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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background  DDP733, a selective partial 5HT3 receptor agonist, increases lower oesophageal sphincter pressure in experimental animal models. However, its effect on gastro-oesophageal reflux or lower oesophageal sphincter pressure in humans remains unknown.

Aim  To evaluate the effect of DDP733 on reflux episodes in healthy volunteers receiving a refluxogenic meal.

Methods  A randomized, double-blind, placebo-controlled cross-over study evaluated the pharmacodynamic effects of DDP733 (0.5, 0.8 and 1.4 mg). Healthy subjects underwent oesophageal manometry and intra-oesophageal multichannel intraluminal impedance and pH after a refluxogenic meal.

Results  DDP733 0.5 mg significantly (P = 0.013) reduced the rate of reflux episodes after a refluxogenic meal from 10 (±2.2) on placebo to 6 (±1.2) on drug over a 2-h period. DDP733 0.8 and 1.4 mg had no significant effect on reducing the number of reflux episodes. Significant differences in resting lower oesophageal sphincter pressure and the proportion of time pH was <4 (placebo minus drug) after a refluxogenic meal were not observed. No serious adverse events were reported.

Conclusion  In healthy subjects, the partial 5HT3 agonist DDP733 at a dose of 0.5 mg significantly reduces the rate of reflux events, but did not result in a significant change in lower oesophageal sphincter pressure at 1 h postdosing.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Gastro-oesophageal reflux disease (GERD) is a very common condition with 20% of adults reporting one episode per week and about 60% of people reporting any symptoms of heartburn and regurgitation over the course of a year.1 Although currently the use of proton pump inhibitors (PPIs) has become the mainstay of treatment, 15–20% of patients continue to have symptoms while taking gastric acid inhibitors, including PPIs, and many patients have evidence of acid and non-acid reflux in the oesophagus while on treatment.2, 3 Defects in oesophagogastric motility are believed to be central to the pathogenesis of GERD4 and, furthermore, a number of studies5–9 have shown that transient relaxation of the lower oesophageal sphincter (LES) is the major mechanism underlying reflux in normal subjects and in most patients with reflux disease. Thus, modulation of motility is now considered to be an important target to treat GERD.10

DDP733 is an investigational agent that is a thienopyridine derived 5HT3 receptor partial agonist with gastrointestinal prokinetic activities.11 It activates 5HT3 receptors that are widely distributed in the enteric nervous system but has limited systemic absorption.11 Animal models suggest that DDP733 may be useful in the treatment of GERD, by increasing lower oesophageal sphincter pressure (LESP) and so reducing gastro-oesophageal reflux.12 The effect of DDP733 on LESP has been primarily evaluated in cats,12 a species in which the smooth muscle portion of the distal oesophagus shows anatomical and manometric functional correlates with the human oesophagus.13 There is no study of DDP733 effects on oesophageal parameters in humans. Pharmacokinetic studies in animals and humans indicate that oral absorption of DDP733 is poor, resulting in limited systemic availability.12, 14, 15 The anticipated low therapeutic dose requirement and low systemic availability of DDP733 suggests a favorable safety margin.

We therefore evaluated the safety and tolerability of DDP733 and compared the effects of three DDP733 doses and placebo on oesophageal related pharmacodynamic measurements, including reflux episodes, LESP and specific symptoms (heartburn, non-acid regurgitation or acid regurgitation) in healthy volunteers receiving a standard refluxogenic meal.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Design

A randomized, double-blind, placebo-controlled, cross-over study was undertaken to evaluate the safety, tolerability and oesophageal-related pharmacodynamic effects of three dose levels of DDP733 or matching identical placebo.

