Arne R. J. Schneider MD, Medical Department I, Johann Wolfgang Goethe-University Frankfurt, Theodor-Stern-Kai 7, D-60590 Frankfurt/Main, Germany. Tel: ++49 69 6301 6775; fax: ++49 69 6301 6448; e-mail: email@example.com
Abstract STW 5, a herbal extract, is effective for the treatment of symptoms in patients with functional dyspepsia (FD). However, its mode of action is still unclear and a modulation of gastric motility is hypothesized. This multicentre, placebo-controlled double-blind study addressed the question of whether STW 5 accelerates gastric emptying in patients with FD and gastroparesis. One-hundred and three patients diagnosed with FD were randomly assigned to a treatment with either STW 5 or a liquid placebo for 28 days. The primary end point of the study was a change of a validated gastrointestinal symptom (GIS) score under treatment. Additionally, patients underwent a 13C octanoic acid breath test for the assessment of the gastric half-emptying time (t1/2). Patients with prolonged t1/2 were diagnosed with gastroparesis and requested to repeat the test at the end of treatment. A change of t1/2 was defined a secondary study end point. t1/2 was prolonged in 48.6% of patients in the STW 5 group and in 43.8% of the placebo group. During treatment, t1/2 increased non-significantly in patients treated with STW 5 (+23 ± 109 min; P = 0.51) and slightly accelerated among patients in the placebo arm (−26 ± 51 min; P = 0.77) (P = 0.49). The improvement of the GIS (P = 0.08) and the proportion of patients with a treatment response (P = 0.03) were more pronounced in the STW 5 group. Our findings suggest that the clinical effects of STW 5 in patients with FD and gastroparesis are not directly mediated by an acceleration of gastric emptying. A clear-cut correlation with symptom improvement is still lacking.
Functional dyspepsia (FD) is a gastrointestinal disorder frequently encountered in clinical practice.1–5 As objective diagnostic criteria are lacking, FD is defined by subjective symptoms. Patients may complain of epigastric pain, heartburn, postprandial fullness, nausea and a vast range of other abdominal symptoms. The absence of a detectable organic cause is a prerequisite for the diagnosis. The pathophysiological background of FD still remains vague.6–9 Studies on visceral sensitivity and nociception, psychological factors and gastric motility have rendered no clear-cut results.10–19 The threshold of abdominal pain perception seems to be decreased in a considerable proportion of patients with FD.18,20 In contrast, psychological stress may be a contributory factor, but typical psychopathologies associated with FD are lacking.21–23 With respect to gastric accommodation and emptying, results from previous studies also failed to demonstrate a definite concept. Though up to 50% of patients have an impaired postprandial accommodation, the current workup of FD neither involves diagnostic testing with a barostat nor recommends treatment with appropriately modulating drugs.24,25 A variety of studies have focused on the question of whether delayed gastric emptying accounts for the symptoms associated with FD. On the other hand, only one-third of patients with FD have gastroparesis and gastric motility poorly correlates with symptoms.
The therapeutic approach most often confines to acid inhibition with proton pump inhibitors and/or prokinetics. These drugs exert positive effects in additional 10–15% of patients with FD, compared with placebo.26–28 A herbal preparation, namely STW 5 (Iberogast, Steigerwald GmbH, Darmstadt, Germany) has been applied in the treatment of FD already for decades. The clinical efficacy of STW 5, which consists of nine plant extracts, has been shown in a considerable number of trials.29–34 Throughout all studies, STW 5 proved superior to placebo in enhancing the symptoms of FD. Additionally, the improvement of the clinical gastrointestinal symptom (GIS) score for STW 5 was not statistically significant from cisapride.33 These results suggested a modulating effect of STW 5 on gastric motility. Further trials described regional effects of STW 5 components on antral motility and accommodation in the fundus.35,36 A recent study reported on the effects of STW 5 on gastric motility in vivo:37 briefly, STW 5 slightly slowed gastric emptying of liquids, but improved proximal gastric accommodation and antral pressure waves substantially. In view of these results, we aimed to further elucidate whether STW 5 has an influence on gastric emptying in patients with FD and gastroparesis.
