Gastroesophageal reflux disease (GERD) and pathologic reflux are terms reserved for those patients in whom reflux is complicated by esophagitis, respiratory difficulty, or failure to thrive (1). The pathophysiology of GERD is multifactorial (2,3); however, dysmotility of the esophagus (impaired clearance), inadequacy of the antireflux barrier (low basal esophageal sphincter pressure, transient relaxation of the lower esophageal sphincter), and dysmotility of the stomach and duodenum (delayed gastric emptying) are all motor disorders recognized as major contributing factors.
It is generally recommended that infants with frequent, symptomatic, or complicated reflux be treated (1,3-5). Mild reflux in infants will often improve in response to more frequent, smaller volumes of thickened feedings, and to positioning. With more significant reflux, pharmacologic agents that decrease the volume, frequency, and duration of reflux (primarily prokinetic agents), or those that antagonize acid secretion (antacids, H2 antagonists, or proton-pump inhibitors) are often prescribed.
The benzimidazole derivative cisapride is a nondopaminergic, noncholinergic gastro-prokinetic agent that acts through the release of acetylcholine from the myenteric plexus in the gut (5-8). Results of clinical pharmacologic studies have shown that cisapride exerts its effects throughout the gastrointestinal tract. In the esophagus, cisapride increases peristaltic activity and raises pressure in the lower esophageal sphincter; in the stomach, cisapride increases contractility, antroduodenal coordination, and gastric emptying; and in the bowel, cisapride increases propulsive activity and decreases transit time. Information collected in clinical trials in adults has demonstrated cisapride's usefulness in the treatment of esophagitis, gastroparesis, dyspepsia, and constipation (4,6). The role of cisapride in the treatment of GERD in infants and children has been less well studied. Only two double-blind, placebo-controlled trials of cisapride have been reported (9,10).
The primary objective of this study was to evaluate the efficacy of long-term therapy with oral cisapride for the treatment of pediatric GERD. Lower esophageal manometry, monitoring of esophageal pH, diaries of regurgitation frequency, and global response were used to evaluate efficacy.
This was a randomized, multicenter, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of an oral cisapride suspension in children with gastroesophageal reflux. The trial was performed in accordance with the Declaration of Helsinki and its subsequent revisions. Ethics committee approval was obtained at each of the involved centers (University of Alberta, University of Calgary, and University of Montreal) before initiation of the study. The nature of the trial and the risks involved were explained to the patients and guardians by the investigator, and all were required to provide written informed consent before the patient enrolled in the trial.
The trial commenced in April 1989, and enrollment ceased in January 1993. The guardian of any child 6 weeks to 2 years of age who had been referred to the gastroenterology service at a participating center for the evaluation and management of frequent or persistent daily regurgitation or vomiting was approached with information regarding the study and a request for participation. Only those infants who had daily regurgitation or vomiting that persisted during the baseline study period (despite the age-appropriate use of thickened feedings and the elevation of the head, with the infant in the prone position during sleep) and who had had at least one episode of gastroesophageal reflux (defined by the sensitivity limits of the pH monitoring equipment as an episode where esophageal pH is <4 for more than 20 seconds) identified by 18-hour monitoring of esophageal pH were randomized to the cisapride or the placebo treatment group. Infants were excluded from the study if they did not meet these inclusion criteria; were premature; had undergone previous gastrointestinal surgery other than for appendicitis; had known illnesses or conditions that could interfere with the assessment of the study drug; were being treated with or required concomitant therapy with drugs interfering with assessment of the study drug (e.g., antacids, H2 antagonists, metoclopramide, bethanechol, prostaglandins, domperidone, sucralfate, neuroleptics, anticholinergic agents, theophylline); had reflux caused by known anatomic abnormalities, underlying disease, or infection of the gastrointestinal tract or other organ system; or had parents who were incapable of expressing their concerns or were unable to comply with the study schedule or to complete patient diaries.
Patients were not enrolled in the randomized trial if they were asymptomatic during the baseline period. Those enrolled in the trial withdrew and were not evaluated if the parents or guardians requested withdrawal, if they were noncompliant (less than 80% of medication taken), if there was a significant adverse reaction, if the patient was adversely affected by conditions of the trial in the investigators' opinion, or if there was a protocol violation.
The trial consisted of a 1-week, single-blind (patient-parents) interval during which all patients were administered placebo and baseline data were obtained. Subsequently, eligible patients were randomized to a double-blind trial of 6 weeks of oral therapy with a suspension of either four daily 0.2-ml/kg doses of cisapride administered every six hours (1 mg/ml) or four daily 0.2-ml/kg doses of a matching suspension of placebo administered every six hours. The timing of each patient visit, randomization to the cisapride or placebo treatment group and the parameters assessed on each visit are summarized in Table 1. Subjects were studied as outpatients except for two brief inpatient admissions to obtain 24-hour esophageal pH data, esophageal manometry, and an esophageal biopsy at baseline and at the end of the trial.
