GASTROENTEROLOGY

1992:102:109-118

Two Doses of Omenrazole Versus Placebo in Symptomatic Erkive Esophagitis: The U.S. Multicenter Study

STEPHEN J. SONTAG, BASIL 1. HIRSCHOWITZ, STEPHEN HOLT, MALCOLM G. ROBINSON, JOSE BEHAR, MALCOLM M. BERENSON, ARTHUR McCULLOUGH, ANDREW F. IPPOLITI, JOEL E. RICHTER, GEORGE AHTARIDIS, RICHARD W. McCALLUM, DANIEL J. PAMBIANCO, REN0 Z. VLAHCEVIC, DAVID A. JOHNSON, MARTIN J. COLLEN, DAVID T. LYON, THOMAS J. HUMPHRIES, ANGELINE CAGLIOLA, and RAYANNE S. BERMAN Veterans Administration Hospital, Hines, Illinois; University of Alabama School of Medicine, Birmingham, Alabama; Southern Illinois University School of Medicine, Springiìeld, Illinois; University of Oklahoma, Oklahoma City, Oklahoma; Brown University School of Medicine, Providence, Rhode Island; University of Utah Medical Center, Salt Lake City, Utah; Metropolitan Genera1 Hospital, Cleveland, Ohio; University of California, Los Angeles, California; Bowman-Gray School of Medicine, Winston-Salem, North Carolina; Graduate Hospital, Philadelphia, Pennsylvania; University of Virginia Health Sciences Center, Charlottesville, Virginia; Medical College of Virginia, Richmond, Virginia; National Naval Medical Center, Bethesda, Maryland; Loma Linda University Medical Center, Loma Linda, California; Long Island College Hospital, Brooklyn, New York; and Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania

Two hundred thirty patients with reflux symptoms and endoscopically proven erosive esophagitis were enrolled from 15 U.S. centers into a randomized, double-blind, dose-ranging study comparing placebo with omeprazole, 20 or 40 mg given once daily in the morning. Esophagitis grade 2 was present in 44% of patients, grade 3 in 37% of patients, and grade 4 in 19% of patients. Endpoints, defined as complete relief of hearthurn and complete esophageal mucosal healing, were assessed after 4 and 8 weeks of treatment. J3oth omeprazole doses were significantly superior to placebo in complete endoscopic healing. After 8 weeks of treatment, 73.5% of patients in the 20-mg omeprazole group and 74.7% in the 40-mg omeprazole group, compared with 14.0% in the placebo group, had complete healing of the esophageal mucosa. At the end of the study, complete relief of daytime heartburn was obtained in 79.5% of patients in the 20-mg omeprazole group, 81.8% in the 40-mg omeprazole group, and 37.2% in the placebo group (P I 0.05).Complete relief of nighttime heartburn was noted by 79.5% of patients in the 20-mg omeprazole group, 85.1% in the 40-mg omeprazole group, and 34.9% in the placebo group (P 5 0.05). The median time to complete relief of daytime and nighttime heartburn occurred earlier

in the Jo-mg group than in the 20-mg group (9 vs. 17 days and 9 vs. 20 days, respectively); however, these differences were not statistically significant. Relief of acid regurgitation and dysphagia also occurred earlier in the 40-mg group. Omeprazole was wel1 tolerated in this group of patients. NO unexpected adverse experiences occurred. The results of this study confirm those of six multicenter, international trials in which omeprazole in doses of 20-80 mg provided a degree of esophageal mucosal healing and complete relief of reflux symptoms superior to any other medical treatment.

