d i nd continuous glucose monitoring in diabetes: …...version: 03 125 1. abbreviations and...

1 PROTOCOL 2

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Multiple Daily Injections and Continuous Glucose Monitoring in Diabetes: 5

DIaMonD Study 6 7 8 9 Protocol Number: PTL-901148 10 11 12 Study Sponsor: Dexcom, Inc. 13 6340 Sequence Drive 14 San Diego, CA 92121 15 Tel: (858) 200-0200 16 Fax: (858) 200-0201 17 18 19 Study Contact: Eileen Casal, RN, MSN 20 Senior Director, Clinical Affairs 21 Tel: (858) 875-9774 22 Fax: (858) 332-0192 23 Email: [email protected] 24 25 26 Version Date: 20 May 2015 27 28 29 Version Number: 03 30 31

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TABLE OF CONTENTS 39 1. ABBREVIATIONS AND DEFINITIONS ........................................................................................ i 40 2. INVESTIGATOR SIGNATURE SHEET ...................................................................................... iv 41 3. PROTOCOL SYNOPSIS .................................................................................................................. v 42 4. INTRODUCTION .............................................................................................................................. 1 43 5. STUDY OBJECTIVES ...................................................................................................................... 3 44 6. PRIMARY ENDPOINTS .................................................................................................................. 3 45 7. SECONDARY ENDPOINTS ............................................................................................................ 3 46 8. STUDY POPULATION .................................................................................................................... 4 47 9. STUDY ELIGIBILITY ..................................................................................................................... 4 48

9.1 Inclusion Criteria ............................................................................................................................... 4 49 9.2 Exclusion Criteria .............................................................................................................................. 4 50

10. STUDY DESIGN .............................................................................................................................. 5 51 10.1 Design Summary ................................................................................................................................ 5 52

11. PATIENT PARTICIPATION .......................................................................................................... 7 53 12. STUDY DURATION ......................................................................................................................... 7 54 13. CLINICAL RESEARCH SITE(S) ................................................................................................... 7 55 14. OVERVIEW of STUDY DEVICES ................................................................................................. 7 56

14.1 Dexcom G4 Continuous Glucose Monitoring System (System) ........................................................ 7 57 14.2 Insulin Pump Overview ..................................................................................................................... 8 58 14.3 Blood Glucose Meter Overview ........................................................................................................ 8 59

15. OVERVIEW OF PRO INSTRUMENTS ......................................................................................... 9 60 15.1 Patient Reported Outcome (PROs) Measures .................................................................................... 9 61

16. DATA COLLECTION AND DATA MANAGEMENT ............................................................... 11 62 17. STATISTICAL ANALYSIS ............................................................................................................ 11 63

17.1 Randomization ................................................................................................................................. 11 64 17.2 Data Analysis ................................................................................................................................... 11 65 17.3 Cost-effectiveness Analysis: ............................................................................................................ 13 66 17.4 Sample Size Justification ................................................................................................................. 13 67

18. STUDY PROCEDURES (Run-in Period) ...................................................................................... 14 68 18.1 Visit S1 –Screening, Consenting, and Blinded CGM Initiated (Time = 0-14) ................................ 14 69 18.2 Visit S2 – Week 1 – Blinded CGM Use (Time = 0- 7 days; Window ± 2 days) ............................. 15 70 18.3 Visit S3 – Week 2 - Run-In Completion, Subject Compliance Assessment, Randomization (Time = 71

0; Window ± 2 days) Note: .................................................................................................................................... 16 72 19. STUDY PROCEDURES (PHASE 1) 17 73

19.1 Visit 1 – Week 1 – CGM Troubleshooting - CGM Group Only (Window ± 2 days) ...................... 17 74 19.2 Phone Visits (Week 2 Phone & Week 3 Phone): Window ± 2 days) ............................................... 18 75 19.3 Visit 2 – Week 4 – Follow-Up (Window ± 4 days) ......................................................................... 18 76



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19.4 Visit 3 – Week 11 – Blinded CGM - SMBG Group only (Window ± 5 days) ................................. 19 77 19.5 Visit 4 – Week 12 – (Month 3) – Mid Phase 1 Assessment (Window ± 1 days – SMBG; ± 7 days – 78

CGM) .......................................................................................................................................................... 19 79 19.6 Visit 5 – Week 23 – Blinded CGM - SMBG Group Only (Window ± 5 days) ................................ 20 80 19.7 Visit 6 -- Week 24 (Month 6) – Phase 1 Final Assessments (Window ± 1 days – SMBG; ± 7 days – 81

CGM) & Commencement of Phase 2 ..................................................................................................................... 20 82 20. STUDY PROCEDURES (PHASE 2 – Follow-up Study) ............................................................. 21 83

20.1 Visit 1 - Week 26 – Follow-up – CGM/CSII Group Only (Window ± 4 days) ................................ 22 84 20.2 Visit 2 – Week 30 - Follow-Up (Window ± 4 days) ........................................................................ 22 85 20.3 Visit 3 – Week 38 (Month 9) –Follow-Up (Window ± 7 days) ....................................................... 22 86 20.4 Visit 4 – Week 52 (Month 12) – Final Assessment (Window ± 7 days) .......................................... 23 87 20.5 Device Replacements ....................................................................................................................... 24 88

21. RISKS ............................................................................................................................ 24 89 21.1 Sensor Insertion/Use/Removal ......................................................................................................... 24 90 21.2 Hypoglycemia .................................................................................................................................. 24 91 21.3 Diabetic Ketoacidosis (DKA) .......................................................................................................... 25 92

22. Non-Significant Risk Rationale ....................................................................................................... 25 93 23. ADVERSE EVENTS ....................................................................................................................... 26 94

23.1 Adverse Event (AE) 26 95 23.2 Serious Adverse Event (SAE) .......................................................................................................... 27 96 23.3 Severity of Adverse Events .............................................................................................................. 27 97 23.4 Relationship of Adverse Event to the Study, Disease, or Device .................................................... 27 98 23.5 Anticipated Adverse Device Effects ................................................................................................ 28 99 23.6 Unanticipated Adverse Device Effects ............................................................................................ 29 100 23.7 MDR Reportable Events/MDR Reporting ....................................................................................... 29 101

24. ETHICAL CONSIDERATIONS .................................................................................................... 29 102 24.1 Informed Consent ............................................................................................................................ 29 103 24.2 Institutional Review Board .............................................................................................................. 30 104

25. DATA COLLECTION .................................................................................................................... 30 105 26. DEVICE ACCOUNTABILITY ...................................................................................................... 30 106 27. MONITORING ............................................................................................................................ 30 107 28. STUDY TERMINATION ............................................................................................................... 31 108 29. INVESTIGATOR RESPONSIBILITIES ...................................................................................... 31 109 30. SPONSOR RESPONSIBILITIES .................................................................................................. 31 110 31. CONFIDENTIALITY OF RECORDS .......................................................................................... 32 111 32. REFERENCES ............................................................................................................................ 33 112 33. APPENDICES ............................................................................................................................ 35 113 Appendix A: Informed Consent ................................................................................................................ 36 114 Appendix B: Overall Study Flowchart ..................................................................................................... 37 115 Appendix C: Clinician Guidelines: General Diabetes Education .......................................................... 38 116



