To assess the efficacy and safety of enteric coated capsules containing a fixed combination of 90 mg peppermint oil and 50 mg caraway oil (PCC; Enteroplant) in patients with functional dyspepsia.
To assess the efficacy and safety of enteric coated capsules containing a fixed combination of 90 mg peppermint oil and 50 mg caraway oil (PCC; Enteroplant) in patients with functional dyspepsia.
A total of 96 out-patients received one capsule twice daily of PCC or placebo for 28 days. Primary efficacy variables were the intra-individual change in (i) pain intensity and (ii) sensation of pressure, heaviness and fullness between days 1 and 29, and the investigators’ rating of (iii) global improvement (Clinical Global Impressions [CGI] item 2) on day 29. A global type I error of α=0.05 was controlled by a priori ordering of hypotheses.
All patients were evaluable for efficacy and safety. On day 29, the average intensity of pain was reduced by 40% vs. baseline in the PCC group and by 22% in the placebo group. With regards to pressure, heaviness and fullness, a 43% reduction was observed for PCC vs. 22% for placebo. In CGI item 2, 67% (PCC) vs. 21% (placebo) of the patients were described as much or very much improved. In all three target parameters, the superiority of PCC over placebo was statistically significant. Six patients (PCC: 5; placebo: 1) reported adverse events, either unrelated to the trial, or attributable to an aggravation of the disease under investigation. Eructation with peppermint taste did not occur.
These results demonstrate the good tolerability and the favourable risk–benefit ratio of PCC for the treatment of functional dyspepsia.
According to recent epidemiological data, approximately 25–30% of the population of the Federal Republic of Germany are suffering from chronic, recurrent gastrointestinal complaints. It is estimated that about one-quarter of the affected individuals consult a physician for professional aid.1 At least 60% of these patients do not show any organ pathology, but have symptoms that are of functional origin, with functional dyspepsia, irritable bowel syndrome, or both. The annual costs of functional gastrointestinal diseases are estimated as approximately US $3.8 billion to the health insurance companies in Germany alone. On top of that are the costs for over-the-counter medication, loss of working hours, etc.
Functional dyspepsia (non-ulcer dyspepsia) is a motility disturbance characterized by postprandial sensations of fullness, non-acid eructation, dysphagia, nausea and vomiting, epigastric pain, heartburn and premature feelings of repleteness, without a discernible organic cause. Pharmacological treatment for functional dyspepsia includes synthetic gastroprokinetics which primarily aim at increasing the motility function (e.g. metoclopramide, domperidone, cisapride), but also angiotensin and antagonists of gastrointestinal hormones, acid-reducing drugs, or bismuth preparations.2 Additionally, phytomedical drugs, which often show a broader pharmacological spectrum and better tolerability than synthetic drugs, have a long tradition in the treatment of functional gastrointestinal diseases.3–5
In Germany, the Federal Institute for Drugs and Medical Devices’ expert working party on phytopharmacological drugs has issued positive risk–benefit assessments of over 30 herbal extracts for the indication ‘dyspepsia’. These include peppermint oil and caraway oil, whose pharmacological effects, clinical efficacy, and tolerability have been investigated as single agents or as a combination of both in several studies.1, 6–13 Due to its calcium-antagonistic properties, the activity of peppermint oil is primarily spasmolytic.14 Caraway oil shows antimeteoric and choleretic effects and increases the muscular tone. Positive monographs of the German regulatory authorities have been available for several years for caraway oil, peppermint oil, and for combinations of both.15–17 Due to the great variety of symptoms associated with functional dyspepsia, a combination of the two ethereal oils appears to be particularly appealing, as their action principles can be expected to show a synergistic effect. The efficacy and excellent tolerability of a fixed combination of 90 mg peppermint oil and 50 mg caraway oil (PCC) has already been demonstrated in four clinical trials.8–10, 18
This study aimed to investigate the therapeutic efficacy and safety of the fixed peppermint oil/caraway oil combination PCC vs. placebo, at a dosage lower than the one used in our former study.9 By therapeutic efficacy we understand the ability of the preparation to bring about symptom relief in patients suffering from functional dyspepsia. The study was approved by the appropriate Independent Ethics Committee. Legal and ethical requirements and current scientific standards (German Drug Law, European Good Clinical Practice guidelines, Declaration of Helsinki) were adhered to. Our study hypotheses for confirmatory testing predicted that patients receiving PCC would: (i) show a larger reduction of the intensity of pain as well as (ii) a larger decrease vs. baseline in the intensity of sensations of pressure, heaviness and fullness; and (iii) display a more favourable global improvement (as measured with CGI: Clinical Global Impressions item 2) than those treated with placebo.19 Note that in the CGI, smaller numbers denote a more favourable change in the patient’s condition.
