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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Summary

Aim

To investigate the efficacy and safety of renzapride, a potent 5-hydroxytryptamine type-4 receptor full agonist and 5-hydroxytryptamine type-3 receptor antagonist in patients with constipation-predominant irritable bowel syndrome.

Methods

In this dose-escalating pilot study, 17 patients with constipation-predominant irritable bowel syndrome received placebo, renzapride 2 mg o.d. and renzapride 2 mg b.d. sequentially for 28 days. Response was determined by radio-opaque marker measurement of overall gastrointestinal and segmental colonic transit and patients’ assessment of their irritable bowel syndrome symptoms.

Results

Renzapride reduced mean overall gastrointestinal transit time (placebo, 2.9 ± 1.6 days; renzapride 2 mg o.d., 2.6 ± 1.4 days; renzapride 2 mg b.d., 1.9 ± 1.6 days) (P = 0.024) and accelerated segmental colonic transit, with statistically significant differences for renzapride 2 mg b.d. over placebo in caecum/ascending colon (P = 0.019) and descending colon (P = 0.022). Renzapride also reduced abdominal pain, increased the number of pain-free days and improved stool consistency. The frequency of reported adverse events was similar on renzapride and placebo.

Conclusions

Renzapride is well-tolerated, stimulates gastrointestinal transit and improves symptoms in patients with constipation-predominant irritable bowel syndrome, particularly at the 2 mg b.d. dose, where improvements in gastrointestinal symptoms were evident over placebo. This study has established proof of concept and supports further investigation of renzapride in patients with constipation-predominant irritable bowel syndrome.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Irritable bowel syndrome (IBS) is the most common chronic gastrointestinal (GI) disorder in the community; studies around the globe have demonstrated a prevalence of between 10% and 20%.1–6 IBS is characterized by symptoms of abdominal pain or discomfort, bloating and disordered bowel habits, in the absence of organic disease that readily explains them. According to the Rome consensus, IBS is defined by the presence of abdominal discomfort or pain, which is associated with any two of the following features: pain relieved with defecation; onset of pain associated with a change in bowel habit; onset of pain associated with a change in form (appearance) of stool.2, 7–10 The aetiology and physiology of IBS is not fully understood, but is most likely to be multifactorial. Alterations in GI motility, visceral perception and psychosocial factors contribute to overall symptom expression.11

Currently, there are few therapeutic agents available that effectively treat the global symptoms associated with IBS. Treatment, therefore, focuses primarily on individual symptom patterns (i.e. constipation or diarrhoea) and associated biopsychosocial factors.12 Therapeutic recommendations have included the use of supplemental dietary fibre for constipation; opioids for diarrhoea; and, in patients with sustained pain or bloating, low doses of anti-depressants such as tricyclic agents and selective serotonin reuptake inhibitors.13 Limited efficacy and prominent side effects have restricted these therapeutic approaches for many patients with IBS.

Recent approaches to the treatment of IBS have focused, in particular, on modulation of the effects of 5-hydroxytryptamine (5-HT, serotonin). Serotonin is a key enteric neurotransmitter, with an important role both in visceral sensation and in the functions of the enteric nervous system, including secretion and motility, and there is strong evidence to suggest that approaches based on modulation of the 5-HT type-3 and type-4 receptors may significantly impact the symptoms of IBS.14–16 5-HT3 receptor antagonists slow colonic transit, decrease colonic sensitivity to distension and can be used therapeutically in diarrhoea-predominant IBS,17–21 while partial 5-HT4 receptor agonists promote peristaltic motility and may be effective in treating constipation-predominant IBS (c-IBS).22–25

Renzapride is a novel substituted benzamide with a unique pharmacological profile, possessing both 5-HT4 receptor full agonist26 and 5-HT3 receptor antagonist properties (Meyers NL, unpublished data).26, 27 Consequently, the beneficial effects of renzapride, which is currently in development for the treatment of patients with c-IBS,28–31 may extend to a wider range of IBS subtypes compared with a selective 5-HT4 receptor agonist alone. Furthermore, renzapride has negligible affinity for dopamine D1, D2 and D3 receptors, α1-adrenoceptors, the 5-HT2A receptor and the human ether-à-go-go-related gene (hERG) channel receptor (Meyers NL, unpublished data),32, 33 while in pre-clinical and clinical studies it has been shown to have no significant effect on prolactin levels (Meyers NL, unpublished data). These observations suggest an improved adverse event profile for renzapride compared with other benzamides. Importantly, renzapride is excreted via the renal route, primarily unchanged, and is not metabolized by cytochrome P450 enzymes, nor does it interfere with cytochrome P450 enzyme-mediated metabolism of other drugs (Meyers NL, unpublished data). This differentiates renzapride from another benzamide, cisapride, which was withdrawn from active marketing due to reports of QT/QTc prolongation and the development of serious cardiac dysrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes.34–37 This effect occurred, in part, as a result of the non-selective pharmacology of cisapride and its metabolism via cytochrome P450 enzymes.38In vitro studies have shown that renzapride is unlikely to induce cardiac dysrhythmia (Meyers NL, unpublished data).

