Closed Loop System With Pramlintide Versus Exenatide
Condition: Type 1 Diabetes
MeSH terms: Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 1

Summary: 
      Post-prandial hyperglycemia occurs despite meticulous carbohydrate counting and rapid acting
      insulin therapy. Furthermore, this occurs even in the setting of the closed loop system.
      Currently the algorithm used for calculating the glucose-responsive insulin delivery cannot
      respond in a timely fashion to the glucose absorption resulting from a meal. In diabetes,
      there is paradoxical immediate post-prandial hyperglucagonemia that results in immediate
      post-prandial hyperglycemia. Amylin deficiency and/or dysregulated GLP-1 seems to be the
      etiology. Pharmacologic replacement of these hormones alleviates immediate post-prandial
      hyperglycemia in diabetes. With this protocol, the investigators would like to optimize
      treatment of T1DM by physiologic replacement of hormones in addition to insulin and in the
      process also optimize the insulin algorithm.

      This is 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.

      The investigators 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.
      The investigators would also begin the study with the 21-25 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 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, the investigators will at that time amend the protocol to include this group of
      subjects.
    

Detailed description: 
      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 and 600 minutes.
      Pramlintide will be administered as a subcutaneous injection just prior to lunch and dinner.
      A partial bolus of insulin will be administered for breakfast in addition to closed loop
      system (since the system is not expected to have calibrated by the time of breakfast).

      For study C: Subjects will receive 2.5 mcg of exenatide subcutaneously just before 300 and
      600 min. Exenatide will be administered as a subcutaneous injection just prior to lunch and
      dinner. A partial bolus of insulin will be administered for breakfast in addition to closed
      loop system (since the system is not expected to have calibrated by the time of breakfast).

      At 0 mins, subjects will drink a standard liquid meal of Boost High Protein Drink 9.6 oz (360
      calories, 40 g of carbohydrate) over a period of 10 min. This meal will not be counted in the
      final analysis since the closed loop system will not have had enough time to adjust to the
      basal conditions of the meal. A partial bolus of insulin will be administered for breakfast
      in addition to closed loop system (since the system is not expected to have calibrated by the
      time of breakfast).

      At 300 minutes, subjects will receive a solid meal based on Estimated Energy Requirements
      (EER) as reported by the Institute of Medicine Dietary Reference Intakes macronutrients
      report, 2002. The carbohydrate content of the meal will be 75 g. Pramlintide 30 mcg/
      Exenatide 2.5 mcg will be administered subcutaneously before lunch and dinner. Insulin will
      be administered based on ePID algorithm by the closed loop system in response to glucose
      concentrations detected by subcutaneous sensing. Blood samples for glucose concentrations
      will be drawn every 15min-half hour (more frequently immediately after meals) after
      initiating closed loop system. Blood samples for hormone analysis (insulin,
      pramlintide/exenatide and glucagon) will be drawn at approximately every 15 min to half hour
      intervals after lunch which will be served at approximately around Noon in the first hour and
      then every half to one hour until dinner. Dinner will be served at approximately around 5 PM
      (the carbohydrate content of the meal will be similar to lunch). Blood glucose will be
      measured at the bedside using a YSI glucose analyzer every half hour. The study will end at
      885 minutes.

      Total blood volume drawn for studies A, B, and C will be approximately 97cc, 133cc and 133cc
      respectively.

      The subject's will be always monitored by nursing staff of the CRC, study staff and the PI is
      available by phone and on call during the study. Medtronic personnel will be present for the
      first four studies to ensure all the equipment is working optimally and to provide guidance
      related to the closed loop system.

      During the study, if subject's blood glucose values are less than 70 mg/dl, oral glucose
      (5-15 g) will be administered for countering low blood glucose to achieve euglycemia (90-130
      mg/dl). 1-2 doses of oral glucose should correct hypoglycemia. If more than 4 consecutive
      doses are required to achieve euglycemia the study will be terminated, and the subject will
      be offered a meal tray and blood sugar rechecked to ensure euglycemia. Additional 0.2 cc
      blood samples for glucose may be necessary to ensure safety during an episode of hypoglycemia
      and these may be done before the scheduled time for blood draws.

      If blood glucose by Analox machine is greater than 300mg/dl, blood ketones will be measured
      and if ketones are above 1.5 mmol/L we will terminate the study.

      At the end of the study the subject will be evaluated by the research staff for the need to
      receive a snack. A snack will be served before discharge only if BG of subject is less than
      70mg/ dl at the end of the study. If the Principal Investigator or the attending physician
      feels that the subject needs to be observed for a longer period of time then it would be at
      his/her discretion.

      The subjects will return two additional times (2-4 weeks apart) to complete the exact same
      study, with the difference that if the patient received pramlintide on the last occasion
      he/she will get either exenatide or just insulin via the closed loop system at the subsequent
      visits. (Total of 3 visits).

      Female subjects would have a stat serum HCG pregnancy test is done prior to the start of the
      study for each visit. Subjects will have stat CBC prior to initiating closed loop study.
      Serum Electrolytes will be done at the onset of the study and then will be repeated if the
      patient had vomiting at the end of the study. Serum amylase would be done at each visit and
      the results would be tracked on the case report forms. Capillary blood glucose check would be
      done when necessary as an extra safety measure in addition to subject's blood glucose being
      monitored through YSI and interstitial glucose monitored through glucose sensor.

      For uniformity sake, we would be using only using Insulin Aspart for the entire duration of
      the study.

      If at least four subjects develop grade 3 nausea, with the 30 mcg dosage of pramlintide or
      with the 2.5 mcg of exenatide then the protocol would be modified so that the subjects
      receive only a 15 mcg dose of pramlintide and 1.25 mcg of exenatide.

      TREATMENT FOR SEVERE NAUSEA: If severe nausea develops during the study, Zofran 0.15 mg/kg IV
      will be given. The maximum dose is 8 mg. If the subject still has emesis, the study subject
      would be stopped.

      Study drugs and study laboratory tests will be provided at no cost to the subject. The
      subjects will receive $70 at screening and $210 for the three subsequent study visits. The
      total compensation involved for the study would be $ 700.
    

Intervention name(s): Medtronic ePID 2.0
Intervention type(s): Device
Intervention description(s): Closed loop system is an automated insulin delivery system based on body blood sugar. It consists of an Insulin pump, glucose sensor, and a device presently a laptop with all the algorithms.
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Closed loop; type 1 diabetes; Symlin; Byetta; diabetes; insulin; insulin pump