Before the study, a barium contrast study or upper intestinal endoscopy was performed to exclude anatomic abnormalities of the esophagus or stomach. At the initial visit, a complete history and physical examination of the patient was performed. As stated above, subjects were not permitted concomitant therapy with drugs that might interfere with assessment of 24-hour esophageal pH measurements. Medications that were required for other intercurrent conditions were permitted and fully documented on the case record form at each visit. As much as possible, doses of concomitant medications stayed the same throughout the trial.
The experimental drug cisapride was supplied as a 1-mg/ml suspension by Janssen Pharmaceutica Inc., (North York, Ontario, Canada) and the placebo suspension, which was the normal vehicle for the commercial preparation and thus identical in appearance to the drug used in the treatment group, was also provided by Janssen Pharmaceutica Inc. The drug vehicle and the placebo suspension were both obtained from the company's Belgian offices and contained sucrose. The volume of suspension to be administered (0.2 mg/kg in six hourly doses) was calculated according to the patient's weight and adjusted at each visit as necessary. The randomization code for the allocation of patients to cisapride or placebo suspension was generated by computer. All drugs were packaged in identical boxes and identified by patient and week number. The double-blind code was to be broken only in the event of an emergency. To assess compliance, a record was kept of the number of bottles dispensed, the dose administered, the volume returned, and the percentage of medication taken.
The effectiveness of therapy was assessed using primary (monitoring of esophageal pH), secondary (esophageal manometry and biopsy), and tertiary (the patient's clinical parameters, global assessment of the patient's condition by the guardian and physician, and daily dairies kept by the guardian) parameters.
Primary Parameters-Esophageal pH Monitoring
Within 1 week before randomization, patients underwent monitoring of esophageal pH (Proxima Light 2 Digitrapper, Synectics Medical, Stockholm, Sweden; and MI-506 pH electrode, Microelectrodes Inc., Londonderry, New Hampshire, U.S.A.) both to confirm gastroesophageal reflux and also to provide a baseline measurement for this parameter. The probe was positioned 3 cm above the lower esophageal sphincter (LES), determined by manometry. The number of reflux episodes in the postprandial or fasted states, in the upright or supine position, their average duration, the number of episodes lasting longer than 5 minutes, the duration of the longest episode, and the percentage of time during which esophageal pH was lower than 4 were automatically calculated. The complete record of esophageal pH measurements and a summary table were generated at the end of each study.
The pH probe was repeated and the same parameters were measured during the final week of double-blind treatment while the patients were still on medication. As closely as possible, the conditions of the baseline tests were duplicated (that is, timing and content of meals, duration of recording, and duration of supine and upright periods). Throughout the trial, patients continued their established regimens of positioning and thickened feedings, when appropriate.
As the length of the recording time for the pH probe data varied from 16.9 to 24 hours in all patients, numerical data (number of episodes upright, supine, postprandial, or >5 minutes' duration) were converted to a standardized number of episodes in 24 hours by dividing the actual number of episodes by the length of the recording time (in hours) and multiplying the result by 24. The differences from baseline scores were then calculated on the basis of these standardized numbers of episodes in 24 hours.
Secondary Parameters-Esophageal Manometry and Biopsy
Esophageal manometry was performed to position the pH probe appropriately or for suction esophageal biopsies and to obtain measurements of both lower esophageal sphincter and average swallow pressure.
At baseline, the presence or absence of esophagitis was determined by esophageal biopsy (blind suction or endoscopic grasp-forceps biopsy) obtained 3 cm above the lower esophageal sphincter as determined by manometry for suction biopsies or visually for endoscopic biopsies. Biopsy was repeated at the end of the trial only if esophagitis was present at baseline. Histologic sections from the biopsies of each patient were assessed for evidence of esophagitis by a single pathologist blinded to patient treatment on the basis of published morphometric criteria (11).