The present investigation was conducted as a double-blind, randomized, parallel group evaluation of enteric coated capsules containing 90 mg peppermint oil and 50 mg caraway oil per capsule (PCC) vs. placebo. According to the protocol, approximately 60 out-patients without relevant protocol deviations (30 in each treatment group) were to be included into the trial until performance of a planned adaptive interim analysis.18 The interim analysis was actually conducted after 96 patients (48 in each treatment group, 79 patients without relevant protocol deviations) had completed the trial. All 96 study participants were evaluable for efficacy according to intention-to-treat.
Eligible patients had to be at least 18 years of age and were required to have a secured diagnosis of functional dyspepsia (diffuse, unspecific, variable, moderately intense epigastric pain with at least four points on the visual analogue scale, at least one additional dyspeptic key symptom, organ pathology excluded by in-depth clinical examination sonography and oesophago-gastro-duodenoscopy), with a current episode lasting for at least 14 days. Major specific exclusion criteria were: severe organic disorders, disorders that could cause gastrointestinal symptoms, severe functional disorders other than dyspepsia, severe diarrhoea, inability to discontinue concomitant medication that could be expected to interact with the assessment of the study’s outcome variables (e.g. prokinetics, agonists and antagonists of gastric hormones, acid-reducing drugs, bismuth preparations, sedatives, laxatives, non-steroidal antiphlogistics), history of major gastrointestinal surgery, presence of gastrointestinal ‘alarm symptoms’ pointing to a malignoma, ulcer, reflux oesophagitis, or reflux dyspepsia.
After receiving the patients’ written informed consent, screening examinations during a period of up to 7 days before baseline assessment were performed, during which no trial-specific medication was administered. Individuals who had been receiving a drug prohibited by the study protocol observed an adequate washout period. Patients who complied with the inclusion and exclusion criteria were then randomized to one of two treatment groups: (a) 2 × 1 enteric coated capsule PCC per day (one in the morning, one at lunch time), each containing 90 mg peppermint oil and 50 mg caraway oil; (b) 2 × 1 capsule containing placebo. The study drugs were identical in all aspects of their appearance.
A computer-generated randomization procedure in blocks of four was used. According to the protocol, eligible patients in each centre were to be randomly assigned to one of the two treatment groups on study day 1, in accordance with the order of their patient numbers. The randomization schedule was known only to the sponsor’s packaging unit. Treatment allocation was concealed from all investigators, but in case of an emergency the investigators had access to sealed envelopes containing the treatment code.
After being randomized, the patients underwent 4 weeks of double-blind treatment, with an intermediate visit on day 15 and final evaluation on day 29.2 Efficacy was assessed at all visits by obtaining the patients’ ratings of intensity of gastric pain and sensations of pressure, heaviness and fullness with a standardized self-rating questionnaire using continuous 10 cm visual analogue scales (VAS; 0=absent to 10=maximum intensity). In addition, the investigators filled in CGI item 2 (global improvement, days 15 and 29 only), which yields values between 1 (‘very much improved’) and 7 (‘very much worse’). As a secondary efficacy variable, the patients recorded the frequency of pain on a visual analogue scale of the type described above and the investigators assessed their condition on CGI items 1 (severity of illness; 1=‘not at all ill, … 7=‘among the most extremely ill patients’) and 3 (therapeutic effect). In addition, a Dyspeptic Discomfort Score (DDS) according to Madisch et al. was computed, which integrates the results of various parameters from the areas of dyspeptic symptoms, intestinal symptoms and vegetative symptoms and may take on values between 0 (minimum impairment) and 84 (maximum impairment).18 All investigators were familiarized with the protocol and in the application of the diagnostic criteria and ratings.
For safety assessment, adverse events were documented at all visits starting on day 1, after general and specific patient questioning. Blood samples were taken for routine haematology and biochemistry screens (haemoglobin, haematocrit, leucocytes, erythrocytes, platelets, thromboplastin time, ESR, ALT, γ-GT, serum creatinine) during screening and on day 29, and vital signs were recorded. Compliance was monitored by pill counting and by questioning the patients at the treatment end.
