Bayesian fitting of a logistic dose-response curve with numerically derived priors.

In this report we describe the Bayesian analysis of a logistic dose-response curve in a Phase I study, and we present two simple and intuitive numerical approaches to construction of prior probability distributions for the model parameters. We combine these priors with the expert prior opinion and compare the results of the analyses with those obtained from the use of alternative prior formulations.

Clinical benefits with oseltamivir in treating influenza in adult populations : results of a pooled and subgroup analysis.

BACKGROUND: Influenza is a potentially life-threatening illness that affects approximately 10% of the population annually, with resulting personal misery and societal disruption. Oseltamivir is a novel influenza treatment that has been extensively investigated. We describe a series of retrospective analyses investigating various measures of clinical efficacy across different populations of influenza-infected patients enrolled in studies of oseltamivir (Tamiflu((R))) that were conducted within the clinical development programme. METHODS: Adolescents and adults (13-97 years, n = 4015) presenting within 36 hours of onset of influenza symptoms were randomised to receive oseltamivir 75mg or placebo twice daily for 5 days during local influenza outbreaks. Of these patients, 2413 had laboratory-confirmed influenza and are included in the analysis. Approximately 30% (n = 739) of patients were 'high risk'; 20% were healthy elderly subjects (n = 488) and 10% (n = 251) were patients with chronic respiratory and/or cardiac conditions. The primary endpoint was time to alleviation of a seven-symptom cluster in influenza-infected patients. Supplementary analyses were conducted using a variety of illness definitions and symptom clusters to investigate the sensitivity of the assessment of overall efficacy to differing disease definitions and also to explore efficacy in important subpopulations. RESULTS: A total of 2413 patients had confirmed influenza infection (placebo: n = 1063; oseltamivir: n = 1350). Across all populations, the time to alleviation of illness was reduced by 19% (median duration 100.6 hours [95% CI 94.8-104.7]) compared with placebo (124.5 hours [95% CI 117.7-132.3], p < 0.0001). Oseltamivir recipients returned to normal health status, regained ability to perform usual activities and regained normal sleep patterns significantly faster than placebo recipients. The median duration of troublesome influenza symptoms was significantly reduced by oseltamivir treatment, e.g. fatigue by 29% and myalgia by 26% (both p < 0.0001). After 48 hours of treatment, 57% more placebo than oseltamivir recipients remained febrile, despite greater use of acetaminophen by placebo recipients. In addition, the median duration of acute febrile illness was significantly shortened by oseltamivir treatment compared with placebo in patients with cardiac disease (44.0 hours vs 64.7 hours, p = 0.026) or chronic obstructive airways disease (37.9 hours vs 53.8 hours, p = 0.004).Efficacy was similar among influenza A- and influenza B-infected patients. Oseltamivir was well tolerated, with transient gastrointestinal effects (observed in one in seven oseltamivir-treated patients compared with one in 12 patients on placebo) that only rarely resulted in study discontinuation. CONCLUSIONS: Oral oseltamivir is a well tolerated and effective treatment for influenza in adolescents and adults, including the elderly and patients with chronic cardiac and/or respiratory disease.

Efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor Flu Treatment Investigator Group.

