Cisapride 20 mg b.d. for preventing symptoms of GERD induced by a provocative meal

Abstract

Background

: Cisapride is a substituted piperidinyl benzamide indicated for the symptomatic treatment of patients with nocturnal heartburn due to gastro-oesophageal reflux disease (GERD). The currently recommended dosing regimen for cisapride is 10 mg q.d.s., but the elimination half-life of 8–10 h supports b.d. dosing with 20 mg.

Methods

: This multicentre, randomized, double-blind, placebo-controlled trial was undertaken to determine the efficacy and safety of cisapride 20 mg b.d. dosing in reducing or preventing heartburn and other meal-related symptoms after challenge with a provocative fatty meal. In phase 1 of the study, 137 patients with at least a 3-month history of symptoms suggestive of GERD and at least five episodes of GERD on 7-day diary were eligible to receive single-blind treatment with placebo for 7 (range ± 3) days and then ingested a provocative meal. One hundred and twenty-two patients (45 men and 77 women, 22–65 years of age) who experienced heartburn during the 3 h after ingestion of the meal qualified for the double-blind phase of the study and were randomly assigned to either cisapride 20 mg or matching placebo b.d. for 7 (±3) days. At the end of this period, 118 patients again ate a fatty meal and were assessed for symptoms of GERD.

Results

: Heartburn was prevented in a significantly higher percentage of cisapride-treated patients (40%; 24 out of 60) than placebo-treated patients (21%; 12 out of 58) after the repeat provocative meal at the end of the double-blind phase (P = 0.017). Cisapride was also significantly more effective in reducing the severity of postprandial heartburn, belching, and regurgitation (P < 0.05). Twice-daily dosing with cisapride 20 mg was well tolerated; the number of cisapride- and placebo-treated patients who experienced at least one adverse event was similar (31% and 22%, respectively). The most common adverse events were diarrhoea (cisapride, 18%; placebo, 0%) and rhinitis (cisapride, 2%; placebo, 5%).

Conclusions

: These results demonstrate that cisapride 20 mg b.d. is effective in preventing or reducing symptoms of heartburn in patients who developed heartburn after ingesting a provocative fatty meal. Cisapride was also effective in reducing the severity of heartburn-related symptoms such as belching and regurgitation.

INTRODUCTION

Repeated exposure of the oesophageal epithelium to the potentially corrosive contents of the stomach due to defects in the mechanisms that prevent reflux lead to gastro-oesophageal reflux disease (GERD).^1, 2 GERD is multifactorial in aetiology;² however, one important component is impaired volume clearance and acid clearance time in the oesophagus.² Recently, motility abnormalities (i.e. decreased oesophageal motor function and delayed gastric emptying) have been statistically associated with gastrointestinal (GI) disorders.³ It is clear that postprandial heartburn is among the most common manifestations of gastro-oesophageal reflux, and that the gastric distension secondary to food ingestion is an important stimulus in producing transient lower oesophageal sphincter (LES) relaxations.^2, 4 An important element in the treatment of GERD is therefore to prevent postprandial reflux and concomitant symptoms.

Prokinetic drugs such as cisapride and metoclopramide have an important advantage over the other classes of agents used to treat GERD (antacids, H₂-receptor antagonists and proton pump inhibitors), in that they act upon the potential motility disturbance underlying GERD, rather than merely the symptoms.^3, 5, 6 Both of these prokinetic drugs have been used effectively to treat GERD, but metoclopramide is limited by important central nervous system (CNS) side-effects, including extrapyramidal effects.^3, 6 Although chemically-related, CNS side-effects are significantly less in cisapride-treated patients compared to metoclopramide-treated patients.⁵ Cisapride acts by enhancing the release of acetylcholine from postganglionic nerve endings of the myenteric plexus in GI smooth muscle. Cisapride has no antidopaminergic or direct cholinomimetic effects, unlike metoclopramide.⁷ Both short- and long-term clinical trials⁸[9][10]^–11 show that cisapride prevents or reduces symptoms of GERD and is well tolerated.^1, 9, 12

At present, the recommended dosing regimen in the USA for cisapride is 10 mg q.d.s. (tablet or suspension), at least 15 min before each meal and at bedtime.¹² However, the mean terminal half-life for cisapride ranges from 6 to 12 h¹² and may permit a longer dosing interval. Historical observations confirm that increased dosing compliance is observed with a b.d. regimen (70%) vs. a q.d.s. regimen (42%).¹³ The present study was conducted to determine whether cisapride 20 mg b.d. can significantly prevent or reduce the frequency and severity of meal-induced heartburn and other related symptoms such as belching and regurgitation.

