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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References

Background:

Prokinetic agents have shown variable efficacy in the treatment of functional dyspepsia. Mosapride is a new prokinetic 5-hydroxytryptamine-4 agonistic agent.

Aim:

To evaluate the efficacy of three dosage regimens of mosapride compared with placebo in the treatment of functional dyspepsia.

Methods:

Patients were randomly allocated to treatment with placebo or mosapride (5 mg b.d., 10 mg b.d. or 7.5 mg t.d.s.) in a double-blind, prospective, multicentre, multinational study. The change in symptom severity score from an untreated baseline week to the sixth week of treatment was used to compare treatment efficacy.

Results:

There were 141, 140, 143 and 142 patients valid for evaluation in the intention-to-treat population in the placebo, mosapride 5 mg b.d., mosapride 10 mg b.d. and mosapride 7.5 mg t.d.s. groups, respectively. The mean changes in the overall dyspeptic symptom score were – 0.90, – 0.94, – 0.88 and – 0.89, respectively, and the proportions of patients feeling better at the end of the treatment period were 60%, 59%, 59% and 61%, respectively. No statistically significant difference was seen.

Conclusions:

Treatment of functional dyspepsia with mosapride was not superior to placebo. The result raises the question of whether treatment with prokinetic agents is appropriate for functional dyspepsia.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References

Persistent or recurrent pain or discomfort centred in the upper abdomen is a common cause of complaint. Discomfort is a term used to describe a subjective, negative feeling that the patient does not interpret as pain, which can include upper abdominal fullness, early satiety, bloating, nausea, belching and vomiting.1 The prevalence varies from 25% to 40% in Western countries,1, 2 and the cause of these symptoms may vary considerably. If structural abnormalities, such as peptic ulcer, oesophagitis or gallstones, can be excluded by the use of upper endoscopy and abdominal ultrasound, the syndrome may be defined as functional dyspepsia.1 However, several other syndromes may have an overlapping symptomatology. Patients with heartburn and/or regurgitation as the predominant symptom, with or without endoscopic findings, should not be classified as having functional dyspepsia because, by definition, they most often have gastro-oesophageal reflux disease.3 In addition, individuals with symptoms of irritable bowel syndrome, such as pain or discomfort related to bowel pattern, are not considered as having functional dyspepsia.1, 3

The aetiology and pathophysiology of functional dyspepsia are unclear.4–7 It is assumed to involve heterogeneous pathophysiological mechanisms, such as gastrointestinal motor and secretion dysfunction, visceral perception alterations, psychosocial factors and Helicobacter pylori infection,4, 5, 8–14 but the role of these factors is still unknown. Delayed gastric emptying and disturbed intestinal motility have been proposed to be of importance in many cases.13, 15–20 Clinical studies have demonstrated the beneficial effect of promotility drugs, such as cisapride and domperidone,3, 21–24 but negative results have also been published.22, 25–30

Mosapride is a novel 5-hydroxytryptamine-4 (5-HT4) agonistic compound, and its primary metabolite, M1, has 5-HT4 agonistic as well as 5-HT3 antagonistic properties. Mosapride has prokinetic effects similar to cisapride,31–35 and has demonstrated a dose-dependent effect in reducing upper abdominal symptoms related to functional dyspepsia.36

The primary aim of this study was to compare the effect of three dosage regimens of mosapride with placebo for the relief of overall dyspeptic symptoms from an untreated baseline week to the sixth week of treatment in patients seeking medical attention due to symptoms and findings in accordance with functional dyspepsia.

Secondary aims were to compare mosapride and placebo with regard to the change in severity of specific functional dyspepsia symptoms, i.e. upper abdominal pain, bloating, post-prandial fullness, early satiety, belching, nausea and vomiting.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References

This was an international, multicentre study conducted in Denmark, Germany, France, Sweden and the UK.

