CLINICAL STUDIES

14 Duodenal Ulcer In a U.S.

multicenter, double-blind, placebo-controlled, dose-response (15, 30, and 60 mg of PREVACID once daily) study of 284 patients with endoscopically documented duodenal ulcer, the percentage of patients healed after two and four weeks was significantly higher with all doses of PREVACID than with placebo.

There was no evidence of a greater or earlier response with the two higher doses compared with PREVACID 15 mg.

Based on this study and the second study described below, the recommended dose of PREVACID in duodenal ulcer is 15 mg per day ( Table 7).

Table 7: Duodenal Ulcer Healing Rates Week PREVACID Placebo 15 mg daily 30 mg daily 60 mg daily (N=68) (N=74) (N=70) (N=72) 2 42.4% (p≤0.001) versus placebo.

35.6% 39.1% 11.3% 4 89.4% 91.7% 89.9% 46.1% PREVACID 15 mg was significantly more effective than placebo in relieving day and nighttime abdominal pain and in decreasing the amount of antacid taken per day.

In a second U.S.

multicenter study, also double-blind, placebo-controlled, dose-comparison (15 and 30 mg of PREVACID once daily), and including a comparison with ranitidine, in 280 patients with endoscopically documented duodenal ulcer, the percentage of patients healed after four weeks was significantly higher with both doses of PREVACID than with placebo.

There was no evidence of a greater or earlier response with the higher dose of PREVACID.

Although the 15 mg dose of PREVACID was superior to ranitidine at four weeks, the lack of significant difference at two weeks and the absence of a difference between 30 mg of PREVACID and ranitidine leaves the comparative effectiveness of the two agents undetermined ( Table 8) [see Indications and Usage (1.1)].

Table 8: Duodenal Ulcer Healing Rates PREVACID Ranitidine Placebo Week 15 mg daily 30 mg daily 300 mg h.s.

(N=80) (N=77) (N=82) (N=41) 2 35.0% 44.2% 30.5% 34.2% 4 92.3% (p≤0.05) versus placebo and ranitidine.

80.3% (p≤0.05) versus placebo.

70.5% 47.5% H.

pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Randomized, double-blind clinical studies performed in the U.S.

in patients with H.

pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) evaluated the efficacy of PREVACID in combination with amoxicillin capsules and clarithromycin tablets as triple 14 day therapy or in combination with amoxicillin capsules as dual 14 day therapy for the eradication of H.

pylori.

Based on the results of these studies, the safety and efficacy of two different eradication regimens were established: Triple therapy: PREVACID 30 mg twice daily/amoxicillin 1 g twice daily/clarithromycin 500 mg twice daily Dual therapy: PREVACID 30 mg three times daily/amoxicillin 1 g three times daily All treatments were for 14 days.

H.

pylori eradication was defined as two negative tests (culture and histology) at four to six weeks following the end of treatment.

Triple therapy was shown to be more effective than all possible dual therapy combinations.

Dual therapy was shown to be more effective than both monotherapies.

Eradication of H.

pylori has been shown to reduce the risk of duodenal ulcer recurrence.

A randomized, double-blind clinical study performed in the U.S.

in patients with H.

pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of PREVACID triple therapy for 10 and 14 days.

This study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating H.

pylori ( Tables 9 and 10) [see Indications and Usage (1.2)].

Table 9: H.

pylori Eradication Rates – Triple Therapy (PREVACID/amoxicillin/clarithromycin) Percent of Patients Cured [95% Confidence Interval] (Number of patients) Study Duration Triple Therapy Evaluable Analysis Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H.

pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest, histology and/or culture.

Patients were included in the analysis if they completed the study.

Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the evaluable analysis as failures of therapy.

Triple Therapy Intent-to-Treat Analysis Patients were included in the analysis if they had documented H.

pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year).

All dropouts were included as failures of therapy.

M93-131 14 days 92 (p<0.05) versus PREVACID/amoxicillin and PREVACID/clarithromycin dual therapy.

[80.0-97.7] (N=48) 86 [73.3-93.5] (N=55) M95-392 14 days 86 (p<0.05) versus clarithromycin/amoxicillin dual therapy.

[75.7-93.6] (N=66) 83 [72.0-90.8] (N=70) M95-399 The 95% confidence interval for the difference in eradication rates, 10 day minus 14 day is (-10.5, 8.1) in the evaluable analysis and (-9.7, 9.1) in the intent-to-treat analysis.

