Efficacy and Safety of Lansoprazole in Adolescents with Symptomatic Erosive and Non-erosive Gastroesophageal Reflux Disease

Abstract

Objectives: 

To assess the efficacy and safety of lansoprazole in the treatment of adolescents with symptomatic, endoscopically proven, non-erosive gastroesophageal reflux disease and erosive esophagitis.

Methods: 

Adolescents between 12 and 17 years of age with esophagitis were enrolled in this open-label trial and treated with lansoprazole 15 mg (non-erosive) or 30 mg (erosive) once daily for 8 weeks. If unhealed at week 8, those with erosive esophagitis were treated with an additional 4 weeks of lansoprazole 30 mg once daily.

Results: 

Lansoprazole produced a significant reduction from baseline in the median percentage of days with reflux symptoms (91 to 43% in the 64 adolescents with non-erosive disease and 85 to 16% in the 23 adolescents with erosive esophagitis, P ≤ 0.001 for each comparison). At week 8, mucosal healing had occurred in 95% (21 of 22) of those with erosive esophagitis. Treatment-related adverse events were reported by 19% of patients with non-erosive and 4% of patients with erosive esophagitis. Headache (7%), abdominal pain (5%), nausea (3%) and dizziness (3%) were the most frequently reported adverse events. One patient discontinued treatment early because of dizziness and vomiting. An elevation in mean serum gastrin from baseline (59 pg/mL at pretreatment to 80 pg/mL at final visit) was observed.

Conclusion: 

Lansoprazole 15 mg or 30 mg once daily reduced symptoms of gastroesophageal reflux in adolescents with non-erosive gastroesophageal reflux disease and erosive esophagitis, respectively. Lansoprazole 30 mg once daily for 8 weeks was effective in healing erosive esophagitis. Both treatment regimens were considered safe.

INTRODUCTION

Nearly 15% of healthy adolescents between 10 and 17 years of age report abdominal pain, heartburn, regurgitation or other symptoms suggestive of gastroesophageal reflux disease (GERD) (¹). Studies involving children with developmental disabilities, neurologic injury or asthma suggest a prevalence of gastroesophageal reflux disease that may be several-fold higher (^2-10).

Gastroesophageal reflux disease tends to be a chronic, lifelong condition requiring continuous treatment for symptom relief and complication management (¹¹). Proton pump inhibitors are safe and efficacious in the treatment of acid-related disorders in adults and are often used by pediatricians in managing patients of all ages with reflux disease. From 1997 to 2003, drug and diagnosis auditing data have noted a greater than fivefold increase in proton pump inhibitor prescriptions written for children 0 to 17 years. Of more than 23 million prescriptions written for proton pump inhibitors during 2003, more than 650,000 were for infants, children, and adolescents between 0 and 17 years (¹²).

This open-label, multicenter study assessed the efficacy and safety of once daily administration of lansoprazole 15 mg or 30 mg in the treatment of adolescents with endoscopically proven non-erosive GERD and with erosive esophagitis, respectively.

METHODS

Patient Selection

Male and non-pregnant female adolescents between 12 and 17 years with active symptomatic gastroesophageal reflux and a history of reflux symptoms (e.g., regurgitation, sour taste, heartburn, retrosternal pain, vomiting) for at least 3 months were eligible for enrollment. To be eligible for the study, subjects had to have recorded at least one episode of moderate, severe, or very severe GERD symptoms in the pretreatment diary during the 6 days before study initiation. Adolescents were excluded if they had: extra-esophageal symptoms only (e.g., wheezing, cough, hoarseness); duodenal or gastric ulcers of at least 3 mm in diameter; current esophageal stricture requiring dilatation; acute upper gastrointestinal hemorrhage; coexisting systemic disease affecting the esophagus (e.g., scleroderma, eosinophilic esophagitis confirmed by history, endoscopy and esophageal biopsy, viral or fungal infection); recent radiation to the esophagus; caustic or physiochemical trauma to the esophagus; possible Zollinger Ellison syndrome; esophageal varices; symptomatic pancreaticobiliary tract disease; cholecystitis; juvenile rheumatoid arthritis or lupus; malignancy requiring treatment or unstable disease affecting a major organ system; history of gastric, duodenal or esophageal surgery; >12 doses per month use of ulcerogenic drugs - nonsteroidal anti-inflammatory drugs, oral or intravenous systemic corticosteroids (≥ 10 mg per day of prednisone); used a proton pump inhibitor within 2 weeks of the pretreatment period; evidence of alcohol or drug abuse in the past 12 months.