Patients

Primary care patients, aged 18–75 years, with a history of at least 3 months of persistent or recurrent symptoms of pain and/or discomfort (i.e. bloating, post-prandial fullness, early satiety, belching, nausea and vomiting), centred in the upper abdomen, were eligible to participate in the study if upper endoscopy and abdominal ultrasonography revealed no abnormalities that could be the cause of the symptoms. If the patient's most troublesome symptoms were heartburn and/or regurgitation, indicating gastro-oesophageal reflux disease, or if the predominant symptoms were those of irritable bowel syndrome, the patient was not included in the study. Previous abdominal surgery, other than appendectomy or surgery on the gynaecological tract, was not permitted. Patients with any symptom indicating serious or malignant disease were not eligible to participate in the study. Other exclusion criteria included any other chronic disease, drug or alcohol abuse, pregnancy, lactation or the need for an interpreter. The body mass index (BMI=weight (kg)/height (m)2) was in the range 19–31 kg/m2. Significant intake of any anti-ulcer medication, antacids, prokinetics, prostaglandins, NSAIDs or antispasmodics was not allowed for 4 weeks preceding the upper endoscopy investigation, before inclusion and during the study.

Study design

A randomized, double-blind, double-dummy design with four parallel treatment groups was used. All patients should have undergone upper endoscopy 7 days to 1 year before the first visit, and abdominal ultrasonography 7 days to 18 months before the first visit. The patients should have received the information that no pathological findings could be seen in these investigations at least 1 week before the first visit.

First visit.

At the first visit, the patient was interviewed about his/her symptoms and medical history. To be eligible for inclusion, the patient should have had overall dyspeptic symptoms of at least mild severity (on a four-grade scale) for at least 3 days during the week before the first visit. One of the following symptoms was registered as the most troublesome: upper abdominal pain, bloating, post-prandial fullness, early satiety, belching, nausea or vomiting. A physical examination, urea breath test for the determination of Helicobacter pylori infection and a laboratory screen were performed. The patient was randomized to one of the four treatment groups. A diary was given to the patient who was instructed to register the severity of his/her overall dyspeptic symptoms and specific symptoms (i.e. upper abdominal pain, bloating, post-prandial fullness, early satiety, belching, nausea and vomiting) during a treatment-free baseline week, starting on the day of the first visit. During this week, no medication was permitted.

Second visit and treatment dosage regimens. Seven days after the first visit the patient visited the clinic in order to return and review the diary and to collect the study drug and a new diary. In accordance with the randomization performed at the first visit, the patient was allocated to a 6-week treatment period with one of the following regimens: placebo, mosapride 5 mg b.d., mosapride 10 mg b.d. or mosapride 7.5 mg t.d.s. The patient was instructed to continue to register his/her overall dyspeptic symptoms daily in the diary during the treatment period. In addition, during the sixth treatment week, the patient was asked to register his/her specific symptoms in the diary. Two days before the start of the sixth treatment week the investigational staff contacted the patient.

Third visit.

At the third visit, after 6 weeks of treatment, the patient was asked about his/her symptoms and satisfaction with the treatment. The physical examination and laboratory screen were repeated and the patient was asked about any adverse events. The diary and any remaining study drug were collected.

Efficacy variables

The primary efficacy variable was the change in the severity of the overall dyspeptic symptom score (mean) from the untreated baseline week to the sixth week of treatment, as assessed by the records in the diaries. The patient registered his/her symptom severity daily using the following seven-grade Likert-type scale: 0, no symptoms; 1, minor symptoms; 2, mild symptoms; 3, moderate symptoms; 4, quite severe symptoms; 5, severe symptoms; 6, very severe symptoms.

In addition, during the baseline week and the sixth week of treatment, the patient recorded the severity of each of the following specific dyspeptic symptoms: upper abdominal pain, bloating, post-prandial fullness, early satiety, belching, nausea and vomiting. The severity of these symptoms was also classified according to the scale given above.

At the third visit, the investigator also asked the patient to answer `Yes' (a little or much better) or `No' (worse or unchanged) to the question: `Have your symptoms improved since you started your medication?'.

Statistics

The change in mean diary score for the overall and specific dyspeptic symptoms was calculated as the difference between the mean value of the severity recorded during the sixth week of treatment and the mean value of the severity recorded during the baseline week.

The change in severity of the overall dyspeptic symptoms between the baseline week and the sixth week of treatment, i.e. the primary variable, was analysed in a linear model, using an analysis of covariance (ANCOVA), with treatment and country as factors and the mean diary score for the baseline week as a covariate. The three doses of mosapride, 5 mg b.d., 10 mg b.d. and 7.5 mg t.d.s., were compared to placebo. To adjust for the three primary comparisons, the tests were performed using a significance level of 1.7%. The results are presented in terms of the estimated difference between each of the three mosapride doses and placebo, together with the 98.3% confidence interval for the difference and the P value from the corresponding test.