S

reflux (GER) are ymptoms of gastroesophageal common in the genera1 population and are probably responsible for the large consumption of ad libiturn antacids.’ Indeed, GER symptoms are experienced at least once daily by 7% of the adult population,’ and pathological changes in the esophageal mucosa occur in up to 40% of adults with typical GER symptoms3 These changes range from esophageal mucosal congestion to erosion, ulceration, stric0 1992 by the American

Gastroenterological

0018-5085/92/$3.00

Association

110

SONTAG ET AL.

ture, and metaplastic or dysplastic columnar epithelium (Barrett’s esophagus). Factors contributing to pathological GER include lower esophageal sphincter incompetence,4,5 delayed esophageal clearance of refluxed gastric contents,6*7 especially while asleep,’ and delayed gastric emptying.g-‘l Although components of gastric contents such as bile and pancreatic juice have been suggested as contributors to esophageal mucosal injury and symptoms,‘2-15 prolonged exposure of the esophageal mucosa to acid and pepsin is thought to be most important.‘6*g Omeprazole, a substituted benzimidazole H+/ K+-ATPase inhibitor that is able to suppress up to 80% of gastric acid secretion for up to 24 hours,20-22 is a likely agent to heal acid-induced reflux esophagitis. Therefore, we compared omeprazole, 20 and 40 mg, with placebo for up to 8 weeks in patients with GER symptoms and macroscopic erosive or ulcerative esophagitis (grades 2-4) to evaluate omeprazole’s tolerability and efficacy in the relief of GER symptoms and the healing of moderate to severe esophagitis.

Materials and Methods Study Design The study was conducted as a double-blind, randomized, dose-ranging, placebo-controlled, multicenter clinical trial in which patients received either 20 or 40 mg of omeprazole or placebo, each given once daily in the morning. Twice as many patients were assigned to the active treatment groups than to the placebo group. The double-dummy technique was used. Randomization was performed within 3 days of the baseline endoscopic demonstration of erosive esophagitis. Endoscopy was repeated at the end of treatment week 4, and if the patient was not healed, again at week 8. Directed esophageal biopsies were taken at the initial and final endoscopic examinations only if the presence of Barrett’s esophagus (defined as the presence of specialized columnar epithelium at any leve1 of the tubular esophagus) was suspected. Esophageal mucosal healing was defined as complete reepithelialization of al1 ulcers and erosions. Patients Two hundred thirty patients between 20 and 83 years of age from 15 medical facilities, including university centers, Veterans Administration hospitals, and private clinics, were enrolled in the study. Patients were eligible for enrollment if they had the following: symptoms of GER (such as heartburn), endoscopic evidente of esophagitis of grade 2 or greater (Table l), and no history of taking therapeutic doses of H,-receptor antagonists for more than 2 weeks immediately before beginning coded medication. Patients were excluded from the study if they had no GER symptoms; if there was an established primary esophageal motility disorder; if they had esophageal stricture or

GASTROENTEROLOGY Vol. 102, No. 1

Table

1. Endoscopic

Classijication

of Esophagitis

Grade 0 Normal mucosa with no abnormalities Grade 1 Erythema or hyperemia of the esophageal mucosa, with no macroscopic e .nsion Grade 2 Superficial ulceration or erosions involving 40% of the last 5 cm of the esophageal squamous mucosal surface Grade 3 Superficial ulceration or erosions involving >lO%50% of the last 5 cm of the esophageal squamous mucosal surface Grade 4 Deep ulceration anywhere in the esophagus or confluent erosion of ~0% of the last 5 cm of the esophageal squamous mucosal surface

Reprinted with permission (26).

esophagitis associated with scleroderma; if an active gastric, pyloric Channel, or duodenal ulcer was present: or if there was concurrent serious disease, suggested or confirmed malignancy, or clinically significant abnormal laboratory values. In addition, patients were excluded if there was concurrent need for nonsteroidal antiinflammatory drugs, corticosteroids, anticoagulants, anticholinergics, antidepressants, salicylates, or motility drugs or if any dose of antireflux drugs had been taken within 1 week before inclusion. Patients with Barrett’s esophagus were allowed in the study if they had grade 2,3, or 4 esophagitis. Endoscopic

Assessment

Endoscopy was performed at baseline, at and, if there was no esophageal mucosal healing, 8. The severity of the esophagitis was scored from to grade 4 (Table 1). The esophageal mucosa was ered healed if al1 erosions and ulcers had healed or 1).