Study Design

The study was a Phase 2, multicenter (20 United States investigative sites as listed in the Appendix), open-label study consisting of a pretreatment period (7 to 14 days based on patient schedules) and an 8-week treatment period with the option of an additional 4 weeks of treatment in erosive esophagitis patients if unhealed at the week 8 visit. Approval for the study was obtained from the Institutional Review Board at each participating site. Informed consent was obtained from a parent/legal guardian for all participants and assent was obtained from the participant (if required by the Institutional Review Board) before the performance of any study-related procedure.

Pretreatment Period

During the pretreatment period, the following measures were used to determine patient eligibility: complete medical history and physical examination, endoscopy and laboratory evaluations. Subjects were provided with antacid (Mylanta® Liquid, J&J Merck) to be taken as needed for relief of symptoms during the pretreatment period. Adolescents (parents/guardians as necessary) were instructed to maintain a daily diary of the severity of gastroesophageal reflux symptoms and the frequency and amount of antacid use.

Treatment Period

Adolescents completing all pretreatment procedures and meeting inclusion criteria were assigned to one of two treatment groups based on the esophagitis grade observed at pretreatment endoscopy Those with non-erosive gastroesophageal reflux disease (defined as grade 1 or less by a predefined grading scale as described in Table 1) were treated with lansoprazole 15 mg once daily for 8 weeks. Adolescents with erosive esophagitis (defined as grade 2 or more by the grading scale in Table 1) were treated with lansoprazole 30 mg for 8 weeks and, if unhealed at the 8 week visit, were treated for an additional 4 weeks. The doses of lansoprazole used in the study were based on a Written Request from the United States Food and Drug Administration. Subjects were to administer the lansoprazole capsules (Takeda Chemical Industries Ltd., Osaka, Japan) orally each morning before breakfast or the first meal of the day. Adolescents who were unable to swallow the intact capsule were allowed to open the capsule and empty the granules into a tablespoon of applesauce or an alternative listed in the product label before oral administration. Antacid was also dispensed and subjects instructed not to take the antacid within 30 minutes of lansoprazole administration. Subjects or guardians were given a diary in which to record daily the severity of gastroesophageal reflux symptoms.

TABLE 1: Endoscopic Esophagitis Grading Scale

Adolescents returned to the investigative site after 4 and 8 weeks of treatment. During each visit subjects had a physical examination, measurement of vital signs, assessment of adverse events and current medications, fasting serum gastrin level, assessment of compliance by capsule count, evaluation of antacid use from diary review and assessment of gastroesophageal reflux symptoms based on investigator interview. The subject (parent/caregiver if necessary) completed a question on overall gastroesophageal reflux symptom relief during the preceding week as compared with symptoms existing before treatment in the daily diary. Adolescents with erosive esophagitis (30mg/day lansoprazole) underwent follow-up endoscopy at the week 8 visit. Those with healed erosive esophagitis (grade 1 or less) completed study participation at this visit. Adolescents with unhealed mucosa were treated for an additional 4 weeks. Follow-up endoscopy to assess healing was performed in these adolescents at the week 12 visit and medical and laboratory procedures performed at the week 4 and 8 visit were repeated.

Patient Evaluations

Endoscopy

Endoscopy with biopsy and photographic documentation was performed during the pretreatment period to determine the presence and severity of esophagitis (using the grading scale summarized in Table 2) and to rule out eosinophilic esophagitis, Barrett's esophagus with or without dysplastic changes, esophageal stricture requiring dilatation, esophageal varices, acute upper gastrointestinal hemorrhage and gastric or duodenal ulcer of 3 millimeters or more in diameter. During each endoscopy three esophageal biopsies were taken using grasp forceps from an area 2.5 to 5.0 cm above the Z-line or 4 to 6 cm above the top of the gastric fold (if the Z-line was not clearly visualized) to evaluate for histologic esophagitis and exclude those subjects with eosinophilic esophagitis. Follow-up endoscopy was performed at weeks 8 and 12 (if applicable) in those with erosive esophagitis at the pretreatment procedure. Biopsies were also taken from the stomach and duodenum and to rule out Helicobacter pylori infection.