Patients and methods
One-hundred and three patients (n = 30 male) aged 18–85 years (mean 46.8 years) participated in a double-blind, randomized, placebo-controlled, multicentre study. All patients were diagnosed with FD according to the Rome II criteria.38 The main criteria for the diagnosis were epigastric pain and/or discomfort, centred in the upper abdomen during the preceding 12 months, with a duration of at least 12 weeks. Three or more items on a GIS Profile had to be judged at least ‘moderate’ (grade ‘2’) to meet the inclusion criteria (see below). Clinically, relevant organic diseases of the upper gastrointestinal tract and abdominal organs have had to be ruled out by an abdominal ultrasound examination and an oesophagogastroduodenoscopy within the preceding 3 months. Patients with endoscopically proven oesophageal erosions, Barrett’s oesophagus, gastroduodenal ulcers or erosions were excluded. Inclusion criteria also required the Helicobacter pylori status to be determined, but H. pylori positive patients were not excluded from the study. Among several other exclusion criteria, patients with diabetes mellitus, a history of abdominal surgery (apart from appendectomy and cholecystectomy) or predominant gastro-oesophageal reflux disease were not eligible for the study.
Patients were randomly assigned to either the verum group, treated with STW 5 tincture (20 drops tid for 28 days), or the placebo group. The latter group received a liquid placebo, mimicking organoleptic properties of STW 5 by the addition of flavours and colour, but lacking the active herbal extracts (20 drops tid for 28 days). None of the constituents of the placebo preparation was similar to STW 5, as approved by independent chemical analysis.
Before the treatment phase, patients were scheduled for a screening visit (visit 1, day −7 ± 2), when the diagnosis of FD and inclusion/exclusion criteria were checked. After screening, a washout-phase of 7 days preceded the beginning of the placebo-controlled treatment period (visit 2, day 0 ± 2). During this period and throughout the entire study period, patients had to refrain from drugs known to influence intestinal motility, including prokinetics, antacids, beta-blockers, calcium-antagonists, antidepressants, antibiotics and laxatives. Additionally, non-steroidal anti-inflammatory drugs were prohibited apart from a regular medication with acetylsalicylic acid for cardiovascular indications of maximum 100 mg per day. On visit 2, patients also underwent a 13C octanoic acid breath test (13C-OBT) for the assessment of gastric emptying. Patients with gastroparesis, defined by a prolonged gastric half-emptying time, underwent an additional 13C-OBT at the end of the treatment period of 28 ± 2 days (visit 3).
13C-octanoic acid breath test
After an overnight fast, patients received a standardized breakfast. The meal consisted of two slices of toast, 5 g margarine, 150 mL water and 100 mg of [13C]octanoic acid (1-13C, 99%; Euriso-Top SA, Saint-Aubin, France) incorporated into a baked egg. Patients were encouraged to consume the test meal within 5 min. Breath samples were collected before, every 15 min during the first 2 h and every 30 min during the following 2 h after the ingestion of the substrate. Samples were analysed for the ratio of 13CO2 to 12CO2 using non-dispersive isotope-selective infrared spectrometry (IRIS system; Wagner Analysentechnik, Bremen, Germany). Gastric half-emptying time (t1/2), lag phase (tlag) and gastric emptying coefficients (GEC) were calculated using a standardized algorithm which involves a nonlinear regression formula.39,40 The individual CO2-production was estimated using the formula by Haycock for the calculation of the body surface area, assuming an endogenous CO2-production of 5 mmol m−2 min−1.41 A half-emptying time of >150 min was considered delayed and defined gastroparesis.
Primary and secondary end points
The primary end point was a change of the ‘GIS score’, representing a validated combination of 10 questions, regarding different specific dyspeptic symptoms (abdominal cramps, epigastric/upper abdominal pain, early satiety, fullness, loss of appetite, vomiting, sickness, nausea, retrosternal pain, acid eructation/heartburn).42 Each symptom was graded on a validated five-point Likert scale, ranging from 0 (no problem) to 4 (very severe problem, markedly influencing daily activities or requiring rest). Accordingly, the maximum result of the GIS was 40. A minimum of three parameters had to be judged at least ‘moderate’ (grade 2) by patients to be included in the study. Patients who reported higher values for the items ‘retrosternal discomfort’ and/or ‘acid eructation/heartburn’ compared with other symptoms of the GIS were excluded from the study, because non-erosive gastro-oesophageal reflux disease was suspected. The GIS score was assessed on all three scheduled visits.