Study subjects

Thirty-five healthy subjects, aged between 18 and 60 years, were recruited by advertisement. After screening, seven subjects were not eligible for our study by inclusion and exclusion criteria and 28 healthy subjects were enrolled (Figure 1). These were either healthy males (n = 5) or nonpregnant, nonbreast feeding healthy female volunteers (n = 23). Eligible subjects were required to have a body mass index between 20 and 30 kg/m2, and to have no significant medical history, physical examination findings, or clinical laboratory abnormalities. Appropriate birth control for female participants was required during this study. Patients with the following characteristics were excluded: (i) previous or planned gastrointestinal tract surgical procedures with the exception of cholecystectomy or polypectomy, (ii) presence or known history of reflux oesophagitis, endoscopic Barrett’s oesophagus or significant dysplastic changes in the oesophagus, primary oesophageal motility disorders, or any significant systemic disease. Subjects were not allowed to be on any medications except birth control, hormone replacement therapy and stable thyroid replacement. Medications that may alter gastrointestinal motility or gastric acid including metoclopramide, domperidone, PPIs, H2-antagonists and anticholinergic agents were prohibited. The study was approved by the Mayo Foundation’s Institutional Review Board. Eligible subjects freely gave their written consent prior to starting the study in all cases.

image

Figure 1.  Flowchart of the subjects from initial screening to completion of the study.

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Randomization, concealed allocation and study medications

Each subject was assigned a unique patient number to ensure blinded allocation of both treatment group and sequence. Subjects were randomized to a treatment sequence of dosing with one week of placebo and one week of oral DDP733 (0.5, 0.8 or 1.4 mg). These doses were chosen on the basis of efficacy data demonstrating increased LESP in cats,12 and phase I studies demonstrating the prokinetic effects, and safety and tolerability of single doses up to 4 mg.15 Subjects were randomized in a ratio of 1:2:1 to the 0.5 mg group: 0.8 mg group: 1.4 mg group, respectively.

Study procedures

The screening period included two study visits and during this period, subjects underwent screening procedures within 10 days prior to randomization into the trial. During the screening period, informed consent was obtained, eligibility for study entry was assessed and baseline assessments were conducted. Subjects were randomly assigned to one of six treatment sequences. Each subject was exposed to one dose level of DDP733 and to placebo in a random sequence and completed approximately 1 week of dosing with each of the two dosing regimens.

After the subject was randomized and entered the treatment period, he/she took the study medication on six days of each of the two dosing periods. On the first day of each dosing period (days 1 and 8), study medication was administered in the morning under supervision at the study site. Afternoon and evening doses were not administered on days 1 and 8. On days 2–6 and 9–13 of the dosing periods, subjects took three doses of study medication 30 min to 1 h prior to breakfast, lunch and dinner. On days 7 and 14, no study medication was taken. The subject returned to the clinic on day 15 for final study evaluations. The subject was asked to return to the clinic within a week of this visit for follow-up of abnormal clinical laboratory tests, at the discretion of the investigator.

On days 1 and 8, subjects were evaluated by manometry to measure LESP under fasting conditions. Multichannel intraluminal impedance and pH (MII-pH) procedures to measure reflux events and pH in association with a standard refluxogenic meal were performed (Figure 2). Specific symptoms were also assessed. Adverse events were monitored from the time of the first dose of study medication on day 1 through day 15 of the study or until resolution. Concomitant medication use was monitored throughout the study.

image

Figure 2.  Study protocol.

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Manometry

Study medication was administered in the clinic approximately 45 min prior to the placement of a manometry catheter. Oesophageal manometry was performed by using a step-by-step ‘pull through’ of the catheter through the high pressure zone between the oesophagus and the stomach. LESP was measured over a 15-min period, and the mean resting pressure in each 15 s inter-swallow period was recorded. The manometry catheter was removed after completion of this assessment and an MII-pH probe was inserted into the appropriate oesophageal position (5 cm) above the LES.

Multichannel intraluminal impedance and pH

A standard refluxogenic meal [defined as a sausage with egg muffin (60% fat) with an eight ounce cup of coffee]16 was administered to all subjects. MII-pH assessment started in the immediate postprandial phase 5 min after the last act of eating. Subjects were placed in the right lateral decubitus position and oesophageal intraluminal impedance and pH was recorded for 2 h.

