BACKGROUND:Exenatide (exendin-4) exhibits dose-dependent glucoregulatory activity, but causes dose-limiting nausea and vomiting. This study was designed to formally assess the possibility of inducing tolerance to the side effects of nausea and vomiting at therapeutic doses of exenatide, using a dose-escalation methodology. METHODS: In this two-arm, triple-blind, multicenter study, 123 subjects with type 2 diabetes were enrolled and randomized; 99 (80.5%) of them completed the study. Subjects in the exenatide-primed arm received subcutaneous exenatide, starting at 0.02 micro g/kg three times a day (TID) and increasing in 0.02 micro g/kg per dose increments every 3 days for 35 days. Subjects in the exenatide-naive arm received placebo TID for 35 days. At the end of this 35-day regimen, subjects in both arms received the same highest dose of exenatide (0.24 micro g/kg TID) for 3 days. Thus, the exenatide-naive arm received exenatide for the first time on Day 35. RESULTS: The exenatide-primed arm had a lower proportion of subjects experiencing nausea and vomiting in response to exposure to the highest dose of exenatide (27 vs 56% in the exenatide-naive arm; p = 0.0018). Kaplan-Meier estimates of cumulative incidence were 0.28 in the exenatide-primed arm, compared with 0.68 in the exenatide-naive arm (p </= 0.001). As predicted by the study design, fewer subjects in the exenatide-primed arm reported severe nausea (29%) and vomiting (10%) than those in the exenatide-naive arm (48 and 31%, respectively). In the exenatide-primed arm, fasting serum glucose progressively declined over the first 35 days of dosing, but was unchanged in the exenatide-naive arm (placebo phase) during the same interval. CONCLUSION: Gradual dose-escalation of exenatide successfully reduced the proportion of subjects experiencing dose-limiting nausea and vomiting, with no loss of glucoregulatory activity, thus demonstrating the value of gradual dose-escalation in mitigating the gastrointestinal side effects of exenatide. Copyright 2004 John Wiley & Sons, Ltd.
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BACKGROUND:Exenatide (exendin-4) exhibits dose-dependent glucoregulatory activity, but causes dose-limiting nausea and vomiting. This study was designed to formally assess the possibility of inducing tolerance to the side effects of nausea and vomiting at therapeutic doses of exenatide, using a dose-escalation methodology. METHODS: In this two-arm, triple-blind, multicenter study, 123 subjects with type 2 diabetes were enrolled and randomized; 99 (80.5%) of them completed the study. Subjects in the exenatide-primed arm received subcutaneous exenatide, starting at 0.02 micro g/kg three times a day (TID) and increasing in 0.02 micro g/kg per dose increments every 3 days for 35 days. Subjects in the exenatide-naive arm received placebo TID for 35 days. At the end of this 35-day regimen, subjects in both arms received the same highest dose of exenatide (0.24 micro g/kg TID) for 3 days. Thus, the exenatide-naive arm received exenatide for the first time on Day 35. RESULTS: The exenatide-primed arm had a lower proportion of subjects experiencing nausea and vomiting in response to exposure to the highest dose of exenatide (27 vs 56% in the exenatide-naive arm; p = 0.0018). Kaplan-Meier estimates of cumulative incidence were 0.28 in the exenatide-primed arm, compared with 0.68 in the exenatide-naive arm (p </= 0.001). As predicted by the study design, fewer subjects in the exenatide-primed arm reported severe nausea (29%) and vomiting (10%) than those in the exenatide-naive arm (48 and 31%, respectively). In the exenatide-primed arm, fasting serum glucose progressively declined over the first 35 days of dosing, but was unchanged in the exenatide-naive arm (placebo phase) during the same interval. CONCLUSION: Gradual dose-escalation of exenatide successfully reduced the proportion of subjects experiencing dose-limiting nausea and vomiting, with no loss of glucoregulatory activity, thus demonstrating the value of gradual dose-escalation in mitigating the gastrointestinal side effects of exenatide. Copyright 2004 John Wiley & Sons, Ltd.