On visit 3 at the end of treatment, both patients and physicians assessed the treatment efficacy on a six-point Likert scale [good (1)–very poor (6)]. Further evaluation included the proportion of responders, defined by a GIS-improvement of at least 40% from visit 2 to visit 3. The efficacy of STW 5 was characterized in different subgroups of FD. The subgroups were defined according to the Rome II criteria: ulcer-like (predominant pain), dysmotility-like (predominant discomfort, vomiting and/or postprandial fullness) and unspecific (compound symptoms without predominance). Patients with reflux-like FD had been excluded from the study.
Safety and tolerability were also analysed, using the documentation of adverse events, clinically relevant changes in laboratory parameters from baseline to the study end and the global assessment of tolerability on a six-point Likert scale by both patients and physicians.
The secondary target parameters comprised a change of the gastric half-emptying time (t1/2) from baseline (visit 2) to the end of the study (visit 3) in patients in whom a delayed gastric emptying time was documented on visit 2.
The primary objective was to prove the superiority of STW 5 over placebo during the treatment period (from day 0 to day 28). Considering a two-sided α-level of 0.05 and a power of 80%, 54 patients per study arm would have been required. In consideration of a 10% drop-out rate, the study aimed to recruit 60 patients in each treatment arm.
Originally, the study was planned as a single-centre trial. Due to the fact that the enrolment of patients proceeded slowly, the study was extended to a multicentre (n = 15) study approximately 1 year after the initiation.
For statistical analysis, different sets of patients were defined: all enrolled patients, non-randomized population (all patients enrolled into the study, but not randomized), intention-to-treat (ITT) population (all randomized patients who took any study medication) and per-protocol population (all patients from the ITT-population who essentially completed the study in compliance with the protocol).
Statistic evaluation of the primary variable GIS was performed by an analysis of variance (anova). anova was also applied for continuous secondary parameters, whereas a logistic regression model was used for categorical data. In cases when the assumption of normality in the linear models was not fulfilled (13C-octanoic acid breath test parameters), a non-parametric Wilcoxon signed rank test was applied. For all tests, a P ≤ 0.05 was considered significant.
Statistics were calculated using the Statistical Analysis System sas (SAS Institute Inc., Cary, NC, USA), vers. 8.2.
The study was approved by the Ethical Committee by the Faculty of Medicine of the Johann-Wolfgang-Goethe University Frankfurt (approval No.164/02). The other participating centres obtained an approval from proper ethical committees, referring to the approval of the principal centre.
A total of 103 subjects were recruited. The study was terminated prematurely after more than 2 years because of a protracted recruitment. This decision was made in accordance with an expert statistical appraisal, stating that data met the requirements for a valid statistical analysis. Ten patients were not randomized due to a withdrawal of consent (n = 6), new intercurrent diseases (n = 2), a violation of in-/exclusion criteria (n = 1) or for other reasons (n = 1). Of the remaining randomized 93 patients, 86 (92.5%) were included in the ITT population (STW 5 n = 44; placebo n = 42). In each group, 41 patients remained for the ‘per protocol’ analysis, whereas three patients in the verum- and one patient in the placebo group were excluded due to time frame deviations (n = 2) or a lack of compliance (n = 2).
Demographics, subgroups of FD and medical history
Comparison of demographic data showed a good homogeneity among the ITT-STW 5- and the -placebo group, regarding age, gender, body mass index, height and weight (P > 0.05). In both groups, about 50% of patients suffered from dysmotility-like FD (Table 1). The remainder equally distributed among the ulcer-like and the non-specific FD subgroup. Helicobacter pylori was positive in nine patients (20.5%) treated with verum and four patients of the placebo group (9.5%) (P = 0.16).
Table 1. Demographics, dyspepsia subtypes, medication, Helicobacter pylori status and gastric emptying parameters (mean ± SD)
STW 5 (n =44)
Placebo (n =42)
BMI, body mass index; GIS score, gastrointestinal symptom score; PPI, proton pump inhibitor; GEC, gastric emptying coefficient.