BACKGROUND: Use of some antiviral drugs for influenza infection is limited by potential rapid emergence of resistance. We studied the efficacy and safety of oseltamivir, the oral prodrug of the neuraminidase inhibitor GS4071, in adults with naturally acquired laboratory-confirmed influenza. METHODS: We did a randomised controlled trial of 726 previously healthy non-immunised adults with febrile influenza-like illness of up to 36 h duration. Patients were assigned oral oseltamivir 75 mg (n=243), oseltamivir 150 mg (n=245), or placebo (n=238) twice daily for 5 days. We assessed recovery by questionnaire and temperature recordings. The primary endpoint was time to resolution of illness in influenza-infected patients. FINDINGS: 475 (66%) patients had confirmed infection. Duration of illness was significantly shorter by 29 h (25% reduction, median duration 87.4 h [95% CI 73.3-104.7], p=0.02) with oseltamivir 75 mg and by 35 h (30%, 81.8 h [68.2-100.0], p=0.01) with oseltamivir 150 mg than with placebo (116.5 h [101.5-137.8]). The effect of oseltamivir was apparent within 24 h of the start of treatment. In patients treated within 24 h of symptom onset, symptoms were alleviated 43 h (37% reduction) and 47 h (40%) earlier with oseltamivir 75 mg and 150 mg, respectively, compared with placebo (75 mg 74.5 h [68.2-98.0], p=0.02; 150 mg 70.7 h [54.0-89.4], p=0.01; placebo 117.5 h [103.0-143.8]). Oseltamivir was associated with lower [corrected] symptom scores, less viral shedding, and improved health, activity, and sleep quality, and was well tolerated. INTERPRETATION: Oseltamivir was effective and well tolerated in the treatment of natural influenza infection in adults. The efficacy, tolerability, and ease of administration warrant further investigation in children, elderly patients, and at-risk patients.

Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. US Oral Neuraminidase Study Group.

CONTEXT: Previous studies have shown oseltamivir, a neuraminidase inhibitor, to be effective in preventing influenza and treating experimental influenza. OBJECTIVE: To evaluate the efficacy and safety of oseltamivir in the treatment of naturally acquired influenza infection. DESIGN: Randomized, placebo-controlled, double-blind study conducted January through March 1998. SETTING: Sixty primary care and university health centers throughout the United States. PARTICIPANTS: A total of 629 healthy nonimmunized adults aged 18 to 65 years with febrile respiratory illness of no more than 36 hours' duration with temperature of 38 degrees C or more plus at least 1 respiratory symptom and 1 constitutional symptom. INTERVENTIONS: Individuals were randomized to 1 of 3 treatment groups with identical appearing pills: oral oseltamivir phosphate, 75 mg twice daily (n = 211) or 150 mg (n = 209) twice daily, or placebo (n = 209). MAIN OUTCOME MEASURES: Duration and severity of illness in individuals infected with influenza. RESULTS: Two individuals withdrew before receiving medication and were excluded from further analyses. A total of 374 individuals (59.6%) were infected with influenza. Their duration of illness was reduced by more than 30% with both oseltamivir, 75 mg twice daily (median, 71.5 hours; P < .001), and oseltamivir, 150 mg twice daily (median, 69.9 hours; P = .006), compared with placebo (median, 103.3 hours). Severity of illness was reduced by 38% (median score, 597 score-hours; P < .001) with oseltamivir, 75 mg twice daily, and by 35% (median score, 626 score-hours; P < .001) with oseltamivir, 150 mg twice daily, vs placebo (median score, 963 score-hours). Oseltamivir treatment reduced the duration of fever and oseltamivir recipients returned to usual activities 2 to 3 days earlier than placebo recipients (P < or = .05). Secondary complications such as bronchitis and sinusitis occurred in 15% of placebo recipients compared with 7% of combined oseltamivir recipients (P = .03). Among all 629 subjects, oseltamivir reduced illness duration (76.3 hours and 74.3 hours for 75 mg and 150 mg, respectively, vs 97.0 hours for placebo; P = .004 for both comparisons) and illness severity (686 score-hours and 629 score-hours for 75 mg and 150 mg, respectively, vs 887 score-hours for placebo; P < .001 for both comparisons). Nausea and vomiting occurred more frequently in both oseltamivir groups (combined, 18.0% and 14.1%, respectively; P = .002) than in the placebo group (7.4% and 3.4%; P < .001). CONCLUSIONS: Our data suggest that oral oseltamivir treatment reduces the duration and severity of acute influenza in healthy adults and may decrease the incidence of secondary complications.

Use of the oral neuraminidase inhibitor oseltamivir in experimental human influenza: randomized controlled trials for prevention and treatment.