Tertiary Parameters-Clinical Data, Global Evaluations, and Daily Diary
Data pertaining to weight, height, temperature, pulse, and systolic-diastolic blood pressure were collected. Assessments of the patient's condition during each 2-week period were performed by the parents and investigators, using a visual analogue scale of 100 mm anchored by two phrases: “the worst it's ever been” (0 mm) and “completely recovered” (100 mm). In addition, the parents and investigators each made a global evaluation of the patients' overall response to treatment at the end of the study by choosing one of the following five responses:
- deteriorated (symptoms worse)
- poor (no improvement)
- fair (slight improvement, persistence of some symptoms)
- good (improvement with only occasional symptoms)
- excellent (complete relief of symptoms)
The patients' guardians were asked to record the number of episodes and severity of vomiting and regurgitation in daily diaries throughout the course of the trial. Each episode of regurgitation recorded in the diary was scored as follows:
- slight regurgitation of secretions only, no evidence of meal
- small mouthful of food is regurgitated, most of the meal is retained
- most of the meal is regurgitated or the child vomits contents of stomach
These data were summarized as the total number of episodes of mild regurgitation, moderate regurgitation, or severe regurgitation and vomiting. Then, before the difference scores were calculated, the episode data were converted to a number of episodes per day by dividing the raw score for each period by the number of days in the recording period. All difference scores were calculated from the baseline score, which was recorded at visit 2. A combined score for regurgitation-vomiting was also calculated by assigning a weighted factor to each of the individual categories: (mild regurgitation episodes × 1) + (moderate regurgitation × 2) + (severe regurgitation × 3) + (vomiting × 3).
Any adverse event that occurred during the trial period (including intercurrent diseases) and that was either recorded in the patient's diary or obtained after nonleading questioning of the parents was noted by the investigator. Descriptions of events included date of onset and duration; and all were graded by the investigators for intensity (mild, moderate, severe); frequency (once, occasionally, continuous); action taken (none, treated, study discontinued, modified dosage); outcome (recovered, ongoing, some impairment after drug stopped, converted to chronic condition, other); and relation to the study medication (cause unknown, possibly related to underlying disease or associated condition, possibly related to concomitant medication, possibly related to study medication, probably related to study medication).
Clinical Laboratory Data
All patients underwent routine hematology, blood chemistry, and urinalysis testing at screening and at the end of the trial. Laboratory values outside the normal range were assessed and commented on by the investigator.
Data Quality Assurance and Statistical Analysis
Each center was inspected before selection. A representative of Janssen Pharmaceutica Inc. met with each investigator and staff to review procedures before any patients were enrolled. The site was visited by a representative of Janssen Pharmaceutica Inc. at regular intervals during the trial to review case record forms for accuracy and completeness and to assess adherence to protocol. All of the case record forms were checked against source documents.
On the assumption that 70% of the patients in the cisapride group and 30% in the placebo group would respond to therapy, it was calculated that 30 evaluable patients per treatment group, for a total of 60 patients, would be required for this difference to be detected at the 5% significance level (two-tailed test) with a power of 80%.
An efficacy analysis was performed on those patients who were determined to be evaluable for efficacy. The main statistical tests used in the analysis were the Cochran-Mantel-Haenszel test (employed to analyze categorical data and global visual analogue scale assessments to test for a difference between treatments, controlling for investigator), and the stratified extension of the Wilcoxon rank sum test-the van Elteren test (employed to analyze primary, secondary, and tertiary efficacy parameters to test for differences between baseline and final visits, or between treatments, controlling for investigator). The van Elteren test was employed because there was a high degree of variability in the data between patient visits, and a nonparametric approach was required. The adverse events were presented descriptively.
Patient and Treatment Information
Eight investigators participated in this trial, which took place at three study sites: Montreal (Drs. Roy, Ferreira, and Lohoues), Calgary (Drs. Scott and Machida) and Edmonton (Drs. Jones and Smith). Patient recruitment started in April 1989, and the last patient completed the study in January 1993. Of 55 patients enrolled, 6 were excluded as screening failures (violations of the exclusion criteria not recognized at the time of enrollment: 3 patients failed to have daily regurgitation during the baseline study period, 1 patient's parents failed to provide baseline daily diary data, and 2 patients were withdrawn during the baseline study period at parental request). Forty-nine patients were randomized; however, 4 were later excluded from efficacy analysis because of protocol violations (1 patient had not had daily regurgitation during the baseline study period and had still been randomized, I had failed to have at least one episode of gastroesophageal reflux documented on the baseline pH study and had still been randomized, 1 patient's parents failed to provide daily diary data, and 1 patient's treatment was disrupted on three occasions during the study, and the subject was excluded for noncompliance). Of the remaining 45 evaluable patients, 21 were assigned to cisapride and 24 to placebo.