Sixty-seven of 86 patients (77.9%; STW 5 n = 35, placebo n = 32) performed the 13C-OBT for the assessment of gastric motility on visit 2 (day 0 of the treatment phase). Mean gastric half-emptying times did not differ significantly between both groups [STW 5: 163 ± 59 min vs Placebo: 171 ± 138 min; P = 0.83 (mean ± SD)]. The same was observed with respect to the duration of the lag phase tlag (STW 5: 104 ± 38 min vs Placebo: 107 ± 56 min; P = 0.81) and the GEC (STW 5: 2.97 ± 0.76 vs Placebo: 3.04 ± 0.629; P = 0.41).
Gastric half-emptying time was prolonged in 17/35 (48.6%) of patients in the STW 5 group and in 14/32 (43.8%) of the placebo group (STW 5: 208 ± 50 min and Placebo: 179 ± 28 min) with a tlag of 128 ± 32 and 120 ± 25 min respectively. The GEC in this subgroup was 2.54 ± 0.43 (STW 5) and 2.68 ± 0.55 (Placebo).
Among patients with initially prolonged gastric half-emptying times, 13/17 participants of the verum- and 9/14 in the placebo group underwent an additional 13C-OBT at the end of the treatment period (visit 3). Mean gastric half-emptying times (Fig. 1) had increased non-significantly in patients treated with STW 5 (+23 ± 109 min, P = 0.51) and slightly accelerated among patients in the placebo arm (−26 ± 51 min, P = 0.77). The differences in gastric emptying alterations under treatment between the verum and the placebo group were also not significant (P = 0.49). The tlag and the GEC had also remained roughly unchanged by the end of the treatment period (17 ± 71 vs 7 ± 35 min, P = 0.70 and 0.03 ± 0.51 vs 0.14 ± 0.37, P = 0.44).
Though the GIS score decreased both under verum and placebo treatment, In STW 5-treated patients, the GIS score (mean ± SD) decreased from 11.6 ± 4.4 to 5.0 ± 4.3, while placebo-treated patients showed a decrease from 12.0 ± 4.7 to 7.5 ± 6.6. This improvement was more pronounced in the STW 5 group (6.5 ± 4.6) than in the control group (4.6 ± 5.5). The appropriate statistical analysis model [analysis of covariance (ancova) including the factors treatment centre and covariate: baseline] showed a statistically significant difference of 2.2 points between the groups in favour of STW 5 (P = 0.03). An improvement of 40% or more of the GIS score was observed in 33/44 (75%) of patients treated with STW 5 and 23/42 (54.8%) patients treated with placebo (P = 0.03). Accordingly, the percentage improvement in the GIS score was 55.3 ± 35.0 (STW 5) and 39.8 ± 42.9 (Placebo) respectively (P = 0.06).
Patients with dysmotility-like dyspepsia profited most from STW 5 and reported a decrease in the GIS score of −7.8 ± 4.4 (vs−4.7 ± 6.7 in the placebo group). The corresponding values for patients with ulcer-like and non-specific dyspepsia were −4.5 ± 3.9 (placebo −5.1 ± 5.3) and −5.5 ± 5.0 (placebo −4.0 ± 3.4) respectively.
There occurred 17 adverse events during the study. Eight adverse events were observed in a possible or probable causal relationship to study medication (STW 5: three adverse events – stomatitis, abdominal pain and diarrhoea; placebo: five adverse events – rhinitis, diarrhoea, dyspepsia, vomiting and genitourinary tract infection). There were no clinically relevant changes in laboratory and vital parameters in both groups during study.
Global assessment of efficacy
Thirty-one patients (70.4%) and 32 physicians (72.7%) in the STW 5 group assessed the treatment efficacy as ‘very good’, ‘good’ or ‘moderate’. The corresponding proportions in the placebo group were 22 (52.4%) and 26 (61.9%) respectively. Logistic regression model analysis showed a trend for a better subjective efficacy of STW 5, but this did not reach statistical significance [P = 0.24 (for patients) and P = 0.15 (for physicians)].
The therapeutic efficacy of STW 5 for the relief of symptoms associated with FD has been thoroughly demonstrated in several trials.29–34 STW 5 showed equal efficacy to cisapride and in a retrospective cohort study a superior efficacy to metoclopramide.43 We were also able to demonstrate the superiority of STW 5 compared with placebo in the study outlined here. The drug consists of hydroethanolic extracts of nine plants and therapy is well-tolerated without relevant adverse effects. Though the clinical effects of STW 5 have been well documented, the pathophysiological mechanisms of the therapeutic effects are still not fully elucidated.
