Performance of the Population Bioequivalence (PBE) Statistical Test with Impactor Sized Mass Data.

This article extends previous work studying performance characteristics of the population bioequivalence (PBE) statistical test recommended by the US Food and Drug Administration (FDA) for orally inhaled and nasal drug products. Based on analysis of a metered dose inhaler database for impactor sized mass, a simulation study was designed to compare performance of the recommended PBE approach with several modified or alternative approaches. These included an extended PBE that separately modeled within-batch (can) and between-batch (batch) variability and average bioequivalence (ABE) tests that modeled with or without between-batch variability and with or without log-transformation. This work showed that separately modeling within- and between-batch variability while increasing the number of sampled batches addressed previously identified issues of the PBE approach when between-batch variability was present, namely, (a) increased risk for falsely concluding equivalence and (b) low probability of correctly concluding equivalence. The same modifications were also required of the ABE to achieve expected performance. However, these modifications did not successfully address the issue of equivalence conclusions that depended on the direction of product mean differences (asymmetric performance). This work highlights the importance of understanding decision-making error rates in developing regulatory recommendations to standardize bioequivalence outcomes across products.

Performance of the Population Bioequivalence (PBE) Statistical Test Using an IPAC-RS Database of Delivered Dose from Metered Dose Inhalers.

This article reports performance characteristics of the population bioequivalence (PBE) statistical test recommended by the US Food and Drug Administration (FDA) for orally inhaled products. A PBE Working Group of the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) assembled and considered a database comprising delivered dose measurements from 856 individual batches across 20 metered dose inhaler products submitted by industry. A review of the industry dataset identified variability between batches and a systematic lifestage effect that was not included in the FDA-prescribed model for PBE. A simulation study was designed to understand PBE performance when factors identified in the industry database were present. Neglecting between-batch variability in the PBE model inflated errors in the equivalence conclusion: (i) The probability of incorrectly concluding equivalence (type I error) often exceeded 15% for non-zero between-batch variability, and (ii) the probability of incorrectly rejecting equivalence (type II error) for identical products approached 20% when product and between-batch variabilities were high. Neglecting a systematic through-life increase in the PBE model did not substantially impact PBE performance for the magnitude of lifestage effect considered. Extreme values were present in 80% of the industry products considered, with low-dose extremes having a larger impact on equivalence conclusions. The dataset did not support the need for log-transformation prior to analysis, as requested by FDA. Log-transformation resulted in equivalence conclusions that depended on the direction of product mean differences. These results highlight a need for further refinement of in vitro equivalence methodology.

Gastroesophageal Acid Reflux Control 5 Years After Antireflux Surgery, Compared With Long-term Esomeprazole Therapy.

BACKGROUND & AIMS: We compared the ability of laparoscopic antireflux surgery (LARS) and esomeprazole to control esophageal acid exposure, over a 5-year period, in patients with chronic gastroesophageal reflux disease (GERD). We also studied whether intraesophageal and intragastric pH parameters off and on therapy were associated with long-term outcomes. METHODS: We analyzed data from a prospective, randomized, open-label trial comparing the efficacy and safety of LARS vs esomeprazole (20 or 40 mg/d) over 5 years in patients with chronic GERD. Ambulatory intraesophageal and intragastric 24-hour pH monitoring data were compared between groups before LARS or the start of esomeprazole treatment, and 6 months and 5 years afterward. A secondary aim was to evaluate the association between baseline and 6-month pH parameters and esomeprazole dose escalation, reappearance of GERD symptoms, and treatment failure over 5 years in patients receiving LARS or esomeprazole. RESULTS: In the LARS group (n = 116), the median 24-hour esophageal acid exposure was 8.6% at baseline and 0.7% after 6 months and 5 years (P < .001 vs baseline). In the esomeprazole group (n = 151), the median 24-hour esophageal acid exposure was 8.8% at baseline, 2.1% after 6 months, and 1.9% after 5 years (P < .001, therapy vs baseline, and LARS vs esomeprazole). Gastric acidity was stable in both groups. Patients who required a dose increase to 40 mg/d had more severe supine reflux at baseline, and decreased esophageal acid exposure (P < .02) and gastric acidity after dose escalation. Esophageal and intragastric pH parameters, off and on therapy, did not predict long-term symptom breakthrough. CONCLUSIONS: In a prospective study of patients with chronic GERD, esophageal acid reflux was reduced greatly by LARS or esomeprazole therapy. However, patients receiving LARS had significantly greater reductions in 24-hour esophageal acid exposure after 6 months and 5 years. Esophageal and gastric pH, off and on therapy, did not predict long-term outcomes of patients. Abnormal supine acid exposure predicted esomeprazole dose escalation. ClinicalTrials.Gov identifier: NCT00251927 (available: http://clinicaltrials.gov/ct2/show/NCT00251927).

Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD: the LOTUS randomized clinical trial.

CONTEXT: Gastroesophageal reflux disease (GERD) is a chronic, relapsing disease with symptoms that have negative effects on daily life. Two treatment options are long-term medication or surgery. OBJECTIVE: To evaluate optimized esomeprazole therapy vs standardized laparoscopic antireflux surgery (LARS) in patients with GERD. DESIGN, SETTING, AND PARTICIPANTS: The LOTUS trial, a 5-year exploratory randomized, open, parallel-group trial conducted in academic hospitals in 11 European countries between October 2001 and April 2009 among 554 patients with well-established chronic GERD who initially responded to acid suppression. A total of 372 patients (esomeprazole, n = 192; LARS, n = 180) completed 5-year follow-up. Interventions Two hundred sixty-six patients were randomly assigned to receive esomeprazole, 20 to 40 mg/d, allowing for dose adjustments; 288 were randomly assigned to undergo LARS, of whom 248 actually underwent the operation. MAIN OUTCOME MEASURE: Time to treatment failure (for LARS, defined as need for acid suppressive therapy; for esomeprazole, inadequate symptom control after dose adjustment), expressed as estimated remission rates and analyzed using the Kaplan-Meier method. RESULTS: Estimated remission rates at 5 years were 92% (95% confidence interval [CI], 89%-96%) in the esomeprazole group and 85% (95% CI, 81%-90%) in the LARS group (log-rank P = .048). The difference between groups was no longer statistically significant following best-case scenario modeling of the effects of study dropout. The prevalence and severity of symptoms at 5 years in the esomeprazole and LARS groups, respectively, were 16% and 8% for heartburn (P = .14), 13% and 2% for acid regurgitation (P < .001), 5% and 11% for dysphagia (P < .001), 28% and 40% for bloating (P < .001), and 40% and 57% for flatulence (P < .001). Mortality during the study was low (4 deaths in the esomeprazole group and 1 death in the LARS group) and not attributed to treatment, and the percentages of patients reporting serious adverse events were similar in the esomeprazole group (24.1%) and in the LARS group (28.6%). CONCLUSION: This multicenter clinical trial demonstrated that with contemporary antireflux therapy for GERD, either by drug-induced acid suppression with esomeprazole or by LARS, most patients achieve and remain in remission at 5 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00251927.

Phase I, multicenter, randomized, open-label study evaluating the pharmacokinetics and safety profile of repeated once-daily doses of intravenous esomeprazole in children 0 to 17 years of age.