14 days 85 [77.0-91.0] (N=113) 82 [73.9-88.1] (N=126) 10 days 84 [76.0-89.8] (N=123) 81 [73.9-87.6] (N=135) Table 10: H.

pylori Eradication Rates – 14 Day Dual Therapy (PREVACID/amoxicillin) Percent of Patients Cured [95% Confidence Interval] (Number of patients) Study Dual Therapy Evaluable Analysis Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H.

pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest, histology and/or culture.

Patients were included in the analysis if they completed the study.

Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy.

Dual Therapy Intent-to-Treat Analysis Patients were included in the analysis if they had documented H.

pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year).

All dropouts were included as failures of therapy.

M93-131 77 (p<0.05) versus PREVACID alone.

[62.5-87.2] (N=51) 70 [56.8-81.2] (N=60) M93-125 66 (p<0.05) versus PREVACID alone or amoxicillin alone.

[51.9-77.5] (N=58) 61 [48.5-72.9] (N=67) Long-Term Maintenance Treatment of Duodenal Ulcers PREVACID has been shown to prevent the recurrence of duodenal ulcers.

Two independent, double-blind, multicenter, controlled trials were conducted in patients with endoscopically confirmed healed duodenal ulcers.

Patients remained healed significantly longer and the number of recurrences of duodenal ulcers was significantly less in patients treated with PREVACID than in patients treated with placebo over a 12 month period ( Table 11) [see Indications and Usage (1.3)].

Table 11: Endoscopic Remission Rates Percent in Endoscopic Remission %=Life Table Estimate Trial Drug No.

of Pts.

0-3 0-6 0-12 #1 PREVACID 15 mg daily 86 90% (p≤0.001) versus placebo.

87% 84% Placebo 83 49% 41% 39% #2 PREVACID 30 mg daily 18 94% 94% 85% PREVACID 15 mg daily 15 87% 79% 70% Placebo 15 33% 0% 0% In trial #2, no significant difference was noted between PREVACID 15 mg and 30 mg in maintaining remission.

Gastric Ulcer In a U.S.

multicenter, double-blind, placebo-controlled study of 253 patients with endoscopically documented gastric ulcer, the percentage of patients healed at four and eight weeks was significantly higher with PREVACID 15 mg and 30 mg once a day than with placebo ( Table 12) [see Indications and Usage (1.4)].

Table 12: Gastric Ulcer Healing Rates PREVACID Placebo (N=64) Week 15 mg daily (N=65) 30 mg daily (N=63) 60 mg daily (N=61) 4 64.6% (p≤0.05) versus placebo 58.1% 53.3% 37.5% 8 92.2% 96.8% 93.2% 76.7% Patients treated with any PREVACID dose reported significantly less day and night abdominal pain along with fewer days of antacid use and fewer antacid tablets used per day than the placebo group.

Independent substantiation of the effectiveness of PREVACID 30 mg was provided by a meta-analysis of published and unpublished data.

Healing of NSAID-Associated Gastric Ulcer In two U.S.

and Canadian multicenter, double-blind, active-controlled studies in patients with endoscopically confirmed NSAID-associated gastric ulcer who continued their NSAID use, the percentage of patients healed after eight weeks was statistically significantly higher with 30 mg of PREVACID than with the active control.

A total of 711 patients were enrolled in the study, and 701 patients were treated.

Patients ranged in age from 18 to 88 years (median age 59 years), with 67% female patients and 33% male patients.

Race was distributed as follows: 87% Caucasian, 8% Black, 5% Other.

There was no statistically significant difference between PREVACID 30 mg daily and the active control on symptom relief (i.e., abdominal pain) ( Table 13) [see Indications and Usage (1.5)].

Table 13: NSAID-Associated Gastric Ulcer Healing Rates Actual observed ulcer(s) healed at time points ±2 days Study #1 PREVACID 30 mg daily Active Control Dose for healing of gastric ulcer Week 4 60% (53/88) (p≤0.05) versus the active control 28% (23/83) Week 8 79% (62/79) 55% (41/74) Study #2 PREVACID 30 mg daily Active Control Week 4 53% (40/75) 38% (31/82) Week 8 77% (47/61) 50% (33/66) Risk Reduction of NSAID-Associated Gastric Ulcer In one large U.S., multicenter, double-blind, placebo- and misoprostol-controlled (misoprostol blinded only to the endoscopist) study in patients who required chronic use of an NSAID and who had a history of an endoscopically documented gastric ulcer, the proportion of patients remaining free from gastric ulcer at four, eight, and 12 weeks was significantly higher with 15 or 30 mg of PREVACID than placebo.

