Preventing Hypoglycemia in Clinical Trials: Rethinking the Role of Glucose Solutions for Adverse Event Prevention

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, combined with our bioanalysis capabilities, has enabled the development of a standard of care for administering such drugs, fostering safer and more effective Phase 1 clinical trial practices.

1.0 – Introduction

Each class of hypoglycemic agents exhibits distinct mechanisms of action to lower blood glucose levels, broadly generalized as:

• Enhancement of insulin secretion
• Improvement of insulin sensitivity
• Inhibition of hepatic glucose production
• Delay of carbohydrate absorption
• Promotion of glucose excretion
• Modulation of incretin hormones

The selection of pharmacological agents for diabetes management is individualized based on various factors, and similarly, the response to HGAs also varies from person to person, as well as the manifestation of hypoglycemic adverse events (AE). In bioequivalence trials of HGAs in healthy volunteers, as an extra-precautionary approach to prevent hypoglycemia , FDA specific guidance for antihyperglycemic drugs suggests co-administration of “240 mL of a 20% glucose solution in water, followed by 60 mL of the glucose solution administered every 15 min for up to 4 hours after dosing.” – example from FDA Draft Guidance for bioequivalence studies using Empagliflozin-Metformin.

On the other hand, EMA and TPD do not specifically indicate the use of glucose solution prevention. This leads to inconsistencies in the preventive and monitoring procedure of hypoglycemia events in the studies of HGAs. The true question is which directions could provide more favorable safety and tolerability profiles to BA/BE and Phase 1 clinical trial study participants.

2.0 – Glucose Solution: Friend or Enemy

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:

1. a decrease in pancreatic β-cell insulin secretion,
2. an increase in pancreatic α-cell glucagon secretion and
3. an increase in adrenomedullary epinephrine secretion.

This is to promote making new glucose and limit how much glucose is used by insulin-sensitive tissues, and subsequently raise the blood glucose level back to normal range (Figure 1).

Adapted from Cryer PE. Hypoglycemia, Pathophysiology, Diagnosis and Treatment. NewYork: Oxford University Press, 1997, pp. 184, with permission from the author and publisher

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.

3.0 – What Should We Do?

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:

1. Without glucose solution administration and
2. With the FDA-recommended glucose solution administration during and after dosing.

It turns out that with the glucose administration, the frequency of total reported AEs was up to 38.1% in this study, with about 19.0-28.6% subjects experienced at least one AE, among which nausea/vomiting and fatigue were the most frequently reported AE. Conversely, in study without glucose solution administration, only 2.9% subjects reported an AE, which was unrelated to treatment (catheter site bruise). 

Similar phenomenon was also observed in the literature, where 20% glucose solution consumed during and after another common HGA combination Glipizide/Metformin, did not prove its role in preventing the hypoglycemic events in healthy volunteers, under both fast and fed conditions.4,5 (Figure 2).

Why Choose BioPharma Services for Your Next Drug Development Project?

In brief, hypoglycemia is an expected AE when dosing HGA, such AEs are generally asymptomatic and do not impact overall safety and tolerability of the healthy volunteers, even at the maximum recommended daily dose in most cases. There are various practices for prepare and handling the hypoglycemia in  Phase 1 clinical trial following dosing of a HGA, and routine capillary glucose monitoring with glucose recuse has been a consistent practice at BioPharma Services following an extensive experience with various HGAs as both single and multiple dose setting.

In the context of Phase 1 clinical trials, the management of hypoglycemia is anticipated to be inherently intricate, owing to the novel nature of the compound under investigation and the consequent lack of established safety parameters. Engaging a partner such as BioPharma Services for your drug development process ensures that you are working with professionals who are well-versed in these challenges. Recognizing the delicacy in balancing participants’ overall well-beings and the compliance with agency’s guidance, the BioPharma Services team possesses the requisite expertise to assess and anticipate possible scenarios, thereby formulating a study proposal that justify all queries from agency, ensuring strict adherence to expected safety and efficacy standards, as well as the feasibility of the overall projects.

Thuy Van Nguyen

Pharmacokinetic Scientist

BioPharma Services, Inc., a HEALWELL AI and clinical trial services company, is a full-service Contract Clinical Research Organization (CRO) based in Toronto, Canada, specializing in Phase 1 clinical trials 1/2a, Human Abuse Liability(HAL) and Bioequivalence clinical trials for international pharmaceutical companies worldwide. BioPharma Services conducts clinical research operations from its Canadian facility, with access to healthy volunteers and special populations.