BACKGROUND: Several oral proton pump inhibitors (PPIs) are currently approved for use in pediatric patients in North America and Europe. However, when use of oral therapy is not possible or appropriate, intravenous formulations of PPIs may be helpful. Intravenous esomeprazole is approved in the United States for the short-term treatment of gastroesophageal reflux disease (GERD) with erosive esophagitis in adults and in pediatric patients 1 month to 17 years of age (inclusive) as an alternative to oral therapy. Four open-label, randomized, 2-way crossover studies in adults with GERD found no clinically relevant differences in acid suppression between repeated doses of oral and intravenous esomeprazole. However, the pharmacokinetics of intravenous esomeprazole has not been studied extensively in children. OBJECTIVE: The aim of this study was to evaluate steady-state pharmacokinetics and tolerability of repeated doses of intravenous esomeprazole in children. METHODS: In this multicenter, open-label study, hospitalized patients (0-17 years of age) considered for acid suppression therapy received once-daily intravenous esomeprazole sodium for injection at 0.5 mg/kg (0-1 month of age), 1.0 mg/kg (1-11 months of age), 10 mg (1-5 years of age), 10 or 20 mg (6-11 years of age), or 20 or 40 mg (12-17 years of age) for 4 days. Children 6 to 11 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 10 or 20 mg, and adolescents 12 to 17 years of age (inclusive) were randomized in a 1:1 ratio to receive esomeprazole 20 or 40 mg. Blood samples were drawn pre- and post-dose. Plasma esomeprazole was measured using reversed-phase liquid chromatography and mass spectrometry. Pharmacokinetic variables were derived using mixed-effects modeling. Adverse events (AEs) were assessed. RESULTS: Fifty-nine patients were randomized and 57 received the study drug. A majority of patients were white (44 white, 5 black/African American, 3 Asian, 5 other) and male (35/57). Fifty patients were eligible for pharmacokinetic analysis, including 6 to 8 patients in each age group. Esomeprazole pharmacokinetics was dose proportional and related to weight and age. Clearance increased with increasing weight and age. The mean AUC(τ) ranged from 6.9 µmol · h/L (10 mg, 6-11 years) to 17.6 µmol · h/L (40 mg, 12-17 years). The mean C(ss,max) ranged from 3.7 µmol/L (0.5 mg/kg, 0-1 month) to 10.5 µmol/L (40 mg, 12-17 years). Thirty-one patients experienced 1 or more AEs; 6 patients experienced 1 or more treatment-unrelated serious AEs. CONCLUSIONS: Intravenous esomeprazole at doses resulting in targeted AUC(τ) and C(ss,max) similar to therapeutic exposure in adults appeared to be reasonably well tolerated in this small, select pediatric population. ClinicalTrials.gov identifier: NCT00474019.

The new oral immunomodulating drug DiNAC induces brachial artery vasodilatation at rest and during hyperemia in hypercholesterolemic subjects, likely by a nitric oxide-dependent mechanism.

OBJECTIVES: To investigate if the immunomodulator drug DINAC (1) affects arterial dimensions in asymptomatic patients with hypercholesterolemia, (2) has effects on leucocyte markers of inflammation and (3) has in vitro effects on nitric oxide synthase (NOS) in human umbilical vein endothelial cells (HUVEC). METHODS AND RESULTS: One hundred and fifty-three patients with asymptomatic hypercholesterolemia were randomized to either 100 or 500 mg of DINAC or placebo in a double-blind, parallel-group fashion for 24 weeks. Treatment at the highest dose induced a significant increase in resting brachial artery diameter measured by ultrasound and also induced a significant increase in vessel diameter during hyperemia. However, flow-mediated vasodilation (FMD) and the vasodilatory response to nitroglycerin, lipid levels or leukocyte count were unaltered. Expression of several cell surface markers of inflammation, like CD11b and CD25, were reduced by treatment. In vitro, DINAC counteracted TNF-alpha induced reductions in NO levels and in NOS protein and mRNA levels. CONCLUSION: The immunomodulator drug DINAC increased brachial artery diameter at rest and during hyperemia in asymptomatic subjects with hypercholesterolemia without affecting blood lipid levels. Based on parallel in vitro studies this effect is likely due to an enhancement of NOS activity.