A total of 537 patients were enrolled in the study, and 535 patients were treated.

Patients ranged in age from 23 to 89 years (median age 60 years), with 65% female patients and 35% male patients.

Race was distributed as follows: 90% Caucasian, 6% Black, 4% other.

The 30 mg dose of PREVACID demonstrated no additional benefit in risk reduction of the NSAID-associated gastric ulcer than the 15 mg dose ( Table 14) [see Indications and Usage (1.6)].

Table 14: Proportion of Patients Remaining Free of Gastric Ulcers % = Life Table Estimate Week PREVACID 15 mg daily (N=121) PREVACID 30 mg daily (N=116) Misoprostol 200 mcg four times daily (N=106) Placebo (N=112) 4 90% 92% 96% 66% 8 86% 88% 95% 60% 12 80% 82% 93% 51% (p<0.001) PREVACID 15 mg daily versus placebo; PREVACID 30 mg daily versus placebo; and misoprostol 200 mcg four times daily versus placebo.

(p<0.05) Misoprostol 200 mcg four times daily versus PREVACID 15 mg daily; and misoprostol 200 mcg four times daily versus PREVACID 30 mg daily.

Gastroesophageal Reflux Disease (GERD) Symptomatic GERD: In a U.S.

multicenter, double-blind, placebo-controlled study of 214 patients with frequent GERD symptoms, but no esophageal erosions by endoscopy, significantly greater relief of heartburn associated with GERD was observed with the administration of lansoprazole 15 mg once daily up to eight weeks than with placebo.

No significant additional benefit from lansoprazole 30 mg once daily was observed.

The intent-to-treat analyses demonstrated significant reduction in frequency and severity of day and night heartburn.

Data for frequency and severity for the eight week treatment period are presented in Table 15 and in Figures 1 and 2: Table 15: Frequency of Heartburn Variable Placebo (n=43) PREVACID 15 mg (n=80) PREVACID 30 mg (n=86) Median % of Days without Heartburn Week 1 0% 71% (p<0.01) versus placebo.

46% Week 4 11% 81% 76% Week 8 13% 84% 82% % of Nights without Heartburn Week 1 17% 86% 57% Week 4 25% 89% 73% Week 8 36% 92% 80% Figure 1 Figure 2 In two U.S., multicenter double-blind, ranitidine-controlled studies of 925 total patients with frequent GERD symptoms, but no esophageal erosions by endoscopy, lansoprazole 15 mg was superior to ranitidine 150 mg (twice daily) in decreasing the frequency and severity of day and night heartburn associated with GERD for the eight week treatment period.

No significant additional benefit from lansoprazole 30 mg once daily was observed [see Indications and Usage (1.7)].

Figure 1 Figure 2 Erosive Esophagitis In a U.S.

multicenter, double-blind, placebo-controlled study of 269 patients entering with an endoscopic diagnosis of esophagitis with mucosal grading of two or more and grades three and four signifying erosive disease, the percentages of patients with healing are presented in Table 16: Table 16: Erosive Esophagitis Healing Rates Week PREVACID Placebo (N=63) 15 mg daily (N=69) 30 mg daily (N=65) 60 mg daily (N=72) 4 67.6% (p≤0.001) versus placebo.

81.3% , (p≤0.05) versus PREVACID 15 mg.

80.6% , 32.8% 6 87.7% 95.4% 94.3% 52.5% 8 90.9% 95.4% 94.4% 52.5% In this study, all PREVACID groups reported significantly greater relief of heartburn and less day and night abdominal pain along with fewer days of antacid use and fewer antacid tablets taken per day than the placebo group.

Although all doses were effective, the earlier healing in the higher two doses suggests 30 mg daily as the recommended dose.

PREVACID was also compared in a U.S.

multicenter, double-blind study to a low dose of ranitidine in 242 patients with erosive reflux esophagitis.

PREVACID at a dose of 30 mg was significantly more effective than ranitidine 150 mg twice daily as shown below ( Table 17).

Table 17: Erosive Esophagitis Healing Rates Week PREVACID 30 mg daily (N=115) Ranitidine 150 mg twice daily (N=127) 2 66.7% (p≤0.001) versus ranitidine.