We report here the results of the initial dose-escalating study designed to assess the safety and efficacy of renzapride in patients with c-IBS. This study was a small, pilot dose-finding study, which has since permitted selection of the doses for larger mechanistic studies in c-IBS patients.28–30

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patients

Patients between 18 and 65 years of age with a diagnosis of IBS at least 2 months prior to study entry were considered for enrolment. Diagnosis of IBS was made using the Rome diagnostic criteria,39, 40 modified to include only the constipatory subpopulation of IBS sufferers in the absence of organic GI disease. Patients included in the study had the following recurrent symptoms for at least 6 months: abdominal pain/discomfort with at least one of the following; pain relieved by defecation, associated with a change in stool frequency and/or a change in stool consistency. In addition, each patient had to experience at least two of the following symptoms for at least 25% of the time (i.e. 2 days/week): altered stool frequency (defined as <3 bowel movements per week); altered stool form (lumpy/hard); altered stool passage (straining, urgency or a feeling of incomplete evacuation); passage of mucus, bloating or a feeling of abdominal distension. Patients were excluded from the study if they had diarrhoea (defined as >3 bowel movements per day), if they were receiving any treatment for IBS, prokinetic drugs, drugs with known activity at 5-HT4 and/or 5-HT3 receptors, anti-spasmodics/prokinetics and/or laxatives (unless patients were willing to undergo a wash-out prior to enrolment) or drugs known to interact with cisapride. Women of child-bearing potential or who were pregnant or lactating were also excluded from this study.

Study design

This was a 14-week, multicentre, single-blind, placebo-controlled, sequential dose-escalating comparison study conducted at four centres in the UK and Belgium. After an initial 12-day screening phase (allowing for wash-out of any prohibited concomitant medications), patients received placebo b.d. for 4 weeks, followed by an active treatment phase, beginning with renzapride 2 mg o.d. for 4 weeks, increasing to 2 mg b.d. (4 mg/day) for a further 4 weeks. Patients had to satisfy clinical, cardiovascular, biochemical and somatic safety criteria prior to entering the active treatment phase and prior to dose escalation. Patients failing to satisfy all of these criteria were withdrawn from the study. Visits to the clinic for assessment were made during screening (visit 1), at the start of the placebo phase (day 0; visit 2) and every 14 days thereafter, with the final visit (visit 8) on day 84. Upon completion of treatment patients were followed-up for a further 7 days (14 days if the patient had an adverse event ongoing at visit 8 or if an adverse event occurred during the 7-day follow-up).

Both placebo and renzapride were taken orally in capsule form with food; one capsule in the morning and a matching capsule (placebo or active drug) in the evening. The interval between doses was approximately 12 hours.

Assessment of efficacy

The primary efficacy measure was the change from baseline (defined as GI motility at the end of the placebo phase, visit 4) in GI motility assessed using GI transit and segmental gut transit times. Overall GI transit times and segmental transit times were also obtained at visits 6 and 8 (the end of the renzapride 2 mg o.d. and 2 mg b.d. phases respectively). Overall GI transit and segmental gut transit times were measured using radio-opaque markers according to the method described by Abrahamsson et al.41 Patients ingested a capsule containing radio-opaque markers (rings) for 6 days preceding each assessment visit. The markers were visualized on plain abdominal radiographs and gut transit times calculated from the number of markers visualized and the number of markers ingested per day. Overall GI transit time was measured as the mean time to excrete 50% of the ingested doses of markers. Segmental transit time was calculated by dividing the number of markers present in a given segment by the total number of markers ingested per day, to give a measurement of transit time in days. An independent reviewer performed all transit time calculations. Additional radio-opaque markers (rods) were ingested the day before each of the three motility assessment visits. The distribution of these markers across the different segments of the colon was used to assess colonic dysfunction.