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Appendix D: Clinician Guidelines for Follow-Up Visits ........................................................................ 39 117 Appendix E: Visit Flowchart .................................................................................................................... 40 118 Appendix F: Diabetes Management Guidelines Using CGM ................................................................. 41 119 Appendix G: Patient Reported Outcome (PRO) Measures ...................................................................... 42 120 Appendix H: Test and Exam Table ......................................................................................................... 43 121 Appendix I: Sample CGM Information Guide ........................................................................................ 44 122 Appendix J: OmniPod Guidance Documents .......................................................................................... 45 123

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1. ABBREVIATIONS AND DEFINITIONS 125 126

A1C Hemoglobin A1C (aka HbA1C) 127

AE Adverse Event 128

BGM Blood Glucose Meter 129

BLINDED CGM Receiver does not display CGM values, trends, or glucose 130 alerts/alarms in real time. Receiver provides use prompts and 131 features such as calibration requests, device failures, troubleshooting 132 icons, event markers, etc. 133

Carb counting Carbohydrate counting, or "carb counting," is a meal planning 134 technique for managing blood glucose. Carbohydrate counting helps 135 to keep track of how much carbohydrate is consumed. A limit for a 136 maximum amount of carbohydrate is set to maintain glucose levels 137 within a targeted range. 138

CBC Complete Blood Count 139

CF Glucose Correction Factor; as known as insulin sensitivity factor 140

CGM Continuous Glucose Monitoring 141

CMP Complete Metabolic Panel 142

CRA Clinical Research Associate 143

CRF Case Report Form 144

CSII Continuous Subcutaneous Insulin Infusion 145

CT Computed Tomography 146

DCCT Diabetes Control & Complications Trial 147

DKA Diabetic Ketoacidosis (as defined by the DCCT) involves all of the 148 following symptoms such as polyuria, polydipsia, nausea, or 149 vomiting; serum ketones >1.5 mmol/L or large/moderate urine 150 ketones; either arterial blood pH <7.30 or venous pH <7.24 or serum 151 bicarbonate <15; and treatment provided in a health care facility. 152

DM Diabetes Mellitus 153

EDC Electronic Data Capture 154

eGFR Estimated Glomerular Filtration Rate: a renal function test 155 determined by a blood test for creatinine 156

EQ5D EuroQol 5D PRO measure 157

HCP Health Care Professional 158

Hypoglycemia, Severe Reduced cognitive function, diaphoresis, tachycardia, coma and 159 seizure. Hypoglycemia is deemed severe if the event required 160 assistance of another person due to altered consciousness to actively 161 administer carbohydrate, glucagon, or other resuscitative actions. 162 This means that the participant was impaired cognitively to the point 163 that the subject was unable to treat his or herself, was unable to 164



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verbalize his or her needs, was incoherent, disoriented, and/or 165 combative, or experienced seizure or coma. 166

IAH Impaired awareness of hypoglycemia 167

I:C Insulin to carb ratio, used to determine dosing parameters 168

ICER Incremental Cost Effectiveness Ratios 169

IFG Impaired Fasting Glucose 170 IFU Instructions for Use 171

IGT Impaired Glucose Tolerance 172

IRB Institutional Review Board 173

ITT Intent to treat (analysis) 174

MDI Multiple Daily Injections: Includes a minimum of 3 injections total: 175 2 injections a day of rapid acting human insulin or analog (an 176 injection with each major meal) along with 1 daily basal insulin 177 (NPH, detemir, or glargine). 178

MDR Medical Device Reporting 179

mg/dL milligrams per deciliter 180

MRI Magnetic Resonance Imaging 181

PC Personal computer, specifically using Intel hardware & MicroSoft 182 software; not Apple computers 183

PDM Personal Diabetes Manager: Insulet’s insulin delivery programmer 184 used with the OmniPod insulin pump. 185

Personal RT-CGM Personal RT-CGM refers to frequent and continued use of CGM, 186 owned by the user. 187

Professional RT-CGM Professional CGM (real time or blinded) is defined as episodic use of 188 CGM as provided by HCP and owned by physician’s practice. 189

POC Point of Care (Approved Guideline) 190

PP Per Protocol (analysis) 191

PRO Patient Reported Outcome 192

QALY Quality-Adjusted Life-Years 193

QoL Quality of Life 194

RCT Randomized Controlled Trial 195

RT-CGM Real-Time Continuous Glucose Monitoring System 196

SAE Serious Adverse Event 197

SMBG Self-Monitored Blood Glucose 198

SC Study Coordinator 199

T1DM Type 1 Diabetes Mellitus 200

T2DM Type 2 Diabetes Mellitus 201



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UADE Unanticipated Adverse Device Effect 202

VAS Visual Analog Scale 203

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2. INVESTIGATOR SIGNATURE SHEET 205

I have read the attached protocol and hereby agree that it contains all the necessary details for 206 performing the study. 207

I will provide details of the protocol to all members of the study team responsible for conducting 208 the study. 209

I will discuss the protocol with them to ensure that all participating staff members are fully 210 informed regarding the study device and the conduct of the protocol. 211

Once the Institutional Review Board approves the protocol, I will not modify study procedures 212 without obtaining prior approval of the Sponsor and, if required, of the Institutional Review 213 Board (and FDA, as applicable). 214

I will submit any protocol and/or any informed consent modifications to the Sponsor and the 215 Institutional Review Board (and FDA, as applicable) and approval will be obtained before any 216 modifications are implemented. 217

218 219 220

Investigator's Signature Date Investigator’s Printed Name

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3. PROTOCOL SYNOPSIS 222

TITLE Multiple Daily Injections and Continuous Glucose Monitoring in Diabetes: DIaMonD Study

SPONSOR Dexcom, Inc. STUDY DEVICE Dexcom G4® Continuous Glucose Monitoring System

(“System”) STUDY DESIGN Prospective, randomized, parallel arm, controlled trial with 2

phases HYPOTHESIS Addition of real time continuous glucose monitoring (RT-

CGM) improves glycemic outcome in patients using multiple daily injections (MDI) and self-monitored blood glucose (SMBG), who are not at target A1C.

STUDY OBJECTIVES 1) To assess glycemic, health-economic, and quality of life (QoL) benefits of adding and using RT-CGM in MDI patients with Type 1 Diabetes Mellitus (T1DM) or Type 2 Diabetes Mellitus (T2DM), not at their A1C goal and relying on SMBG for diabetes-management decisions.

2) To assess the incremental benefits of changing the insulin delivery method from MDI to continuous subcutaneous insulin infusion (CSII) in patients with T1DM already using RT-CGM.

Specific health economics objectives are to evaluate cost effectiveness and quality of life measures between the two groups.

• For cost effectiveness: Evaluate within-trial cost-effectiveness attributable to the use of continuous glucose monitoring (CGM), as well as, the lifetime cost-effectiveness of the intervention attributable to the use of CGM.

• For quality of life measures: Evaluate diabetes-related health states and measure health care utilization and economic consequences attributable to the CGM group compared to the SMBG group.

