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Evaluation of Counter-regulatory Hormone Responses during Hypoglycemia and the Accuracy of Continuous Glucose Monitors in Children with T1DM

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Version 5.0 January 18, 2007

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DirecNet Counter-Reg Study Protocol 1-18-07.doc

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Coordinating Center

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Jaeb Center for Health Research

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Roy W. Beck, M.D., Ph.D. (Director)

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Katrina J. Ruedy, M.S.P.H. (Assistant Director)

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15310 Amberly Drive, Suite 350

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Tampa, FL 33647

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Phone (813) 975-8690

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Fax (813) 903-8227

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Email: [email protected]

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Protocol Chair

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Eva Tsalikian M.D.

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Children's Hospital of Iowa

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University of Iowa Hospital and Clinics

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200 Hawkins Drive

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Iowa City, IA 52242

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Phone: (319) 356-1833

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Fax: (319) 356-8170

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Email: [email protected]

DirecNet Counter-Reg Study Protocol 1-18-07.doc

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Table of Contents 1. Chapter 1: Introduction ........................................................................................................ 1-1 1.1 Introduction and Rationale ............................................................................................. 1-1 1.1.1 Hormone Responses during Hypoglycemia...................................................... 1-1 1.1.2 Evaluation of Continuous Glucose Monitoring Systems.................................. 1-3 1.1.2.1 Background on Guardian-RT............................................................. 1-3 1.2 Study Objectives............................................................................................................. 1-3 1.3 Synopsis of Study Protocol ............................................................................................ 1-4 2. Chapter 2: Subject Eligibility and Enrollment ................................................................... 2-1 2.1 Study Population ............................................................................................................ 2-1 2.2 Eligibility and Exclusion Criteria................................................................................... 2-1 2.2.1 Eligibility .......................................................................................................... 2-1 2.2.2 Exclusion........................................................................................................... 2-1 2.3 Patient Enrollment and Baseline Data Collection .......................................................... 2-1 2.3.1 Historical Information and Physical Exam ....................................................... 2-2 2.3.2 Informed Consent.............................................................................................. 2-2 2.3.2.1 Authorization Procedures................................................................... 2-2 2.3.2.2 Special Consent Issues....................................................................... 2-2 2.3.3 Hemoglobin A1c Determination....................................................................... 2-2 2.3.4 Instructions for Home Procedures .................................................................... 2-2 3. Chapter 3: Subcutaneous Insulin Infusion Test.................................................................. 3-1 3.1 CRC Admission.............................................................................................................. 3-1 3.2 Pre-Subcutaneous Insulin Infusion Test......................................................................... 3-1 3.2.1 Blood Glucose Measurements .......................................................................... 3-1 3.3 Subcutaneous Insulin Infusion Test ............................................................................... 3-1 3.3.1 Blood Glucose Measurements .......................................................................... 3-2 3.3.2 Blood Samples for Hormone Concentrations ................................................... 3-2 3.4 Post-Subcutaneous Insulin Infusion Test ....................................................................... 3-3 3.5 Daily Activities............................................................................................................... 3-3 3.6 Diet ................................................................................................................................. 3-3 4. Chapter 4: Evaluation of Continuous Glucose Monitors................................................... 4-1 4.1 Overview ........................................................................................................................ 4-1 4.2 Inpatient Accuracy Evaluation ....................................................................................... 4-1 4.2.1 Volume of Blood Draws ................................................................................... 4-1 4.2.2 Quality Control Specimens ............................................................................... 4-1 4.2.3 Sensor Considerations during CRC Admission................................................ 4-1 4.2.3.1 Sensor Calibrations ............................................................................ 4-2 4.2.3.2 Sensor Failure ................................................................................... 4-2 4.2.3.3 Sensor Downloading.......................................................................... 4-2 5. Chapter 5: Adverse Events ................................................................................................... 5-1 5.1 Definitions ...................................................................................................................... 5-1 5.2 Recording of Adverse Events......................................................................................... 5-1 5.3 Reporting Serious or Unexpected Adverse Events ........................................................ 5-1 5.4 Data and Safety Monitoring Board ................................................................................ 5-2 DirecNet Counter-Reg Study Protocol 1-18-07.doc

