alphabetical order) abdominal cramps, abdominal pain, alopecia, bronchitis, constipation, diarrhea, dizziness, gastrointestinal complaints increased, gastrointestinal pain, hypersensitivity, hypertension, nausea, esophagitis, pruritus, skin rash, sore throat, stomatitis, and vomiting. No serious adverse drug reactions occurred and the studies also found no clinically relevant deviations of laboratory values. STW 5 was well tolerated in the populations examined, independent of concomitant diseases and without drug interactions.
In addition to the clinical or observational studies included in Table 4, the spontaneous reporting system in Germany and worldwide elicited a comparatively very small number of adverse events assessed as possessing a possible or probable causal relationship to STW 5 (n = 111), given that the exposed cohort is estimated at more than 25 million patients since the market launch of STW 5 over 50 years ago. The summary of product characteristics of STW 5 complements this information by specifying that hypersensitivity reactions may occur very rarely and may take the form of pruritus, dyspnea, or skin reactions in pre-disposed patients .