Symptomatic

week 4, at week grade 0 consid(grade 0

Assessment

At each visit, patients were given diary cards and asked to record the daily frequency and severity of their GER symptoms (heartburn, dysphagia, and acid regurgitation). The severity of heartburn was determined by patient self-evaluation on a 5-point scale from 0 to 4 with 0 indicating no heartburn; 1, mild heartburn present but causing little or no discomfort; 2, moderate heartburn, annoying but not interfering with daily routine; 3, severe heartburn causing marked discomfort and some interference with daily routine (daytime) or sleep (nighttime); and 4, disabling heartburn interfering considerably with daily routine (daytime) or sleep (nighttime). Gelusil tablets (Parke-Davis, Morris Plains, NJ], to be taken for heartburn, were dispensed at each visit along with study medication. Although no special diet was prescribed during the study, patients were encouraged to avoid foods that exacerbated the symptoms of their disease and to limit their consumption of caffeine, alcohol, and tobacco. Standard conservative measures were also encouraged. A medical and social history including information on tobacco use and alcohol and caffeine consumption as wel1 as an evaluation of symptoms was obtained on admission to the study. A

January 1992

physical examination was performed at each study visit, and laboratory safety tests (hematology, serum creatinine, bilirubin, alkaline phosphatase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, and urinalysis) were performed. Fasting serum gastrin levels were obtained at baseline, every 4 weeks until the esophageal mucosa was healed, and 2 weeks after treatment.

Statistical Analysis The allocation schedule for this study was triple blinded. The data base was not unblinded until al1 the data were screened and protocol violators identified. The analysis of efficacy at each time point was performed as an endpoint analysis to avoid the misrepresentation of data that would occur at 8 weeks if patients who had healed earlier or dropped out were not included. Two approaches to data analysis, differing only in the manner in which exclusions were handled, were used: The “per protocol” approach analyzed the data from al1 patients who completed the study according to protocol; the “al1 patients treated” approach (also known as the “intent-to-trest” approach) analyzed the data from al1 patients who signed the informed consent whether or not their outcomes were known (al1 patients were considered “unhealed” unless proven to be healed). The proportions of patients healed (cumulatively) at each time point were compared between treatment groups using Fisher’s Exact Test, whereas the effect on healing of various concomitant factors was assessed using the Mantel-Haenszel method.23 The time to healing and the effect of various concomitant factors on time to healing were assessed using the Mantel-Haenszel and other survival analysis methods.24~25 The time points used for analysis were week 4, week 8, and after week 8 for the patients whose final endoscopy was performed after day 60. Daytime heartburn, nighttime heartburn, acid regurgitation, and dysphagia were assessed by analyzing the time until relief. Relief was defined as a score of 0 with no recurrente and was assessed using the Mantel-Haenszel method, stratifying on baseline score. Within-group tests were performed using Wilcoxon’s signed rank test. For dichotomous demographic or concomitant variables (e.g., sex and smoking), paired differences between treatment groups were assessed using Fisher’s Exact Test. Clinical adverse experiences were analyzed using Fisher’s Exact Test. The analysis of the distribution of patients by predefined limits of change for laboratory measurements was performed using the x2 test. The study was designed to detect a 30 percentage point differente in healing of erosive esophagitis between the treatment groups with 95% power (a = 0.05, two-tailed test). Approval for the study was obtained from the human studies committee of each participating center. Results

In total, 230 patients were randomized to the three treatment groups: zO-mg omeprazole, 93 patients; 40-mg omeprazole, 91 patients; and placebo,

OMEPRAZOLE VS. PLACEBO IN EROSIVE ESOPHAGITIS 111

The three treatment groups were comparable at baseline with respect to age, sex, habits, grade of esophagitis, and presence of Barrett’s esophagus (Figure 1).

46 patients.

