AcipHex: Package Insert and Label Information (Page 5 of 7)

14 CLINICAL STUDIES

Mean Daytime Heartburn Scores RAB-USA-2Mean Nighttime Heartburn Scores RAB-USA-2Mean Daytime Heartburn Scores RAB-USA-3Mean Nighttime Heartburn Scores RAB-USA-3

14.1 Healing of Erosive or Ulcerative GERD in Adults

In a U.S., multicenter, randomized, double-blind, placebo-controlled study, 103 patients were treated for up to eight weeks with placebo, 10 mg, 20 mg, or 40 mg ACIPHEX delayed-release tablets once daily. For this and all studies of GERD healing, only patients with GERD symptoms and at least grade 2 esophagitis (modified Hetzel-Dent grading scale) were eligible for entry. Endoscopic healing was defined as grade 0 or 1. Each rabeprazole dose was significantly superior to placebo in producing endoscopic healing after four and eight weeks of treatment. The percentage of patients demonstrating endoscopic healing was as follows:

Table 7: Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) Percentage of Patients Healed
WeekACIPHEX delayed-release tabletsPlaceboN=25
10 mg once dailyN=2720 mg once dailyN=2540 mg once dailyN=26
463%*56%*54%*0%
893%*84%*85%*12%

* (p<0.001 versus placebo)

In addition, there was a statistically significant difference in favor of the ACIPHEX 10 mg, 20 mg, and 40 mg doses compared to placebo at Weeks 4 and 8 regarding complete resolution of GERD heartburn frequency (p≤0.026). All ACIPHEX groups reported significantly greater rates of complete resolution of GERD daytime heartburn severity compared to placebo at Weeks 4 and 8 (p≤0.036). Mean reductions from baseline in daily antacid dose were statistically significant for all ACIPHEX groups when compared to placebo at both Weeks 4 and 8 (p≤0.007).

In a North American multicenter, randomized, double-blind, active-controlled study of 336 patients, the percentage of patients healed at endoscopy after four and eight weeks of treatment was statistically superior in the patients treated with ACIPHEX delayed-release tablets compared to ranitidine:

Table 8: Healing of Erosive or Ulcerative Gastroesophageal Reflux Disease (GERD) Percentage of Patients Healed
Week20 mg ACIPHEX delayed-release tablets once dailyN=167Ranitidine 150 mg four times dailyN=169
459%*36%
887%*66%

* (p<0.001 versus ranitidine)

A dose of 20 mg once daily of ACIPHEX delayed-release tablets was significantly more effective than ranitidine 150 mg four times daily in the percentage of patients with complete resolution of heartburn at Weeks 4 and 8 (p<0.001). ACIPHEX was also more effective in complete resolution of daytime heartburn (p≤0.025), and nighttime heartburn (p≤0.012) at both Weeks 4 and 8, with significant differences by the end of the first week of the study.

The recommended dosage of ACIPHEX delayed-release tablets is 20 mg once daily for 4 to 8 weeks.

14.2 Long- T erm Maintenance of Healing of Erosive or Ulcerative GERD in Adults

The long-term maintenance of healing in patients with erosive or ulcerative GERD previously healed with gastric antisecretory therapy was assessed in two U.S., multicenter, randomized, double-blind, placebo-controlled studies of identical design of 52 weeks duration. The two studies randomized 209 and 285 patients, respectively, to receive either 10 mg or 20 mg of ACIPHEX delayed-release tablets once daily or placebo. As demonstrated in Tables 10 and 11 below, patients treated with ACIPHEX delayed-release tablets were significantly superior to placebo in both studies with respect to the maintenance of healing of GERD and the proportions of patients remaining free of heartburn symptoms at 52 weeks. The recommended dosage of ACIPHEX delayed-release tablets is 20 mg once daily.

Table 9: Percent of Patients in Endoscopic Remission
ACIPHEX delayed-release tabletsPlacebo
10 mg once daily20 mg once daily
Study 1N=66N=67N=70
Week 483%*96%*44%
Week 1379%*93%*39%
Week 2677%*93%*31%
Week 3976%*91%*30%
Week 5273%*90%*29%
Study 2N=93N=93N=99
Week 489%*94%*40%
Week 1386%*91%*33%
Week 2685%*89%*30%
Week 3984%*88%*29%
Week 5277%*86%*29%
COMBINED STUDIESN=159N=160N=169
Week 487%*94%*42%
Week 1383%*92%*36%
Week 2682%*91%*31%
Week 3981%*89%*30%
Week 5275%*87%*29%

* (p<0.001 versus placebo)