The difference in the change in severity of specific dyspeptic symptoms between the three mosapride doses and placebo was analysed in the same way.

Both intention-to-treat and per protocol analyses were performed for the primary variable. For the change in each of the specific symptoms, intention-to-treat analyses were performed.

The proportions of patients whose symptoms were worse, unchanged, a little better or much better at the third visit were analysed using the Kruskal–Wallis test.

Determination of study sample size

With 125 patients per group, it would be possible to detect a true mean difference of 0.5 between each mosapride group and the placebo group in the change in the mean score of the overall dyspeptic symptom severity from the baseline week to the sixth week with a power of 80%. The calculation was based on an expected standard deviation of 1.20, and the significance level was set to 1.7% to adjust for three primary comparisons.

Compliance

Tablet count was used to measure and document treatment compliance. Treatment compliance was defined as the percentage of used tablets. A treatment compliance of at least 75% was considered to be acceptable.

Adverse events

An adverse event was defined as any unfavourable or unintended sign, whether or not considered to be causally related to the study drug, and was recorded in the Case Record Form. At the third visit, the patients answered the standardized question: `Have you had any health problems since you started to take the study drug'.

Ethics

The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice and applicable regulatory requirements.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References

Six hundred and six patients were randomized into the study. Of these, 30 were from one centre in Denmark, 82 were from 15 centres in France, 97 were from nine centres in Germany, 187 were from 19 centres in Sweden and 210 were from 35 centres in the UK. Four hundred and seventy-seven patients completed the study. The reasons for withdrawal are given in Table 1.

Table 1.  . Reasons for withdrawal per treatment group among 606 patients with functional dyspepsia randomized to receive placebo, mosapride 5 mg b.d., mosapride 10 mg b.d. or mosapride 7.5 mg t.d.s. Thumbnail image of

The intention-to-treat population included 566 patients. Of these, 141 were randomized to receive placebo, 140 to receive mosapride 5 mg b.d., 143 to receive mosapride 10 mg b.d. and 142 to receive mosapride 7.5 mg t.d.s. The baseline demographics and characteristics of the intention-to-treat population are summarized in Table 2. The treatment groups were well matched with regard to age, sex, race, BMI, H. pylori status and history of dyspepsia at entry. The treatment groups were also well matched with regard to the overall dyspeptic symptom severity at inclusion, with approximately 60% of patients in each group recording moderate symptoms. The distribution of the most troublesome symptom did not differ between the groups. Upper abdominal pain was registered at inclusion as the most troublesome symptom by 58%, 51%, 59% and 56% in the placebo, mosapride 5 mg b.d., mosapride 10 mg b.d. and mosapride 7.5 mg t.d.s. groups, respectively. Bloating, post-prandial fullness, early satiety, belching, nausea and vomiting were registered as the most troublesome symptoms by similar proportions of patients in all groups.

Table 2.  . Patient characteristics at randomization among 566 patients (intention-to-treat population) with functional dyspepsia randomized to receive placebo, mosapride 5 mg b.d., mosapride 10 mg b.d. or mosapride 7.5 mg t.d.s. Thumbnail image of

The per protocol population included 356 patients: 98, 87, 88 and 83 in the placebo, mosapride 5 mg b.d., mosapride 10 mg b.d. and mosapride 7.5 mg t.d.s. groups, respectively.

The analysis of the primary efficacy variable was made on the basis of both the intention-to-treat and per protocol populations. The results were very consistent. In the following, the analyses are based on the intention-to-treat population.

Primary efficacy analysis

During the baseline, non-treatment week, the mean overall dyspeptic symptom severity scores were 2.72, 2.77, 2.73 and 2.76 in the placebo, mosapride 5 mg b.d., mosapride 10 mg b.d. and mosapride 7.5 mg t.d.s. groups, respectively.

The primary efficacy variable, the mean change in severity of the overall dyspeptic symptoms between the baseline period and the last week of treatment, showed a mean change of – 0.90 in the placebo group and − 0.94, – 0.88 and – 0.89 in the mosapride 5 mg b.d., mosapride 10 mg b.d. and mosapride 7.5 mg t.d.s. groups, respectively. Treatment comparisons for the three mosapride groups vs. placebo are shown in Table 3. No significant differences between the mosapride groups and the placebo group were found.