Healing Rates Per protocol analysis. Seventeen patients (10 in zO-mg omeprazole, 4 in 40-mg omeprazole, and 3 in placebo group) were excluded from the per protocol analysis for reasons shown in Table 2. The healing rates for the 213 evaluable patients are shown in Figure 2. At week 4, the percentage of patients with complete healing was 38.6% for the 20mg omeprazole group, 44.8% for the 40-mg omeprazole group, and 7.0% for the placebo group. After 8 weeks of treatment, the healing rates were 73.5%, 74.7%, and 14.0% for the three treatment groups, respectively, signifying a large and significant difference between omeprazole treatment and placebo (P I 0.01). Al1 patients treated analysis. The al1 patients treated analysis was similar to the per protocol analysis. At week 4, the percentage of patients with complete healing was 38.7% for the 20-mg omeprazole group, 44.0% for the 40-mg omeprazole group, and 6.5% for the placebo group. After 8 weeks of treatment, the healing rates were 73.1%, 72.5%, and 15.2% for the three groups, respectively (P I 0.01). Concomitant factors, including smoking, alcohol, caffeine, age, sex, Barrett’s esophagus, and grade of esophagitis, were analyzed to determine if they had any effect on the healing of esophagitis. Figure 3 gives the number and percentage of patients healed, stratified by these factors. The differences between the omeprazole groups and the placebo group prevailed regardless of the concomitant factors considered.

Symptom

Improvement

Figure 4 shows the percentages of patients with complete relief of heartburn. For daytime heartburn, the percentages of patients with complete relief at the end of the study were 79.5% for the 20-mg omeprazole group, 81.6% for the 40-mg omeprazole group, and 37.2% for the placebo group. For nighttime heartburn, the percentages of patients with complete relief at the end of the study were 79.5% for the 20-mg omeprazole group, 85.1% for the 40-mg omeprazole group, and 34.9% for the placebo group. Both omeprazole doses were significantly better than placebo (P I 0.01) in relief of both daytime and nighttime heartburn. Figure 5 shows the median time in days to relief of acid regurgitation, dysphagia, and daytime and nighttime heartburn for each treatment group. The

112

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GASTROENTEROLOGY Vol. 102, No. 1

100,

Percelnt

Aw

Males

Grade 2

Grade 3

Grade 4

Barrett’s Stokers

Esophagitis

omeprazole groups were significantly better than placebo (P < 0.01) in time to relief of al1 four parameters. The 40-mg omeprazole group was relieved of heartburn sooner than the 20-mg omeprazole group (9 days vs. 17 days for daytime and 9 days vs. 20 days for nighttime); however, these differences were not statistically significant. Complete Symptom

Relief Over Time

Significant reductions from baseline occurred in al1 symptoms for al1 three treatment groups during

Table 2. Reasons For Exclusions From Per Protocol Analysis of Ejjicacy Omeprazole Group

20 mg

40 mg

Placebo

No. of patients entered No. of patients excluded Reason excluded Study medication not begun within 3 days of baseline endoscopy Failed to take study medications for 5 consecutive days Took prior therapy prohibited by protocol (e.g., H, blockers) Took concomitant therapy prohibited by protocol (e.g., H, blockers) No. of oatients evaluable

93 10

91

46 3

4

Alcohol Caffeine

I

2

2

0

2

2

1

6

0

1

Figure 1. Comparability of tbe treatment groups at baseline showing similarity among treatment groups for each characteristic. H, 20 mg omeprazole; EI,40 mg omeprazole; , placebo.

the study. For daytime heartburn, there were significant reductions from baseline for al1 three treatment groups starting at day 1 (P I 0.01 for both omeprazole groups; P 5 0.05 for the placebo group). For nighttime heartburn, there were significant reductions from baseline for the two omeprazole treatment groups starting at day 1 (P I 0.01) and for the placebo group starting at day 3 (P I 0.05). For severity of acid regurgitation and dysphagia, there were significant reductions from baseline in both omeprazole groups starting at day 1 (P 5 0.01). For acid regurgitation, the placebo group had significant reductions from baseline in severity at day 1, day 5, week 4, and week 8 (P I 0.05); for dysphagia, the placebo group had significant reductions starting at day 1 (P I 0.05). Figure 6 shows the cumulative percentages of patients with complete symptom relief in (a) daytime heartburn, (b) nighttime heartburn, (c) acid regurgitation, and (d) dysphagia. Antacid Consumption Seventy-two patients (77.4%) in the 20-mg omeprazole group, 69 patients (75.8%) in the 40-mg omeprazole group, and 45 patients (97.8%) in the placebo group used antacids during the study. The mean and median average daily antacid consumption for each treatment group is shown in Table 3. The two omeprazole groups used significantly less antacid than the placebo group (P 5 0.01). Tolerability

0 83

0 87

1

43

A broad definition of an adverse experience was used in this study, encompassing any unfavor-

OMEPRAZOLE

January 1992

VS. PLACEBO IN EROSIVE ESOPHAGITIS

113

100

p IO.0 1 vs. placebo 80

60 44.8

Percent 40

LU

Figure 2. Percentage of patients with complete endoscopic healing at 4 and 8 weeks by per protocol analysis. H, 20 mg omeprazole; Cl, 40 mg omeprazole; placebo.

