14 CLINICAL STUDIES
PROTONIX Delayed-Release Tablets were used in the following clinical trials.
14.1 Erosive Esophagitis (EE) Associated with Gastroesophageal Reflux Disease (GERD)
A US multicenter, double-blind, placebo-controlled study of PROTONIX 10 mg, 20 mg, or 40 mg once daily was conducted in 603 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above (Hetzel-Dent scale). In this study, approximately 25% of enrolled patients had severe EE of grade 3, and 10% had grade 4. The percentages of patients healed (per protocol, n = 541) in this study are shown in Table 8.
|Week||10 mg daily
(n = 153)
|20 mg daily
(n = 158)
|40 mg daily
(n = 162)
|(n = 68)|
In this study, all PROTONIX treatment groups had significantly greater healing rates than the placebo group. This was true regardless of H. pylori status for the 40 mg and 20 mg PROTONIX treatment groups. The 40 mg dose of PROTONIX resulted in healing rates significantly greater than those found with either the 20 mg or 10 mg dose.
A significantly greater proportion of patients taking PROTONIX 40 mg experienced complete relief of daytime and nighttime heartburn and the absence of regurgitation, starting from the first day of treatment, compared with placebo. Patients taking PROTONIX consumed significantly fewer antacid tablets per day than those taking placebo.
PROTONIX 40 mg and 20 mg once daily were also compared with nizatidine 150 mg twice daily in a US multicenter, double-blind study of 243 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above. The percentages of patients healed (per protocol, n = 212) are shown in Table 9.
|Week||20 mg daily
(n = 72)
|40 mg daily
(n = 70)
|150 mg twice daily
(n = 70)
Once-daily treatment with PROTONIX 40 mg or 20 mg resulted in significantly superior rates of healing at both 4 and 8 weeks compared with twice-daily treatment with 150 mg of nizatidine. For the 40 mg treatment group, significantly greater healing rates compared to nizatidine were achieved regardless of the H. pylori status.
A significantly greater proportion of the patients in the PROTONIX treatment groups experienced complete relief of nighttime heartburn and regurgitation, starting on the first day and of daytime heartburn on the second day, compared with those taking nizatidine 150 mg twice daily. Patients taking PROTONIX consumed significantly fewer antacid tablets per day than those taking nizatidine.
Pediatric Patients Ages 5 Years through 16 Years
The efficacy of PROTONIX in the treatment of EE associated with GERD in pediatric patients ages 5 years through 16 years is extrapolated from adequate and well-conducted trials in adults, as the pathophysiology is thought to be the same. Four pediatric patients with endoscopically diagnosed EE were studied in multicenter, randomized, double-blind, parallel-treatment trials. Children with endoscopically diagnosed EE (defined as an endoscopic Hetzel-Dent score ≥2) were treated once daily for 8 weeks with one of two dose levels of PROTONIX (20 mg or 40 mg). All 4 patients with EE were healed (Hetzel-Dent score of 0 or 1) at 8 weeks.
14.2 Long-Term Maintenance of Healing of Erosive Esophagitis
Two independent, multicenter, randomized, double-blind, comparator-controlled trials of identical design were conducted in adult GERD patients with endoscopically confirmed healed EE to demonstrate efficacy of PROTONIX in long-term maintenance of healing. The two US studies enrolled 386 and 404 patients, respectively, to receive either 10 mg, 20 mg, or 40 mg of PROTONIX Delayed-Release Tablets once daily or 150 mg of ranitidine twice daily. As demonstrated in Table 10, PROTONIX 40 mg and 20 mg were significantly superior to ranitidine at every timepoint with respect to the maintenance of healing. In addition, PROTONIX 40 mg was superior to all other treatments studied.
20 mg daily
40 mg daily
150 mg twice daily
|Note: PROTONIX 10 mg was superior (p <0.05) to ranitidine in Study 2, but not Study 1.|
|Study 1||n = 75||n = 74||n = 75|
|Study 2||n = 74||n = 88||n = 84|
PROTONIX 40 mg was superior to ranitidine in reducing the number of daytime and nighttime heartburn episodes from the first through the twelfth month of treatment. PROTONIX 20 mg, administered once daily, was also effective in reducing episodes of daytime and nighttime heartburn in one trial, as presented in Table 11.
40 mg daily
150 mg twice daily
|Month 1||Daytime||5.1 ± 1.6*||18.3 ± 1.6|
|Nighttime||3.9 ± 1.1*||11.9 ± 1.1|
|Month 12||Daytime||2.9 ± 1.5*||17.5 ± 1.5|
|Nighttime||2.5 ± 1.2*||13.8 ± 1.3|
14.3 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome
In a multicenter, open-label trial of 35 patients with pathological hypersecretory conditions, such as Zollinger-Ellison Syndrome, with or without multiple endocrine neoplasia-type I, PROTONIX successfully controlled gastric acid secretion. Doses ranging from 80 mg daily to 240 mg daily maintained gastric acid output below 10 mEq/h in patients without prior acid-reducing surgery and below 5 mEq/h in patients with prior acid-reducing surgery.
Doses were initially titrated to the individual patient needs, and adjusted in some patients based on the clinical response with time [see Dosage and Administration (2)]. PROTONIX was well tolerated at these dose levels for prolonged periods (greater than 2 years in some patients).