Changes in GI symptoms were assessed by means of diary cards, which were completed by each patient at the end of each day on-study. Patients recorded the duration (hours experienced per day) and severity [on a scale from 1 = none (absent), 2 = mild (present but not bothersome), 3 = moderate (bothersome) to 4 = severe (interfering with daily activities)] of their symptoms – abdominal pain or discomfort, bloating, sense of urgency or incomplete evacuation. The frequency of bowel movements and stool consistency (1 = hard, 2 = lumpy, 3 = formed, 4 = mushy, 5 = watery) were also recorded.

Safety

Adverse events and vital signs were recorded at each study visit. Clinical chemistry, haematology, urinalysis (visits 1, 2, 4, 6 and 8), ECG (visits 1, 4, 6 and 8) and prolactin levels (visits 1 and 8) were also monitored. ECGs were assessed in parallel by an independent cardiologist and a physician electrocardiographer.

Statistical methods

In view of the small size of this pilot study, no formal statistical comparisons were performed on the efficacy data as part of the analyses reported in the clinical study report. However, post hoc, a within-patient mixed model has been used to estimate transit times for placebo and both renzapride treatment groups (2 mg o.d. and 2 mg b.d.). The dose group was treated as a fixed effect and patient as a random effect. Pairwise comparisons were calculated between the treatments and are presented with two-sided 95% confidence intervals.

A signed rank test was used to calculate pairwise comparisons between the treatments for diary card data, which are presented with median differences and two-sided 95% confidence intervals (Hodges–Lehmann estimates).

Efficacy data is summarized by study phase for patients in the per protocol population and also presented for the intention-to-treat (ITT) population. The per protocol population included all patients who received at least one dose of renzapride, had valid X-ray results taken at visit 6 and were not excluded as a result of a protocol violation (n = 14). The ITT population included all patients who had completed visit 2, at the end of the screening phase (n = 20). Summary statistics for GI motility data included number of observations, mean, median, s.d., range, lower and upper quartiles. Changes from baseline in motility data were also calculated and summarized. The percentage of abdominal pain-free days and of discomfort-free days have been calculated for each patient and summarized using number of observations, median, lower and upper quartiles. Other diary card data were similarly summarized. The safety population included all patients who received at least one dose of renzapride. The safety data for this population is summarized by study phase.

A post hoc efficacy analysis of responders (response analysis) was also conducted. A responder was defined as a patient who demonstrated a reduction of ≥20% in transit time or symptom duration, or an improvement of ≥1 for each of the symptom scores in one or both of the renzapride treatment periods compared with the placebo period. Patients were included in the analysis if their level of symptoms during the placebo phase met pre-defined criteria, i.e. a mean GI transit time of >1.5 days; a percentage of pain-free and/or discomfort-free days of ≤70%; the mean number of hours per day a given symptom was experienced of ≥1 h; the median severity of a given symptom of >1; stool consistency was not considered by patients as ‘normal’. Each eligible patient, based on the presence of symptoms, was then classified as a responder or a non-responder and the number and percentage of responders, in terms of GI motility and each symptom, were determined.

Ethical considerations

This study was conducted in accordance with Good Clinical Practice and the Declaration of Helsinki and was approved by Independent Ethics Committees. Written informed consent was obtained from all patients prior to entry into the study.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patients

Twenty-two patients entered the screening phase and 20 patients (eight male, 12 female; 20–60 years of age) were enrolled into the study, although the safety population only comprised 17 patients, as two patients were lost to follow-up and one withdrew consent prior to commencing dosing with placebo. The symptoms of all 20 enrolled patients at screening and a summary of prohibited concomitant medication use prior to enrolment by the 17 patients who completed the placebo phase (the safety population) are shown in Table 1. Of these, 17 subsequently received renzapride 2 mg o.d. and 15 were subsequently escalated to a dose of renzapride 2 mg b.d., with 11 patients completing this final phase. Nine patients withdrew from the study: three during the placebo phase (two lost to follow-up, one withdrew consent); two during the renzapride 2 mg o.d. phase (adverse events); and four during the renzapride 2 mg b.d. phase (three due to adverse events, one lost to follow-up). Seventeen patients were included in the safety population, 20 in the ITT population and 14 in the per protocol population.