0+

I

able or unexpected change in clinical signs, symptoms, or laboratory test results, regardless whether the investigator considered the change related to study medication. Table 4 summarizes the number of patients in each treatment group reporting one or more clinical adverse events, the number of patients reporting at least one serious adverse event, and the number of patients withdrawn from the study because of an adverse event. The differente between the total number of patients with adverse events in the three treatment groups was not statistically significant. When possible relationship to treatment was judged by the investigator, the numbers were smaller but stil1 similar among treatment groups, i.e., 20-mg omeprazole, 12 patients (12.9%); 40-mg omeprazole, 9 patients (9.9%); and placebo, 7 patients (15.2%). Table 5 sum-

90

60

70

Percent Healed

60 50 40 30 20 10 0

36.6

weeR

4

Week 8

marizes the clinical adverse events that lead to withdrawal from the study. Adverse experiences that occurred during the study with an incidence of at least 2.5% in any of the three treatment groups are shown in Table 6. There were no significant differences between treatment groups in the proportion of patients with these adverse experiences. There were no significant differences between the three treatment groups in regard to laboratory measurements of hepatic enzymes, creatinine, blood counts, or urine. There were significant differences in the mean and median increases from baseline in fasting serum gastrin levels in both omeprazole groups at the end of the study (P s 0.01). Figure 7 shows the mean and median fasting serum gastrin levels, the interquar-

Figure 3. Relationship of concomitant factors to esophagitis healing. The only significant treatment factor interaction when the two omeprazole treatment groups were compared was the presence of Rarrett’s esophagus (P = 0.04). This interaction was caused by a higher healing rate in the omeprazole U)-mg group than in the omeprazole 40-mg group. *P = 0.04,20 vs. 40 mg omeprazole. ?? , 20 mg omeprazole (n = 83); ER,40 mg omeprazole (n = 87); ?,?placebo (n = 43).

114

GASTROENTEROLOGYVol.102,No.l

SONTAG ET AL.

100

‘p S0.01 VS placebo

‘p S0.01 VS placebo

1

??

80

1

Percent 34.9

Week 2

Week 4

Week 0

Week 2

tile ranges, and the range of levels at baseline, last value during treatment, and 2 weeks after treatment for each of the treatment groups. Sixteen patients (19.8%)in the 20-mg omeprazole group, 23 patients (28.1%)in the 40-mg omeprazole group, and no patients in the placebo group had one or more of their fasting serum gastrin values >150 pg/mL during the study. The highest reported ontherapy serum gastrin leve1 was 369 pg/mL for the 20-mg omeprazole group and 816 pg/mL for the 4Omg omeprazole group. Two weeks after therapy, 6 patients (9.1%) in the 20-mg omeprazole group, 3 patients (4.4%) in the 40-mg omeprazole group, and 2 patients (6.7%)in the placebo group had fasting serum gastrin levels that were >15O pg/mL (P = NS). Discussion

The results of this U.S. multicenter study in patients with moderate or severe reflux esophagitis showed the superiority of 20 and 40 mg of omepra-

Week 4

Week 8

Figure 4. Percentage of patients with complete relief of daytime (A) and nighttime (B) hearthurn by per protocol analysis. ?? , 20 mg omeprazole; Cl, 40 mg omepra_~_ _ zole; H, placebo.