The mean ±SD and range of the age of the cisapride patients was 8.4 + 3.2 months (range, 2-17 months) and of the placebo patients 8.3 + 4.2 months (range, 2-20 months). Both treatment groups had the same mean duration (6.7 months) of GERD history. All infants had had persistent daily reflux despite the age-appropriate use of thickened feedings in bottle-fed infants and prescribed positioning after meals and during sleep. None of the infants were taking other prokinetic agents, antacids, or H2 antagonists at the time of referral. The ratio of male to female patients was 12:9 in the cisapride group and 12:12 in the placebo group. The rate of recurrent respiratory infections was 14% (3 of 21) for the cisapride treatment group and 12% (3 of 24) for the placebo group. There were no significant differences between the treatment groups in any of these parameters.
Primary Parameters-Esophageal pH Monitoring
Except for significant decreases in the average duration of the longest reflux episode and supine reflux in the cisapride-treated group, as well as a significant increase in number of reflux episodes in 24 hours that lasted more than 5 minutes in the placebo group, there were no significant temporal changes in either group compared with baseline values (Table 2). Treatment with cisapride was associated with a significant decrease in the average duration of both upright and supine reflux but did not alter the percentage of time during which esophageal pH was lower than 4; the number of postprandial reflux episodes and the number occurring with the subject in upright or supine position; the number of episodes in 24 hours that lasted more than 5 minutes; or the average duration of the longest episodes (Table 2).
Secondary Parameters-Esophageal Manometry and Biopsy
Within treatment groups there was no significant temporal change in either mean LES pressure or swallow pressure at the last visit compared with pressures at baseline (Table 3). Nor did cisapride exert any effect on mean LES pressure or mean swallow pressure compared with the effect of placebo on those pressures.
Patients with abnormal findings in biopsies (consistent with reflux esophagitis) at screening were tested again at termination. Of the 43 evaluable patients undergoing biopsies (37 with endoscopic grasp forceps and 6 with blind capsule-suction biopsy) at the time of initial screening, 20 (46.5%) had abnormal findings. Of these, 11 patients were randomized to receive cisapride and 9 to receive placebo. At the end of treatment, 63.6% (7 of 11) of the cisapride-treated patients had abnormal findings in biopsies, compared with 55.5% (5 of 9) of the placebo patients (p = ns).
Tertiary Parameters-Clinical Data, Global Evaluations, and Daily Diary
There was a significant increase (improvement) in both parental and physician's visual analogue scale assessments of symptoms at visit 6 compared with values at baseline (p < 0.005); however, there were no significant differences between groups in either parental or physician's global assessments (Figure 1).
The parental global response rate (“good + excellent”) for the cisapride-treated group was 52.4% compared with 54.6% for the placebo-treated group. The physician's global response rate (“good + excellent”) for the cisapride-treated group was 28.6% compared with 45.5% for the placebo-treated group. None of the differences observed in the overall global rating were statistically significant.
Except for a significant decrease in the weighted regurgitation-vomiting scores at the week 4 and week 6 visits in the cisapride-treated group, there were no significant temporal changes in either treatment group at any of the visits, compared with baseline values (Table 4). Nor were there significant differences in the number of mild, moderate, or weighted regurgitation-vomiting episodes in the cisapride-treated group compared with the number of those events in the placebo-treated group.
Safety-Physical Parameters, Laboratory Findings, Adverse Events
No significant differences were found either within treatment groups or between treatment groups for temperature, pulse, blood pressure, or respiratory parameters. Statistically significant increases in body weight and height compared with baseline values were observed at week 6 for both treatment groups because of normal growth. However, no treatment-induced differences were detected between the two groups.
There were no significant differences between cisapride and placebo treatment groups in abnormal laboratory values or in changes in laboratory values throughout the course of the study.
A total of 85 adverse events were associated with 26 patients. Of the 85 adverse events, 63 were of unique description (33 in the cisapride-treated group and 30 in the placebo-treated group), and the remaining 22 represented the reporting of one of these unique adverse events on more than one occasion in the same patient. One or more adverse events were reported in 14 cisapride-treated patients (60.8%) and in 13 placebo-treated patients (50.0%). There were no significant differences between treatment groups.
The most common adverse events were: fever, (reported in 6 cisapride and in 5 placebo patients), diarrhea (5 cisapride, 5 placebo patients), common cold (3 placebo patients), insomnia (2 cisapride patients), nervousness (2 cisapride patients), cough (1 cisapride, 2 placebo patients) and upper respiratory infection (2 cisapride, 2 placebo patients). All other adverse events were reported in fewer than two patients per treatment group.