STUDY ENDPOINTS Primary Endpoint at Month 6: Change in A1C from baseline to six months between groups. Primary Endpoint at Month 12: Change in %Time-in-Range as determined by CGM from month 6 between groups. Secondary Endpoints

Month 6 (within and between groups analyses): • Percent A1C ≤ 7% • %Time-in-Range • %Time-in-Hypoglycemia • %Time-in-Hyperglycemia • QoL changes • Cost effectiveness



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• Incidence of severe hypoglycemia • Change in hypoglycemia awareness • Changes in glucose variability • Change in SMBG frequency over time Month 12 (within and between groups analyses) • Percent A1C ≤7% from month 6 • Change in A1C from month 6 to month 12 • %Time-in-Hypoglycemia • %Time-in-Hyperglycemia • Incidence of severe hypoglycemia • QoL changes • Cost effectiveness • Change in hypoglycemia awareness • Changes in glucose variability

SAMPLE SIZE 338 randomized (assuming a 15% drop rate in Phase 1) for 294 subjects to complete Phase 1: 147 for each diabetes cohort (T1DM and T2DM). Up to 169 subjects will be randomized per cohort, assuming a 15% drop-out rate in Phase 1. Up to 500 subjects may be enrolled to achieve randomization of 338 subjects.

STUDY CENTER Up to 35 sites ENVIRONMENT OF USE

Home Use

PATIENT POPULATION Adults diagnosed with diabetes mellitus without optimized glycemic control, using MDI.

INCLUSION CRITERIA

Individuals may be included if they meet the following criteria:

1. Age 25 years or older 2. Diagnosis of T1DM or insulin-requiring T2DM 3. Followed regularly by a physician or diabetes educator

for their diabetes management – with at least 2 office visits in last year as documented by clinical history

4. Using MDI for at least 12 months prior to study entry 5. Sub-optimal glycemic control, defined as persistent

hyperglycemia, confirmed initially by historical or local (POC or site’s lab) A1C of ≥7.7% to ≤10%, then followed with a confirmatory result by central lab of ≥7.5% to ≤10%. NOTE: Use of a historical local A1C test must be within 1 month of study entry.

6. Desire to lower A1C such as a goal of 7% 7. Stable control of diabetes, as determined per

investigator assessment



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8. Stable diabetes medication regimen for 3 months prior to study entry

9. Stable weight maintained 3 months prior to study entry, per investigator’s assessment, and not planning any structured weight reduction interventions such as prescription weight loss medications, bariatric surgery, or protein sparing modified fast during the course of the study

10. Willing to wear a device (CGM/pump) 11. Willing to avoid use of acetaminophen medications

throughout the study 12. Currently performing SMBG management (by history):

Type 1 – an average of 3 or more times per day; and Type 2 – an average of 2 or more times per day

13. Able to speak, read, and write English 14. For Phase 2, total daily insulin dose is <100 units

EXCLUSION CRITERIA Individuals will be excluded for any of the following criteria: 1. Use of personal RT-CGM 3 months prior to study

entry (professional CGM use is allowed, whether it was blinded or un-blinded)

2. Use of CSII 3 months prior to study entry (including patch pumps)

3. Plan to use personal CGM and/or pump during the course of the study

4. Addition of any new oral or injectable hypoglycemic agents (including GLP-1 analogues, Pramlintide, and SGLT-2 inhibitors – these agents are only for T2DM subjects) within 3 months prior to study entry. (Use of these agents does not affect eligibility if used 3 or more months prior to study entry.) For these medications, must be on a stable dose, and the GLP-1 medication will be maintained throughout the study. Note: These agents should not be added or modified during course of the study; if use of this class medication is planned, the patient is not eligible.

5. Use of pre-mixed insulin (e.g. 70/30 or 50/50) 6 months prior to study entry

6. Current or anticipated acute uses of glucocorticoids (oral, injectable, or IV), that will affect glycemic control and impact A1C – such as frequent steroid bursts required for inflammatory arthritis or inflammatory bowel disease, recurrent lumbar epidural steroid injections, etc. (Long-term stable glucocorticoid doses are allowed, such as when used for the treatment of rheumatoid arthritis or Addison’s disease).

7. Pregnancy (as demonstrated by a positive test at study entry screening) or are planning to become pregnant during the study



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8. Medical conditions that, per investigator determination, make it inappropriate or unsafe to target an A1C of <7%, such as, but not limited to, recent cardio- or cerebrovascular disease, malignancy, severe recurrent hypoglycemia, or cognitive decline

9. History of visual impairment which would hinder subject’s participation in the study and perform all study procedures safely, as determined by investigator

10. History of psychiatric, psychological disorder, or psycho-social issues that could limit adherence to the required study tasks

11. Renal disease defined as estimated Glomerular Filtration Rate (eGFR) <45)

12. Extensive skin changes/disease that preclude wearing the sensor on normal skin (e.g. extensive psoriasis, recent burns or severe sunburn, extensive eczema, extensive scarring, extensive tattoos, dermatitis herpetiformis)

13. Known allergy to medical-grade adhesives 14. Current participation in another investigational study

(must have completed any previous studies at least 30 days prior to being enrolled in this study)

15. Recent hospitalization or emergency room visit in the 6 months prior to screening resulting in a primary diagnosis of uncontrolled diabetes

16. Currently abusing illicit drugs, alcohol, or prescription drugs

17. Any condition per investigator assessment, that could impact reliability of the A1C measurement, such as (but not limited to) hemoglobinopathy, hemolytic anemia, chronic liver disease; chronic GI blood loss, recent red blood cell transfusion or erythropoietin administration within 3 months prior to screening

STUDY OVERVIEW This is a prospective, randomized, parallel, controlled study to be conducted in two phases:

Phase 1- Comparing outcomes of diabetes management using RT-CGM vs. SMBG alone

Phase 2- Comparing outcomes of insulin delivery via a pump vs. injections in RT-CGM users. The DIaMonD study comprises a Run-in period and two randomization phases. Subjects must successfully complete the run-in period by demonstrating appropriate self-management and compliance with CGM and SMBG prior to being randomized.

Prior to Phase 1, subjects will be asked to undergo a two week Run-in period, using blinded CGM, for the purpose of assessing if willing and able to use CGM in the study and to collect



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baseline glucose data.

Eligible subjects will continue on to Phase 1 and will be randomized to either use RT-CGM (Group 1- CGM) or to manage their diabetes based on use of SMBG (Group 2- SMBG).

A1C levels will be obtained by central lab determination at baseline, 3, 6, 9, and 12 months with subjects and site blinded to central lab results. At six months, subjects in Group 1–CGM with T2DM and Group 2-SMBG, will complete their participation in the study.

At six months, subjects with T1DM, in Group 1-CGM who have been using CGM regularly, are willing to continue RT-CGM, are using <100 units of insulin a day, and are willing to use an insulin pump, will proceed on to Phase 2 and undergo a second randomization. Subjects will all use CGM and will either continue MDI (Group 1a-CGM/MDI) or change insulin delivery to CSII (Group 1b-CGM/CSII).

All health utilization will be tracked via 2 mechanisms – self reporting (e.g., hospital visits, emergency services, home glucagon use, etc.) and clinic reporting (extra office visits, additional education, etc.).

Patient reported outcome (PRO) measurements will be obtained at the beginning and end of each study phase.

STUDY VISIT OVERVIEW

Run-in Period: Eligible subjects will participate in a run-in period using blinded CGM for up to 3 weeks. The Run-in period comprises up to 4 clinic visits and concludes with an assessment of the subject’s compliance to use study devices (including ability to self-deploy sensors) to continue on to Phase 1 or terminate from the study. During the Run-in, subjects will be trained on the study-assigned meter and CGM use in blinded mode. Baseline data and labs will be collected. All subjects will return to the clinic after the first sensor session for assessment and deployment of a second sensor for the second week of blinded CGM use. For subjects eligible to continue on to Phase 1, additional diabetes and device training will be provided, baseline clinical data will be collected, and baseline PRO instruments will be administered. Any subject who does not provide ample data from two sensor sessions due to device issues (i.e., adhesive or sensor failures) may extend the run-in period in order to collect the total required baseline data. Phase 1: Comprises up to 5 clinic visits over 6 months, depending on randomization group. Frequency of clinic visits for all subjects is at month 1, 3, and 6.