zole over placebo. Omeprazole was superior to placebo in endoscopic healing after 4 and 8 weeks of therapy; in the percentage of patients with daytime and nighttime heartburn relief; and in the median time in days to the relief of daytime and nighttime heartburn, acid regurgitation, and dysphagia. The symptomatic responses in both omeprazole groups were reflected by greatly reduced consumption of antacid tablets. The high rate of endoscopic healing and symptom relief shown by omeprazole in this study is comparable with that seen in a similar placebo-controlled study conducted overseasz6 Unlike the overseas study, in which 40 mg of omeprazole produced a higher healing rate than 20 mg of omeprazole in the more severe grades of esophagitis, our study found no significant differences in the healing rates between the two omeprazole doses, even when grade of baseline esophagitis was considered. However, there were numerical differences favor>60

Figure 5. The median time to complete relief of regurgitation, dysphagia, and daytime and nighttime heartburn. *P ZZ0.01, omeprazole vs. placebo. ?? , 20 mg omeprazole; 0, 40

20 40 P Acid Regurgitation

>60

20 40 P

20 40 P

20 40 P

Dysphagia

Daytime Heartburn

Nighttime Heartbum

OMEPRAZOLE

January 1992

Figure 6. The cumulative percentages of patients with complete symptom relief for (A) daytime hearthurn, (B) nighttime hearthum, (C) acid regurgitation, and (D) dysphagia. Reduction of symptoms from haseline is not shown. For daytime hearthurn, there were significant reductions from haseline starting at day 1 for al1 three treatment groups. For nighttime hearthurn, significant reductions from haseline started at day 1 for the two omeprazole groups and at day 3 for the placebo group.

Daily Antacid

Consumption Median

Omeprazole 20 mg (n = 93) Omeprazole 40 mg (n = 91) Placebo (n = 46)

0.21” o.15a 2.37

NOTE. Consumption in number of tablets. ’ P < 0.01vs.placebo.

Mean o.71a 0.76' 2.99

115

Days

Days

ing the JO-mg dose over the 20-mg dose with respect to al1 symptom parameters, including daytime and nighttime heartburn, acid regurgitation, dysphagia, and median time to relief of daytime heartburn (an 8-day differente) and nighttime heartburn (an llday differente). The differences between the two doses of omeprazole in median time to complete relief of daytime and nighttime heartburn suggest a beneficial clinical effect favoring 40 mg omeprazole for some patients. Indeed, obtaining complete relief of severe reflux symptoms 9-11 days faster may be clinically relevant. The more favorable response to 40 mg omeprazole is likely attributable to the variability of the antisecretory response to the lower dose and to the fact that the higher dose is more likely than the lower dose to “assure” an effect. In six comparative overseas studies, clear superiority of omeprazole over H, blockers was shown.27-32 Omeprazole dosages of 20-60 mg per day achieved complete mucosal healing in up to 85% of patients at 4 weeks and up to 96% at 8 weeks; ranitidine and cimetidine achieved complete healing in up to 45% at 4 weeks and 66% at 8 weeks. However, it should

Tabie 3. Average

VS. PLACEBO IN EROSIVE ESOPHAGITIS

be noted that higher healing rates are often obtained in al1 treatment groups when the study is not placebo controlled. Twenty-four-hour esophageal pH studies have been conducted in both overseas and U.S. study populations.33s34 These studies compared the effects of 20 and 40 mg of omeprazole on 24hour esophageal acid exposure expressed as the percentage of the 24hour period during which esophageal pH was ~4. The overseas study showed statistical superiority for 40 mg of omeprazole than for 20 mg of omeprazole for decreased acid exposure, whereas the similar U.S. study showed that the effects of both doses of omeprazole were equivalent. Thus, the 24-hour esophageal pH studies corroborate the clinical findings in both study populations. The percentage of patients enrolled in our study

Table 4. Adverse Events in Each Treatment

Grour,

Omeprazole 20 mg (n = 93) No. of patients with adverse events (%) No. of patients with serious adverse events (%) No. of patients withdrawn due to adverse events (%)

40 mg (n = 91)

Placebo (n = 46)

42 (45.2) 38 (41.8) 22 (47.8) 4 (4.3)

2 (2.2)

1 (2.2)

4 (4.3)

5 (5.5)

2 (4.3)

NOTE. The differente between the total number of patients with adverse events in the three treatment groups was not statistically significant.

