Closed Loop System With Pramlintide Versus Exenatide

Diabetes complications can be minimized or forestalled with the use of intensive insulin management. In the post-Diabetes Control and Complications Trial (DCCT) era, diabetologists around the globe are engaged in developing better methods of improving glycemic control in patients with type 1 diabetes mellitus (T1DM). To achieve the DCCT-recommended glycemic and hemoglobin A1C (HbA1c) goals, in addition to physicians, engineering and pharmaceutical companies are augmenting our ability to improve control by innovative compounds and technologies such as continuous glucose monitoring. Despite these substantial advances, hyper- and hypoglycemia continue to be problematic in the management of T1DM, especially in children. Current T1DM management involves checking blood glucose pre-prandially and once at bedtime (4 times/day), and making insulin dose adjustments based on these 4 blood glucose measurements. This approach is woefully inadequate. Post-meal hyperglycemia is missed, and low blood glucose is undetected until the patient has symptomatic hypoglycemia. Moreover, we depend on patients to make appropriate dose modifications to basal rates of insulin when on the pump, without the guidance of adequate blood glucose measurements. The continuous glucose monitoring system (CGMS) is increasingly studied as a tool to examine glucose trends, and is helping to combat inadequate self-monitoring. However, the CGMS still relies on the patient's ability to make accurate insulin dose adjustments based on glucose readings. To address this issue the closed loop system is now under investigation. The closed loop system is developed to closely emulate physiologic insulin delivery. The algorithm was developed by modeling beta cells and validated by hyperglycemic clamp studies using the subcutaneous site for measurement of blood glucose and insulin delivery. The algorithm is known as the external Physiologic Insulin Delivery (ePID). Current studies suggest that basal requirements are detected accurately, and the algorithm responds effectively. However, meal related elevation in blood glucose remains a challenge, as when blood glucose levels begin to rise and are seen in the subcutaneous glucose sensor signal, it is already too late to administer insulin in a way that will effectively minimize the postprandial glucose peak. Improvements in the ePID algorithm have been studied to improve the postprandial response with some success, but require user intervention for best results, and despite that glucose excursions fail to normalize in the post-prandial period. It is likely that further improvements in postprandial glycemia will be limited with insulin monotherapy. Besides insulin there are other dysregulated hormones such as glucagon and amylin, which contribute to post-prandial hyperglycemia. The autoimmune destruction of insulin-secreting beta cells of the pancreas is presumed to cause T1DM. In addition to insulin, other hormones such as glucagon and amylin play a role in normalizing glucose excursions. Failure of glucagon suppression results in immediate postprandial hyperglycemia, and a loss of glucagon response to hypoglycemia results in late postprandial hypoglycemia. Despite the increasing use of subcutaneous continuous insulin administration and newer insulin analogs, insulin replacement remains imperfect, and glucose excursions are inadequately controlled in diabetes. This suggests that other factors, in addition to diet and insulin management, may need to be addressed if postprandial glucose excursions are to be normalized in T1DM. The recent discovery of the hormone amylin has enhanced our understanding of postprandial glucose homeostasis. Patients with T1DM have deficiencies of both insulin and amylin. Amylin, a 37-amino acid polypeptide hormone, is co-secreted from the pancreatic beta cells in conjunction with insulin in response to nutrient stimuli. Amylin, in the immediate postprandial period, may mediate part of its effect by suppressing glucagon secretion, resulting in the suppression of hepatic glucose production and the slowing of gastric emptying. Pramlintide acetate is a synthetic analog of the naturally occurring human hormone amylin. It effectively reproduces amylin agonist activity in an equipotent fashion. Pramlintide acetate has been reported to improve glycemic control in adults with both type 1 and type 2 diabetes mellitus. Specifically, postprandial glucose excursions are improved with adjunctive pramlintide use compared with insulin monotherapy. Exenatide is a synthetic analog of exendin-4. It is FDA approved for use in adults with type 2 diabetes mellitus (T2DM). Clinical studies indicate that exenatide is very effective in decreasing postprandial glucose excursions. The investigator's brochure for exenatide suggested that in adults with T2DM, exenatide was well tolerated at 0.1 mcg/ kg/ dose, and resulted in glucose lowering. Our preliminary data in children with