Specific symptoms (heartburn, non-acid regurgitation and acid regurgitation) were assessed in conjunction with the refluxogenic meal and the MII-pH assessment. Immediately prior to the start of each MII-pH assessment, subjects were asked to press a button on a recording device corresponding to heartburn, non-acid regurgitation or acid regurgitation when they experience one of these symptoms during the assessment period in order to determine the exact timing of any symptoms. Subjects were not reminded to report symptoms after placement of the MII-pH probe; no attempt was made to quantify the severity of any reported symptoms.

Two independent experts in the interpretation of oesophageal impedance–pH studies were used to evaluate the impedance, pH and symptom data in a blinded fashion. They determined the number of reflux events for each subject, designated each event as an acid or non-acid event and correlated any reported symptoms with a reflux event. In the event of non-agreement, a third blinded expert was included to ensure a final decision.

Impedance and pH were used to identify the total number of reflux episodes, as described by Vela et al.16 and Wildi et al.17 An impedance event was defined as a sequential decrease in impedance to a minimum of 50% of the baseline value beginning at the most distal recording site and reaching the second most distal recording site. To accommodate baseline shifts, the baseline value was the average impedance baseline in a 5-s period immediately preceding the reflux episode. The end of episode was defined as when the impedance value had returned to more than 50% of the baseline value. Any events identified from pH recordings that were not identified during the impedance assessments were included in the total number of reflux episodes for each subject.

Each identified reflux event was characterized as an acid or a non-acid reflux event based upon the pH recordings. An event was considered an acid reflux event, if there was an abrupt decrease in pH to <4.0 for a minimum of 5 s within 10 s after the impedance-detected event. If there was no concomitant decrease in pH during the impedance-detected episode, the event was considered non-acid.

Symptoms of heartburn, non-acid regurgitation and acid regurgitation reported by the subject during the MII-pH evaluations were reviewed for association with a reflux event by evaluating the timing of the symptom in relation to a reflux episode (acid or non-acid). If a symptom was reported within a 2-min interval immediately after a recorded reflux event, it was considered associated with reflux.16–18 Should more than one reflux episode be recorded within the same 2-min interval, the symptom was associated only with the reflux episode immediately preceding the symptom. Symptoms that were not associated with a reflux episode were listed separately.

Statistical analysis

All continuous data are given as mean (±S.E.M.). The primary efficacy analysis was the change in the total number of reflux events within subjects comparing DDP733 0.5, 0.8 or 1.4 mg vs. placebo administration. The secondary endpoints included change in the proportion (%) of time that pH was <4 during a provocative procedure as measured by MII-pH, and change in mean LESP (mmHg). A pooled anova of the within subject deltas (placebo-drug) over all three dose groups, adjusting for order of administration, was used to assess overall drug effects. In addition, three dose specific tests for no difference (placebo vs. drug) were examined (Bonferroni adjusted α = 0.017). This analysis followed the intention-to-treat (ITT) paradigm by imputing the missing values in dropouts using the overall mean in subjects with nonmissing data and a corresponding downward adjustment to the error degrees of freedom in the anova (subtracting one degree of freedom for each missing value imputed). The exact binomial computation in McNemar’s test was used to assess the differences (placebo vs. drug) in the proportions of subjects who reported symptoms (heartburn, non-acid regurgitation, or acid regurgitation) related to a refluxogenic meal.

Safety evaluations were based on the incidence, severity and type of adverse events, and clinically significant changes or abnormalities in the subject’s physical examination, vital signs, clinical laboratory tests and ECG results.

