Outpatient Study Protocol



Cognitive and Neuroanatomical Consequences

of Type 1 Diabetes in Young Children

Version 1.3

May 11, 2010

Protocol Chair: Nelly Mauras, M.D.

Co-chairs: Allan Reiss, M.D. and Tamara Hershey, Ph.D.

Coordinating Center

Jaeb Center for Health Research

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

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

Tampa, FL

Table of Contents

CHAPTER 1: INTRODUCTION 1

1.1 Background and Rationale 1

1.2 Objective 4

1.3 Summary of Study Design and Protocol for Diabetic Subjects 4

1.3.1 Schedule of Study Visits and Examination Procedures (Diabetic Subjects) 5

1.4 Summary of Protocol for Nondiabetic Subjects 5

1.4.1 Schedule of Study Visits and Examination Procedures (Nondiabetic Subjects) 5

1.5 General Considerations 5

CHAPTER 2: ELIGIBILITY AND BASELINE PROCEDURES FOR DIABETIC SUBJECTS 1

2.1 Study Population 1

2.2 Eligibility and Exclusion Criteria 1

2.2.1 Eligibility 1

2.2.2 Exclusion 1

2.3 Subject Enrollment and Baseline Data Collection 2

2.3.1 Historical Information and Physical Exam 2

2.3.2 Informed Consent 2

2.3.2.1 Authorization Procedures 2

2.3.2.2 Special Consent Issues 2

2.3.3 HbA1c 2

2.4 Run-in Phase for CGM Use 3

2.4.1 Assessment of Successful CGM Use 3

2.5 Study Enrollment 3

2.5.1 Cognitive Testing 3

2.5.2 Brain MRI 4

2.5.3 Schedule of Baseline Testing 4

CHAPTER 3: FOLLOW-UP 1

3.1 Follow-up Visit Schedule 1

3.2 Procedures at 3-month Follow-up Visits 1

3.3 Data Collection of Severe Hypoglycemic and Hyperglycemic Events 1

3.4 Additional Procedures at 18 Months 1

3.5 Return of Blinded CGM 2

CHAPTER 4: NONDIABETIC SUBJECTS 1

4.1 Recruitment 1

4.2 Inclusion Criteria 1

4.3 Exclusion Criteria 1

4.4 Visits and Testing 1

CHAPTER 5: COGNITIVE AND MOTOR SKILL TESTING 1

5.1 Introduction 1

5.2 Cognitive Testing 1

5.2.1 Certification of Individuals Administering the Testing 1

5.2.2 Cognitive Tests 1

5.2.3 Testing Procedures 2

5.3 Motor Skill Testing 2

CHAPTER 6: BRAIN MAGNETIC RESONANCE IMAGING 1

6.1 Introduction 1

6.2 Preparation of the Subject 1

6.3 Image Acquisition Protocol 1

6.3.1 Special Considerations 2

6.4 Standardization of Image Acquisition across Sites 2

6.5 Data Review and Sharing of Information with Families 2

6.6 Transmission of Scans 2

6.7 Imaging Coordinating Center Procedures 2

6.8 Analysis of MRI Data 3

CHAPTER 7: ADVERSE EVENTS 1

7.1 Definition 1

7.2 Recording of Adverse Events 1

7.3 Reporting Serious or Unexpected Adverse Events 1

7.4 Risks And Discomforts 2

7.4.1 CGM and Skin Reactions 2

7.4.2 Fingerstick Blood Glucose Measurements 2

7.4.3 Neuropsychological Testing and Psychosocial Questionnaires 2

7.4.4 Brain MRI 2

7.4.5 Loss of Privacy 2

7.5 Data and Safety Monitoring Board 2

CHAPTER 8: MISCELLANEOUS CONSIDERATIONS 1

8.1 Benefits 1

8.2 Reimbursement 1

8.3 Subject Withdrawal 1

8.4 Confidentiality 1

CHAPTER 9: STATISTICAL CONSIDERATIONS 1

9.1 Sample Size 1

9.2 Analysis Plan 1

9.2.1 Calculation of Outcome Measures and Covariates 1

9.2.2 Statistical Methods 3

9.2.2.1 Comparison of Diabetic vs. Nondiabetic Subjects 3

9.2.2.2 Impact of Hypoglycemia and Hyperglycemia (diabetic subjects only) 3

9.2.2.3 Secondary Analyses 3

9.2.2.4 Regression Diagnostics 4

9.2.2.5 Missing Data 4

9.2.2.6 Multiple Comparisons 4

9.2.3 Follow-up at 18 Months 4

CHAPTER 10: REFERENCES 1

CHAPTER 1: INTRODUCTION

1 Background and Rationale

Tight glycemic control in young children with diabetes is limited by hypoglycemia and the associated risk of impaired cognitive development. There are a number of factors that contribute to the risk of hypoglycemia in this age group, including irregular patterns of eating, inability to recognize and report hypoglycemia, inability to self-manage low blood glucoses, and unpredictable peaks and valleys in long-acting basal insulins. Young children are also very sensitive to small changes in insulin doses and the inability to deliver insulin by very small increments can only be possible via pump therapy. Nighttime is the most vulnerable period for hypoglycemia in youth with T1DM, since sleep blunts the counterregulatory responses to hypoglycemia even in non-diabetic children (1). During the 1st funding cycle of DirecNet we studied overnight counterregulatory responses to spontaneous hypoglycemia in young (3-8y/o) vs. older (12-18y/o) children with T1DM and observed that the catecholamine response to spontaneous hypoglycemia is blunted, even in young children (2; 3). Similarly, experimental evidence in animals and humans suggest that chronic hyperglycemia may affect white matter volume, myelin glycosylation and even processing speed in diabetes.

Diabetes-Associated Neuropsychological Changes

There is concern that severe hypoglycemic events can cause permanent cognitive-behavioral sequelae in children. However, there has been limited direct investigation of this possibility and the existing data remain mixed and at times conflicting. A recent meta-analysis of a sample of 1393 children with T1DM and 751 controls suggests that pediatric diabetes generally relates to lower cognitive scores across most cognitive domains (4). Many studies in adults and school-aged children have documented an association between severe hypoglycemia (with concomitant seizures or loss of consciousness) and either cognitive deficits (5-12) or neurological changes (13-17). Deficits in the domains of attention, (18; 19) episodic memory, (19) spatial working memory, (20) executive functions, (18) perceptual-motor skills (19) and processing speed (18; 19) have all been noted. A very recent study by Melbourne investigators following a cohort of 106 subjects with type 1 diabetes diagnosed at ................
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