38.7% 4 82.5% 52.0% 6 93.0% 67.8% 8 92.1% 69.9% In addition, patients treated with PREVACID reported less day and nighttime heartburn and took less antacid tablets for fewer days than patients taking ranitidine 150 mg twice daily.

Although this study demonstrates effectiveness of PREVACID in healing erosive esophagitis, it does not represent an adequate comparison with ranitidine because the recommended ranitidine dose for esophagitis is 150 mg four times daily, twice the dose used in this study.

In the two trials described and in several smaller studies involving patients with moderate to severe erosive esophagitis, PREVACID produced healing rates similar to those shown above.

In a U.S.

multicenter, double-blind, active-controlled study, 30 mg of PREVACID was compared with ranitidine 150 mg twice daily in 151 patients with erosive reflux esophagitis that was poorly responsive to a minimum of 12 weeks of treatment with at least one H 2-receptor antagonist given at the dose indicated for symptom relief or greater, namely, cimetidine 800 mg/day, ranitidine 300 mg/day, famotidine 40 mg/day or nizatidine 300 mg/day.

PREVACID 30 mg was more effective than ranitidine 150 mg twice daily in healing reflux esophagitis, and the percentage of patients with healing were as follows.

This study does not constitute a comparison of the effectiveness of histamine H 2-receptor antagonists with PREVACID, as all patients had demonstrated unresponsiveness to the histamine H 2-receptor antagonist mode of treatment.

It does indicate, however, that PREVACID may be useful in patients failing on a histamine H 2-receptor antagonist ( Table 18) [see Indications and Usage (1.7)].

Table 18: Reflux Esophagitis Healing Rates in Patients Poorly Responsive to Histamine H 2-Receptor Antagonist Therapy Week PREVACID 30 mg daily (N=100) Ranitidine 150 mg twice daily (N=51) 4 74.7% (p≤0.001) versus ranitidine.

42.6% 8 83.7% 32.0% Long-Term Maintenance Treatment of Erosive Esophagitis Two independent, double-blind, multicenter, controlled trials were conducted in patients with endoscopically confirmed healed esophagitis.

Patients remained in remission significantly longer and the number of recurrences of erosive esophagitis was significantly less in patients treated with PREVACID than in patients treated with placebo over a 12 month period ( Table 19).

Table 19: Endoscopic Remission Rates Percent in Endoscopic Remission Trial Drug No.

of Pts.

0-3 mo.

0-6 mo.

0-12 mo.

%=Life Table Estimate PREVACID 15 mg daily 59 83% (p≤0.001) versus placebo.

81% 79% #1 PREVACID 30 mg daily 56 93% 93% 90% Placebo 55 31% 27% 24% PREVACID 15 mg daily 50 74% 72% 67% #2 PREVACID 30 mg daily 49 75% 72% 55% Placebo 47 16% 13% 13% Regardless of initial grade of erosive esophagitis, PREVACID 15 mg and 30 mg were similar in maintaining remission.

In a U.S., randomized, double-blind, study, PREVACID 15 mg daily (n = 100) was compared with ranitidine 150 mg twice daily (n = 106), at the recommended dosage, in patients with endoscopically-proven healed erosive esophagitis over a 12 month period.

Treatment with PREVACID resulted in patients remaining healed (Grade 0 lesions) of erosive esophagitis for significantly longer periods of time than those treated with ranitidine (p<0.001).

In addition, PREVACID was significantly more effective than ranitidine in providing complete relief of both daytime and nighttime heartburn.

Patients treated with PREVACID remained asymptomatic for a significantly longer period of time than patients treated with ranitidine [see Indications and Usage (1.8)].

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome In open studies of 57 patients with pathological hypersecretory conditions, such as Zollinger-Ellison syndrome (ZES) with or without multiple endocrine adenomas, PREVACID significantly inhibited gastric acid secretion and controlled associated symptoms of diarrhea, anorexia and pain.

Doses ranging from 15 mg every other day to 180 mg per day maintained basal acid secretion below 10 mEq/hr in patients without prior gastric surgery and below 5 mEq/hr in patients with prior gastric surgery.

Initial doses were titrated to the individual patient need, and adjustments were necessary with time in some patients [see Dosage and Administration (2.1)].

PREVACID was well tolerated at these high dose levels for prolonged periods (greater than four years in some patients).

In most ZES patients, serum gastrin levels were not modified by PREVACID.

However, in some patients, serum gastrin increased to levels greater than those present prior to initiation of lansoprazole therapy [see Indications and Usage (1.9)].