Sample size assessment

The sample size for this study was based on earlier studies11, 12, 14, 15 which indicate that 7–14 subjects per group would be sufficient to assess safety, tolerability and oesophageal-related pharmacodynamic effects of DDP733. In addition, the power to detect differences in the mean LESP (mmHg) between active treatment and placebo separately for each dose group was assessed using the paired t-test. These were computed using an estimate of variation from a previous study.19 The between-subject s.d. of within subject differences (active treatment vs. placebo) was computed assuming the s.d. on treatment to be equal to the s.d. on placebo and a within subject correlation of 1. These s.d. were assumed to be 13 for LESP and 7 for upright acid exposure.19 The estimated effect size detectable with 80% power (at a two-sided alpha level of 0.05) was 58%. The effect size is the difference in group means as a percentage of the overall mean. This corresponds to an LESP of 2819 and assumed seven subjects per group.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Participant characteristics

A total of 28 subjects were enrolled into the study after screening 35 volunteers. Two subjects on DDP733 1.4 mg dropped out (one because of procedure intolerance, and the other had a motor vehicle accident and could not appear for the study) (Figure 1). Thus, the ITT analyses imputed values for these two subjects and adjusted the error degrees of freedom downward by two in the anova.

Oesophageal reflux events and symptoms during a provocative procedure

Comparisons of number of reflux episodes on placebo and DDP733 are shown in Table 1 and Figure 3. DDP733 0.5 mg significantly (P = 0.013) reduced the rate of reflux episodes after a refluxogenic meal by almost 40% [from 10.4 (±2.2) on placebo to 6.3 (±1.2)] on drug over a 2-h period. However, DDP733 0.8 mg [8.9 (±1.1) vs. 6.9 (±1.1) on placebo] and 1.4 mg [9.3 (±2.1) vs. 12.0 (±1.3) on placebo] did not significantly reduce reflux episodes (P = 0.07 and P = 0.34, respectively).

Table 1.   Reflux events, post-treatment mean lower oesophageal sphincter pressure (LESP), and proportion time that time pH <4 on drug or placebo (mean ± S.E.M.)
ParameterDDP733 0.5 mgDDP733 0.8 mgDDP733 1.4 mg
Drug (n = 7)Placebo (n = 7)P-valueDrug (n = 14)Placebo (n = 14)P-valueDrug (n = 6)Placebo (n = 5)P-value
  1. P-value from an intention-to-treat anova model adjusting for sequence of drug administration.

Reflux events (n)6.3 ± 1.210.4 ± 2.20.018.9 ± 1.1 6.9 ± 1.10.079.3 ± 2.112.0 ± 1.30.34
Mean LESP over 45–60  min (mmHg)21.8 ± 1.620.7 ± 4.00.7320.7 ± 2.022.3 ± 1.90.4620.9 ± 3.119.7 ± 1.90.67
Proportion (%) time that pH <46.8 ± 2.512.0 ± 4.80.2311.1 ± 2.4 7.4 ± 1.90.245.0 ± 1.312.5 ± 5.20.18
Mean amplitude of distal oesophageal peristalsis during wet swallowing (mmHg)83.0 ± 18.767.3 ± 19.50.00890.4 ± 10.3 79.8 ± 9.60.0188.0 ± 5.374.4 ± 5.60.05
image

Figure 3.  Number of reflux episodes during impedance-pH study over 2 h on DDP733 0.5, 0.8, 1.4 mg or placebo in healthy volunteers.

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On active drug, a total of only twelve subjects (out of 26 with complete data) had symptoms of any type (8, 8 and 5 subjects had heartburn, non-acid regurgitation and acid regurgitation, respectively). While on placebo, 13 subjects (out of the 26) had symptoms of any type (11, 10 and 3 subjects had heartburn, non-acid regurgitation, and acid regurgitation, respectively). McNemar’s test comparing drug with placebo on number of subjects with symptoms was not significant (P = 1.0, 0.45, 0.63 and 0.63 for any symptom, heartburn, non-acid regurgitation and acid regurgitation, respectively).

Proportion of time that pH <4 during impedance study

The proportion of time pH was <4 after a refluxogenic meal on placebo and DDP733 are shown in Table 1. DDP733 0.5 and 1.4 mg reduced the proportion time that pH <4 by mean differences of 5% and 8%, respectively compared to placebo, but these were not statistically significant (P = 0.23 or P = 0.18, respectively). DDP733 0.8 mg slightly increased the proportion time that pH <4 by an average of 4% compared to placebo, but was also not significant.