Table 1.   Incidence of symptoms reported by patients enrolled into the study [intention-to-treat (ITT) population] at screening and prior concomitant medication usage* (safety population)
Symptom at screening (ITT population; n = 20)Patients (%)
  1. * Within 28 days prior to enrolment into the study.

  2. † Safety population only numbered 17, as two patients were lost to follow-up and one withdrew consent prior to commencing dosing with placebo.

Constipation65
Abdominal pain56
Abdominal discomfort78
Feeling of urgency35
Feeling of incomplete evacuation51
Bloating75
Loose stools41
Diarrhoea10
Flatulence9
Nausea12
Insomnia6
Previous concomitant medication use (safety population; n = 17)†
 Patients taking at least one82.4
 Antacids/drugs for treatment of peptic ulcers and flatulence57.1
 Laxatives35.7
 Anti-spasmodics/anticholinergic agents/propulsives42.9
 Psycholeptics35.7

Gastrointestinal motility

Treatment with renzapride reduced the mean overall GI transit time relative to placebo, with the higher daily dose, given as 2 mg b.d., producing a statistically significant reduction in overall transit time compared to placebo (P = 0.024) (Figures 1 and 2). Mean segmental colonic transit times during treatment with renzapride were also reduced relative to placebo. Renzapride 2 mg o.d. reduced mean segmental transit times for the descending colon and recto sigmoid, while renzapride 2 mg b.d. reduced mean segmental transit times for all segments, achieving statistically significant difference compared to placebo, in the caecum/ascending colon (P = 0.019) and in the descending colon (P = 0.022). Mean segmental transit times for the caecum and ascending colon, transverse colon and descending colon were all further reduced relative to the lower active dose (Figure 1).

image

Figure 1.  Change from baseline in overall gastrointestinal transit and segmental colonic transit times in the per protocol population. Transit times were assessed from adjudicated X-ray data collected at visits 4, 6 and 8; at the end of treatment with placebo, renzapride 2 mg o.d. and renzapride 2 mg b.d. Change was calculated relative to the value obtained for each patient during the placebo phase of the study. * statistically significant difference compared with placebo (P < 0.05).

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image

Figure 2. Post hoc response analysis of overall gastrointestinal and segmental colonic transit times. The number of evaluable patients is shown in parentheses. Only patients satisfying specific minimum symptom level criteria during the placebo phase were selected for the responder analysis. Responders were defined as patients demonstrating a ≥20% reduction in transit time compared to baseline (i.e. end of placebo phase).

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The responder analysis demonstrated that renzapride was associated with reductions in both overall GI transit time and segmental transit time (Figure 2). Nine patients of the 11 who completed both treatment phases were classified as responders, most of whom were also responders for reductions in segmental colonic transit in at least two of the individual colonic segments.

In the renzapride 2 mg o.d. phase, eight of the 11 evaluable patients (c. 73%) showed a ≥20% reduction in GI transit time compared with the placebo phase, compared to seven of nine evaluable patients (c. 78%) in the renzapride 2 mg b.d. phase. Although the response data for individual colonic segment transit times exhibited a degree of inter-patient variability, in general, patients in the 2 mg b.d. phase demonstrated a greater number of segmental responses than in the 2 mg o.d. phase. The proportion of responders was greater for the caecum and ascending colon and descending colon during the renzapride 2 mg b.d. phase (100%) than in the renzapride 2 mg o.d. phase (36%).

Data from the assessment of colonic dysfunction are presented in Figure 3. For all segments, the mean number of rod markers present was higher in the renzapride 2 mg o.d. phase than in the placebo phase, with the greatest increase seen in the caecum and ascending colon and transverse colon, indicating increased movement of the rods through the GI tract during the time from when they were ingested, the previous day. In the renzapride 2 mg b.d. phase, the mean number of rod markers was lower in the caecum and ascending colon and transverse colon than in either the renzapride 2 mg o.d. or placebo phases, but slightly higher further down the GI tract in the descending colon and recto sigmoid, due to some of the rod markers being evacuated by the time X-rays were taken. These data are entirely consistent with the GI transit time data and indicate that renzapride enhances propulsion through the colon.

image

Figure 3.  Assessment of colonic dysfunction based on numbers of radio-opaque rod-shaped markers in each colonic segment (per protocol population).

