In healthy volunteers, DR-DMF was well tolerated over 4 days of dosing, with a PK profile consistent with that previously reported and no evidence of accumulation. Aspirin pretreatment reduced the incidence and intensity of flushing without affecting GI events or the DR-DMF PK profile. Elevated levels of PGD2 in some DR-DMF-treated individuals suggest that flushing may be, at least in part, prostaglandin mediated. ClinicalTrials.gov identifier: ID: NCT01281111.
Aim
To compare the safety and efficacy of bexagliflozin administered as monotherapy at three dosage strengths over a 12‐week period to patients with type 2 diabetes who were either naïve to pharmacotherapy or were previously prescribed one oral hypoglycaemic agent and underwent a 6‐week period of medication abstinence.
Methods
Adults with type 2 diabetes (n = 292) having an HbA1c of between 7.0% and 8.5% were randomized to receive one of three dosage strengths of bexagliflozin (5, 10 or 20 mg) or placebo. The primary endpoint was the change from baseline to week 12 in the %HbA1c. Secondary endpoints included the changes from baseline in fasting plasma glucose (FPG), systolic blood pressure and diastolic blood pressure, body mass and fraction of patients achieving an HbA1c of <7%.
Results
The mixed model repeated measure estimates of the placebo‐adjusted change in %HbA1c from baseline to week 12 for the 5, 10 and 20 mg groups were −0.55% (95% CI: −0.76%, −0.34%, P < 0.0001), −0.68% (95% CI: −0.89%, −0.47%, P < 0.0001) and −0.80% (95% CI: −1.01%, −0.59%, P < 0.0001), respectively. Significant and dose‐dependent placebo‐adjusted mean reductions from baseline to week 12 in FPG and body mass were observed. The fraction of subjects achieving an HbA1c of <7% was significantly greater in the 20 mg bexagliflozin group. The incidence of adverse events was similar for participants in all active arms (42.3%) compared with the rate measured in those receiving placebo (40.3%).
Conclusions
Bexagliflozin confers substantial and dose‐dependent benefits on subjects with type 2 diabetes and has an acceptable safety profile. Further evaluation of bexagliflozin for the control of type 2 diabetes in adults is warranted.
This study was conducted to assess the safety and efficacy of zileuton controlled release [CR] 1,200 mg BID added to usual care (UC) in 926 patients with moderate asthma (619 patients randomized to zileuton CR and 307 to placebo). Sustained improvements in AM and PM peak expiratory flow (PEF) were observed in the zileuton CR group compared to placebo. The adverse event profile was similar in the two treatment groups. Eleven patients (1.8%) receiving zileuton CR and 2 (0.7%) receiving placebo experienced elevations of alanine aminotransferase (ALT) >or= 3X the upper limit of normal (ULN). These elevations typically occurred (81.8%) during the first 3 months of exposure and most resolved within 21 days after discontinuation.
Ojien, clinical trial results are reported and used for claiming a treatment effect without adjusting for the multiplicity arising from the presence of multiple endpoints. It is well recognized that this practice is likely to inflate the type I error rate unless the endpoints are highly correlated. To control such an inflation of the type 1 error rate, two approaches, both appropriate on their own grounds, are in use. One is the 'global' approach which aims at demonstrating overall treatment effect and considers all given endpoints simultaneously. The other approach, often called the 'endpoint-specific ' approach, assesses significance for each endpoint separately, assuring meaningful control of the overall type 1 error rate. This paper addresses and discusses some of these global multiple endpoint adjustment methods in the context of clinical trial applications where two treatments are being compared (for example, active treatment with a placebo), andgives some simulation results to assess their peqormance regarding the a-level protection and power:
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