In vitro studies of gastric motility have shown that ethanol-free lyophilisates of STW 5 exert pleiotropic effects on the muscles of different gastric regions.35,36 Remarkably, the individual components produce differential effects on the myogenic action of the proximal and the distal stomach, i.e. that calcium-mediated actions of the constituents can be converse between the fundic and the antral region. FD has been shown to be associated with an impairment of gastric accommodation in the fundus and antral hypomotility. Consequently, STW 5 seems to improve gastric dysmotility by a relaxation of the proximal stomach and an enhancement of antral motility. An additional effect may result from a modulation of visceral nociceptive stimuli.
Data on the motility-modulating effects of STW 5 in vivo are scarce. A recently published study on a limited number of healthy men confirmed that the substance increased proximal gastric volume, a surrogate marker for gastric accommodation.37 Furthermore, antral motility improved after the oral ingestion of STW 5. Gastric emptying of liquids increased to some extent, whereas the retention of a solid meal remained unaffected.
The study design of the current trial was planned before the above mentioned results regarding the effects of STW 5 on gastric motility were available. We aimed to determine whether the substance exerts its clinical effects by an enhancement of gastric emptying. The study focused on the emptying kinetics of solid meals in FD patients with idiopathic gastroparesis, because gastric processing of solids is more complex than of fluids; therefore, gastroparesis and tachygastry primarily affect gastric emptying of solids in the majority of cases. However, our study failed to show a substantial impact of STW 5 on gastroparesis. In contrast, there was a tendency for a prolongation of gastric emptying in patients treated with STW 5, although symptoms of FD were significantly improved. How can these results be explained?
Numerous studies have shown that delayed gastric emptying is present in about 20–60% of patients with FD.44–47 This proportion is in accordance with our study that showed a prevalence of gastroparesis in approximately 45% of patients. Subjective symptoms do not quite correlate with the degree of gastroparesis, though FD-patients with severe fullness and vomiting are more likely to suffer from gastroparesis.48 Gastric accommodation – the adequate relaxation of the fundus region following the ingestion of a meal, thereby preserving a constant intragastric pressure – is impaired in about 40% of patients suffering from FD.25 5-HT1 agonists have been deemed a promising class of drugs that modulate intestinal motility by improving gastric accommodation.49 On the other hand, the 5-HT4-agonist cisapride as well as the well-known dopamine D2-receptor antagonists metoclopramide and domperidone are also better than placebo.50–59
In the study presented here, gastroparesis did not correlate with clinical symptoms, as defined in the ‘GIS score’. For this reason, acceleration of gastric emptying does not seem to be the central mechanism of action that mediates the clinical effects of STW 5. Pilichiewicz et al.37 demonstrated that STW 5 did not affect the gastric emptying of solids in eight healthy controls. We can confirm these findings for patients with FD and gastroparesis. A drawback of our study is a lack of information on patients with normal or enhanced gastric emptying. Therefore, we are not able to provide further details on the effects of STW 5 in these subgroups beyond clinical efficacy data. Generally, gastroparesis appears of minor importance in FD: erythromycin, a strong motilin receptor agonist, greatly enhanced gastric emptying, but failed to improve symptoms in patients with FD.60
We conclude that STW 5 has the potential to produce symptomatic relief in patients with FD. In our study, this effect did not seem to be correlated to an acceleration of gastric emptying, whereas it is questionable if the velocity of gastric emptying is correlated to the symptoms of FD. In this context, differential effects of STW 5 on gastric accommodation and visceral hypersensitivity seem to be more important and need to be further investigated by future pathophysiological studies.
Conflict of interest disclosure
Dr Vinson is an employee of the Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany. The other authors (B.B., W.C., N.B., A.S.) do not have conflicts of interest to declare.
List of recruiting german centres and corresponding primary investigators:
W. Caspary, Frankfurt; N. Börner, Mainz; A. Rambow, Frankfurt; J. Schattenberg, Wiesbaden, M. Schöfer, Langen; K. Metz, Aschaffenburg; P. Berg, Darmstadt; A. Hackelsberger, Wiesbaden; Frieling, Krefeld; M. Singer, Mannheim; J. F. Riemann, Ludwigshafen; G. Holtmann, Essen; A. Madisch, Dresden; P. Malfertheiner, Magdeburg; R. Raedsch, Wiesbaden.