MATERIALS AND METHODS

This multicentre trial employed a randomized, double-blind, placebo-controlled, parallel-group design. It included two phases: a single-blind treatment with placebo 30 min before morning and evening meals for 7(±3) days (phase 1), followed by a double-blind administration of either 20 mg cisapride or matching placebo before morning and evening meals for 7(±3) days (phase 2).

Patients

Patients must have had at least a 3-month history of symptoms suggesting GERD and must have experienced at least moderate intensity heartburn for at least 3 days and at least 1 night (minimum total of 5 days and nights) in the 7-day period before visit 2 (day – 7). Patients were required to consume a provocative fatty meal that would probably cause heartburn and other meal-related symptoms. Women with bilateral tubal ligation or total hysterectomy, postmenopausal women and women of childbearing potential who were using an accepted method of birth control could be included in the trial; pregnant or lactating women were excluded.

Patients with a history of irritable bowel syndrome, scleroderma, Chagas’ disease, muscular dystrophy, partial gastrectomy, diabetes mellitus, or inflammatory bowel disease were excluded. So too were patients with previous surgery for GERD or abdominal surgery within 3 months of the start of the trial; patients currently being treated for oesophagitis or an ulcer of the oesophagus, stomach and/or duodenum; and those patients using H₂ antagonists or omeprazole/lansoprazole within 2 or 4 weeks, respectively, before the start of the trial. Patients who regularly used oral steroids, aspirin, non-steroidal anti-inflammatory drugs, azole derivatives, macrolide antibiotics, or any medication that could alter the effects of cisapride were also excluded, as were those patients who had used an investigational drug within 30 days of the start of the trial. Patients with conditions including severe cardiovascular, renal, GI, hepatic, or pulmonary disease; malignancy; HIV-positive status; drug or alcohol abuse; or conditions associated with prolongation of the QT interval were also excluded from the trial. Patients who were unable to provide written informed consent, adequately express subjective complaints, or complete a daily diary were also excluded.

Patients were not allowed to consume the fatty test meal if they reported heartburn immediately before the provocative meal challenge, or if they used an antacid within 3 h, consumed more than 4 oz of 80-proof alcohol within 24 h, or failed to fast for 6 h prior to each test meal. Patients were allowed to withdraw from the trial at any time.

Screening.

Patients underwent screening 2 weeks before the start of the trial (visit 1), at which time they gave written informed consent. A medical/GI history was obtained and a physical examination, including vital signs and a 12-lead electrocardiogram (ECG), was performed. Patients discontinued all disallowed medications at this time and were given a 7-day diary to record their assessment of GERD symptoms each night before going to bed, once satisfactory washout from disallowed medication was acknowledged.

Single-blind placebo treatment (phase 1).

At visit 2 (day – 7), patients who met the entry criteria for severity and frequency of heartburn on the basis of diary entries (moderate intensity heartburn for at least 3 days and at least 1 night; minimum total of 5 days and nights) underwent further evaluation according to the above entry and exclusion criteria. Eligible patients then received single-blind treatment with placebo and were instructed to take one tablet 30 min before the morning and evening meals for 7 (±3) days. At the end of this period, patients returned to the study centre (visit 3), took their morning dose of medication (placebo), and 1 h later consumed a blinded provocative fatty meal consisting of one McDonald's Egg McMuffin with sausage sandwich (28 g fat, 27 g carbohydrate, 19 g protein) and 16 oz of Hershey's chocolate milk (18 g fat, 56 g carbohydrate, 16 g protein), to be consumed within 20 min. Patients who were asymptomatic before the meal, but who had any degree of heartburn symptoms within 3 h after the meal, were entered into the double-blind treatment phase of the study.

Double-blind treatment (phase 2).