TABLE 2: Esophageal History Grading Scale

Symptom Assessments

Gastroesophageal reflux symptom relief was assessed by the change from pretreatment period in the daily diary response to the question on overall gastroesophageal symptoms occurring during the previous week and by the overall gastroesophageal symptom assessment determined by the investigator interview.

Daily Diary

At the pretreatment visit the adolescent's predominant gastroesophageal reflux symptoms were identified by investigator interview. Adolescents or their guardians were instructed to assess the symptoms and grade their severity daily and record these data in the daily diary. Symptom severity was graded as none, mild (bothered a little or symptoms present part of day or night but causing little or no discomfort and not interfering with sleep), moderate (bothered some or symptoms present half of day or night, annoying but not interfering with daily routine or occasionally interfering with sleep), severe (bothered a lot or symptoms present most of the day or night or interfering with daily routine or sleep), or very severe (bothered intensely or constant symptoms or marked interference with daily routine or sleep). Adolescents (caregivers or parents) were also asked to record the frequency of antacid use and lansoprazole administration. At weeks 4, 8 and 12 (if applicable), adolescents (parents/caregivers as necessary) recorded the answer to the question asking how the overall gastroesophageal reflux symptoms were during the preceding week as compared with symptoms occurring before treatment in the daily diary.

Investigator-Elicited Gastroesophageal Reflux Symptom Assessment

The investigator assessed overall gastroesophageal reflux symptoms at each visit to determine the severity of the symptoms the adolescent experienced during the week before the visit. Symptom severity was graded by the investigator as none = 0, mild = 1 (symptom did not last long and was easily tolerated), moderate = 2 (symptom caused discomfort and interrupted usual activities) or severe = 3 (symptoms caused great interference with usual activities and may have been incapacitating).

Safety Assessments

The safety of lansoprazole was monitored by reports of adverse events, complete physical examination including vital signs and laboratory evaluations (hematology, chemistry, urinalysis, pregnancy test for females and serum gastrin determinations).

Adverse events were rated by the investigator as mild (transient and easily tolerated), moderate (caused discomfort and interrupted usual activities) or severe (caused considerable interference with usual activities and may have been incapacitating or life-threatening), and the relationship to study medication was judged as definite (event followed a reasonable temporal sequence from administration of the drug and satisfied any of the following: reappearance of similar reaction by repeated exposure, positive results in drug sensitivity tests or toxic levels of the drug in the blood or other body fluid), probable (event followed a reasonable temporal sequence from administration of the drug and the possibilities of factors other than the drug such as underlying disease, concomitant drugs or concurrent treatment were excluded), possible (event followed a reasonable temporal sequence from administration of the drug and the possibility of drug involvement could not be excluded; other factors such as underlying disease, concomitant drugs or concurrent treatment were presumable), unlikely (event had an improbably temporal sequence from administration of the drug or it could have been reasonably explained by other factors, including underlying disease, concomitant drugs or concurrent treatment) or not related (event had no temporal sequence from administration of the drug or it could be explained by other factors, including underlying disease, concomitant drug or concurrent treatment).

Statistical Analyses

Demographic Parameters and Efficacy Evaluations

Demographic and baseline variables were summarized. Severity of overall gastroesophageal reflux symptoms based on investigator interview was tabulated by scores 0-4 as described. Frequency and severity of gastroesophageal reflux symptoms as recorded in pretreatment diaries were summarized using scores of 0-4 as described. The percentage of days antacid was used during the pretreatment period was calculated.

The change in the frequency (average percentage of days with symptoms for the evaluated period) and severity (average severity for the evaluated period) of gastroesophageal reflux symptoms based on patient diary entries from the pretreatment period to the first 8 weeks treatment period (primary efficacy variable) and the first 4 weeks of treatment period were analyzed using the sign test. The frequency and severity of sign statistic was used to test the changes from baseline to the week 4, week 8 and final visits in overall gastroesophageal symptoms assessments based on investigator interview and the numbers of subjects who answered the question as having better (scored as 1), no change (0) or worse (−1) gastroesophageal symptoms over the past week in the daily diary. The percentage of adolescents with endoscopically documented healing of erosive esophagitis at the week 8 or week 12 (if applicable) visit was calculated. During the treatment period, mean percent of drug compliance was assessed by analysis of variance.

