A 6-month open-label extension study of the safety and efficacy of subcutaneous belimumab in patients with systemic lupus erythematosus.

Objective To evaluate the safety, tolerability and efficacy of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE) beyond 1 year. Methods This was a 24-week, open-label extension following a 52-week, double-blind, placebo-controlled trial of belimumab SC. Patients who completed the double-blind phase were eligible to enter the open-label phase. All patients received weekly belimumab 200 mg SC plus standard SLE therapy. Outcome measures included safety and efficacy (SLE Response Index (SRI) and SLE Flare Index (SFI) rates), and changes in biomarker and B cell levels. Results Of 677 patients who completed the 52-week, double-blind phase, 662 entered the open-label phase; 206 had previously received placebo and 456 had previously received belimumab. Despite differences in total belimumab exposure (24 weeks in the placebo-to-belimumab group versus 76 weeks in the belimumab group), the proportions of patients experiencing more than one adverse event (AE) or a serious AE in the open-label phase were similar between groups (placebo-to-belimumab: 51.5 and 6.8%; belimumab: 48.2 and 5.5%, respectively). Most AEs were mild/moderate in severity. Efficacy was maintained through the extension phase. An SRI response was achieved by 16.1% of patients in the placebo-to-belimumab group and 76.3% patients in the belimumab group. Furthermore, 1.0% of patients in the placebo-to-belimumab group and 2.6% of patients in the belimumab group experienced a severe SFI flare. Conclusion Belimumab SC was well tolerated and efficacy was maintained during the extension phase of this study. The safety profile of belimumab SC is consistent with that of previous experience with belimumab. Trial registration ClinicalTrials.gov identifier: NCT01484496.

A randomized, open-label study to investigate the effect of belimumab on pneumococcal vaccination in patients with active, autoantibody-positive systemic lupus erythematosus.

Objective Intravenous belimumab 10 mg/kg is approved as an add-on therapy in patients with active, autoantibody-positive systemic lupus erythematosus. This study aimed to assess the impact of belimumab on immune response to pneumococcal vaccination in patients with systemic lupus erythematosus. Methods This was a Phase 4, open-label study (GSK BEL115470; NCT01597492) conducted in the United States. Patients were randomized (7:9) to receive a 23-valent pneumococcal vaccination four weeks prior to (pre-belimumab cohort) or 24 weeks after (belimumab-concurrent cohort) commencing four-weekly belimumab 10 mg/kg intravenous treatment plus standard systemic lupus erythematosus therapy. Analyses of vaccine titers were performed on the as-treated population (received ≥1 dose of belimumab). The primary endpoint was the proportion of patients with positive antibody responses (≥2-fold increase from pre-vaccination levels, or post-vaccination level ≥ 0.6 µg/mL if pre-vaccination levels were unquantifiable) to ≥1 of 23 pneumococcal vaccine serotypes, four weeks post vaccination. Other endpoints included the proportion of patients with positive antibody responses to ≥2 to ≥10, and ≥11-23 (post hoc analysis) of serotypes. Safety was assessed by monitoring adverse events. Results Seventy-nine patients received pneumococcal vaccination (pre-belimumab cohort, n = 34; belimumab-concurrent cohort, n = 45). The majority (87.3% [69/79]) completed the study; 10 (12.7%) withdrew (patient request, n = 3; adverse event, n = 3; lost to follow-up, n = 2; other, n = 2). At Week 4 post-vaccination, 97.0% (32/33) and 97.6% (40/41) of patients (pre-belimumab and concurrent belimumab cohorts, respectively) had a positive response to ≥1 of 23 pneumococcal serotypes. Over 85% of patients in both cohorts responded to ≥10 of serotypes, approximately 80% responded to ≥12 serotypes, and approximately two-thirds responded to ≥16 serotypes. Little difference was observed between cohorts across a broad response, up to 23 serotypes. Eight (23.5%) patients experienced an adverse event considered by the investigator to be treatment-related in the pre-belimumab cohort and four (8.9%) in the belimumab-concurrent cohort; seven patients experienced non-fatal serious adverse events (pre-belimumab cohort, 11.8% [ n = 4]; concurrent-belimumab cohort, 6.7% [ n = 3]), and no deaths were reported. Conclusion The proportion of patients generating a response to ≥1 pneumococcal serotype did not differ between the pre-belimumab and belimumab-concurrent cohorts; the proportions were also comparable across a broader response (from ≥2 serotypes to 23 serotypes).