Patients who qualified were randomized to double-blind treatment with cisapride 20 mg or matching placebo, which was to be taken before the morning and evening meals, as in the single-blind treatment phase. After 7 (±3) days of treatment, patients returned to the study centre (visit 4), took the morning dose of their medication, and 1 h later consumed another provocative fatty meal. Patients were then monitored hourly for the 3-h period immediately following the meal and assessed for the symptoms of GERD.

Assessments

Heartburn.

Severity of heartburn, defined as ‘burning pain behind the breast bone’, was rated on a 5-point scale (0 = no symptoms, 1 = slight, 2 = moderate, 3 = severe, and 4 = very severe). The percentage of patients with a score ≥ 1 was calculated before and hourly for 3 h after the provocative meals at visit 3 (single-blind, placebo phase) and visit 4 (double-blind treatment phase). The primary efficacy parameter was the percentage of patients not experiencing heartburn after the repeat provocative meal at visit 4.

Additional meal-related symptoms.

The secondary efficacy parameters were the severity scores for other meal-related GERD symptoms. These included belching, regurgitation (sensation of food coming back into my throat), postprandial fullness (an unpleasant sensation of persistent food in the abdomen), bloating (feeling like one has a lot of gas in the belly), nausea, and upper abdominal discomfort/pain (a feeling of pressure or pain in the belly). Symptom severity was evaluated at visits 3 (day 0) and 4 (day 7) using the same 5-point scale described for heartburn.

Safety.

All adverse events experienced during the 1-week period both before and during visits 3 and 4 were recorded. Adverse events were summarised by incidence, severity, relationship to trial drug, and patient outcome.

Statistical analysis

Demographic characteristics for the patients in the placebo and cisapride groups were compared by means of the Cochran–Mantel–Haenszel (CMH) test and by a two-way analysis of variance (ANOVA) with treatment and investigator as factors. The CMH test was also used to analyse primary and secondary efficacy parameters (i.e. heartburn and severity of meal-related symptoms) for both treatments. The primary analysis for heartburn collapsed all severity scores into heartburn present (score = 1) and absent (score = 0). Analysis of symptom severity distribution used the maximum of the three scores recorded for each symptom after the second meal challenge at visit 4 (day 7).

RESULTS

Patient demographics

One hundred and forty patients entered the single-blind phase of the study. Approximately 70% of patients reported taking an over-the-counter or prescription medication for heartburn.

Eighteen patients were disqualified or discontinued during the single-blind (placebo) treatment phase. Of the 137 patients who consumed the provocative test meal in the single-blind phase, only 11% (n = 15) failed to demonstrate heartburn. One hundred and twenty-two were randomized to receive double-blind treatment with cisapride (62 patients) or placebo (60 patients). The demographic and baseline characteristics for these patients are summarized in Table 1. Diaries showed that patients in the cisapride group experienced significantly more days of moderate heartburn (6.2 [±1.3] days vs. 5.6 [±1.3] days; P = 0.01) than those in the placebo group, although the number of nights in which patients experienced moderate heartburn was comparable between the two treatment groups. Also, the placebo group included a significantly larger percentage of women (46 out of 60; P = 0.003).

Table 1.  . Demographic and baseline characteristics for patients who received double-blind treatment with cisapride 20 mg b.d. or placebo

A total of 118 patients completed the trial. One patient in the cisapride group discontinued because of stomach spasms and one due to a family emergency. One patient in the placebo group discontinued because of GERD symptoms and one was lost to follow-up. The discontinuation rate in each treatment group was 3%.

Efficacy

Cisapride was significantly more effective than placebo in preventing heartburn after repeat challenge with a provocative fatty meal (Figure 1). Forty per cent (n = 24) of the 60 evaluable patients who received cisapride had no heartburn, compared with 21% (n = 12) of the 58 evaluable patients who received placebo (P = 0.017). This difference was maintained when adjusted for gender (P = 0.027).

Figure 1. .  Percentages of patients with no heartburn after challenge with a fatty meal.

Cisapride also significantly reduced the severity of heartburn relative to baseline and to placebo (Figure 2). At baseline, 74% (n = 46) of the patients in the cisapride group experienced moderate to very severe heartburn, compared with 64% (n = 38) of the patients in the placebo group. Following the challenge meal at the end of double-blind treatment, these values were 19% (n = 11) and 31% (n = 18), respectively. Overall, cisapride treatment significantly reduced the severity of heartburn relative to placebo (P = 0.049).