Safety Assessments

The number and percentage of patients reporting adverse events was tabulated by COSTART term and body system with and without a breakdown by lansoprazole dose. Descriptive statistics for changes from the pretreatment period in laboratory tests and vital signs were computed for each dose group and analyzed by one-sample Student t-test.

RESULTS

Study Population

Eighty-seven adolescents (34 males and 53 females) of mean age 14.1 ± 1.6 years years (SD, range 11 to 17) were enrolled in the study. A less than 1-year history of gastroesophageal reflux was reported by 30 (34%) adolescents, a 1- to 2-year history in 13 (15%), a >2-year and <5-year history in 28 (32%) and 16(18%) adolescents had a greater than 5-year history of reflux. Fifty-three (61%) of the 87 adolescents had received previous therapy with antacids or gastric acid antisecretory agents: 18 (21%) adolescents had been previously treated with a proton pump inhibitor.

Non-erosive gastroesophageal reflux was found in 64 (74%) adolescents and was treated with lansoprazole 15 mg once daily. Among the 64 adolescents with non-erosive esophagitis, 18 had grade 0 and 46 had grade 1 esophagitis. Of the 23 (26%) of adolescents found to have erosive esophagitis and treated with lansoprazole 30 mg once daily, 20 were classified as grade 2, three were classified as grade 3 and no subject had grade 4 involvement. At baseline, there was a statistically significant correlation between esophagitis grade and the most abnormal histology grade (Spearman correlation coefficient = 0.32, P = 0.003).

Demographic variables at baseline of age, weight for males and females, ethnicity, and H. pylori status were comparable between the lansoprazole treatment groups (Table 3). One patient with non-erosive gastroesophageal reflux was enrolled in the study 27 days before his 12th birthday. Five adolescents in the lansoprazole 15 mg treatment group were prematurely discontinued from the study (three symptomatic therapeutic failures, one adverse event and one poor compliance). None of the erosive esophagitis subjects treated with lansoprazole 30 mg were prematurely discontinued from the study. The majority of adolescents, 76% (66 of 87), were more than 90% compliant with their lansoprazole regimen; 22% (19 of 87) were between 70% and 90% compliant and 2% (2 of 87) were less than 70% compliant.

TABLE 3: Demographic Characteristics at Baseline

Symptom Assessments

Pretreatment Daily Diary and Investigator Interview

Epigastric pain (21.8%, 19 of 87), heartburn (19.5%, 17 of 87), abdominal/stomach pain (17.2%, 15 of 87), regurgitation (13.8%, 12 of 87), nausea/vomiting (12.6%, 11 of 87), retrosternal pain (9.2%, 8 of 87), chest pain (5.7%, 5 of 87) and dysphagia (2.3%, 2 of 87) were the predominant symptoms of gastroesophageal reflux that were reported at the pretreatment assessment. Some subjects reported more than one predominant symptom. Among those with non-erosive disease, symptoms of gastroesophageal reflux occurred on a median of 91% of days, with an average daily symptom severity of 1.56. In these subjects antacids at an average daily dose of 1.35 teaspoonfuls were used on a median of 55% of days. Among those with erosive esophagitis, symptoms of gastroesophageal reflux occurred on a median of 85% of days with an average daily symptom severity of 1.89. In these subjects antacids at an average daily dose of 1.56 teaspoonfuls were used on a median of 50% of days. Based on investigator-elicited gastroesophageal reflux symptom assessment approximately 70% of adolescents with either non-erosive (45 of 64) or erosive (16 of 23) disease were considered to have moderate symptoms (symptoms caused discomfort and interrupted usual activities): four adolescents in the non-erosive group and five in the erosive group were considered to have severe symptoms (symptoms caused great inference with usual activities and may have been incapacitating) of reflux.