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5.5 Risks and Discomforts.................................................................................................... 5-2 5.5.1 Hypoglycemia ................................................................................................... 5-3 5.5.2 Guardian-RT ..................................................................................................... 5-4 5.5.3 HypoMon .......................................................................................................... 5-4 5.5.4 Fingerstick Blood Glucose Measurements ....................................................... 5-4 5.5.5 IV Risks ............................................................................................................ 5-4 5.5.6 Blood Volume Requirements............................................................................ 5-4 6. Chapter 6: Miscellaneous Considerations in Follow Up .................................................... 6-1 6.1 Benefits........................................................................................................................... 6-1 6.2 Subject/Parent Reimbursement ...................................................................................... 6-1 6.3 Subject Withdrawal ........................................................................................................ 6-1 6.4 Confidentiality................................................................................................................ 6-1 7. Chapter 7: Statistical Considerations .................................................................................. 7-1 7.1 Sample Size .................................................................................................................... 7-1 7.2 Analysis Plan.................................................................................................................. 7-1 7.2.1 Counterregulatory Responses during Insulin-induced Hypoglycemia ............. 7-1 7.2.1.1 Hormone Concentrations ................................................................... 7-1 7.2.1.2 Glucose Level Triggering a Counterregulatory Response................. 7-2 7.2.1.3 Hypoglycemic Symptoms.................................................................. 7-2 7.2.2 Continuous Glucose Monitor (CGM) Data...................................................... 7-2 7.2.2.1 Glycemic Indices ............................................................................... 7-2 7.2.2.2 Accuracy ............................................................................................ 7-3 8. References............................................................................................................................... 8-1

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CHAPTER 1 INTRODUCTION 1.1 Introduction and Rationale 1.1.1 Hormone Responses during Hypoglycemia Hypoglycemia is a life-threatening side effect of intensive insulin therapy in patients with Type 1 diabetes (1, 2) This is especially the case in children and adolescents and it is observed as an acute problem in very young children.(3) In all aspects of the daily care of children with diabetes the degree of burden is higher in younger children than in older children, adolescents or adults. The recent increase in the number of very young children diagnosed with diabetes and the ever-present dilemma between good glucose control and the risk of hypoglycemia in these children have brought to light the problem of detection of hypoglycemia and the factors affecting the response to hypoglycemia in these children.(4) The use of new methods of continuous glucose monitoring has revealed multiple instances of asymptomatic hypoglycemia both nocturnal and during awakening. This phenomenon, although present in all children and adolescents, is much more frequent in younger children. As a result, these very young children have a higher frequency of seizures, nocturnal or otherwise, which may result in possible neurocognitive deficits at a later age.(5) In children with Type 1 diabetes, the phenomena associated with hypoglycemia such as counter regulatory hormone responses and autonomic responses to hypoglycemia have not been evaluated as extensively as in adults.(6) In adults, extensive studies have addressed the effect of diabetes and other factors on counter-regulatory hormone and symptomatic responses to hypoglycemia.(1, 2) These studies were made possible by the development of insulin infusion protocols and the hypoglycemic clamp technique to provide a controlled, safe, and reproducible hypoglycemic stimulus in different groups of subjects or in the same subjects under different conditions. Using these techniques, it has been shown that long diabetes duration, intensive insulin treatment, exercise, sleep and antecedent hypoglycemia reduce adrenomedullary (plasma epinephrine), central sympathetic (plasma norepinephrine), and symptomatic response to hypoglycemia.(7) In most of these studies, reductions in sympathetic responses were related to a lowering of the plasma glucose level that was required to stimulate a rise in plasma catecholamine levels. In contrast, plasma epinephrine responses to hypoglycemia are increased in older children and adolescents with or without diabetes compared to corresponding responses in adults with or without diabetes (8) due to an upward shift in the plasma glucose threshold for release of catecholamines.(9) In addition, studies in adults with Type 1 diabetes have addressed the effect of duration of diabetes as well as recent antecedent hypoglycemia on glucose counter-regulatory hormones response and autonomic response manifested as hypoglycemic symptoms.(10) In a number of elegant studies in adults with diabetes and normal subjects, several groups have experimentally induced hypoglycemia and measured the responses to hypoglycemia on days following normoglycemia or following another episode of hypoglycemia. There is consensus that antecedent hypoglycemia reduces adrenomedullary epinephrine, sympathetic neural nerepinephrine, neurogenic symptoms and glucagon on subsequent hypoglycemia, whereas Growth hormone and cortisol responses have been found to be unaltered in normal subjects.(11, 12) In addition exercise and the counterregulatory hormone response to antecedent exercise have been shown to reduce epinephrine and growth hormone response to subsequent (next few days) hypoglycemia while cortisol, norepinephrine, glucagon and neurogenic symptoms were not affected.(13) The ability to detect hypoglycemia depends on several systems that encompass the spectrum of neurocognitive maturity and level of hormonal counter-regulatory response maturity.(14) It is not DirecNet Counter-Reg Study Protocol 1-18-07.doc