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Additional group-specific visits: Group 1-CGM subjects will have a follow-up clinic

visit after the first week of un-blinded CGM use to trouble-shoot device issues

Group 2-SMBG subjects will use blinded CGM for 1 week at months 3 and 6 to collect glycemic data

During Phase 1 visits, subjects will: 1) be assessed for any AEs or device issues; 2) have their devices downloaded; 3) have their diabetes management decisions evaluated by clinicians with possible adjustments to the diabetes therapy; 4) complete PRO instruments and 5) have A1C levels drawn. Ad hoc visits may be conducted throughout the study as needed. Eligibility to continue on to Phase 2 will be determined upon completion of Phase 1. Subjects in Group 1-CGM who have T1DM, have regularly used CGM in month 6, and who are using <100 units of insulin a day are eligible to continue on to Phase 2 and undergo a second randomization. Subjects will be randomized to either remain on MDI therapy with CGM (Group 1a-CGM/MDI) or CSII therapy with CGM (Group 1b-CGM/CSII).

Phase 2: Eligible subjects with T1DM will continue on study for an additional six months to evaluate the outcome of diabetes management delivering insulin via CSII vs. MDI in RT-CGM users. This phase comprises up to 4 clinic visits over 6 months, depending on secondary randomization group. Group 1b-CGM/CSII will have additional training and an additional follow-up visit to troubleshoot for any device issues. In addition, the insulin regimen will be modified as necessary. During Phase 2 visits, subjects will 1) be assessed for any AEs or device issues, 2) have their devices downloaded, 3) have their diabetes management decisions evaluated with possible adjustments to the diabetes therapy , 4) be asked to complete PRO instruments and 5) have A1C levels drawn. This phase and the study conclude upon review of final CGM data and completion of PRO measures.

PATIENT DURATION Up to 15 months to allow for screening, follow-up, and scheduled visit windows.

STUDY DURATION Total study duration is estimated at 2 years. Full recruitment is estimated at 9-12 months. Follow-up period is estimated at 13 months.



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4. INTRODUCTION 223

Diabetes mellitus is a group of diseases characterized by abnormally high blood glucose levels. There 224 are two major classifications of diabetes mellitus: Type 1 Diabetes Mellitus (T1DM), autoimmune 225 destruction of the insulin producing pancreatic beta cells resulting in diminished or absent insulin 226 secretion; and Type 2 Diabetes Mellitus (T2DM), resulting from constellation of defects including but 227 not limited to impaired insulin action, decreased insulin production, and enhanced hepatic glucose 228 production.1 The Centers for Disease Control and Prevention reported that diabetes affects 229 approximately 25.8 million people in the United States, or roughly 8.3% of the population, with 230 approximately 1.9 million new cases being diagnosed each year. There are also 79 million people in 231 the United States with impaired glucose tolerance (IGT) or impaired fasting glucose (IFG).2 The 232 global prevalence of diabetes in 2003 was 189 million and it is projected that 324 million people will 233 have diabetes by the year 2025.3 234

Large-scale, randomized, prospective trials of various interventional therapies in patients with both 235 T1DM and T2DM have clearly shown that improved glycemic control significantly reduces the 236 development and progression of microvascular complications of diabetes in both adults and 237 adolescents. The Diabetes Control and Complications Trial (DCCT) and the Kumamoto Trials 238 showed that intensive treatment methods reduced the incidence of these complications by 239 approximately 50 to 70%.4, 5, 6 These studies have demonstrated that intensive monitoring and better 240 control of blood glucose in people with T1DM and T2DM both delays the onset and reduces the 241 progression of diabetic retinopathy, nephropathy, and neuropathy. However, the lower A1C in the 242 intensively managed treatment arm came at the cost of nearly three-fold increase in the risk of severe 243 hypoglycemia. 244

Subsequent studies have shown that performing as many as seven finger sticks per day was not 245 sufficient to detect a number of severe hypoglycemic and hyperglycemic events.7 A study by Bode et 246 al. using a blinded continuous glucose monitoring system (CGM) found that even when patients 247 performed capillary finger stick measurements as frequently as nine times per day, there were still, on 248 average, approximately two hours per day of clinical hypoglycemia (<70 mg/dL) and seven hours per 249 day of clinical hyperglycemia (>180 mg/dL).8 250

For the above reasons, as well as, to provide the direction and rate of glucose change to help guide 251 diabetes management decisions, there has been interest in developing devices that measure glucose 252 frequently, accurately, and automatically. All real-time CGM systems are adjunctive devices with 253 user-configurable low and high glucose alerts. The Dexcom G4® PLATINUM CGM System (FDA 254 approved) was deemed safe and effective for use in persons with diabetes 18 years of age and older. 255 In addition, formative and summative usability studies were conducted on adults using the Dexcom 256 G4™ PLATINUM CGM System. These studies validated the effectiveness of the training, labeling, 257 and product design. 258

Two intensive insulin therapies exist for people with T1DM and insulin-requiring T2DM: multiple 259 daily injections (MDI) and subcutaneous insulin infusion (CSII). In MDI therapy, insulin is 260 administered via vial and syringe or insulin pen. In CSII, insulin is infused via a catheter inserted 261 under the skin attached to an external pump. It is estimated that 80% percent of insulin used in the 262 United States is administered by MDI therapy and that many people still have suboptimal glycemic 263 control. 264

People with diabetes who treat using MDI therapy have challenges achieving target A1C levels for 265 numerous reasons. It is known that increased frequency of self-monitoring of blood glucose (SMBG) 266 levels is correlated with better A1C levels, however, for practical reasons, most patients only perform 267 no more than four to five glucose measurements per day. 268



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Consequently, postprandial hyperglycemia and nocturnal hyperglycemia often remain unnoticed, 269 even in individuals with well-controlled diabetes (by A1C). Therefore, detecting and treating these 270 events may improve the patient’s glycemic control and have an impact on quality of life. 9 271

The use of CGM has been studied as an adjunct to intensive insulin therapy with most studies 272 performed in CSII using patients only. In other studies, there has been little to no distinction made 273 between MDI and CSII use.10-17 274

Detailed below, are four studies which compared the response to CGM between study subjects using 275 CSII and those using MDI; three studies were randomized clinical trials (RCTs), and one was a 276 prospective-observational study. 277

In the JDRF study11 in adults greater than 25 years old, 83% of subjects used CSII, 17% used MDI 278 (9/52 in CGM arm, 7/56 in the control arm). The MDI CGM users reduced A1C −0.54 ± 0.85% vs. 279 control MDI users raising A1C +0.04 ± 0.34%. In the CSII users, A1C reduced by −0.50 ± 0.51% vs. 280 control CSII users raising their A1C +0.02 ± 0.47%. 281

In the Battelino hypoglycemia reduction study12, 24% of subjects in the CGM group used MDI; 282 whereas, in the control group, 41% used MDI. In this study, time spent hypoglycemic was greater in 283 the MDI group compared to the pump group -59% vs. -41%, however, the A1C reduction was less 284 A1C,-0.06% vs. -0.39%. 285