A dose-ranging, placebo-controlled, randomized trial of alosetron in patients with functional dyspepsia.

BACKGROUND: Functional dyspepsia is characterized by upper abdominal pain or discomfort. AIM: To assess the benefit of the 5-HT3-receptor antagonist alosetron in a pilot, dose-ranging, placebo-controlled, multicentre, randomized clinical trial. METHODS: A total of 320 functional dyspepsia patients received placebo (n=81), or alosetron 0.5 mg b.d. (n=77), 1.0 mg b.d. (n=79) or 2.0 mg b.d. (n=83) for 12 weeks, followed by 1 week of follow-up. Primary efficacy was the 12-week average rate of adequate relief of upper abdominal pain or discomfort. Secondary endpoints assessed pain and upper gastrointestinal symptoms. RESULTS: Twelve-week average rates of adequate relief of pain or discomfort were 46% (95% CI: 37-54%), 55% (95% CI: 46-63%), 55% (95% CI: 47-64%) and 47% (95% CI: 38-55%) in the placebo, 0.5 mg, 1.0 mg and 2.0 mg alosetron groups, respectively. Alosetron 0.5 mg or 1.0 mg showed potential benefit over placebo for early satiety and postprandial fullness. Females showed greater responses compared to males. Patients with adequate relief had significantly (P < 0.001) greater reductions in severity and frequency of functional dyspepsia symptoms than those without adequate relief. Constipation was the most commonly reported adverse event. CONCLUSIONS: Alosetron showed potential benefit in relieving functional dyspepsia symptoms compared to placebo. Patients with adequate relief of upper abdominal pain or discomfort showed improvements in multiple functional dyspepsia symptoms.

Managing heartburn at the 'base' of the GERD 'iceberg': effervescent ranitidine 150 mg b.d. provides faster and better heartburn relief than antacids.

BACKGROUND: Many individuals with heartburn self-medicate with antacids for relief of their symptoms. AIM: To compare efficacy of effervescent ranitidine to as-needed calcium carbonate antacids in subjects who self-treat heartburn. METHODS: A total of 155 subjects with frequent antacid-responsive heartburn were randomized to receive effervescent ranitidine 150 mg tablets b.d., or as-needed calcium carbonate 750 mg for 12 weeks. Endoscopic oesophagitis severity and mucosal histology were assessed at baseline, and at weeks 6 and 12. Heartburn frequency, severity, and antacid consumption were recorded daily, and quality of life was assessed at baseline, and at weeks 6 and 12. RESULTS: Heartburn frequency and severity were significantly decreased after 1 day of ranitidine (P < 0.02). By week 6, ranitidine had significantly decreased rescue antacid consumption (7.3 tablets, P < 0.001) vs. antacids (14.1 tablets). Endoscopic oesophagitis healing (

Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease. North American Azathioprine Study Group.

BACKGROUND & AIMS: Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response. METHODS: A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of

Heartburn requiring frequent antacid use may indicate significant illness.