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Patient assessment of GI symptoms

The pattern of change in GI symptoms recorded by the patients varied according to the specific symptom. Abdominal pain decreased in the per protocol population, as shown by the number of hours/day that it was experienced, the severity of the symptoms and the percentage of pain-free days (Figure 4). The pattern of change in the mean number of hours a symptom was experienced, and its severity was less clear for abdominal discomfort, the feeling of urgency to pass a stool, the feeling of incomplete bowel emptying and the feeling of bloating (data not shown).

image

Figure 4.  Diary card data on abdominal pain for constipation-predominant irritable bowel syndrome (c-IBS) patients in the per protocol population. Abdominal pain was assessed by (a) the number of hours/day it was experienced, (b) the percentage of pain-free days and (c) symptom severity.

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The greatest number of responders (i.e. a ≥20% improvement compared with baseline, defined as the end of the placebo phase) was seen for the mean number of hours that abdominal discomfort was experienced. In patients symptomatic for abdominal discomfort, the responder rate was 50% in the renzapride 2 mg o.d. phase and 64% in the renzapride 2 mg b.d. phase. This analysis also showed that there was at least one responder for each IBS symptom in each of the renzapride dose groups (Table 2). Overall, the pattern of responses seemed to indicate that renzapride was more effective at reducing the duration of symptoms, rather than decreasing their severity (data only shown for abdominal pain; Figure 4).

Table 2.   Summary of the number and percentage (%) of responders for a reduction in the number of hours/day that each symptom was experienced (intention-to-treat population)
 Study phase
Renzapride 2 mg o.d. (n = 17*)Renzapride 2 mg b.d. (n = 15*) Overall (n = 17*)
  1. * Data not available for all patients because of missing diary card data and patient withdrawals. Figures in parentheses show the percentages of those evaluable patients classified as responders.

Abdominal pain4 (57.1)3 (50.0)4 (57.1)
Abdominal discomfort6 (50.0)7 (63.6)9 (69.2)
Urgency1 (25.0)1 (25.0)1 (25.0)
Incomplete emptying1 (14.3)3 (42.9)3 (37.5)
Bloating4 (36.4)3 (30.0)5 (41.7)

Treatment with renzapride increased the average number of bowel movements each day (placebo: 1.0 ± 0.4; renzapride 2 mg o.d.: 1.2 ± 0.4; renzapride 2 mg b.d. 1.2 ± 0.4) and resulted in a softer stool consistency, as seen by increased scores (1 = hard to 5 = watery) for the minimum (hardest) stool consistency and the maximum (softest) stool consistency (data not shown). Patient concern relating to the frequency of bowel movements decreased correspondingly during the course of the study, although concern relating to stool consistency did not follow a consistent pattern, with approximately the same proportion with positive concern in the renzapride 2 mg b.d. phase as in the placebo phase (data not shown).

Safety

The most common treatment emergent adverse events were abdominal pain, headache and constipation, and were reported with similar frequencies in each phase of the study (Table 3). Diarrhoea was reported with similar frequency during the renzapride 2 mg o.d. and renzapride 2 mg b.d. phases, but was not reported during the placebo phase. Five patients withdrew due to adverse events which were considered to be either possibly or probably related to study medication; three during the renzapride 2 mg o.d. phase, two patients because of urinary frequency and urinary incontinence and one due to bradycardia and headache (bradycardia had been noted on the screening ECG, although the patient was still randomized); and two during the 2 mg b.d. phase, one patient with abdominal pain, fever, headache and dizziness and one due to abdominal pain and flatulence.

Table 3.   The most commonly reported treatment-emergent adverse events for the safety population
Adverse eventStudy phase
Placebo (n = 17)Renzapride 2 mg o.d. (n = 17)Renzapride 2 mg b.d. (n = 15)
Number of patients (%)Number of eventsNumber of patients (%)Number of eventsNumber of patients (%)Number of events
Abdominal pain4 (23.5)56 (35.3)74 (26.7)5
Headache5 (29.4)74 (23.5)44 (26.7)4
Constipation4 (23.5)115 (29.4)72 (13.3)5
Diarrhoea004 (23.5)43 (20.0)3
Nausea3 (17.6)31 (5.9)12 (13.3)5
Vomiting3 (17.6)122 (11.8)900
Urinary frequency1 (5.9)13 (17.6)300
Flatulence1 (5.9)1003 (20.0)4
Pain003 (17.6)300
Insomnia3 (17.6)300000

One patient, with a history of depression, experienced a serious adverse event, classified as possibly related to study medication (mild acute depression, resulting in hospitalization) while receiving renzapride 2 mg o.d. However, this patient continued with renzapride treatment, was escalated to the higher active dose and completed the study.