In the French Evadiac study13, approximately half the participants used MDI. The average A1C 286 reduction was less in the MDI users, -0.28% vs. -0.67% in those using CSII. 287

Finally, in the Garg prospective observational study14, the reduction in hypoglycemia was greater in 288 subjects using MDI, -30% vs. subjects using CSII -21%. However, whether the analysis was intent to 289 treat (ITT) or per protocol (PP), MDI users had less reduction in the time spent hyperglycemic (ITT- 290 8.2 to 8.0 hours hyper/day in MDI users, 8.9-6.9 hours hyper/day in CSII users; PP- 8.8 to 8.6 hours 291 hyper/day in MDI users, 8.4-6.8 hours hyper/day in CSII users). 292

There have been no prospective randomized controlled studies exploring the clinical benefits of CGM 293 use solely in poorly-controlled MDI users compared with those who use SMBG as their glycemia 294 monitoring tool. Therefore, this study will examine the potential benefit of adding CGM to patients 295 with sub-optimal glycemic control using MDI therapy, and also the potential benefit of adding CSII 296 therapy in patients randomized to CGM alone. 297

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5. STUDY OBJECTIVES 299

The purpose of this study is to: 300

1) Assess glycemic, health-economic, and quality-of-life (QoL) benefits of adding and using RT-301 CGM in MDI patients with T1DM and T2DM not at their A1C goal and relying on SMBG for 302 diabetes management decisions 303

2) Assess incremental benefits of changing the insulin delivery method from MDI to CSII in patients 304 with T1DM already using RT-CGM who are not at their glycemic goals 305

306 Specific health economics objectives are to evaluate cost-effectiveness and quality-of-life measures 307 between the two groups. 308 • For cost effectiveness: Evaluate within-trial cost-effectiveness attributable to use of CGM, as 309

well as, the lifetime cost-effectiveness attributable to the use of CGM. 310 • For quality-of-life measures: Evaluate diabetes-related health states for patients and measure 311

health care utilization and economic consequences attributable to the CGM group compared to 312 the SMBG group. 313

314

6. PRIMARY ENDPOINTS 315

• Primary endpoint at Month 6: Change in A1C from baseline to six months between groups. 316 A 0.4% or greater difference between Group 1-CGM and Group 2-SMBG is considered 317 clinically significant. 318

• Primary endpoint at Month 12: Change in %Time-in-Range (defined as a glucose value of 319 70-180 mg/dL) as determined by CGM from Month 6 between groups. 320

321

7. SECONDARY ENDPOINTS 322

Month 6 (within and between group analyses) endpoints: 323 o Percent A1C ≤ 7% 324 o %Time-in-Range (70-180 mg/dL) 325 o %Time-in-Hypoglycemia 326 o %Time-in-Hyperglycemia 327 o QoL changes 328 o Cost effectiveness 329 o Incidence of severe hypoglycemia 330 o Change in hypoglycemia awareness 331 o Changes in glucose variability 332 o Change in SMBG frequency over time and impact on A1C 333

334 Month 12 (within and between group analyses) endpoints: 335

o Percent A1C ≤ 7% from month 6 336 o Change in A1C from month 6 to month 12 337 o % Time-in-Hypoglycemia 338 o %Time-in-Hyperglycemia 339 o Incidence of severe hypoglycemia 340 o QoL changes 341 o Cost Effectiveness 342 o Change in hypoglycemia awareness 343 o Changes in glucose variability 344



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8. STUDY POPULATION 345

The study population comprises adults with T1DM and T2DM mellitus on MDI therapy in Phase 1, 346 and adults with T1DM in Phase 2. 347

Determination of classification for diabetes will be based on American Diabetes Association Clinical 348 Practice Guidelines, accounting for several patient characteristics such as age of onset, patient’s 349 weight or BMI, history of diabetic ketoacidosis, history of therapy management, and medical records, 350 if available. 351

352 9. STUDY ELIGIBILITY 353

9.1 Inclusion Criteria 354

Individuals may be included if they meet the following criteria: 355 1. Age 25 years of age and older 356 2. Diagnosis of T1DM or insulin-requiring T2DM 357 3. Followed regularly by a physician or diabetes educator for their diabetes management – with 358

at least 2 office visits in last year as documented by clinical history 359 4. Using MDI for at least 12 months prior to study entry 360 5. Sub-optimal glycemic control, defined as persistent hyperglycemia, confirmed initially by 361

historical or local lab (POC or site’s lab) A1C of ≥7.7% to ≤10%, then followed with a 362 confirmatory result by central lab of ≥7.5% to ≤10% 363 NOTE: Use of a historical local A1C test must be within 1 month of study entry. 364

6. Desire to lower A1C such as a goal of 7% 365 7. Stable control of diabetes, as determined per investigator assessment 366 8. Stable diabetes medication regimen for 3 months prior to study entry 367 9. Stable weight maintained 3 months prior to study entry, per investigator’s assessment, and 368

not planning any structured weight reduction interventions such as prescription weight loss 369 medications, bariatric surgery, or protein sparing modified fast during the course of the study. 370

10. Willing to wear a device (CGM/pump) 371 11. Willing to avoid use of acetaminophen medications throughout the study 372 12. Currently performing SMBG management (by history): 373

Type 1 – an average of 3 or more times per day; and 374 Type 2 – an average of 2 or more times per day 375

13. Able to speak, read, and write English 376 14. For Phase 2, total daily insulin dose is <100 units 377

9.2 Exclusion Criteria 378

Individuals will be excluded for any of the following criteria: 379 1. Use of personal RT-CGM 3 months prior to study entry (professional CGM use, blinded or 380

un-blinded, is acceptable) 381 2. Use of CSII 3 months prior to study entry (including patch pumps) 382 3. Plan to use personal CGM and/or pump during the course of the study 383 4. Addition of any new oral or injectable hypoglycemic agents (including GLP-1 analogues, 384

Pramlintide, and SGLT-2 inhibitors – these agents are only for T2DM subjects) within 3 385 months prior to study entry. (Use of these agents does not affect eligibility if used 3 or more 386 months prior to study entry.) For GLP-1 medications, must be on stable dose and the GLP-1 387 medication will be maintained throughout the study. 388



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Note: These agents should not be added or modified during course of the 389 study. If use of this class medication is planned, the patient is not eligible. 390

5. Use of pre-mixed insulin (e.g. 70/30 or 50/50) 6 months prior to study entry 391 6. Current or anticipated acute uses of glucocorticoids (oral, injectable, or IV), that will affect 392

glycemic control and impact A1C – such as frequent steroid bursts required for inflammatory 393 arthritis or inflammatory bowel disease, recurrent lumbar epidural steroid injections, etc. 394 (Long-term stable glucocorticoid doses are allowed, such as when used for the treatment of 395 rheumatoid arthritis or Addison’s disease). 396

7. Pregnancy (as demonstrated by a positive test at study entry) at time of screening or are 397 planning to become pregnant during the study 398

8. Medical conditions that, per investigator determination, make it inappropriate or unsafe to 399 target an A1C of <7%. Conditions may include but are not limited to: 400 • Unstable. recent cardiovascular disease, 401 • Recent myocardial infarction 402 • Significant heart failure 403 • Ventricular rhythm disturbances 404 • Recent transient ischemic attack, or cerebrovascular accident 405 • Significant malignancy 406 • Other conditions resulting in physical or cognitive decline 407 • Recurrent severe hypoglycemia 408