T1DM suggests that 1.25 mcg and 2.5 mcg are good pre-prandial initial doses with a prandial insulin dose reduction of 30%. The principal mechanism of action in T1DM is suppression of glucagon, with a subsequent suppression of hepatic glucose production and decreased immediate post-prandial hyperglycemia. These effects result in further reduction of HbA1c beyond the reduction observed with insulin alone. Additionally, in T2DM, exenatide delays gastric emptying, and decreases food intake through centrally mediated mechanisms causing satiety and improved weight control. The most notable adverse effect of exenatide is nausea, which improves with the duration of treatment and steady dose escalation of exenatide. Hypoglycemia may occur with concurrent use of insulin. In the current exploratory studies we are proposing a novel way to combat immediate postprandial hyperglycemia in subjects with T1DM by using the study medications through the experimental closed loop system. Subjects will not be on the closed loop system prior to eligibility, and would not have used the closed loop system at an earlier time. We will use prandial pramlintide/exenatide in the first protocol, and test the hypothesis that this intervention will be superior to using insulin monotherapy in the closed loop system. This would be a Biologic, phase I, single center study and a paired, randomized, and controlled comparison of pramlintide and insulin versus exenatide and insulin Vs insulin monotherapy using the ePID closed-loop system for insulin delivery. We will stratify the study subjects into the following sub-groups of 5 subjects of 22-30 years old, 4 subjects of 18-21 years old, 4 subjects of 16-18 years old. We would also begin the study with the 22-30 year patient sub-group and then transition to the other sub-groups after evaluating all the safety issues. 22-30 year old ones would be considered as an adult subset, 18-21 year olds would be considered pediatric subset according to the guidelines of FDA's Center for Devices and Radiological Health (CDRH) and 16-18 year olds are considered typical pediatric population. At this time, Spanish-speaking subjects will not be recruited because Medtronic Minimed as yet does not have any literature in Spanish that may be used in explaining the study to this group of patients. When in the future Medtronic is able to provide us with the appropriate Spanish literature, we will at that time amend the protocol to include this group of subjects. Study Procedure: Screening: Screening evaluations will be performed 1-2 months prior to study enrollment, and will consist of an informed consent, medical history, physical examination (including height, weight, and vital signs), and blood samples for clinical laboratory tests. The clinical laboratory tests will include a CBC to check for anemia, hemoglobin A1C (within last month), serum electrolytes, serum amylase, Serum HCG pregnancy test for female subjects. The approximate volume of blood is expected to be less than 5 ml. Following informed consent (and with appropriate subject assent) if subject is found eligible for the study, they will undergo a baseline open-loop evaluation using a Medtronic Data logger continuous glucose monitor (Medtronic Diabetes, Northridge, CA). The data on glucose excursions will be collected on their usual insulin dosages so as to appropriately configure the algorithm of the closed-loop system during the inpatient admission. Basal rates and insulin to carbohydrate ratios will be adjusted during the period between screening and the start of the 3 studies that they will undergo subsequently. After screening, subjects will undergo a 3-period crossover design trial in random order. Study A Subjects will be admitted to the general clinical research center (GCRC) on the evening prior to the study at 6 PM. For female subjects a stat serum HCG pregnancy test is done prior to the start of the study. Two sensors will be placed in the subcutaneous tissue. Insertion of IV line will occur between 9-10 PM. During the night hourly samples of blood glucose will be used to adjust insulin basal or boluses so as to maintain euglycemia. Around 6 a.m. subjects will be started on the closed-loop system for the automated delivery of insulin based on the glucose sensor measurements. An intravenous line will be inserted in the antecubital fossa to maintain blood glucose concentrations within the normal range. Blood samples for basal glucose, insulin, and glucagon concentrations will be drawn at minus 30, minus 10, and 0 min prior to study start. For study A (Control): Subjects will receive meals at 0 minutes (approximately 7 AM breakfast), 300 min (approximately Noon lunch) and dinner at 600 min (approximately 5 PM dinner). A partial bolus of insulin will be administered prior to breakfast in addition to closed loop system (since the system is not expected to have calibrated by the time of breakfast). For study B: Subjects will receive 30 mcg of pramlintide just before 300…