There were no clinically relevant ECG changes recorded and no significant changes in haematology, biochemistry, serum electrolyte or prolactin levels during the study; nor were there changes in vital signs or body weight.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This was the first clinical study to assess the efficacy and tolerability of renzapride in patients with c-IBS. The efficacy of renzapride was assessed in this study using a number of different assessment variables. Not only were the prokinetic effects of renzapride assessed relative to placebo, but also patients’ ratings of symptom intensity were assessed using daily diaries. The results of this study suggest that treatment with renzapride is potentially associated with improvements in both GI motility and symptom severity. From a safety perspective, renzapride was generally well tolerated in this study.

The primary finding of this study was that renzapride had a prokinetic effect, as demonstrated by the increases in overall GI motility, and that this effect appeared to be dose-dependent and statistically significant in the 2 mg b.d. treatment arm. This higher dose of renzapride substantially reduced transit times through all segments of the colon compared with placebo, reaching statistical significance in the caecum/ascending colon and descending colon, while the lower dose appeared to reduce transit times through the distal segments of the colon. A post hoc responder analysis confirmed that renzapride reduced overall GI and segmental transit times. Renzapride has previously been shown to enhance gastric emptying in patients with diabetic gastroparesis.42 Although a contribution of enhanced gastric emptying to the reduction in colonic transit times measured in the present study cannot be excluded, the short duration of gastric emptying compared with colonic transit times suggests that this effect was not a major contributory factor in this study.

The regional colonic function assessment data supported the findings from the assessment of GI motility, emphasizing further the prokinetic effects of renzapride. This data also demonstrated a dose-dependent trend. During treatment with renzapride 2 mg o.d., there was an increase in the mean number of rod markers in all segments of the colon relative to placebo, consistent with more rapid transit through the colon. At the higher renzapride dose, the increased speed of transit was more evident. In the proximal sections of the colon (the caecum/ascending colon and transverse colon) the number of markers was lower than that seen with either placebo or renzapride 2 mg o.d., while in the distal segments (descending colon and recto sigmoid) the mean number was higher than that seen during both placebo and the renzapride 2 mg o.d. phases. This observation suggests that the markers are moved rapidly through the proximal segments of the colon, reaching the distal segments and being evacuated, which is consistent with the observations that renzapride, particularly at the higher dose, reduces colonic transit times.

Importantly, in the majority of cases, patients classified as responders in the overall GI transit time analysis were also responders in the analysis of segmental colonic transit times in the renzapride 2 mg o.d. and renzapride 2 mg b.d. treatment phases, indicating that symptom improvement was not a random occurrence, but was related to taking renzapride.

Patients were selected on presenting symptoms of c-IBS. Renzapride has previously been shown to stimulate upper gastrointestinal motility42 and this might also have been expected to contribute to symptom improvement in patients with concomitant delayed gastric emptying. Although upper gastrointestinal symptoms overlapping with those in functional dyspepsia and gastroparesis are possible in IBS patients, this was not the case in the present study, where the symptoms assessed were wholly consistent with c-IBS. Hence, it is considered that in this study, symptom improvement was related to improvement in the symptoms of c-IBS, rather than improvement in upper GI symptoms.

The prokinetic effect of renzapride observed in c-IBS patients confirms animal pharmacology data and findings from previous clinical studies in healthy subjects and in patients with upper GI conditions of varying aetiologies (Meyers NL, unpublished data).30In vivo studies in conscious animals have demonstrated that renzapride is a potent GI prokinetic agent, stimulating gastric emptying in the rat and enhancing motility from the stomach to the colon in the dog.37 In previous clinical studies, renzapride has also been shown to be a potent stimulator of GI motility, as determined by reductions in oro-caecal transit time and gastric half-emptying time (Meyers NL, unpublished data).28, 30, 31 These effects were reflected in the induction of diarrhoea in phase I studies in healthy subjects and in preliminary phase II clinical studies in patients with gastro-oesophageal reflux disease.28, 30

Consistent with these observations are the reports of diarrhoea as an adverse event only during the renzapride treatment phases of this study. Conversely, constipation was reported as a treatment-emergent adverse event by only half as many patients in the renzapride 2 mg b.d. phase (two of 15 patients) compared with the placebo (four of 17 patients) or renzapride 2 mg o.d. phases (five of 17 patients).