9. History of visual impairment which would hinder subject’s participation in the study and 409 perform all study procedures safely, as determined by investigator 410

10. History of psychiatric, psychological disorder, or psycho-social issues that could limit 411 adherence to the required study tasks 412

11. Renal disease defined as estimated Glomerular Filtration Rate eGFR <45 413 12. Extensive skin changes/disease that preclude wearing the sensor on normal skin (e.g. 414

extensive psoriasis, recent burns or severe sunburn, extensive eczema, extensive scarring, 415 extensive tattoos, dermatitis herpetiformis) 416

13. Known allergy to medical-grade adhesives 417 14. Current participation in another investigational study (must have completed any previous 418

studies at least 30 days prior to being enrolled in this study) 419 15. Recent hospitalization or emergency room visit in the 6 months prior to screening resulting in 420

a primary diagnosis of uncontrolled diabetes 421 16. Currently abusing illicit drugs, alcohol, or prescription drugs 422 17. Any condition, per investigator assessment, that could impact reliability of the A1C 423

measurement, such as (but not limited to) hemoglobinopathy, hemolytic anemia, chronic liver 424 disease; chronic GI blood loss, red blood cell transfusion or erythropoietin administration 425 within 3 months prior to screening 426

427 10. STUDY DESIGN 428

10.1 Design Summary 429

Eligible persons will provide voluntary consent for enrollment into the study (see Appendix A, 430 Informed Consent). 431

This is a prospective, randomized, parallel, controlled study that will be conducted in two phases: 432

Phase 1- Comparing outcomes of diabetes management using RT-CGM vs. SMBG alone 433

Phase 2- Comparing outcomes of insulin delivery via a pump vs. injections in RT-CGM users 434 (see Appendix B Study Flowchart) 435



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Following screening and a Run-in period of blinded CGM use, up to 338 subjects with diabetes 436 mellitus, not at optimal glycemic control, using MDI, will be randomized. Two diabetes cohorts 437 (T1DM and T2DM) will be randomized to be independently powered for change in A1C. 438 Randomization in Phase 1 for the T1DM cohort will be performed using an unbalanced 2:1 439 randomization scheme resulting in two groups. Group 1-CGM uses CGM as part of their 440 diabetes management, and will be twice as large as the SMBG group. Group 2-SMBG uses 441 SMBG as per usual care. 442

Prior to Phase 1, all subjects will have a run-in period lasting up to 3 weeks in which they will use 443 the Dexcom™ G4 PLATINUM System in blinded mode to establish compliance with CGM 444 procedures, willingness to use CGM, and to collect baseline glucose data. Subjects who are 445 willing and adherent will continue on to Phase 1 and be randomized to either use RT-CGM 446 (Group 1-CGM) or to manage their diabetes based on use of SMBG (Group 2-SMBG). 447

Assessment of subject’s willingness to proceed in the study include: 448

1) Demonstrated ability to comprehend study procedures during the run-in phase, as 449 evaluated by appropriate research staff 450

2) Willing to perform required sensor calibrations 451

3) Willing to wear the device(s) continuously throughout the study 452

Subjects in both arms will be provided basic diabetes education (See Appendix C: Clinician 453 Guidelines: General Diabetes Education). Subjects randomized to Group 1-CGM will be 454 instructed to use the CGM as an adjunct to their current diabetes management regimen to help 455 guide diabetes-related decisions. 456

Most of the study visits will be divided into two parts: 457

1) Part 1: Perform study related tasks. These tasks can be performed by clinical 458 coordinators, and include tasks such as collecting SAE info, drawing labs, and 459 administering PRO surveys. 460

2) Part 2: Provide diabetes management. This will be provided by a clinician well-versed in 461 MDI therapy, use of real-time CGM, and use of insulin pumps. The time for these 462 discussions should generally reflect the typical time spent for diabetes management 463 during a routine, follow-up physician visit. Guidelines for these discussions are included 464 in Appendix D, Clinician Guidelines for Follow-Up Visits. 465

466 Additional visits and phone calls between the scheduled visits are allowed if required for device 467 or diabetes management issues. Additional diabetes education, if needed per clinician assessment, 468 is also acceptable in both Groups. Guidelines for follow-up are in Appendix D. 469

For Group 1-CGM, the CGM downloads will be reviewed with subjects and should be considered 470 by clinicians to formulate their diabetes management recommendations. 471

For Group 2-SMBG, downloads will be reviewed with subjects if this is the standard practice of 472 the site. The blinded CGM downloads will not be reviewed with the subjects and should not be 473 used or considered by clinicians for diabetes management recommendations. 474

A1C levels will be obtained at baseline, 3, 6, 9, and 12 months with subjects and sites blinded to 475 the central lab results. 476

Note: A1C testing conducted at the clinical site for clinical management 477 will be obtained at 3, 6, 9, and 12 months by sites’ POC A1C or local 478 lab. These A1C results can be reviewed with the subjects as part of their 479 routine visit care. 480



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At the end of Phase 1, subjects with T2DM, subjects in Group 1-CGM using ≥100 units/day of 481 insulin, and subjects in Group 2-SMBG will complete their participation in the study. 482

Those in Group 1-CGM who have T1DM, have used CGM on 21 of the last 28 days, and are 483 using <100 units/day of insulin are eligible to continue on to Phase 2 and undergo a second 484 randomization. 485

During Phase 2, all subjects will use CGM and will either continue MDI therapy (Group 1a-486 CGM/MDI) or change insulin delivery to CSII (Group 1b-CGM/CSII). Appendix E, Visit 487 Flowchart, provides a graphical illustration of the visits time points. 488

Throughout the course of the study, subjects using CGM will be encouraged to follow diabetes 489 management guidelines (Appendix F, Diabetes Management Guidelines Using CGM). 490

All health utilization will be will be tracked via 2 mechanisms: 491

1. Self-reporting using PRO - Health Service Utilization Form, (e.g. hospital visits, 492 emergency services, home glucagon use, etc.) and 493

2. Clinic reporting using the Care Management Form (extra office visits, additional 494 education, etc.). 495

Patient reported outcome (PRO) measurements will be obtained at the beginning and end of each 496 study phase (see Appendix G, PRO Measures, for list of the PRO instruments). 497

All tests and exams required for the study are listed in Appendix H, Test & Exam Table. 498

499

11. PATIENT PARTICIPATION 500

Up to 15 months to allow for screening, follow-up, and scheduled visit windows. 501 502

12. STUDY DURATION 503

Total study duration estimated at 2 years. 504

Recruitment estimated at 9-12 months. 505

Follow-up period estimated at 13 months. 506

507

13. CLINICAL RESEARCH SITE(S) 508

This study will be conducted at up to 35 sites. 509 510 Investigational centers will be selected across the United States. Selection is based on each 511 Investigator’s experience and qualifications, availability of sufficient resources to carry out the 512 required study procedures and the investigator’s ability to recruit subjects into the study. Enrollment 513 will be competitive. 514 515

14. OVERVIEW of STUDY DEVICES 516

14.1 Dexcom G4 Continuous Glucose Monitoring System (System) 517

The Dexcom G4 PLATINUM CGM System is intended for single-patient use. The System was 518 FDA-approved with Software 505 in October 2014 (PMA# P120005/S018). 519



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The System continuously tracks and reports glucose values and trending information for people 520 with diabetes mellitus. The System is designed to provide continuous measurements of glucose 521 concentrations over a 40-400 mg/dL range. 522