Table 3.  . Overall dyspeptic symptoms: estimated difference in change in mean diary severity score between the baseline week and the sixth week of the treatment period; estimate, 98.3% confidence interval and P value for the comparisons of mosapride 5 mg b.d., mosapride 10 mg b.d. and mosapride 7.5 mg t.d.s. vs. placebo (intention-to-treat population) Thumbnail image of

Secondary efficacy analysis

Specific dyspeptic symptoms.

The three dosage regimens of mosapride were compared with placebo with regard to the change in severity of specific dyspeptic symptoms from the untreated baseline week to the sixth week of treatment. In comparison with placebo, none of the mosapride treatments showed any statistical difference in the change in severity of any of the dyspeptic symptoms.

Investigator's question — symptom improvement.

The result of the investigator's question, `Have your symptoms improved since you started your new medication?', is shown in Table 4. Approximately 60% in each study group reported improvement. No significant difference could be seen between any of the mosapride-treated groups and the placebo group.

Table 4.  . Summary of relief of dyspeptic symptoms based on the investigator's question to the patient (`Have your symptoms improved since you started your new medication?') at the end of the 6-week treatment period with mosapride 5 mg b.d., mosapride 10 mg b.d. and mosapride 7.5 mg t.d.s. (intention-to-treat population) Thumbnail image of

Change in symptom severity over time

Before breaking the treatment codes, it was decided to describe the change in overall dyspeptic symptoms in the three mosapride groups vs. placebo after 2 weeks of treatment. The change in the mean severity of dyspeptic symptoms, measured as the change from baseline to the second week of treatment, showed values of – 0.37 in the placebo group and – 0.51, – 0.34 and – 0.36 in the mosapride 5 mg b.d., mosapride 10 mg b.d. and mosapride 7.5 mg t.d.s. groups, respectively. The mean change in severity of overall symptoms was greater after 6 weeks of treatment than after 2 weeks for all study groups. No significant differences were found when comparing any of the mosapride groups with the placebo group.

Analysis of treatment efficacy by subgroups

Patients with upper abdominal pain as the most troublesome symptom at inclusion were exclusively analysed. When analysing this subgroup with respect to the change in mean overall symptom severity or mean specific symptom severity, no significant differences were noted when comparing each of the mosapride groups with the placebo group.

The same analysis was also made for those patients who did not register pain as their most troublesome symptom. No significant differences were seen when comparing the mosapride groups with the placebo group.

On analysis of the very small number of patients with severe overall symptoms at inclusion (registered as grade 4–6 on a scale of 0–6), there was a tendency for patients receiving mosapride 5 mg b.d. to note better symptom relief after 2 weeks than the other groups.

The prevalence of H. pylori infection was between 24 and 29% in the four groups and the H. pylori status did not influence the treatment outcome in any of the study groups.

Compliance

Eighty-five per cent of patients in the intention-to-treat population had acceptable compliance, and the compliance was similar for all treatment groups.

Adverse events

Slightly more adverse events were reported in the mosapride 10 mg b.d. group, and most patients withdrew from the study due to adverse events in the mosapride 10 mg b.d. and 7.5 mg t.d.s. groups. The distribution of patients noting adverse events and of patients who discontinued the study drug due to an adverse event was similar in all four groups. The most common adverse events were diarrhoea, abdominal pain, headache and nausea.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References

This study demonstrated no significant difference between mosapride 5 mg b.d., mosapride 10 mg b.d., mosapride 7.5 mg t.d.s. and placebo with regard to treatment efficacy in functional dyspepsia. In addition, when comparing the active treatment groups, no significant differences in treatment efficacy were seen. When comparing the change in mean overall symptom severity, based on the diary records, between the baseline non-treatment week and the sixth week of treatment, an improvement with a magnitude of about 0.9 on a scale from 0 to 6 was achieved in all study groups, including the placebo group. It has been demonstrated that the seven-grade Likert-type scale is valid and sensitive to changes in symptom severity, and that an effect size over 0.8 is considered to be a relevant effect for the patient.37 With regard to the investigator's question at the end of the treatment period, about 60% of the subjects in each of the treatment groups and the placebo group reported an improvement in symptoms. Our result thus confirms the importance of the placebo effect in functional dyspepsia.

When analysing the treatment effect on the specific symptoms of functional dyspepsia, i.e. upper abdominal pain, bloating, early satiety, post-prandial fullness, belching, nausea and vomiting, no significant differences were detected between the placebo and active treatment groups or between any of the active treatment groups.