Patient diary card data indicates that the frequency of bowel movements increased slightly during the course of the study, and although the average daily increase in the number of bowel movements was only 0.2 in the two renzapride dose groups compared with placebo, this equates to an increase of 1.4 bowel movements per week. Given that patient concern relating to the frequency of bowel movements decreased correspondingly during the course of the study, this suggests that this small increase in bowel movements is meaningful to patients with c-IBS.

There was also a trend towards softer stool consistency, associated with a decrease in the mean duration, frequency and severity of abdominal pain. The pattern of GI symptoms reported in the patient assessments appears to be consistent with increased movement through the bowel, as suggested by the transit time data.

With regard to the effect of renzapride on patient-reported GI symptoms, the greatest improvements were seen in the duration of abdominal pain and the percentage of pain-free days. The greatest number of responders was seen for the number of hours that abdominal discomfort was experienced. In general, the pattern of responses indicated that renzapride was more effective at reducing the number of hours symptoms were experienced, as opposed to reducing their severity. These findings should be interpreted with caution and await confirmation in future studies. First of all, given the nature of the study, where treatment started with placebo and was followed by two different doses of study drug, symptom evolution may at least in part reflect the natural history and cyclical nature of IBS. Patients are arguably, more likely to be included in a clinical study when symptoms are at their peak level, with a tendency to diminish after this peak period. Secondly, as symptom intensity was considered rather low for patients referred to hospital gastroenterology clinics, with most patients reporting mild or moderately severe pain or discomfort, this may have contributed to the apparently lesser effect of renzapride on symptom intensity compared to duration.

Renzapride was generally well tolerated. The most common treatment emergent adverse events reported were abdominal pain, headache, constipation and diarrhoea (reported only during treatment with renzapride). The adverse event profile is similar to those reported for other 5-HT4 receptor agonists.43, 44 Similar numbers of adverse events were reported during the various treatment phases, the majority of which were mild or moderate in severity. Although five patients withdrew from the study as a result of adverse events thought by the respective investigators to be either possibly or probably related to the study medication, there was no single type of adverse event that led to discontinuation and many were consistent with the potential symptoms of IBS (e.g. diarrhoea and abdominal pain) or conditions reported in the patient's medical history. No clinically significant changes in prolactin levels were observed, consistent with previous data for renzapride in healthy subjects (Meyers NL, unpublished data), and consistent with the absence of dopamine receptor antagonism.

The lack of effect of renzapride on cardiovascular function is particularly important, given the withdrawal from active marketing of the non-selective 5-HT4 receptor agonist, cisapride, due to its association with cardiac dysrhythmias and patient deaths. While previous pre-clinical studies have demonstrated that renzapride is not associated with a potential for cardiac arrhythmia, it was important to establish that no such issues were associated with renzapride treatment in a clinical setting. No clinically relevant ECG abnormalities were observed in patients during treatment with renzapride and importantly, there was no evidence for an effect of renzapride on QT interval or on QRS wave morphology.

In summary, renzapride reduced overall GI transit times and increased segmental colonic motility in a dose-dependent manner in patients with c-IBS. Treatment with renzapride also improved the symptoms associated with IBS. Renzapride, particularly when administered at a dose of 2 mg b.d., is potentially an effective treatment for c-IBS, and is well tolerated. Given the positive outcome of this study, the favourable tolerability data, and the potential of renzapride to treat different IBS subtypes, further investigations in larger controlled clinical trials in patients with IBS are warranted.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The authors acknowledge Covance, for conducting clinical study on behalf of the Sponsor, Alizyme Therapeutics Ltd, Cambridge, UK.

The clinical investigators: Professor J. Tack, University of Leuven, Belgium (Principal Investigator); Dr S. Middleton, Addenbrookes NHS Trust, Cambridge, UK; Dr H. Piessevaux, Clinical University of St Luc, Belgium; Dr M. Horne, Reading Clinical Research Centre, Synexus Limited, Reading, UK.

The work reported in this paper was wholly sponsored by Alizyme Therapeutics Ltd, of which Drs Bloor, Meyers and Palmer are employees. Dr Middleton is an ad hoc consultant to Alizyme. Dr Horne is an employee of Synexus Ltd, a contractor to Alizyme.

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  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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