As part of the System’s instructions for use, users are informed of the following: 523

• System does not replace blood glucose measurements 524 • Blood glucose values may differ from sensor glucose readings and the value from the blood 525

glucose meter should be used for treatment decisions, such as how much insulin to take. 526 The direction, rate of glucose change, and trend graph on the system provide additional 527 information to help with these decisions 528

• Symptoms of high and low glucose should not be ignored. If sensor readings do not fit with 529 symptoms, blood glucose should be measured with a blood glucose meter 530

• If at any time during use a subject requires a magnetic resonance imaging (MRI) scan, 531 computed tomography (CT) scan or diathermy treatment, the subject is advised to 532 discontinue current sensor session prior to the test/treatment, and then replace with a new 533 sensor after completion of the test/procedure 534

• The device is not approved for use in pregnancy and study participation will be terminated 535 if a subject becomes pregnant 536

14.1.1 Dexcom CGM Software 537

A currently-marketed/FDA-approved Dexcom CGM computer software program will be used 538 to transfer glucose data stored in the receiver to a site’s computer system, as per their 539 standard practice. This software may be used in two places: 540

1. At home, if subjects choose to use the reports and have a personal computer (PC) 541

2. At the site, for downloading devices for Group 1-CGM to be used for diabetes 542 management purposes 543

14.2 Insulin Pump Overview 544

The insulin pump to be used in this study is the OmniPod, manufactured by Insulet Corporation. 545 The OmniPod is a wireless, waterproof, insulin pump consisting of two parts: 546

• Wearable Pod 547 • Personal Diabetes Manager (PDM) with a built-in Abbott Freestyle Glucose Meter 548

Contained within the Pod is an insulin reservoir, angled infusion set, automated inserter, pumping 549 mechanism and power supply. The OmniPod can hold up to 200 units of insulin; it requires a 550 minimum of 85 units of insulin to begin operation. Depending on insulin usage, the OmniPod can 551 be used 48-72 hours. 552

Subjects who are randomized to add an insulin pump in Phase 2 will be trained on proper 553 insertion and use. Software used in conjunction with the OmniPod system will be utilized for 554 downloading data at the sites. 555

14.3 Blood Glucose Meter Overview 556

Subjects will use the Bayer Contour Next USB meter to record their blood glucose values 557 throughout Phase 1 of the study. During Phase 2, subjects randomized to the OmniPod will 558 receive test strips compatible with the Abbott Freestyle, as this meter is part of the OmniPod 559 PDM. All other CGM subjects in Phase 2 will continue to use strips for the Bayer Contour Next 560 USB. Appropriate blood glucose test strips will be provided to subjects throughout their 561 participation in the study, based on quantities routinely used by the subjects. Software used in 562 conjunction with Bayer Contour Next USB will be utilized for downloading data at the sites. 563



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564 15. OVERVIEW OF PRO INSTRUMENTS 565

15.1 Patient Reported Outcome (PROs) Measures 566

15.1.1 PRO measures will be administered at Baseline, 6 and 12 months. PROs will assess 567 QoL dimensions – health state, psychological well-being, diabetes management, and 568 interaction with CGM. PROs will also assess treatment satisfaction and behavioral 569 changes throughout the study, as well as capturing health economic benefits. (See 570 Appendix G: Patient Reported Outcome (PRO) Measures). 571

572

The following PROs will be utilized (all PROs will be captured in electronic data capture, except 573 EQ-5D-5L, which is paper based): 574

15.1.2 WHO-5 Well-Being Index18 – This is a validated, 5-question scale, utilized to assess 575 general outlook and overall well-being. This scale also examines aspects other than 576 just the absence of depressive symptoms. Administration time is approximately 5 577 minutes. 578

15.1.3 EuroQol (EQ-5D)19 – An EQ-5D health state (or profile) is a set of observations 579 about a person defined by the descriptive system. An EQ-5D health state may be 580 converted to a single summary index by applying a formula that essentially attaches 581 weights to each of the levels in each dimension. This formula is based on the 582 valuation of EQ-5D health states from general population samples. The EQ-5D-5L 583 consists of a descriptive system and a visual analogue scale (VAS). The EQ-5D-5L 584 descriptive system comprises the following 5 dimensions: mobility, self-care, usual 585 activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no 586 problems, some problems, extreme problems. Time to completion is approximately 5-587 10 minutes. 588

15.1.4 Health Service Utilization Form – 589 This form captures the frequency of Emergency Room visits, calls to 911, after-590 hours/urgent care visits, hospital visits, the number of visits to their health care 591 provider/physician/nurse practitioner office visits, as well as visits to dieticians. This 592 form captures these visits whether diabetes-related or not. Additionally, this form 593 captures self-care time and work/work capability status in relation to their diabetes 594 needs. Time to completion is approximately 10 minutes. 595

15.1.5 Diabetes Distress Scale (DDS)20 – This scale lists 17 potential problem areas that 596 people with diabetes may experience, and can denote the degree to which they are or 597 are not affected. Administration time is approximately 10 minutes. 598

15.1.6 Hypoglycemic Fear Survey, Worry Subscale (HFS-W)21 – This validated survey 599 consists of 18 questions which measure several dimensions of anxiety and fear 600 surrounding hypoglycemia among adults with diabetes. Administration time is 601 approximately 10 minutes. 602

15.1.7 Hypoglycemia Confidence22 – This scale addresses how confident people with 603 diabetes are to stay safe and avoid serious problems related to hypoglycemia. This 604 scale consists of 9 questions, with an approximate administration time of 5 minutes. 605



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15.1.8 Bolus Insulin Questionnaire23 – This scale consists of 8 questions, which asks 606 people with diabetes to look back at the past week to assess their usage of fast-acting 607 insulin over breakfast, lunch, dinner, and snacks; also looks at the ease or difficulty of 608 calculating correct doses. Administration time is approximately 5 minutes. 609

15.1.9 Diabetes Numeracy Test (DNT5)24 – The Diabetes Numeracy Test is a validated 610 tool that consists of 5 questions. This is an actual test to determine how accurately a 611 person with diabetes can calculate commonly ingested carbohydrates. Approximate 612 administration time is 10 minutes. 613

15.1.10 Clarke Hypoglycemia Scale25 – A validated tool that uses 8 questions to assess 614 awareness of hypoglycemia in adults. A score of 1 or 2 is classified as aware; a score 615 of 3 or more is classified as impaired awareness of hypoglycemia (IAH). 616 Approximate administration time is 10 minutes. 617

15.1.11 CGM Expectations Questionnaire26: This questionnaire consists of 5 questions and 618 looks at potential expectations people with diabetes may have prior to using CGM. 619 Administration time is approximately 5 minutes. 620

15.1.12 CGM Attitudes27: This questionnaire consists of 7 questions which will examine 621 how a person feels about using CGM, based on accuracy, convenience, ease-of-use, 622 general performance, as well as their trust and confidence in the device. Approximate 623 time is 5 minutes. 624

15.1.13 CGM Satisfaction28: The CGM Satisfaction scale is a validated tool which consists 625 of 44 questions which assesses satisfaction regarding various aspects of CGM use. 626 Administration time is approximately 10 minutes. 627

Prior to randomization, the baseline PROs will be administered to all subjects as follows: 628