116 SONTAG ET AL.

GASTROENTEROLOGY Vol. 102, No. 1

Toble 5. CJinicaJ Adverse Experiences Leading to Withdrawal From Study Treatment

Patient

Omeprazole 20 mg

Adverse experiences

1

2

Omeprazole 40 mg

Placebo

3 4 1

2 3 4 5 1

2

Drug severity

Headache Nausea Chest pain Nausea

Severe Moderate Moderate Severe

Vomiting Pancytopenia Vomiting collgh Dizziness Diarrhea Nausea Chest pain Rash Rash Dizziness Asthenia Local weakness Pulse abnormality Headache

Severe Moderate Moderate Mild Moderate Mild Mild Moderate Moderate Moderate Severe Severe Severe Severe

Probably not Definite Possibly Possibly Possibly Possibly Definitely not Probably not Possibly Possibly Possibly Possibly Possibly

15 35 13 21 21 21 49 10 14 14 12 12 12 12

Mild

Possibly

12

NOTE. Eleven patients were withdrawn from the study because of a clinical adverse experience. treatment groujs was not statistically significant.

with severe esophagitis (grade 3 or 4 changes in 52% and 55% of the 20-mg and JO-mg omeprazole groups, respectively) indicates that our patient population represented a group with particularly severe reflux esophagitis. This is further supported by the fact that most of the patients had stopped smoking and avoided alcoholic beverages (Figure 1). Despite the severity of esophagitis, the degree of esophageal mucosal healing achieved with omeprazole in this study

TabJe 6. Most Common

CJinicaJ

Adverse

Experiences

Omeprazole

Adverse experience Abdominal pain (%) Diarrhea (%) Duodenal ulcer (%) Duodenitis (%) Gastric ulcer (%) Gastritis (%) Nausea (%) Vomiting (%) Dizziness (%) Headache (%] Cough (%) Upper respiratory infection (%) Rash (%)

Days in study

Drug relationship

20 mg (n = 93)

40 mg (n = 91)

Placebo (n = 46)

3 (3.2) 5 (5.4) 1 (1.1) 2 (2.2) 2 (2.2) 2 (2.2) 5 (5.4) 3 (3.2) 3 (3.2) 10 (10.8) 2 (2.2)

2 (2.2) 4 (4.4) 0 0 2 (2.2) 1 (1.1) 1 (1.1) 2 (2.2) 2 (2.2) 10 (11.0) 3 (3.3)

1 (2.2) 6 (13.0) 2 (4.3) 4 (8.7) 4 (8.7) 2 (4.3) 1 (2.2) 1 (2.2) 1 (2.2) 4 (8.7) 0

2 (2.2) 0

2 (2.2) 3 (3.3)

2 (4.3) 0

NOTE. Incidence 22.5%. There were no significant differences between treatment groups in the proportion of patients with these adverse experiences.

Possihly Possibly Possibly Definitely not Definitely not

The differente

14 14 14 15

between

the three

was far superior to that previously achieved with H, blockersS3’ In the largest placebo-controlled reflux study reported, 41 of 73 patients (56%) receiving 150 mg ranitidine b.i.d. had complete healing of the esophagitis at 6 weeks. Complete healing, however, was also observed in 29 of 71 patients (41%) taking placebo, suggesting that the study population had less than severe esophagitis. Using the same esophagitis grading criteria for both studies, 19% of treated patients in the ranitidine study as opposed to 52%55% of treated patients in our omeprazole study had severe reflux esophagitis. Thus, it appears that omeprazole is superior to H, blockers in the treatment of severe erosive esophagitis. From a clinical safety perspective, this study showed no differente in reported clinical adverse experiences between the two omeprazole doses and the placebo. From a laboratory safety perspective, there were significant differences between the two omeprazole doses and the placebo only in the mean and median fasting serum gastrin levels. The significant increases in the fasting serum gastrin levels seen in both omeprazole groups at the end of treatment resulted from the potent acid-suppressing capabilities of omeprazole. Two weeks after therapy had been stopped, serum gastrin levels were stil1 significantly elevated from baseline in both omeprazole groups, although the levels were decreasing toward normal. The etiology of the significant elevation in serum gastrin levels in the placebo group 2 weeks after ces-

OMEPRAZOLE

January 1992

VS. PLACEBO IN EROSIVE ESOPHAGITIS

117

Upper Limit of Range Third Quartile Median Mean First Quartile Lower Limit of Range

Gastrin (pglml)

300 200

T

1m-I 1 T

Figure 7. Box-whisker plots of fasting serum gastrin values at baseline, last value during treatment, and z weeks after treatment.

