Immunogenicity of a two-dose investigational hepatitis B vaccine, HBsAg-1018, using a toll-like receptor 9 agonist adjuvant compared with a licensed hepatitis B vaccine in adults.

BACKGROUND: Hepatitis B virus infection remains an important public health problem in the United States. Currently approved alum-adjuvanted vaccines require three doses and have reduced immunogenicity in adults, particularly in those who have diabetes mellitus, or are older, male, obese, or who smoke. METHODS: Phase 3 observer-blinded, randomized (2:1 HBsAg-1018 [HEPLISAV-B™]:HBsAg-Eng [Engerix-B®]), active-controlled trial in adults 18-70 years of age. HBsAg-1018 was administered intramuscularly at weeks 0 and 4 and placebo at week 24 and HBsAg-Eng at weeks 0, 4, and 24. The primary immunogenicity endpoint assessed the noninferiority of the seroprotection rate at week 28 in participants with type 2 diabetes mellitus. Secondary endpoints included seroprotection rates in the total trial population and by age, sex, body mass index, and smoking status. RESULTS: Among 8374 participants randomized, 961 participants in the per-protocol population had type 2 diabetes mellitus. In diabetes participants, the seroprotection rate in the HBsAg-1018 group at week 28 was 90.0%, compared with 65.1% in the HBsAg-Eng group, with a difference of 24.9% (95% CI: 19.3%, 30.7%), which met the prospectively-defined criteria for noninferiority and statistical significance. In the total study per-protocol population (N = 6826) and each pre-specified subpopulation, the seroprotection rate in the HBsAg-1018 group was statistically significantly higher than in the HBsAg-Eng group. CONCLUSION: Two doses of HBsAg-1018, administered over 4 weeks, induced significantly higher seroprotection rates than three doses of HBsAg-Eng, given over 24 weeks, in adults with factors known to reduce the immune response to hepatitis B vaccines as well as in those without those factors. With fewer doses in a shorter time, and greater immunogenicity, HBsAg-1018 has the potential to significantly improve protection against hepatitis B in adults at risk for hepatitis B infection. Trial Registration clinicaltrials.gov Identifier: NCT02117934.

Muraglitazar, a dual (alpha/gamma) PPAR activator: a randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with type 2 diabetes.