Symptom Relief by Daily Diary and Investigator Interview during Treatment Period

Both treatment subgroups (Table 4) demonstrated statistically significant (P < 0.001) reductions from the pretreatment period to the week 4, week 8 and final visits in the median percentage of days the subjects experienced symptoms of gastroesophageal reflux (Fig. 1). The average daily severity of the symptoms (Fig 2.), the median percentage of days antacid was used and the average number of teaspoons of antacid taken daily were also significantly reduced from pretreatment to study visits at weeks 4, 8 and the final visit. Among those with erosive esophagitis at pretreatment, the median percentage of days with reflux symptoms as well as the average daily severity of symptoms decreased over fourfold (~85% to ≤19%, P < 0.001) during the first 4 weeks of treatment.

TABLE 4: Summary of Diary Results from Pretreatment Period to Week 4, Week 8, and Final Visit

FIG. 1: Median percentage of days with symptoms of gastroesophageal reflux. *Statistically significant from pretreatment at P < 0.001.

FIG. 2: Median of the average daily severity of gastroesophageal reflux symptoms. *Statistically significant from pretreatment at P < 0.001.

At the final treatment visit, statistically significantly higher percentages of subjects in both treatment categories judged their overall symptoms of gastroesophageal reflux disease to be “better” as compared with before treatment (71% [42 of 59] of non-erosive subjects and 78% [18 of 23] of those with erosive esophagitis) (P < 0.001). Nineteen (23%) adolescents (14 with non-erosive and five with erosive esophagitis) rated their symptoms as “no change” and three adolescents with non-erosive disease rated their symptoms as worse.

By investigator interview, overall symptoms of gastroesophageal reflux disease resolved or improved from pretreatment to the final visit for 74% (63 of 85) of all adolescents (P ≤ 0.001). Among those with non-erosive reflux, 65% (41 of 63) exhibited resolution or improvement. All adolescents with erosive disease (100%, 22 of 22) exhibited symptom resolution or improvement.

Erosive Esophagitis Healing

Twenty-three subjects with erosive esophagitis at baseline had follow-up endoscopy at the final visit. One erosive esophagitis subject had endoscopy (showing healed esophagitis) 7 days post-treatment and was not included in the healing analysis. Among the remaining 22 subjects, 95% (21 of 22) of adolescents with erosive esophagitis treated with lansoprazole 30 mg had endoscopy confirmed mucosal healing by week 8. Only one adolescent was unhealed at week 8 and was treated with an additional 4 weeks of lansoprazole 30 mg. His esophagitis (grade 2) persisted with no change from pretreatment at both the week 8 and week 12 visits.

Safety Assessments

Sixty-six percent (57 of 87) of the adolescents enrolled in the study experienced one or more treatment-emergent adverse events. The two most frequently reported treatment-emergent adverse events were headache (14 of 87, 16%) and abdominal pain (12 of 87, 14%). Fifteen percent (13 of 87) of the adolescents experienced adverse events considered possibly or probably treatment-related, which occurred in 19% (12 of 64) of adolescents with non-erosive gastroesophageal reflux treated with lansoprazole 15 mg once daily and in 4% (1 of 23) of adolescents with erosive esophagitis treated with lansoprazole 30 mg once daily. Although the number of adolescents preclude a statistical comparison, higher percentages of adolescents with non-erosive reflux disease compared with those having erosive esophagitis reported probably or possibly treatment-related headache (9.4% [n = 6] versus 0), abdominal pain (4.7% [n = 3] versus 4.3% [n = 1]) and dizziness (4.7% [n = 3] versus 0). Five of the six non-erosive GERD subjects with treatment-related headache had a history of headaches before receiving their first dose of study drug. One adolescent in each treatment group reported asthenia, diarrhea, and vomiting that were considered possibly or probably treatment-related. Nausea considered possibly or probably treatment-related was reported by two adolescents with non-erosive reflux and one with erosive esophagitis. One adolescent with erosive esophagitis reported anorexia that was considered possibly or probably treatment-related. Most adverse events were considered to be mild or moderate in severity. Three adolescents with non-erosive reflux experienced serious adverse events-one case each of gastroenteritis and dehydration, torn hamstring, cholecystitis and suicide attempt-that were all considered unrelated to study drug administration. One adolescent was terminated prematurely from the study as a result of dizziness and vomiting described as possibly related to study drug. No clinically important trends were observed in the evaluation of physical examinations, vital signs or laboratory results.