The treatment groups were well matched with respect to the inclusion characteristics, most troublesome dyspeptic symptom and severity of dyspeptic symptoms at inclusion and during the baseline non-treatment week. This indicates that there are no confounding factors that might jeopardize the analysis of the study data.

It is well known that the placebo response in studies of functional dyspepsia can be high, exceeding 60%.24, 28, 38, 39 In this study, the placebo response was high when measured by the seven-grade Likert-type scale using a diary and by the investigator's question concerning symptom improvement. In many previous studies, the study population was selected from individuals not responding to placebo treatment. That method of selection may introduce bias and is now not recommended by the Committee on the Design of Treatment Trials for Functional Gastrointestinal Disorders.40

The patients selected are also often heterogeneous, and the outcome measure may differ substantially in studies of the treatment of functional dyspepsia. 24, 28, 38, 39

The selection of the study population and the methods for the measurement of the outcome in this study were in accordance with the Rome Criteria,3, 40 thereby making it possible to compare the results with other studies with the same selection criteria. The exclusion criteria for gastro-oesophageal reflux disease and irritable bowel syndrome are also in accordance with current recommendations, 3, 41 and will facilitate comparisons with trials in the future.

When studying the existing literature, it is interesting to note that studies demonstrating superior efficacy for prokinetic agents in the treatment of functional dyspepsia almost invariably report a low placebo response.21, 23, 24, 28, 42–51 On the other hand, in published studies where the placebo response is in the upper half of the reported response range, prokinetic drugs almost never show a superior efficacy.22, 25, 27–30 Thus, this poses two debatable questions: What is the true placebo response in primary care patients with functional dyspepsia?; Is prokinetic therapy beneficial and superior to placebo? These are important topics that demand further research with well-conducted studies using patient populations and outcome measures that have met consensus for this purpose.

It has been postulated that the placebo effect would be highest shortly after the start of treatment and would level off after some time.39, 52 This was not seen in this study. Instead, the response with regard to the change in the mean severity of overall dyspeptic symptoms was gradually enhanced during the treatment period in both the placebo and the active treatment groups. Therefore, the high placebo response cannot be explained by the study period being too short.

In a previous Japanese, non-placebo-controlled, parallel group, 2-week study of patients with gastrointestinal symptoms in accordance with symptoms of functional dyspepsia, treatment with daily doses of 1.5 mg, 7.5 mg and 15 mg mosapride citrate (corresponding to about 1 mg, 5 mg and 10 mg mosapride) showed a dose-related positive effect on symptom severity.36 The proportion of patients reporting symptom improvement in the Japanese study was between 50 and 76%. The result of our study is in agreement with that of Iyaku et al.,36 with improvement reported by about 60% of patients in all three active treatment groups. We could not, however, demonstrate any effect superior to placebo.

The positive trend in treatment efficacy for patients with severe symptoms at inclusion receiving mosapride 5 mg b.d. could be a chance observation, but might also indicate that prokinetic drugs could be of value in the subgroup of patients with severe symptomatology.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References

Six weeks of treatment with placebo and three different doses of the prokinetic drug mosapride in primary care patients with functional dyspepsia resulted in a reduction in overall dyspeptic symptom severity score of about 0.9, using a seven-grade symptom score scale, in all four treatment groups. Similarly, about 60% in all four treatment groups reported improvement in their overall dyspeptic symptoms. No statistical difference in treatment efficacy could be seen in any respect when comparing the mosapride treatment regimens with placebo. The study confirms the potent role of placebo in patients with functional dyspepsia.

Further studies are needed to elucidate the role of prokinetics in the treatment of functional dyspepsia. The authors' opinion, based on the data in this study and from a review of the literature, is that single-drug therapy with a prokinetic agent in primary care patients with symptoms of functional dyspepsia is questionable and is probably not superior to placebo.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References

The authors wish to express their sincere gratitude to the participating investigators and their staff at the different study centres.

We are also deeply grateful to the co-ordinators in each country: Uwe Schöning, Germany; Birgitta Sköld, Denmark; Elizabeth Lind, UK; Philippe Barthelemy, France; Malin Västernäs, Sweden; Agneta Dalväg, overall co-ordinator. Their enthusiastic work made it possible to conduct this study.

Astra Hässle AB, S-431 83 Mölndal, Sweden, supported this study.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENTS
  9. References
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