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) present a therapeutic target, and simultaneous activation of PPAR-alpha and PPAR-gamma may provide improvements in glycemic control and dyslipidemia in patients with type 2 diabetes. OBJECTIVE: The goal of this study was to evaluate the efficacy and safety of muraglitazar, a dual (alpha/gamma) PPAR activator, in adult patients with type 2 diabetes whose disease was inadequately controlled by diet and exercise. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter, 24-week monotherapy study in drug-naive, type 2 diabetes patients with inadequate glycemic control. Men and women aged 18 to 70 years with a body mass index < or =41 kg/m(2) and serum triglyceride levels < or =600 mg/dL were eligible for study participation. The study included double-blind and open-label treatment phases. Patients with glycosylated hemoglobin (HbA(1c)) levels > or =7.0% and < or =10.0% at screening were enrolled in the double-blind treatment phase. These patients received treatment with muraglitazar 2.5 mg, muraglitazar 5 mg, or placebo. Patients with HbA(1c) levels >10.0% and < or =12.0% who met all other study criteria were eligible for enrollment in a 24-week, open-label evaluation of muraglitazar 5 mg. The primary end point was the mean change from baseline in HbA(1c) levels after 24 weeks of treatment. RESULTS: A total of 340 patients (179 men, 161 women) participated in the double-blind treatment phase of the study. Patients had mean baseline HbA(1c) levels of 7.9% to 8.0%. Monotherapy with muraglitazar 2.5 and 5 mg significantly reduced HbA(1c) levels (-1.05% and -1.23%, respectively) compared with placebo (-0.32%; P < 0.001). At week 24, 58%, 72%, and 30% of the patients receiving muraglitazar 2.5 mg, muraglitazar 5 mg, and placebo, respectively, achieved the American Diabetes Association-recommended HbA(1c) goal of <7.0%. Fasting plasma glucose, free fatty acids, and fasting plasma insulin levels significantly decreased during muraglitazar treatment (P < 0.001), suggesting an increase in insulin sensitivity. Muraglitazar 2.5 and 5 mg provided improvements from baseline in triglyceride (-18% and -27%), high-density lipoprotein (HDL) cholesterol (10% and 16%), apolipoprotein B (-7% and -12%), and non-HDL cholesterol levels (-3% and -5%) (P < 0.05 vs placebo for each). In a parallel, open-label cohort of 109 drug-naive patients (56 men, 53 women; mean baseline HbA(1c) level, 10.6%), muraglitazar 5 mg decreased the overall mean HbA(1c) level from baseline by 2.62% (last observation carried forward) and by 3.49% in the 62 patients completing 24 weeks of study. Changes in lipid parameters during open-label treatment were similar to those observed during double-blind treatment. Muraglitazar was generally well tolerated. Edema-related adverse events of mild to moderate severity occurred in 8% to 11% of patients in all groups. Mean changes from baseline weight in the double-blind treatment groups were 1.1 kg for muraglitazar 2.5 mg, 2.1 kg for muraglitazar 5 mg, and -0.8 kg for placebo (P < 0.001); there was a mean 2.9-kg increase in the open-label muraglitazar 5-mg group. CONCLUSION: In this study, 24 weeks of treatment with muraglitazar 2.5 or 5 mg was an effective treatment option for these patients with type 2 diabetes whose disease was inadequately controlled with diet and exercise.

Time to symptom relief for uncomplicated urinary tract infection treated with extended-release ciprofloxacin: a prospective, open-label, uncontrolled primary care study.

OBJECTIVE: Few studies have investigated symptom relief in urinary tract infections. This innovative exploratory trial aimed to measure the time to improvement of the signs and symptoms of uncomplicated urinary tract infection (UTI) in women receiving extended-release ciprofloxacin. Time to return to normal daily activities was also evaluated. RESEARCH DESIGN AND METHODS: An open-label, multicenter US study in adult female outpatients with uncomplicated UTI. Patients completed serial questionnaires: the Urinary tract infection Symptom Assessment [USA], tracking time to symptom improvement, and the Activity Impairment Assessment [AIA], measuring the time to return to normal daily activities, using hand-held electronic diaries. Severity on the USA questionnaire was categorized using a 4-point Likert-type scale, with improvement defined as a reduction of at least one degree of symptom severity. All patients received once-daily extended-release ciprofloxacin 500 mg tablets for 3 days. RESULTS: Of 276 female patients aged 18-78 years who enrolled at 28 sites, 273 (99%) were safety-valid, 264 (96%) completed at least 24 h of questionnaires and were valid for symptom relief analysis, and 170 (62%) had pre-therapy pathogen(s) > or = 10(3) CFU/mL and were valid for efficacy analysis. Six hours after the first dose of study drug, 50% of patients reported symptom improvement; 87% by 24 h and 91% by 48 h. At study entry, 54% of patients reported considerably decreased time at work or other activities; reduced to 23% by Day 2 and 10% by Day 3. At the test-of-cure visit (5-11 days post-therapy), 96% (163/170) of patients were clinical cures. Drug-related adverse events were reported by 18 (7%) patients and were consistent with previous extended-release ciprofloxacin studies (e.g., gastrointestinal disturbance, fungal superinfections). There were no serious adverse events or discontinuations due to adverse events. CONCLUSION: This open-label, non-comparative trial in adult women demonstrated a rapid improvement in uncomplicated UTI symptom severity (6-24 h) and the ability to return to work within 24 h following extended-release ciprofloxacin treatment. Clinical cure rate and tolerability profile were similar to results of previous extended-release ciprofloxacin studies.