The primary efficacy variables were the absolute intra-individual change in the patients’ ratings of (i) pain intensity and (ii) sensation of pressure, heaviness and fullness between days 1 and 29; and the investigators’ rating of (iii) global improvement according to CGI item 2 on day 29. The last observations of patients withdrawn from the trial prematurely were carried forward. This included the baseline value in the event that no data were available after the start of randomized treatment. For patients who were withdrawn from the trial because of symptom aggravation, the visual analogue scales of the primary target parameters were set to the worst possible outcome (10 points). The over-all type I error rate was α=0.05 (one-tailed), which implied a nominal level of α1=0.0299 for the assessment of statistical significance in the interim analysis.20, 21 The three study hypotheses for confirmatory testing are specified in the introduction; a multiple level of α=0.05 was controlled by a priori ordering of these hypotheses in the specified sequence (i)–(iii) and application of the corresponding testing procedure, so that type I error level adjustment was not required despite multiple testing.22 All additional analyses were purely descriptive. The primary evaluation method laid down in the protocol was an intention-to-treat analysis. In addition, a per protocol analysis was performed. Unless explicitly specified otherwise, the following section shows the results of the intention-to-treat analysis.
The study was conducted in seven centres in Germany, from September 1997 until May 1998. The planned interim analysis was performed after 97 patients had been included into the trial. Ninety-six patients were randomized and were evaluable according to the intention-to-treat principle, resulting in a sample size of 2 × 48 individuals for PCC and placebo, respectively. One additional study participant discontinued trial participation before the first administration of the study drug, due to violation of an exclusion criterion. The evaluable patients’ relevant pre-treatment characteristics are presented in Table 1. Seventeen patients (PCC, 10; placebo, 7) showed major protocol violations, the most frequent of which were the use of disallowed concomitant medication and failure to complete the study period as scheduled. In total, 79 patients could be included into the per protocol analysis (PCC, 38; placebo, 41), including those two patients who were withdrawn because of symptom aggravation. With regard to all relevant baseline characteristics, the two treatment groups were essentially comparable (refer to Table 1).
Between pre-treatment and study day 29, the average intensity of pain in patients receiving PCC decreased by 2.60 ± 2.44 points (mean ± s.d.), or 40% of the initial mean level of 6.50 ± 1.40 points, whilst the placebo group showed a pain intensity reduction of 1.46 ± 1.77 points, or 22% of the pre-treatment level of 6.71 ± 1.13 points. The reduction in pain intensity was thus almost twice as large under PCC (Figure 1).
In the exact, one-sided U-test, a P-value of 0.0003 was determined for the between-groups difference regarding the change between baseline and day 29 in the intensity of pain. The first null hypothesis was therefore rejected at a nominal level of α1=0.0299.
The time courses for the second primary outcome variable, sensation of pressure, heaviness and fullness (Figure 2), were comparable to those obtained for intensity of pain. For PCC, the intensity of the patients’ impairment decreased by 2.79 ± 2.63 points, or 43.5% of the initial mean level of 6.42 ± 1.47 points during the 4-week treatment. For placebo, on the other hand, an intensity reduction of 1.46 ± 2.17 points, or 22.3% of the pre-treatment level of 6.54 ± 1.15 points, was determined. The treatment group difference for this parameter was associated with an exact, one-tailed U-test P-value of 0.0005, whereby the second null hypothesis was also rejected at the nominal significance level α1.
With regard to the patients’ global improvement (CGI item 2) at day 29, the patients in the PCC group showed a median rating of 2 (‘much improved’; 95% CI: 1.74, 2.26), compared to a median of 3 (‘minimally improved’; 95% CI: 2.74, 3.26) in the placebo group (Figure 3). Whilst almost 46% (22 of 48) of the patients under placebo presented an end-of-treatment status which was unchanged from their pre-treatment condition, more than 91% (44 of 48) of the patients under PCC were at least minimally improved, with two-thirds (32 out of 48) in this group much or very much improved. For placebo, these two most favourable ratings were obtained for 20.9% (10 of 48) of the patients. The large-scale differences in favour of PCC were reflected in a very small one-sided, exact U-test P-value of 0.00005. The third null hypothesis was therefore rejected at the nominal significance level as well.
For all three primary target parameters, descriptive, one-sided P-values in favour of PCC could already be found on day 15 (Pi=0.0018, Pii=0.0031 and Piii=0.00005).
The intention-to-treat results were confirmed in the per protocol analysis, where all three primary target parameters showed comparable results. For the per protocol sample, the one-sided U-test P-values for hypotheses (i), (ii) and (iii) were: Pi=0.0015, Pii=0.0035 and Piii=0.00005 in favour of PCC, respectively, with descriptive P-values of Pi=0.0012, Pii=0.0048 and Piii=0.00005 for day 15. Since the null hypotheses for all three confirmatory efficacy parameters were rejected in the interim analysis, the study had reached its primary aim and could be completed early.
