A clinical trial of intravenous peramivir compared with oral oseltamivir for the treatment of seasonal influenza in hospitalized adults.

BACKGROUND: Seasonal interpandemic influenza causes >200,000 annual hospitalizations in the United States. Optimal antiviral treatment in hospitalized patients is not established. METHODS: During three interpandemic influenza seasons, 137 patients hospitalized with suspected acute influenza were randomized to 5-day treatment with intravenous peramivir 400 mg or 200 mg once daily or oral oseltamivir 75 mg twice daily. Time to clinical stability and quantitative changes in viral titres from nasopharyngeal specimens were primary and key secondary end points, respectively. RESULTS: Infection was confirmed in 122 patients with influenza A (H1N1), influenza A (H3N2) or influenza B. Median times (95% CI) to clinical stability were 37.0 h (22.0, 48.7) with peramivir 400 mg, 23.7 h (16.0, 38.9) with peramivir 200 mg and 28.1 h (22.0, 37.0) with oseltamivir (P=0.306). Patients (n=97) who were clinically unstable at enrolment had median times (95% CI) to clinical stability of 24.3 h (21.2, 47.5) with peramivir 400 mg, 31.0 h (17.2, 47.7) with peramivir 200 mg and 35.5 h (23.3, 37.9) with oseltamivir (P=0.541). Titres of influenza A viruses in nasopharyngeal specimens decreased similarly across treatments, but more rapid decreases in titres of influenza B occurred with peramivir treatment. There were no deaths among patients with confirmed influenza and the incidence of adverse events was low and generally similar among treatment groups. CONCLUSIONS: Treatment of acute seasonal influenza in hospitalized adults with either peramivir or oseltamivir resulted in generally similar clinical outcomes. Treatment with peramivir was generally safe and well tolerated and could be of benefit in this population.

The upper gastrointestinal safety of rofecoxib vs. NSAIDs: an updated combined analysis.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are nonspecific cyclo-oxygenase (COX-1/COX-2) inhibitors and are associated with gastrointestinal (GI) toxicity attributable to COX-1 inhibition. Rofecoxib, a COX-2 specific inhibitor, was developed to provide similar efficacy and less GI toxicity than NSAIDs. OBJECTIVE: To update the results of a previously performed analysis of the incidence of upper GI perforations, symptomatic gastroduodenal ulcers, and upper GI bleeding (PUBs) with rofecoxib compared with non-selective NSAIDs. RESEARCH DESIGN AND METHODS: We compared the incidence of PUBs in a combined analysis of 20 randomized, double-blind, clinical trials of rofecoxib versus NSAIDs. Men and women (N = 17,072) from multinational trial sites with osteoarthritis or rheumatoid arthritis were studied. There was no upper age limit in any of the trials. Investigator-reported PUBs were reviewed by a blinded, external adjudication committee using pre-specified criteria. The incidence of confirmed PUBs, the main outcome measure, among patients treated with rofecoxib 12.5 mg, 25 mg, or 50 mg (combined, N = 10 026) was compared to that among patients treated with ibuprofen, diclofenac, nabumetone, or naproxen (combined, N = 7046). RESULTS: The incidence of PUBs over 24.8 months was significantly lower with rofecoxib vs. NSAIDs (cumulative incidence 1.6% vs. 3.1%, p < 0.001; rate/100 patient-years 0.74 vs. 1.87; relative risk 0.36, 95% CI 0.24, 0.54). Results of subgroup analyses and comparisons of rofecoxib with individual NSAID comparators were consistent with the primary result, as was an analysis in patients with no PUB risk factors. DISCUSSION: The analysis demonstrated a consistently lower incidence of confirmed PUBs with rofecoxib than with NSAIDs over 24.8 months. These results confirm those of a previous smaller combined analysis of clinical trials with rofecoxib vs. non-selective NSAIDs in OA patients only, in which the risk reduction for confirmed PUBs was approximately 50%. In addition, this analysis demonstrated risk reductions with rofecoxib vs. NSAIDs in risk subgroups and in patients who did not have any known risk factors for PUBs consistent with the primary result. Some of the studies in this analysis required scheduled endoscopies. Asymptomatic upper GI ulcers or bleeding diagnosed during scheduled procedures were not included in the primary endpoint, which may have caused a bias against rofecoxib. CONCLUSIONS: Treatment with rofecoxib was associated with a statistically significantly (p < 0.001) lower incidence of PUBs than was treatment with NSAIDs. The difference was maintained in subgroups of patients with risk factors, as well as in those with no risk factors, for PUBs.