CONTEXT: Influenza virus neuraminidase is thought to be essential for virus replication in humans; however, to date, available neuraminidase inhibitors are limited to zanamivir, which is topically administered. OBJECTIVE: To determine the safety, tolerability, and antiviral activity of oral neuraminidase inhibitor oseltamivir (GS4104/Ro64-0796) for prevention and the early treatment of influenza in experimentally infected humans. DESIGN: Two randomized, double-blind, placebo-controlled trials conducted between June and July 1997. SETTING: Individual hotel rooms; 2 large US university medical schools. PARTICIPANTS: A total of 117 healthy adult volunteers (aged 18-40 years; median age, 21 years) who were susceptible (hemagglutination-inhibition antibody titer < or =1:8). INTERVENTIONS: All subjects were inoculated intranasally with influenza A/Texas/36/91 (H1N1) virus. For the prophylaxis study, oral oseltamivir (100 mg once daily [n = 12], 100 mg twice daily [n = 12], or matching placebo [n = 13], starting 26 hours before virus inoculation) was administered. For the treatment study, the same drug was given (20 mg, 100 mg, or 200 mg twice daily, 200 mg once daily, or matching placebo [n = 16], in each group starting 28 hours after inoculation). All regimens were continued for 5 days. MAIN OUTCOME MEASURES: Comparing placebo groups with pooled treatment groups, for prophylaxis, outcomes included frequency of infection and viral shedding; for treatment, viral shedding in titers. RESULTS: In the prophylaxis study, 8 (67%) of 12 placebo and 8 (38%) of 21 oseltamivir recipients became infected (P = .16; efficacy, 61%); 6 (50%) placebo compared with 0 oseltamivir recipients shed virus (P<.001; efficacy, 100%), and 33% of placebo but no oseltamivir recipient had infection-related respiratory illness (P<.01). Among infected subjects in the treatment study (n = 69), the viral titer area under the curve of the combined oseltamivir groups (n = 56) was lower (median [interquartile range [IQR]], 80 [23-151] vs 273 [79-306] log10 tissue culture-infective doses50 per milliliter x hour; P = .02) than the placebo group (n = 13), and the median (IQR) duration of viral shedding with therapy was reduced from 107 (83-131) to 58 (35-59) hours (P = .003). Oseltamivir treatment also reduced symptom scores (median [IQR] score-hours, 225 [97-349] vs 400 [189-645]; P = .05), and nasal proinflammatory cytokine levels. Transient mild to moderate nausea after dosing was observed in 15 (17%) of 88 oseltamivir and 2 (7%) of 29 placebo recipients (95% confidence interval for difference, -11% to 68%), which was largely prevented by ingestion with food. CONCLUSIONS: In these trials, prophylaxis and early treatment with oral oseltamivir were both associated with significant antiviral and clinical effects in experimental human influenza.

Meta-analysis of antisecretory and gastrokinetic compounds in functional dyspepsia.

In view of therapeutic advances, we carried out meta-analysis of results from 18 randomized, controlled clinical studies to update a previous meta-analysis and to provide an overview of clinical trials involving treatment of functional dyspepsia. The studies were included only if they satisfied inclusion and exclusion criteria and assessed treatment of functional dyspepsia with the antisecretory compounds cimetidine and ranitidine and the gastrokinetic compounds cisapride and domperidone. Outcomes of each of these trials were classified in terms of differences in therapeutic success between active treatment and placebo. For antisecretory treatments, the 95% confidence intervals for the difference in therapeutic success between active treatment and placebo were inconsistent for cimetidine, but analysis of both ranitidine trials gave favorable results. For the gastrokinetic compounds cisapride and domperidone, the differences in success rates were generally higher and more in favor of active treatment than placebo. By combining the results from both antisecretory treatments and comparing them with the combined results for gastrokinetic compounds, we observed that gastrokinetic compounds had a greater difference in success rates than did antisecretory agents. Overall, our meta-analysis shows that antisecretory treatment with cimetidine or ranitidine offers little advantage over placebo, whereas gastrokinetic treatment with cisapride or domperidone is significantly better than placebo for treatment of functional dyspepsia.