Figure 2. .  Heartburn symptom distribution by severity.

Belching was significantly less severe in cisapride-treated patients (P = 0.037) compared to placebo-treated patients (Figure 3). Twenty-three per cent (n = 14) of cisapride-treated patients experienced no belching with the rechallenge meal compared with only 2% (n = 1) during their baseline meal. Absence of belching was reported in only 9% (n = 5) of placebo-treated patients after the meal at visit 4, similar to the 7% (n = 4) noted at baseline in this group. No cisapride-treated patients experienced severe belching after the meal at visit 4, compared with 8% (n = 5) at baseline. Moreover, 9% (n = 5) of the patients who received placebo experienced severe belching with the rechallenge meal, compared with 7% (n = 4) at baseline.

Figure 3. .  Belching symptom distribution by severity.

Regurgitation was also significantly reduced in the patients who received cisapride (P = 0.021). In fact, 73% (n = 44) of the patients treated with cisapride had no regurgitation at visit 4, compared with 42% (n = 26) in this group at baseline. Fifty-two per cent (n = 30) of the placebo-treated patients had no regurgitation at visit 4, compared with 30% (n = 18) at baseline. None of the cisapride-treated patients experienced severe regurgitation, compared with 5% (n = 3) at baseline. Regurgitation was severe in 9% (n = 5) of the placebo-treated patients at visit 4, compared with 8% (n = 5) at baseline (Figure 4).

Figure 4. .  Regurgitation symptom distribution by severity.

Although there were no significant differences between treatment groups in the severity of individual symptoms of postprandial fullness, bloating, nausea or upper abdominal discomfort/pain, the overall symptom score was significantly reduced on cisapride therapy (P = 0.022) using the average post meal symptom score at baseline as a co-variate on the ANOVA model.

Safety

All 122 patients were included in the safety analysis. Cisapride was well tolerated, with a safety profile generally similar to that for placebo. Adverse events were reported in 31% (n = 19) of cisapride-treated patients and 22% (n = 13) of placebo-treated patients. Adverse events reported by  >3% of patients were diarrhoea (cisapride, 18%; placebo, 0%) and rhinitis (cisapride, 2%; placebo, 5%) (Table 2). Nearly all adverse events in both groups were mild or moderate in severity, including diarrhoea. One episode of severe headache in the cisapride group was considered possibly related to the trial drug, as was one episode of severe nausea in the placebo group.

Table 2.  . Adverse events in ≥3% of patients who received cisapride or placebo during double-blind treatment

DISCUSSION

The results from this trial demonstrate that cisapride 20 mg b.d. is significantly more effective than placebo in reducing or preventing heartburn after ingestion of a provocative fatty meal in patients with a history of mild to moderate GERD symptoms. In addition, cisapride is significantly more effective in reducing the severity of heartburn-related symptoms such as belching and regurgitation.

Recently, Spiegel et al.¹⁴ reported that the H₂ receptor antagonist nizatidine was more effective than placebo in preventing and reducing the severity of postprandial heartburn. The current study differs from this prior study of postprandial heartburn with regard to the nature of the provocative meal (i.e. high fat vs. a screening meal of chilli and cola) and to the current study's assessment, in addition to heartburn, other common meal-related symptoms of GERD.

Cisapride's mechanism of action differs from that of other agents used to treat GERD. It is a prokinetic agent that facilitates or restores motility in the GI tract by enhancing the physiologic release of acetylcholine from postganglionic nerve endings in the myenteric plexus.⁷ It increases the amplitude of oesophageal contractions, improves oesophageal clearing, and improves gastric emptying time.⁷ These effects may act to decrease the symptoms associated with a meal high in fat. A high-fat meal such as was used in this trial slows gastric emptying, has a low buffering capacity to counter gastric acidity, reduces LES pressure and increases the frequency of transient LES relaxation.¹⁵ All of these factors contribute to manifestations of GERD, as seen by the high percentage of symptomatic responders to the test meal in this study and in similar challenge models.¹⁶