Among all adolescents treated with lansoprazole, the mean baseline fasting gastrin level 58.8 pg/mL) was not significantly changed at the week 8 visit (76.3 pg/mL, P = 0.057), although significant increases were noted at the week 4 (89.9 pg/mL, P = 0.005) and final (80.1 pg/mL, P = 0.015) visits. No statistically significant changes in mean fasting serum gastrin levels at baseline (82.2 pg/mL) were noted in adolescents with erosive esophagitis treated with lansoprazole 30 mg (week 4, 93.8 pg/mL; week 8, 94.8 pg/mL; or final visit, 94.7 pg/mL; P > 0.6 for each comparison). Among adolescents with non-erosive reflux treated with lansoprazole 15 mg, the mean fasting gastrin level at pretreatment (50.2 pg/mL) increased significantly (P ≤ 0.002) at the week 4 (88.2 pg/mL), week 8 (67.9 pg/mL) and final (74.8 pg/mL) visits. Five adolescents had fasting serum gastrin levels of 200 pg/mL or more during the study; two returned to normal levels (42 pg/mL and 83 pg/mL: normal range 25 to 111 pg/mL) and two remained elevated (162 and 366 pg/mL) 1 day after treatment discontinuation. No follow-up gastrin value data was available for the remaining adolescent.

DISCUSSION

Our study demonstrated that proton pump inhibitor therapy once daily for 8 weeks provided a high healing rate in adolescents with erosive esophagitis (95% [21 of 22] rate of healing) and a significant reduction in GERD-related symptoms in adolescents with non-erosive reflux disease. These adolescent data confirm similar findings in adults with erosive esophagitis and non-erosive GERD. Adolescents with both erosive or non-erosive disease also reported significant improvement in the symptoms of reflux, with most achieving a maximal therapeutic response within the first 4 weeks of treatment. Although gastroesophageal reflux disease was the suspected etiology of symptoms in those with non-erosive disease, this was not confirmed with pH-metry studies. Thus, the high percentage of these children with relief of symptoms on lansoprazole treatment is remarkable. Three children with non-erosive disease were symptomatic non-responders. It is possible that these subjects may have had a component of functional abdominal pain that persisted during the treatment period in addition to the symptoms caused by esophagitis, whereas the symptoms in subjects with erosive esophagitis were the result of esophagitis only and resolved with mucosal healing. The safety evaluations in this study confirm that lansoprazole 15 mg and 30 mg once daily is well-tolerated in the treatment of adolescents with erosive or non-erosive GERD.

Among children and adolescents, gastroesophageal reflux disease is a significant source of morbidity. Nearly 4% of all pediatric hospital admissions in the United States during 2001 were associated with reflux disease (¹³). Increasing evidence supports the suspicion that several gastrointestinal disorders including reflux disease have their origins in childhood (¹⁴). Evidence from pediatric cohort studies have found that the prevalence of gastroesophageal symptoms such as heartburn increases with age, from less than 2% among children aged 3 to 9 years, to more than 22% in young adults over the age of 18 years (¹). Many of these childhood and adolescent reflux patients grow into adults with reflux disease (¹⁴)-evidence supporting the theory that gastroesophageal reflux disease may be a life-long disease (^1,14,15). A recent prospective study of 54 children between 6 and 17 years of age (mean age, 10.3 years) revealed that 39% had histories of reflux disease during infancy (¹⁶). A family history of gastroesophageal reflux was found in 42% of the children.

