14 CLINICAL STUDIES
14.1 Gastroesophageal Reflux Disease (GERD) Associated with a History of Erosive Esophagitis
A multicenter, double-blind, two-period placebo-controlled study was conducted to assess the ability of PROTONIX I.V. to maintain gastric acid suppression in patients switched from PROTONIX Delayed-Release Tablets to PROTONIX I.V. GERD patients (n=65, 26 to 64 years; 35 female; 9 Black, 11 Hispanic, 44 White, 1 other) with a history of EE were randomized to receive either 20 or 40 mg of oral pantoprazole once per day for 10 days (period 1), and then were switched in period 2 to either daily PROTONIX I.V. or placebo for 7 days, matching their respective dose level from period 1. Patients were administered all test medication with a light meal. Maximum acid output (MAO) and basal acid output (BAO) were determined 24 hours following the last day of oral medication (day 10), the first day (day 1) of intravenous administration and the last day of intravenous administration (day 7). MAO was estimated from a 1 hour continuous collection of gastric contents following subcutaneous injection of 6.0 mcg/kg of pentagastrin.
This study demonstrated that, after 10 days of repeated oral administration followed by 7 days of intravenous administration, the oral and intravenous dosage forms of PROTONIX 40 mg are similar in their ability to suppress MAO and BAO in patients with GERD and a history of EE (see Table 4). Also, patients on oral PROTONIX who were switched to intravenous placebo experienced a significant increase in acid output within 48 hours of their last oral dose (see Table 4). However, at 48 hours after their last oral dose, patients treated with PROTONIX I.V. had a significantly lower mean basal acid output (see Table 4) than those treated with placebo.
|Parameter||PROTONIX Delayed-Release Tablets|
|Mean maximum acid output||6.49|
|Mean basal acid output||0.80|
To evaluate the effectiveness of PROTONIX I.V. as an initial treatment to suppress gastric acid secretion, two studies were conducted.
Study 1 was a multicenter, double-blind, placebo-controlled, study of the pharmacodynamic effects of PROTONIX I.V. and PROTONIX Delayed-Release Tablets. Patients with GERD and a history of EE (n=78, 20 to 67 years; 39 females; 7 Black, 19 Hispanic, 52 White) were randomized to receive either 40 mg PROTONIX I.V., 40 mg PROTONIX Delayed-Release Tablets, or placebo once daily for 7 days. Following an overnight fast, test medication was administered and patients were given a light meal within 15 minutes. MAO and BAO were determined 24 hours following the last day of study medication. MAO was estimated from a 1 hour continuous collection of gastric contents following subcutaneous injection of 6.0 mcg/kg of pentagastrin to stimulate acid secretion. This study demonstrated that, after treatment for 7 days, patients treated with PROTONIX I.V. had a significantly lower MAO and BAO than those treated with placebo (p<0.001), and results were comparable to those of patients treated with PROTONIX Delayed-Release Tablets (see Table 5).
|PROTONIX Delayed-Release Tablets|
|Maximum acid output (mean ± SD)||8.4 ± 5.9|
|6.3 ± 6.6|
|20.9 ± 14.5*|
|Basal acid output|
(mean ± SD)
|0.4 ± 0.5|
|0.6 ± 0.8|
|2.8 ± 3.0*|
Study 2 was a single-center, double-blind, parallel-group study to compare the clinical effects of PROTONIX I.V. and PROTONIX Delayed-Release Tablets. Patients (n=45, median age 56 years, 21 males and 24 females) with acute endoscopically proven reflux esophagitis (Savary/Miller Stage II or III) with at least 1 of 3 symptoms typical for reflux esophagitis (acid eructation, heartburn, or pain on swallowing) were randomized to receive either 40 mg PROTONIX I.V. or 40 mg PROTONIX Delayed-Release Tablets once daily for 5 days. After the initial 5 days, all patients were treated with 40 mg oral pantoprazole daily to complete a total of 8 weeks of treatment. Symptom relief was assessed by calculating the daily mean of the sums of the average scores for these 3 symptoms and the daily mean of the average score for each of the symptoms separately. There was no significant difference in symptom relief between PROTONIX I.V. and PROTONIX Delayed-Release Tablets within the first 5 days. A repeat endoscopy after 8 weeks of treatment revealed that 20 out of 23 (87%) patients treated with PROTONIX I.V. plus PROTONIX Delayed-Release Tablets and 19 out of 22 (86%) of the patients treated with PROTONIX Delayed-Release Tablets had endoscopically proven healing of their esophageal lesions.
Data comparing PROTONIX I.V. to other PPIs (oral or intravenous) or H2-receptor antagonists (oral or intravenous) are limited, and therefore, are inadequate to support any conclusions regarding comparative efficacy.
14.2 Pathological Hypersecretion Associated with Zollinger-Ellison Syndrome
Two studies measured the pharmacodynamic effects of 6 day treatment with PROTONIX I.V. in patients with ZE Syndrome (with and without multiple endocrine neoplasia type I). In one of these studies, an initial treatment with PROTONIX I.V. in 21 patients (29 to 75 years; 8 female; 4 Black, 1 Hispanic, 16 White) reduced acid output to the target level (10 mEq/h or less) and significantly reduced H+ concentration and the volume of gastric secretions; target levels were achieved within 45 minutes of drug administration.
In the other study of 14 patients (38 to 67 years; 5 female; 2 Black, 12 White) with ZE Syndrome, treatment was switched from an oral PPI to PROTONIX I.V. PROTONIX I.V. maintained or improved control of gastric acid secretion.
In both studies, total doses of 160 or 240 mg per day of PROTONIX I.V., administered in divided doses, maintained basal acid secretion below target levels in all patients. Target levels were 10 mEq/h in patients without prior gastric surgery, and 5 mEq/h in all patients with prior gastric acid-reducing surgery. Once gastric acid secretion was controlled, there was no evidence of tolerance during this 7 day study. Basal acid secretion was maintained below target levels for at least 24 hours in all patients and through the end of treatment in these studies (3 to 7 days) in all but 1 patient who required a dose adjustment guided by acid output measurements until acid control was achieved. In both studies, doses were adjusted to the individual patient need, but gastric acid secretion was controlled in greater than 80% of patients by a starting regimen of 80 mg every 12 hours.