The efficacy of twice-daily dosing with cisapride seen in the present trial supports previous pharmacokinetic and clinical findings. Zhou et al.¹⁷ demonstrated that cisapride 20 mg b.d. results in steady-state plasma concentrations similar to those observed after delivery of 10 mg q.d.s. At steady state, the area under the time vs. plasma concentration curve for the first 24 h after dosing for cisapride 10 mg q.d.s. was 1193 ± 397 ng.h/mL, and the minimum plasma concentration was 32 ± 16 ng/mL. The respective values for cisapride 20 mg b.d. were 646 ± 322 ng.h/mL (measured over 12 h) and 34 ± 20 ng/mL.¹⁷

Previous clinical trials also support the effectiveness of dosing with cisapride 20 mg b.d. for the management of GERD. Tytgat et al.¹⁸ demonstrated the effectiveness of dosing with cisapride 20 mg b.d. for preventing relapse in patients with reflux oesophagitis who had experienced healing during treatment with antisecretory drugs. Dosing with cisapride 20 mg b.d. significantly (P < 0.05) prolonged the times to both endoscopic and symptomatic relapse relative to placebo. As in the present trial, cisapride was well tolerated.¹⁸ Castell et al.¹⁹ recently reported additional results which support the effectiveness of twice-daily dosing with 20 mg cisapride. In a large-scale trial, which included 202 cisapride-and 196 placebo-treated patients, those who received cisapride had significantly less daytime and night-time heartburn (P < 0.001), significantly less regurgitation during both periods (P ≤ 0.03), and significantly less eructation and early satiety (P = 0.040 and P = 0.044, respectively). Patients who received cisapride had significantly less use of rescue medication in the daytime (P = 0.024) and at night-time (P < 0.001). Cisapride was well tolerated.

Geldof et al.²⁰ compared cisapride 10 mg q.d.s. with cisapride 20 mg b.d. and ranitidine 150 mg b.d. in 155 patients with reflux oesophagitis. The b.d. dosing schedule for cisapride resulted in a slightly higher rate of endoscopic healing than q.d.s. administration. The grade of oesophagitis was improved in 83% of the patients who received cisapride 20 mg b.d., compared with 68% of the patients treated with cisapride 10 mg q.d.s. and 81% of those given ranitidine 150 mg b.d.²⁰ Similar proportions of patients in the three treatment groups were symptom-free after 12 weeks of treatment (cisapride 10 mg q.d.s., 12%; cisapride 20 mg b.d., 17%; ranitidine 150 mg b.d., 16%).²⁰ Adverse events related to cisapride were transient.²⁰ Geldof et al. concluded that there was no significant difference between the effectiveness of the two cisapride dosing regimens, but that b.d. treatment is preferable because of its potential to improve patient compliance.²⁰ Several studies have indeed demonstrated that compliance is significantly better with b.d. dosing regimens than with those that require t.d.s. or q.d.s. dosing.^13, 21 Improved compliance has the potential to improve therapeutic outcome by maintaining clinically effective drug levels.²²

In summary, cisapride 20 mg b.d. can reduce or prevent heartburn and significantly reduce the severity of other meal-related symptoms in patients prone to symptoms of GERD after ingestion of a provocative meal. Moreover, cisapride 20 mg b.d. is well tolerated and may well be a more convenient dosing regimen.

ACKNOWLEDGEMENT

Research for this project was supported by Janssen Research Foundation, Titusville, NJ.

CIS-USA-89 study investigators

D. Castell, MD, Philadelphia, PA; P. Kahrillas, MD, Chicago, IL; F. Lanza, MD, Houston, TX; R. Levine, MD, Boulder, CO; T. Littlejohn, MD, Winston-Salem, NC; G. MacKay, MD, Oklahoma City, OK; R. Pruitt, MD, Nashville, TN; P. Miner, MD, Oklahoma City, OK; D. Silvers, MD, Metaire, LA.

Janssen Research Foundation

Trial supervision: J. Zeldis, MD, PhD, Director, Medical Development; L. Jokubaitis, MD, Group Director, Medical Development. Trial monitoring: J. Napolitano, RN, BSN, Manager, Medical Development. Statistical analysis: N. Oleka, MS, Biostatistician, Biostatistics. Plasma sample analysis: W. Mechlinski, PhD, Manager, Bioanalytical Laboratory. Medical writing: M. Wojcik, MS, Senior Medical Writer. Outcomes research: C. Farup, MD, Director, Outcomes Research.

Contact research organization

Report writing: Pharmaceutical Information Associates, Ltd, Levittown, PA.