PB0

T

20

40

mg

92

Baseline

sation of therapy is uncertain. The partial decrease in gastrin levels in both omeprazole groups 2 weeks after cessation of therapy accompanied by the significant increase in serum gastrin in the placebo group resulted in no statistical differente in mean or median gastrin levels between the omeprazole groups and the placebo group 2 weeks after cessation of omeprazole therapy. We conclude that omeprazole, in doses of 20 and 40 mg, is superior to placebo in the complete healing of moderate and severe reflux esophagitis and in the complete relief of primary and secondary symptoms associated with GER disease, such as heartburn, acid regurgitation, and dysphagia. The potentially clinically significant differences favoring 40 mg of omeprazole over 20 mg of omeprazole in the time to complete relief of daytime and nighttime heartburn suggest that, for symptom relief, 40 mg of omeprazole may be superior to 20 mg of omeprazole in some patients. References

R, Chejfec G, O’Connel1 S, Moroni B. Endoscopic screening for Barrett’s esophagus, esophageal adenocarcinoma and other mucosal changes in ambulatory subjects with symptomatic gastroesophageal reflux (abstr). Gastroenterology 1985;88:Ai576.

20

40

mg

mg

1

d PB0

E

3

20

40

mg

mg

2 Weeks Post Treatment

4. Dent J, Dodds WJ, Friedman

RH, Sekiguchi T. Hogan WJ, Arndorfer RC, Petrie DJ. Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. J Clin lnvest 1980;65:256-257.

5. Dodds WJ, Dent J, Hogan WJ, Helm JF, Hauser

6.

7. 8.

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Received October 19, 1990. Accepted May 25,1991. Address requests for reprints to: Stephen J. Sontag, M.D., Ambulatory Care Service (IIC3), Hines, Illinois 60141. Supported by a grant from Merck Sharp & Dohme Research Laboratories. The authors thank the following individuals for their assistance in conducting the study: Thomas Schnell and Carole Kurucar from the Veterans Administration Hospital, Hines, Illinois; Jean Mohnen and Jane Gauldin from the University of Alabama School of Medicine, Birmingham, Alabama; Mark Smith and Debra Stapleton from the Southern Illinois University School of Medicine, Springfield, Illinois; David Mcintosh and Dennis Decktor from the University of Oklahoma, Oklahoma City, Oklahoma; Carmel Brodeur from the Brown University School of Medicine, Providence, Rhode Island; Karen Sunman and Jo Cook from the Metropolitan Genera1 Hospital, Cleveland, Ohio; Jill Foster from the University of California, Los Angeles, California; Greg Stark from the Bowman-Gray School of Medicine, Winston-Salem, North Carolina; Patrick Rush and Aurora Neromiliotis from the Graduate Hospital, Philadelphia, Pennsylvania; Karen Fisher and Susan Hoffman from the University of Virginia Health Sciences Center, Charlottesville, Virginia; Renata Hirszel from the National Naval Medical Center, Bethesda, Maryland; Cecelia Ciarleglio and Valerie Stanczak from the Loma Linda University Medical Center, Loma Linda, California; Francis Celentano and Robert Benish from the Long Island College Hospital, Brooklyn, New York. The authors also thank Jean Seidel, Hines, Virginia, for her expertise and technical assistance in helping to prepare the manuscript. Drs. Robinson and Hirschowitz have a financial interest in Merck Sharp & Dohme. Dr. Holt has a financial interest in Astra Pharmaceuticals, Sweden, who licensed omeprazole to Merck Sharp & Dohme.

Two doses of omeprazole versus placebo in symptomatic erosive esophagitis: the U.S. Multicenter Study.

Two hundred thirty patients with reflux symptoms and endoscopically proven erosive esophagitis were enrolled from 15 U.S. centers into a randomized, d...
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