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known if young children with diabetes have an intact counter-regulatory hormone response. In newborn infants it has been shown that a robust counter-regulatory hormone response to hypoglycemia can be elicited but sympathomimetic symptoms are usually lacking.(15) The question of whether autonomic symptoms and counter-regulatory hormone response to hypoglycemia is dependent on age or developmental stage or is impaired by diabetes duration or frequency of antecedent hypoglycemia in children has not been examined adequately. Children have several physiologic factors that may affect response to hypoglycemia, such as developmental and maturity stage as well as hormonal and pubertal stage. Studies to date that have tried to address this issue in children have concluded that there was no difference noted in the different stages of development but the youngest children included in this study were 9 years old.(16) In addition in a different study examining the counter regulatory response to nocturnal hypoglycemia in prepubertal children, a lower hormonal response was only partially responsible for the prolonged nocturnal hypoglycemia observed in these 6-13 year old children.(17) In comparison to children without diabetes, counter regulatory responses were lower in children with diabetes (mean age of 14 years for both groups) but autonomic symptom recognition was similar. Despite the lower counter regulatory hormone response in children with diabetes, the glycemic threshold for adrenaline to increase higher than 2 SD above basal was 63+3 mg/dL in these children.(18) In adolescent children with diabetes epinephrine responses during sleep were lower than in normal children (19) but in a controlled hypoglycemia setting with an insulin clamp, children with and without diabetes had higher epinephrine responses than adults.(8) In a study of insulin induced hypoglycemia (glucose 26.3kg at discard centers) to accommodate the volume of blood required, blood glucose measurements will be made every 30 minutes during the admission to allow for assessment of the accuracy of the Guardian-RT.

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For subjects of sufficient weight to accommodate the volume of blood required, blood glucose measurements will be made every 15 minutes for two hours after dinner. This will allow for assessment of the accuracy of the Guardian-RT in detecting change during a period of rising blood glucose.

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At approximately 8:00 a.m. the subcutaneous insulin infusion test will start.

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o Prior to starting the test, a HypoMon® may be placed around the subject’s chest using an adjustable strap.

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o The glucose concentration as measured by the study HGM must be >110 mg/dL to start the test.

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o At the start of the test, the basal insulin rate will be increased by approximately 25-50% to provide a gradual decline in blood glucose. A small priming bolus dose of insulin equal to approximately one hour of the subject’s usual basal dose may also be given at the discretion of the investigator in addition to the 25-50% increase in the basal insulin.

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o The basal insulin rate may be increased an additional amount and additional bolus insulin doses may be given at the discretion of the investigator in order to get a gradual decline in the glucose concentration.

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o Blood samples will be collected for the laboratory and glucose will be checked with the study HGM with venous blood every 15 minutes until the glucose level reaches 100 mg/dL. Thereafter, the study HGM will be used to check the glucose levels with venous blood every 5-10 minutes depending on the rate of fall of the glucose level until the end of the study.

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o Blood samples will be collected for laboratory determination of hormone concentrations at baseline (before increasing the insulin infusion) and when the glucose levels are