Complications typically associated with gastroesophageal reflux disease in adults (e.g., erosive esophagitis, stricture, hemorrhage and Barrett's esophagus) were once considered rare in children. However, these complications of prolonged gastroesophageal reflux disease appear to be occurring with increasing frequency in children and adolescents (¹³). Although the natural history of gastroesophageal reflux-related mucosal disease is not as well characterized in children and adolescents as it is in adults, a large study of 402 neurologically normal children with reflux disease and without congenital esophageal anomalies found that more than 33% had complications such as erosive esophagitis. (¹⁷) In this as well as another study (¹³), a number of children (<4%) were noted to have suspected or confirmed Barrett's esophagus. A recently completed prospective study of children found no correlation between endoscopic grade of esophagitis and symptoms of gastroesophageal reflux. Among the 54 children with symptoms of reflux 83% had grade I and 17% had grade II esophagitis (¹⁶). Children with neurologic injury, developmental disabilities or other chronic diseases tend to have a higher prevalence of gastroesophageal reflux and its complications than do children with no comorbidities (^2-4). In addition to producing gastroesophageal complications, extra-esophageal manifestations of reflux in children may also produce clinical findings of chronic and acute respiratory diseases such as asthma or pneumonia or otolaryngological manifestations such as sinusitis, laryngitis and otitis media (^10,17-19). The reported prevalence of gastroesophageal reflux disease diagnosed by pH monitoring in children with asthma has been found to range from 25% to 75% (^6-10).

Tolia et al. found that symptoms of gastroesophageal reflux produce significant decreases in quality of life for the child with reflux as well as the parents (²⁰). The morbidity, long-term complications and economic burden of gastroesophageal reflux in adults (²¹) make it easy to infer that early detection and effective treatment during childhood may result in a better long-term outcome. Effective treatment of gastroesophageal reflux disease was also noted to reduce asthma symptoms and the need for bronchodilator therapy in children with reflux-related asthma (^10,22,23). The use of prokinetic agents remains an unproven treatment option for those with gastroesophageal reflux disease (¹⁰), with their routine use being limited by the removal of cisapride from the United States market and the equivocal efficacy results from controlled studies with metoclopramide (^10,24). Concern for the short-term and long-term safety of metoclopramide in addition to its equivocal efficacy comes from its potential for serious adverse neurologic complications (^10,24). Anti-secretory agents such as histamine-2 receptor antagonists and proton pump inhibitors are the agents principally used in children and adolescents with reflux disease. Numerous studies in adults have confirmed that proton pump inhibitors are more effective than histamine-2 receptor antagonists at producing symptom relief and mucosal healing (^25-32). Moreover, placebo-controlled trials of histamine-2 receptor antagonists in pediatric patients with erosive esophagitis demonstrated that >30% of children with erosive esophagitis have persistent endoscopically evident disease after 8 to 12 weeks (¹⁰). This is in comparison with healing rates of virtually 100% with proton pump inhibitor therapy in children with mucosal disease (³³).

The results of this study are consistent with those of recently published studies of children and adolescents that have found high rates of symptom relief and mucosal healing with proton pump inhibitor therapy, even in children whose disease was refractory to histamine-2 receptor antagonists or surgery (^33-38). Gunasekaran et al. (³⁵) specifically evaluated the efficacy and safety of lansoprazole 15 mg or 30 mg once daily in adolescents with gastroesophageal reflux and found that after 5 days of treatment, the majority of 63 treated adolescents reported symptom improvement. In addition the study group demonstrated significant reductions from baseline in the percentage of days and nights with symptoms, the severity of symptoms, the percentage of days antacids were used and the dose of antacids used per day. Franco (³⁷) found that the majority of children (age range, 3 to 15 years) with erosive esophagitis refractory to histamine-2 receptor antagonist therapy exhibited healing after lansoprazole therapy. Similar results were observed by Hassall et al. (³⁴) and Karjoo and Kane (³⁸) in studies of omeprazole given to children ranging in age from 1 to 18 years with histamine-2 receptor antagonist refractory erosive esophagitis.

The incidence of adverse events reported in this study are similar to those found in adults and in previous studies involving children and adolescents (^33,39). Headache was the most frequently reported adverse event in this study, as in other studies. Among the six adolescents who reported headache after treatment with lansoprazole 15 mg, five had a history of headaches before receiving their first dose of study drug.

In conclusion, these findings support anecdotal evidence from clinical practice that lansoprazole, 15 mg or 30 mg per day, is well-tolerated and is effective in reducing gastroesophageal reflux symptoms in adolescents with non-erosive GERD and erosive esophagitis and in healing erosive esophagitis.

Acknowledgments

The authors thank the children and parents for their participation in this study, the study nurses/coordinators for their diligent efforts, and Susan Ruffalo, Pharm.D. of MedWrite, Inc, Newport Coast, California, for her assistance in the editorial development of the manuscript.