BACKGROUND: Many otherwise healthy individuals with episodic heartburn self-medicate with over-the-counter antacids. We evaluated clinical characteristics of subjects who had never been medically diagnosed as having any upper gastrointestinal tract disorder and who used antacids for symptomatic relief of heartburn. SUBJECTS AND METHODS: Subjects with at least 3 months of frequent heartburn relieved by antacids, and with heartburn on at least 4 of 7 days during the week prior to study entry, had their medical history and gastrointestinal pathological characteristics recorded. Tests included esophagogastroduodenoscopy, esophageal motility and sensitivity studies, and 24-hour pH monitoring. RESULTS: Of 178 subjects screened, 13 were excluded on the basis of other gastrointestinal diseases at baseline, including diffuse esophageal spasm, peptic ulcer disease, dysplastic columnar metaplasia of the esophagus (Barrett's esophagus), and adenocarcinoma. Ten subjects were ineligible because of insufficient baseline heartburn. The remaining 155 eligible subjects had heartburn for an average of 11 years. Forty-seven percent had daily symptoms and 70% described heartburn severity as moderate, even though on endoscopy most (53%) had normal-appearing esophageal mucosa (grade 0 or 1). Esophageal acid sensitivity was present in 86% of subjects. Mean lower esophageal sphincter pressures and esophageal contractile amplitudes were at the lower limits of normal and total esophageal acid contact time was slightly increased. CONCLUSIONS: Chronic heartburn can reflect a wide range of diagnostic findings, including important underlying pathological features, and may warrant a full medical examination to detect such abnormal conditions and to permit selection of appropriate therapy.

Effectiveness of ranitidine 150 mg at bedtime as maintenance therapy for healed gastric ulcers.

As many as 89% of gastric ulcer patients experience ulcer recurrences within 1 year of successful healing with conventional antiulcer therapies. Because ranitidine is effective in the healing of gastric and duodenal ulcers and the maintenance of healed duodenal ulcers, we hypothesized that ranitidine would also be effective in the maintenance of healed gastric ulcers. A 48-week, placebo-controlled, randomized, double-blind, multicenter trial was conducted to compare ranitidine 150 mg administered at bedtime with placebo for the maintenance of healed gastric ulcers. Endoscopies were performed at baseline and repeated after 12, 24, 36, and 48 weeks of treatment. Gastric ulcer recurrence rates at each scheduled endoscopy were significantly lower in patients receiving ranitidine (5%, 13%, 16%, and 19%, respectively) compared with those receiving placebo (20%, 30%, 40%, and 50%, respectively). Compared with placebo, ranitidine was more effective in maintaining healed gastric ulcers regardless of previous gastric ulcer history, smoking status, age (< 65 vs > or = 65 years), or sex. There were no significant differences between the two treatment groups in the number of patients experiencing adverse events or laboratory abnormalities. Ranitidine 150 mg administered at bedtime provides safe and effective treatment for the maintenance of healed gastric ulcers.

Ethanol Pharmacodynamics at Low Blood Concentrations.

Ranitidine has been shown to produce increases in blood alcohol concentration (BAC) after low doses of alcohol. The objective of this study was to reproduce, in a controlled setting, the BACs seen after low oral doses of ethanol in the presence and absence of ranitidine and to assess the effect of these concentrations on cognitive performance. An active control group (0.45 g per kg alcohol) was included as a validation of the methodology used. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in eight healthy males. Subjects received a 20-min intravenous infusion of 0.10, 0.15, or 0.45 g per kg alcohol or placebo. Blood samples were obtained to measure BAC and psychometric effects were assessed over 8 h. A pharmacokinetic model was used to fit simultaneously the BAC--time profiles of all three doses for each subject. Cognitive improvement was assessed using digit symbol substitution, continuous tracking, and divided attention tests. Analysis of variance was conducted in order to compare peak blood alcohol impairment (E(max)) and area under the alcohol impairment--time curve (AUEC) across treatments. Observed median peak BAC (C(max)) for 0.10- and 0.15-g/kg dose groups (median BACs 15.2 and 27 mg/dl, respectively) were very similar to the target C(max) (13 and 26 mg/dl). Analysis of variance of AUEC and E(max) showed difference in impairment measures after the 0.10- and 0.15-g/kg doses. A significant difference in impairment measures between placebo and the active control, 0.45 g/kg (median BAC of 110 mg/dl) was observed, indicating that the methodology was capable of detecting significant psychomotor effects at the legal limit of BAC. Results indicated that the BAC increments from 15 to 27 mg/dl are not associated with significantly impaired performance and, hence, it is unlikely that increases in BAC of this magnitude, such as those caused by ranitidine therapy, are of any clinical relevance.