Although strictly controlled, the introduction of therapeutic medications to normal healthy subjects can entail certain risks to the participants. For example, hypoglycemia is notably an anticipated adverse outcome in BA/BE and Phase 1 clinical trials involving hypoglycemic agents (HGAs) which have been addressed by multiple regulatory frameworks and established practices. Nevertheless, a universally optimal approach to mitigate this challenge remains elusive, owing to the considerable variability in these trials of HGAs. At BioPharma Services, our extensive experience in this therapeutic area has enabled the development of a standard of care for administering such drugs, fostering safer and more effective Phase 1 clinical trial practices.
In a healthy population, glucose homeostasis is tightly regulated by a series of hormones and physiologic responses to maintain its normal range. With intact counterregulatory factors, a drop in plasma glucose results in the key physiological defenses against falling plasma glucose concentrations:
Hence, hypoglycemia is a rare occurrence in normal individuals, even when being exposed to the temporary blood glucose lowering effect of the study drug. As a result, most hypoglycemic drugs produced an acceptable and well-tolerated blood glucose levels in normal healthy volunteers. Based on our in-house experience with high dose of mono and combination of hypoglycemic agents in BA/BE and Phase 1 clinical trials, most hypoglycemia events related to drug were asymptomatic, only detected by the capillary glucose monitoring and resolved without further intervention (refer to next section for more information).
Furthermore, routinely providing glucose solution to study participants can trigger a burst of insulin secretion of approximately 3-4-fold rise, that peaks in 3-5 minutes after an intravenous bolus of glucose or 30 minutes after oral ingestion of glucose. This can lead to additional unwanted reactive hypoglycemic symptoms in subjects. This physiological phenomenon was also observed in our in-house BA/BE and Phase 1 clinical trial studies: the AEs rate appears to be higher in studies with glucose solution administration. Especially when 240ml of 20% glucose solution in water may not be everyone’s cup of tea, the higher AE rate was also related to the intolerance of a few subjects to the 20% glucose solution triggering more nausea and vomiting cases.
Along the time, with the changing of the regulatory requirements and the moving of industry practices, BioPharma Services have conducted more than 30 in-house BA/BE and Phase 1 studies, involving more than 600 healthy subjects, with a wide range of anti-hyperglycemic drugs, many of them were potent combinations at their highest strengths; notably, incidents of hypoglycemia events were low, and the majority of AEs were resolved without the need of glucose administration in most cases.
In those BA/BE and Phase 1 clinical trial studies, we had explored multiple approaches to prevent, monitor and handling the hypoglycemia events, such as the FDA-recommended 4-hour routine glucose solution, 4-hour continuous glucose infusion, routine glucose solution with reduced time points, or no glucose administration, etc. Among those practices, a routine capillary glucose monitoring, in additional with injectable/oral glucose rescues provided at investigators’ discretion based on glucose reading and symptoms, are deems the best approach from both safety and tolerability aspect.
For instance, looking into our database on the common HGA fix-dose combination, Sitagliptin/Metformin XR tablets at relatively similar strengths, with which we had perform studies using both approaches:
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