LES pressure

The fasting basal LES pressure on different dosage levels of DDP733 or placebo is shown in Table 2. The fasting overall LES pressure from 45 to 60 min on DDP733 0.5 mg (21.8 mmHg ± 1.6) was similar to that during placebo (20.7 mmHg ± 4.0). There were no effects on the LESP during manometry at all dose levels of DDP733 (Table 1).

Table 2.   The number of healthy subjects experiencing adverse events on DDP733 or placebo
  Placebo (n = 28)DDP 733 0.5  mg (n = 7)DDP7 33 0.8  mg (n = 14) DDP733 1.4 mg (n = 7)
Abdominal pain1100
Nausea2011
Vomiting0100
Diarrhoea0000
Constipation1000
Bloating/gas2001
Flushing2031
Rash1020
Itching0001
Headache3121
Stiff neck1000
Abnormal liver function test2220
Sleep disturbance1000
Vaginal discomfort0001

Distal oesophagus peak pressure

The mean amplitude of distal oesophagus peak pressure was calculated by the amplitude of peak pressure in the distal oesophagus during ten wet swallows. The mean amplitude of distal oesophageal peak pressure on different dosage levels of DDP733 or placebo is shown in Table 1. The mean amplitude of distal oesophagus peak pressure on DDP733 0.5 mg (83.0 mmHg ± 18.7) or 0.8 mg (90.4 mmHg ± 10.3) was higher than that during corresponding placebo periods (67.3 mmHg ± 19.5, P = 0.008 and 79.8 mmHg ± 9.6, P = 0.01, respectively). The amplitude of distal oesophagus peak pressure on DDP733 1.4 mg (88.0 mmHg ± 13.1) was also higher than that during placebo (74.4 mmHg ± 5.6), but this was not statistically significant (P = 0.052).

Safety and tolerability

No serious adverse events were reported as shown in Table 2. Most subjective symptoms, except for vomiting, itching or vaginal discomfort, were also observed after placebo treatment. Abnormalities of blood pressure or ECG were not observed in any of the subjects throughout treatment. Elevation of blood biochemical tests including bilirubin, γ-glutamyltranspeptidase and alanine aminotransferase occurred during treatment with both DDP733 and placebo, and were described as mild and transient.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This is the first study to evaluate the effects of a novel selective 5-HT3 partial agonist on gastro-oesophageal reflux episodes and LESP in humans. DDP733 was well tolerated and at a dose of 0.5 mg significantly reduced the rate of reflux events, although no benefit was demonstrated at the higher doses. In addition, DDP733 at doses of 0.5 and 0.8 mg statistically and significantly increased the mean amplitude of the distal oesophageal contractions. No significant changes were observed in LES pressure by 1 h postdosing or in the proportion of time that pH was <4 during the 2 h of the impedance study.

DDP733 is a 5HT3 receptor partial agonist with gastrointestinal prokinetic activities.11 Venkova et al.12 reported the effect of DDP733 on LESP, oesophageal peristalsis and distal oesophageal pH in anesthetized cats. When administered i.v., DDP733 (0.1–10 mg/kg) demonstrated an immediate and dose-dependent increase in LESP. The increase in LESP (70% change from basal level at 10 mg/kg) reached a maximum within 20–40 min and remained elevated 60 min after administration but did not hinder LES relaxation in response to spontaneous dry swallows. In addition, DDP733 decreased the duration of lower oesophageal exposure to harmful pH levels (pH <4) during LES relaxation. Overall, these data suggest that DDP733 may be useful as a treatment for GERD. The present study has shown that a single oral dose of DDP733 0.5 mg reduced the rate of reflux events by about 40% in normal human subjects compared to the same subjects receiving placebo. However, our study did not show that DDP 733 0.8 or 1.4 mg significantly reduced the rate of reflux events. DDP733 0.8 mg seemed to slightly increase the number of reflux events although this was not significant. However, it is worth noting that the number of reflux events on placebo for subjects receiving DDP733 0.8 mg was lower than that of placebo with subjects on DDP733 0.5 mg or DDP 1.4 mg group. DDP733 0.5 and 0.8 mg significantly increased the mean amplitude of the distal oesophageal peak pressure, while DDP733 1.4 mg showed a trend for an increase. Therefore, it is conceivable that by increasing the contractility of the distal oesophagus, DDP733 might result in a reduction of reflux events.