Maintenance treatment with esomeprazole following initial relief of non-steroidal anti-inflammatory drug-associated upper gastrointestinal symptoms: the NASA2 and SPACE2 studies.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclo-oxygenase-2 (COX-2) inhibitors, cause upper gastrointestinal (GI) symptoms that are relieved by treatment with esomeprazole. We assessed esomeprazole for maintaining long-term relief of such symptoms. Six hundred and ten patients with a chronic condition requiring anti-inflammatory therapy who achieved relief of NSAID-associated symptoms of pain, discomfort, or burning in the upper abdomen during two previous studies were enrolled and randomly assigned into two identical, multicentre, parallel-group, placebo-controlled studies of esomeprazole 20 mg or 40 mg treatment (NASA2 [Nexium Anti-inflammatory Symptom Amelioration] and SPACE2 [Symptom Prevention by Acid Control with Esomeprazole] studies; ClinicalTrials.gov identifiers NCT00241514 and NCT00241553, respectively) performed at various rheumatology, gastroenterology, and primary care clinics. Four hundred and twenty-six patients completed the 6-month treatment period. The primary measure was the proportion of patients with relapse of upper GI symptoms, recorded in daily diary cards, after 6 months. Relapse was defined as moderate-to-severe upper GI symptoms (a score of more than or equal to 3 on a 7-grade scale) for 3 days or more in any 7-day period. Esomeprazole was significantly more effective than placebo in maintaining relief of upper GI symptoms throughout 6 months of treatment. Life-table estimates (95% confidence intervals) of the proportion of patients with relapse at 6 months (pooled population) were placebo, 39.1% (32.2% to 46.0%); esomeprazole 20 mg, 29.3% (22.3% to 36.2%) (p = 0.006 versus placebo); and esomeprazole 40 mg, 26.1% (19.4% to 32.9%) (p = 0.001 versus placebo). Patients on either non-selective NSAIDs or selective COX-2 inhibitors appeared to benefit. The frequency of adverse events was similar in the three groups. Esomeprazole maintains relief of NSAID-associated upper GI symptoms in patients taking continuous NSAIDs, including selective COX-2 inhibitors.

Improvements with esomeprazole in patients with upper gastrointestinal symptoms taking non-steroidal antiinflammatory drugs, including selective COX-2 inhibitors.

OBJECTIVES: Upper gastrointestinal (GI) symptoms are common in patients using non-steroidal antiinflammatory drugs (NSAIDs) including selective cyclooxygenase (COX)-2 inhibitors and may be acid related. We therefore assessed esomeprazole treatment for upper GI symptoms in these patients. METHODS: A total of 794 and 848 continuous NSAID users, free of gastroduodenal ulcers, erosive esophagitis, and Helicobacter pylori, were enrolled into two identical, multinational, multicenter double-blind studies (NASA1, SPACE1). Moreover, 608 and 556 patients were randomized to receive 4 wk esomeprazole 20 mg, or 40 mg, or placebo once daily. The primary variable was the patient-reported change in the upper GI symptom (pain, discomfort, or burning in the upper abdomen) score on a 7-graded severity scale (0-6) from the 7 days prior to treatment to the last 7 days in the study. RESULTS: Esomeprazole was associated with highly significant symptom improvement compared to placebo. Symptom improvements were 2.30 mean [SD 1.63] on esomeprazole 20 mg and 2.03 [1.56] on esomeprazole 40 mg versus 1.64 [1.57] on placebo in NASA1 and 2.17 [1.34] and 2.12 [1.48]versus 1.56 [1.26], respectively, in SPACE1 (all placebo comparisons at least p < 0.001). Esomeprazole-improved symptoms in patients taking selective COX-2 inhibitors, with changes of 2.21 [1.46] and 1.92 [1.38]versus 1.64 [1.46] in NASA1 and 2.20 [1.26] and 2.24 [1.62]versus 1.58 [1.37] in SPACE1 (all placebo comparisons at least p < 0.05), as well as those on non-selective NSAIDs. Esomeprazole was well tolerated and associated with significant improvements in HRQL. CONCLUSION: Esomeprazole 20 mg and 40 mg improve upper GI symptoms associated with continuous, daily NSAID therapy, including selective COX-2 inhibitors.