Self-Directed Treatment of Intermittent Heartburn: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Evaluation of Antacid and Low Doses of an H(2)-Receptor Antagonist (Famotidine).

BACKGROUND: Heartburn, a common symptom, is self-treated with oral antacids. Efficacy of antacids has not been demonstrated for individual, spontaneous heartburn episodes. METHODS: We conducted a double-blind, randomized, placebo-controlled, parallel-group study of self-directed treatment for episodic heartburn comparing famotidine (FAM) 5, 10, or 20 mg and antacid (11 mEq ANC) to placebo (PBO) during a 4-week period. Twenty-nine US investigators enrolled a total of 565 outpatients, ages 18--81 years (mean 44.1 years) with heartburn but not seeking care for heartburn. Treatment of spontaneous heartburn episodes was permitted as needed, up to twice daily, with self-administered test drug. An open-label, backup antacid was provided to use if test drug did not provide adequate relief. Patients assessed heartburn relief hourly and recorded use of backup antacid. Relief was defined as complete relief of symptoms without the use of backup antacid. RESULTS: The media proportion of episodes relieved was: PBO, 41%; FAM 5 mg, 59%, 0.05 less-than-or-equal p < 0.10; FAM 10 mg, 70%, p < 0.001; FAM 20 mg, 69%, p < 0.001; antacid, 62%, p < 0.05 (p-values versus PBO). Supplemental analyses incorporating time to relief confirmed that famotidine and antacid provided more rapid and more frequent relief than placebo (odds ratio for relief relative to PBO: FAM 5 mg, 1.55, p = 0.003; FAM 10 mg, 1.94, p < 0.001; FAM 20 mg, 2.13, p < 0.001; antacid 1.57, p = 0.003). The tolerability profile was similar with famotidine, antacid, and placebo. CONCLUSIONS: The positive results with antacid demonstrated for the first time the efficacy of antacid in self-treatment of individual heartburn episodes and provided internal validation of this study paradigm. Patients in this study self-medicated effectively using low doses of famotidine on an as needed basis for spontaneous episodes of heartburn.

Efficacy and Tolerability of Famotidine in Preventing Heartburn and Related Symptoms of Upper Gastrointestinal Discomfort.

This randomized, double-blind, placebo-controlled, four-way crossover trial was designed to compare the efficacy of famotidine and placebo in preventing meal-provoked upper gastrointestinal symptoms. One hundred twenty-one subjects (58 men and 63 women), aged 20--61 years, were randomly assigned to one of four treatment sequences which included single oral doses of placebo, famotidine 5 mg, famotidine 10 mg, and famotidine 20 mg, spaced approximately 7 days apart. To be eligible for randomization, subjects had to have at least a 2-month history of heartburn and acid/sour stomach occurring at least three times per week. Treatment was administered 1 h prior to ingestion of test meals (chili and wine). Rescue antacid medication (Maalox((R))) was available for subjects who required additional relief. Heartburn severity. acid/sour stomach, and overall discomfort were evaluated on a six-point scale immediately prior to each test meal and every 15 min thereafter for 5 h. A global evaluation of the test medication, using a five-point scale, was performed prior to rescue medication use or at the end of each treatment session. Heartburn and peak acid/sour stomach were rated as significantly milder following prophylactic treatment with famotidine 5, 10, and 20 mg compared to placebo. Treatment with all three doses of famotidine was rated as "good" or "excellent" by significantly more subjects (58--63%) than following treatment with placebo (38%). In addition, rescue medication was used by significantly fewer subjects following famotidine (17--18%) compared to placebo (37%). Famotidine was generally well tolerated in this trial, with type and frequency of reported adverse experiences similar to that observed following placebo. These results indicated that famotidine doses of 5, 10, and 20 mg were significantly more effective than placebo in preventing symptoms of upper gastrointestinal distress when administered 1 h in advance of meal provocation.