Despite the reduction in the rate of reflux episodes, there were no increases in LES tone detected in this study. The smooth muscle LES and crural diaphragm are two key components of the GE junction valve.20 In health, these mechanisms are expected to be intact and to maintain LES competence; one would not necessarily expect LES tone to increase further because of drug treatment. In addition, we cannot exclude the possibility that this study was underpowered for detecting a modest effect of DDP733 increasing the LES in healthy volunteers, or that the LESP measurements were not performed at the best time to detect an effect.

Another possible explanation for reduced reflux events is a change in gastric function with DDP733. Coleman et al.15 reported that a relatively high dose of DDP733 (4 mg) delayed liquid gastric emptying in association with relaxation of the proximal stomach; this was confirmed by echoplanar magnetic resonance imaging. They suggested that 4 mg of DDP733 might therefore be associated with the nausea, but in our study, nausea was reported about by only one subject on 0.8 mg and one on 1.4 mg of DDP733 respectively. Coleman et al.15 showed that a dose lower than 4 mg of DDP733 did not delay gastric emptying or cause a statistically significant fundic relaxation. It is possible that, in our study, relaxation of the gastric fundus at the higher doses of DDP733 offset the beneficial promotility effect because transient lower oesophageal relaxations are triggered by activation of gastric vagal afferents resulting from distension of the stomach, particularly in the subcardiac region.21 More work is needed to understand the effect of low doses of DDP733 on gastric function.

A possible reason that a reduction in reflux events was only established with DDP733 0.5 mg is that the number of reflux events on placebo in the DDP733 0.8 mg group was too small to differentiate a true drug effect. Notably, DDP733 1.4 mg also reduced the rate of reflux episodes after a refluxogenic meal from 12 (±1.3) on placebo to 9 (±2.1) on drug over a 2-h period, although this was not significant, possibly because of the relatively small sample size.

The most common adverse effect of DDP733 in our study was skin symptoms (including flushing, rash, or itching), which was reported about one third of subjects following 0.8 and 1.4 mg, but in none of the subjects receiving the 0.5-mg dose. This is a predictable effect of a 5-HT3 agonist, and is consistent with earlier studies including the study of Coleman et al.15 which suggested that widespread systemic effects of the drug might exist. As has been seen in previous studies, skin symptoms in this study were mild to moderate, transient and did not require treatment. However, the presence of skin symptoms implies systemic drug effects, which need further evaluation. Fujita et al.14 reported that 0.5 mg of DDP733 significantly improved colonic motility in subjects with decreased colonic motility. However, we did not observe any diarrhoea from DDP733 in healthy subjects. We observed no significant cardiovascular events or ECG changes during this study.

In conclusion, in healthy subjects, the partial 5HT3 agonist DDP733 at a dose of 0.5 mg significantly reduced the rate of reflux events and increased distal oesophageal amplitude. DDP733 did not result in a significant change in LES pressure at 1 h postdosing, but this would not necessarily be expected in a healthy volunteer population. Thus, further study of DDP733 in patients with GERD is now warranted, and additional trials are currently being planned.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The authors wish to thank Susan M. Schlichter for her assistance in the preparation of the manuscript. Declaration of personal interests: N. J. Talley received research support from Dynogen Pharmaceuticals, Inc. Declaration of Funding interests: This study was supported by Dynogen Pharmaceuticals, Inc.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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