Table 10: Percent of Patients Without Relapse in Heartburn Frequency and Daytime and Nighttime Heartburn Severity at Week 52
ACIPHEX delayed-release tabletsPlacebo
10 mg once daily20 mg once daily
Heartburn Frequency
Study 146/55 (84%)*48/52 (92%)*17/45 (38%)
Study 250/72 (69%)*57/72 (79%)*22/79 (28%)
Daytime Heartburn Severity
Study 161/64 (95%)*60/62 (97%)*42/61 (69%)
Study 273/84 (87%) 82/87 (94%)*67/90 (74%)
Nighttime Heartburn Severity
Study 157/61 (93%)*60/61 (98%)*37/56 (66%)
Study 267/80 (84%)79/87 (91%) 64/87 (74%)

* p≤0.001 versus placebo 0.001<p<0.05 versus placebo

14.3 Treatment of Symptomatic GERD in Adults

Two U.S., multicenter, double-blind, placebo controlled studies were conducted in 316 adult patients with daytime and nighttime heartburn. Patients reported 5 or more periods of moderate to very severe heartburn during the placebo treatment phase the week prior to randomization. Patients were confirmed by endoscopy to have no esophageal erosions.

The percentage of heartburn free daytime and/or nighttime periods was greater with 20 mg ACIPHEX delayed-release tablets compared to placebo over the 4 weeks of study in Study RAB-USA-2 (47% vs. 23%) and Study RAB-USA-3 (52% vs. 28%). The mean decreases from baseline in average daytime and nighttime heartburn scores were significantly greater for ACIPHEX 20 mg as compared to placebo at week 4. Graphical displays depicting the daily mean daytime and nighttime scores are provided in Figures 2 to 5.

Mean Daytime Heartburn Scores RAB-USA-2
(click image for full-size original)

Figure 2: Mean Daytime Heartburn Scores RAB-USA-2

Mean Nighttime Heartburn Scores RAB-USA-2
(click image for full-size original)

Figure 3: Mean Nighttime Heartburn Scores RAB-USA-2

Mean Daytime Heartburn Scores RAB-USA-3
(click image for full-size original)

Figure 4: Mean Daytime Heartburn Scores RAB-USA-3

Mean Nighttime Heartburn Scores RAB-USA-3
(click image for full-size original)

Figure 5: Mean Nighttime Heartburn Scores RAB-USA-3

In addition, the combined analysis of these two studies showed 20 mg of ACIPHEX delayed-release tablets significantly improved other GERD-associated symptoms (regurgitation, belching, and early satiety) by week 4 compared with placebo (all p values <0.005).

A dose of 20 mg ACIPHEX delayed-release tablets also significantly reduced daily antacid consumption versus placebo over 4 weeks (p<0.001).

The recommended dosage of ACIPHEX delayed-release tablets is 20 mg once daily for 4 weeks.

14.4 Healing of Duodenal Ulcers in Adults

In a U.S., randomized, double-blind, multicenter study assessing the effectiveness of 20 mg and 40 mg of ACIPHEX delayed-release tablets once daily versus placebo for healing endoscopically defined duodenal ulcers, 100 patients were treated for up to four weeks. ACIPHEX was significantly superior to placebo in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing are presented below:

Table 11: Healing of Duodenal Ulcers Percentage of Patients Healed
WeekACIPHEX delayed-release tabletsPlaceboN=33
20 mg oncedailyN=3440 mg once dailyN=33
244%42%21%
479%*91%*39%

* p≤0.001 versus placebo

At Weeks 2 and 4, significantly more patients in the ACIPHEX 20 and 40 mg groups reported complete resolution of ulcer pain frequency (p≤0.018), daytime pain severity (p≤0.023), and nighttime pain severity (p≤0.035) compared with placebo patients. The only exception was the 40 mg group versus placebo at Week 2 for duodenal ulcer pain frequency (p=0.094). Significant differences in resolution of daytime and nighttime pain were noted in both ACIPHEX groups relative to placebo by the end of the first week of the study. Significant reductions in daily antacid use were also noted in both ACIPHEX groups compared to placebo at Weeks 2 and 4 (p<0.001).

An international randomized, double-blind, active-controlled trial was conducted in 205 patients comparing 20 mg ACIPHEX delayed-release tablets once daily with 20 mg omeprazole once daily. The study was designed to provide at least 80% power to exclude a difference of at least 10% between ACIPHEX and omeprazole, assuming four-week healing response rates of 93% for both groups. In patients with endoscopically defined duodenal ulcers treated for up to four weeks, ACIPHEX was comparable to omeprazole in producing healing of duodenal ulcers. The percentages of patients with endoscopic healing at two and four weeks are presented below:

Table 12: Healing of Duodenal Ulcers Percentage of Patients Healed
WeekACIPHEX delayed-release tablets20 mg once dailyN=102Omeprazole20 mg once dailyN=10395% Confidence Interval for the Treatment Difference(ACIPHEX — Omeprazole)
269%61%(–6%, 22%)
498%93%(–3%, 15%)

ACIPHEX and omeprazole were comparable in providing complete resolution of symptoms.

The recommended dosage of ACIPHEX delayed-release tablets is 20 mg once daily for 4 weeks.

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