The results from the secondary efficacy parameters support the findings from the three primary variables in full. Between day 0 and day 29, the frequency of pain decreased by 2.58 points in the PCC group compared with 1.50 points in the placebo group (descriptive, one-sided associated exact U-test: P=0.0011). The groups’ means (± s.d.) regarding the patients’ severity of illness (CGI item 1) decreased from 4.17 (± 0.60) at baseline to 2.96 (± 1.07) at day 29 for PCC, and from 4.25 (± 0.53) to 3.75 (± 0.84) for placebo (one-sided exact U-test: P=0.0008). At day 29, PCC was evaluated to be at least minimally effective in 93.7% of the patients (45 out of 48), very effective in 31.3% (15 out of 48), and as not effective in 6.3% (3 out of 48), compared with 54.2% (26 out of 48), 10.4% (5 out of 48), and 43.8% (21 out of 48), respectively, for placebo (one-sided exact U-test: P=0.00005). The average decrease in the Dyspeptic Discomfort Score (DDS) was almost twice as large in the PCC group compared with the placebo group (one-sided exact U-test: P=0.0005).
During double-blind treatment, adverse events were observed in five (10.4%) patients under PCC and in one (2.1%) under placebo. All events were reported only once. In the placebo group, one patient complained about pain in the neck and shoulder. In the PCC group, three of the events, haemorrhoids, bronchitis and influenza-like symptoms, were evidently caused by circumstances unrelated to the study drug. In the remaining two events, mild eructation and severe, recurrent nausea and vomiting (accompanied by gastric pain), were assessed as unlikely to have a causal relationship with the study drug. In both cases, the symptoms were interpreted as an aggravation of the disease under investigation rather than to be sequels of the administration of PCC, since the patients had reported the same type of complaints already, before being included into the trial. From a drug safety point of view, all adverse events were unexpected and non-serious.
The data presented here were compiled from an evaluation which was originally intended to be an interim analysis. However, the results were so convincing that early rejection of all three null hypotheses was achieved and the trial was terminated successfully. In all parameters assessed for efficacy, the fixed combination of 90 mg peppermint oil and 50 mg caraway oil was superior to placebo. For the three primary parameters (intensity of pain, sensation of pressure, heaviness and fullness, and global improvement [CGI item 2]), the treatment group differences were both statistically significant and clinically relevant. These findings underline the spasmolytic and antimeteoric effect of this herbal combination.
Functional disturbances, which are primarily psychophysiological in nature, generally have a particularly strong subjective component and can hardly be assessed on the basis of ‘hard’, objective data like laboratory parameters. It should therefore be stressed that the parameters assessed here included patient self-ratings as well as investigators’ ratings, indicating that the beneficial treatment effect was obvious to the patient and to his or her physician alike. The results are particularly impressive when considering the large placebo response rate that is usually to be expected for this diagnosis.23 In this trial, the changes from the pre-treatment status in the key parameters after 4 weeks were approximately twice as large under PCC than after placebo administration, and over 90% of the patients treated with PCC showed a notable amelioration of symptoms.
This study supports our earlier findings, which were the first published clinical trial data for a comparison between PCC and placebo, in which we were able to demonstrate superiority of PCC regarding intensity of pain and global improvement (CGI item 2).9 In contrast to the present study, we had used 3 × 1 capsules per day with comparable effects.9 We therefore conclude that 2 × 1 capsules per day PCC may suffice to bring about the desired symptom relief in the vast majority of patients, whilst promoting a good treatment compliance by twice-daily administration. These findings are supported by the results reported by Madisch et al.18
As in the preceding study, eructation with peppermint taste, which was reported quite frequently in earlier trials, was not observed.8 The absence of this reaction can be attributed to the use of an enteric coated capsule. It is also noteworthy that the patients receiving PCC did not experience any side-effects. Our results therefore demonstrate the very good tolerability of PCC and emphasize the favourable risk–benefit ratio of the preparation. It can therefore be recommended for the treatment of functional dyspepsia.
This study was supported by Dr Willnar Schwabe Pharmaceuticals, Karlsruhe, and Spitzner Pharmaceuticals, Ettlingen, Germany.
Marketed in Germany under the trade name Enteroplant by Dr Willmar Schwabe Pharmaceuticals, Karlsruhe, and Spitzner Pharmaceuticals, Ettlingen.
The patients were offered the opportunity to participate in an 11-month, open-label follow-up. After completion of the evaluation, the results will be reported elsewhere.