This is the largest double-blind, placebo-controlled study yet undertaken that objectively evaluates the efficacy and safety of cisapride in GERD in infants. The results show that cisapride suspension, when administered to pediatric patients aged from 6 weeks to 2 years at a dose of 0.2 mg/ml every 6 hours significantly reduces the duration of reflux episodes in the supine and upright positions, compared with the effect of placebo. For other parameters assessed by monitoring of esophageal pH, (number of episodes in upright and supine positions, number of episodes more than 5 minutes in duration, duration of longest episode, and percentage of time during which esophageal pH was less than 4) the efficacy of cisapride was not significantly different from that of placebo. However, compared with baseline values, the duration of the longest reflux episode was significantly shortened in the cisapride-treated group, whereas the number of reflux episodes lasting more than 5 minutes was significantly increased in the placebo-treated control group. Regarding the secondary and tertiary parameters in evaluating efficacy of therapy with cisapride, no significant between-treatment differences were observed in LES pressures assessed by esophageal manometry, frequency and severity of regurgitation-vomiting episodes documented by parents in daily diaries, or global ratings assessed by either parents or physicians. The incidence of adverse events with cisapride was comparable with the number occurring with placebo. No serious adverse experiences were reported during the study, and cisapride was well tolerated.
The role for cisapride in the treatment of GERD in infants and children has been reviewed recently (5,7,8). Cisapride's efficacy has been demonstrated in findings of two previous double-blind, placebo-controlled studies (9,10) and of several noncontrolled clinical studies (12-17), in which continuous monitoring of esophageal pH was used. These investigators cite data showing that cisapride significantly decreases the frequency and duration of reflux episodes, decreases the percentage of time esophageal pH is lower than 4, and increases LES pressure. Data in additional clinical studies (18-20) using relief of symptoms as their main endpoint have demonstrated significant dose-dependent improvement after treatment with cisapride for regurgitation and vomiting in infants.
In this study's results the only significant effect of treatment with cisapride compared with that of placebo was in the shortened duration of reflux episodes, which is an indirect measure of esophageal clearance. In addition, comparisons with baseline values show that cisapride significantly reduced the duration of the longest reflux episode. We attribute the lack of a treatment effect for this latter parameter (no significant difference between effect of cisapride and that of placebo) to the disproportionately large variability of data in the placebo group. At baseline the mean duration of the longest reflux and standard deviation (SD) was 85 ± 132 minutes for the placebo group, with individual values ranging from 1 to 450 minutes. For cisapride these values were 62 ± 61 minutes, with individual values ranging from 4 to 199 minutes.
In view of the available literature emphasizing the efficacy of cisapride in the treatment of GERD in children, the failure of the data in this clinical study to demonstrate convincingly significant improvements, particularly in GERD symptomatology-parent-assessed regurgitation and vomiting-as well as in global improvement ratings must be explained. For instance, it is well established that data collected in studies with parental assessments of symptoms are subject to a great deal of variability and that a substantial placebo response can be expected. Furthermore, the frequency and severity of GERD symptoms seem to be self-limiting and usually decrease during the second 6 months of life, coincident with assumption of an upright position and introduction of solid feeding (1). In this study, the lack of treatment effects also may reflect inadequate patient accrual and a subsequent lack of statistical power. The results were based on data from 43 patients and fell short of the original sample size calculations, which required 60 evaluable patients to show a 40% difference in overall global response rate (alpha = 0.05, beta = 0.8). A larger sample size might have demonstrated additional differences in results of our efficacy measurements. However, our findings are consistent with those reported in two other double-blind, placebo-controlled studies (9,10). Cucchiara et al. (9) reported the 24-hour esophageal pH, manometric, and histologic data on 20 children with reflux esophagitis (age range, 75 days to 47 months) entered into a randomized, double-blind, placebo-controlled trial of cisapride. Seventeen patients completed the trial, 8 of whom were taking the drug, and 9 the placebo. No significant difference was demonstrated in treatment with cisapride versus treatment with placebo. More recently, Vandenplas et al. (10) reported 24-hour esophageal pH data in 29 infants with GERD (2-4 months old) who were randomly allocated to double-blind treatment with cisapride or with placebo. During 13 to 16 days of treatment, the number of reflux episodes lasting longer than 5 minutes was the only parameter for which the degree of improvement was significantly greater in the cisapride group.
Thus, the data for 24-hour esophageal pH reported here and the findings in the two other pediatric, randomized, double-blind, placebo-controlled trials in the literature are consistent in demonstrating that cisapride decreases the duration of reflux episodes.
Acknowledgment: The authors thank Dr. Rein Treffers, Clinical Research Manager, Janssen Pharmaceutica Inc. for compilation of the initial data and for preparation of the internal report, Janet McDougall for statistical analysis, Roberta Funk for typing the manuscript, and the members of the Divisions of Gastroenterology at each of the study sites for their support in completing this protocol.
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