15.1.14 Baseline PROs (Visit S3): 629 1. WHO-5 Well-Being Index 630 2. EQ-5D-5L 631 3. Health Service Utilization Form 632 4. Diabetes Distress Scale (DDS) 633 5. Hypoglycemic Fear Survey, Worry Subscale (HFS-W) 634 6. Hypoglycemia Confidence 635 7. Bolus Insulin Questionnaire 636 8. Diabetes Numeracy Test (DNT5) 637 9. Clarke Hypoglycemia Scale 638 10. CGM Expectations Questionnaire 639

15.1.15 Month 6 PROs: 640 1. WHO-5 641 2. EQ-5D-5L 642 3. Health Service Utilization Form 643 4. Diabetes Distress Scale (DDS) 644 5. Hypoglycemic Fear Survey, Worry Subscale (HFS-W) 645 6. Hypoglycemia Confidence 646 7. Bolus Insulin Questionnaire 647 8. Clarke Hypoglycemia Scale 648 9. CGM Attitudes* 649



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10. CGM Satisfaction* 650 *Only administered to CGM Group 651

15.1.16 Month 12 PROs: 652 1. WHO-5 653 2. EQ-5D-5L 654 3. Health Service Utilization Form 655 4. Diabetes Distress Scale (DDS) 656 5. Hypoglycemic Fear Survey, Worry Subscale (HFS-W) 657 6. Hypoglycemia Confidence 658 7. Bolus Insulin Questionnaire 659 8. Clarke Hypoglycemia Scale 660 9. CGM Satisfaction Scale 661 10. CGM Attitudes 662

663 16. DATA COLLECTION AND DATA MANAGEMENT 664

Data collected during this study will be documented on electronic case report forms (e-CRFs). 665 The Investigator or designee is responsible for completing the Case Report Forms (CRFs). The 666 EDC system will be validated prior to study commencement. Sites will be trained on use of the 667 EDC system by sponsor or designee. Good Documentation Practices principles will be required. 668 Subjects who fail the Run-In Phase will not undergo randomization and thus will be withdrawn 669 from the study, with documentation provided on a termination CRF. 670 A database system, Part 11 compliant, will be created using Jaeb Center’s custom built electronic 671 data capture system for data entry and verification of the data inputted by site personnel. 672

673 17. STATISTICAL ANALYSIS 674

As this is an intent-to- treat (ITT) study, analysis will be conducted on all subjects enrolled at 675 Months 6 and 12. A second analysis will also be conducted at Months 6 and 12 on the sub-group 676 of compliant subjects, using an a priori definition for subject compliance to CGM. Compliance is 677 defined as use of CGM on average a minimum of 6 days during a 7-day wear period (at least 85% 678 of the days). 679

17.1 Randomization 680

For Phase 1, the two diabetes cohorts (T1DM and T2DM) will undergo randomization separately 681 between Group 1-CGM and Group 2-SMBG and will be stratified by A1C result (<8.5% and ≥ 682 8.5%). Randomization will be performed using a 2:1 randomization scheme for the T1DM cohort 683 and a 1:1 randomization scheme will be used for the T2DM cohort. 684

A combination of permuted blocks randomization and stratified randomization will be used. A 685 SAS program will be written to generate the randomization schedule. For Phase 2, randomization 686 will be stratified between Group 1a-CGM/MDI and Group 1b-CGM/CSII to ensure equal 687 distribution for subjects with A1C result ≤ 7%, >7% to <7.5% and ≥7.5%. 688

17.2 Data Analysis 689

For Phase 1, the primary endpoint for this study is change in A1C from baseline to six months 690 between groups. This will be evaluated in the total population and in the T1DM and T2DM 691 cohorts. 692

The study hypothesis is: 693

Ho = A1C delta between Group 1-CGM and Group 2-SMBG = 0 694 H1 = A1C delta between Group 1-CGM and Group 2-SMBG ≠ 0 695



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It is anticipated that subjects with T1DM or T2DM who are sub-optimally controlled will show 696 an improvement in glycemic control with the use of RT-CGM in Group 1-CGM, over and above 697 any improvement in subjects using SMBG in Group 2-SMBG. Improvement in glycemic control 698 will be based on the evaluation of the A1C from baseline to 6 months. The magnitude of the 699 change will be compared between the Group 1-CGM to Group 2-SMBG, using repeated measure 700 of mean variance analysis. 701

For Phase 2, the primary endpoint is change in %Time-in-range (70 to 180 mg/dl) as determined 702 by CGM from month 6 between groups. 703

Secondary analyses will involve descriptive comparisons and specific health economics modeling 704 of the following at month 6 and 12 (unless otherwise stated), as applicable: 705

Month 6 (within and between group analyses) endpoints: 706

• Percent A1C ≤7% 707 • %Time-in-Range (70 to 180 mg/dL) 708 • %Time-in-Hypoglycemia 709 • %Time-in-Hyperglycemia 710 • QoL changes 711 • Cost effectiveness 712 • Incidence of severe hypoglycemia 713 • Change in hypoglycemia awareness 714 • Changes in glucose variability 715 • Change in SMBG frequency over time 716

Month 12 (within and between group analyses) endpoints: 717

• Percent A1C ≤ 7% from month 6 718 • Change in A1C from month 6 to month 12 719 • %Time-in-Hypoglycemia 720 • %Time-in-Hyperglycemia 721 • Incidence of severe hypoglycemia 722 • QoL Changes 723 • Change in hypoglycemia awareness 724 • Changes in glucose variability 725

Data analysis will be conducted at the completion of the data collection period for all subjects. 726

Baseline demographic factors will be summarized. For continuous variables, such as age, the 727 mean, standard deviation, median, and range will be presented. For categorical variables, such as 728 gender, the proportion of subjects in each category will be presented. 729

Summary statistics will include the mean, standard deviation, median, and range. 95% confidence 730 level will be used, when applicable. 731

Changes in continuous parameters (e.g. A1C, SMBG measurements per day, glucose distribution) 732 from baseline to follow-up will be analyzed using repeated measures ANOVA, adjusted for the 733 baseline value and the variables by which the randomization was stratified. Chi-squared tests or 734 Fisher’s Exact test will be used to analyze categorical data. All null hypotheses will be tested 735 against two-sided alternatives at the 5% significance level. 736

Event analysis will be conducted by comparing results experienced by SMBG arm to CGM arm. 737 Any device-related adverse events (AEs) will be tabulated and reported. 738

Missing data will be handled as follows: 739



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For HbA1c data, if the laboratory value is unavailable then the XX value will be used. If neither 740 measurement is available then the value will be imputed based on available previous lab and/or 741 XX HbA1c measurements using Rubin’s method. 742

For CGM data, analyses will include all data available during the randomized trial. Therefore, 743 there will not be imputation for missing data. 744

Final analysis of results will be generated using SAS software 9.2 or higher. 745

17.3 Cost-effectiveness Analysis: 746 In addition to the data analysis focused on clinical outcomes there will also be a companion 747 analysis of the economic impact and cost effectiveness of the intervention. The cost-effectiveness 748 analysis will be detailed in a separate document and is summarized below. 749 The analyses will address the following objectives: 750

• To collect utilities for diabetes-related health states for patients and to measure health 751 care utilization and economic consequences attributable to the Group 1-CGM compared 752 to Group 2- SMBG 753

• To evaluate the within-trial cost-effectiveness of the intervention provided to Group 1-754 CGM group compared to Group 2-SMBG 755

• To estimate the lifetime cost-effectiveness of CGM use utilizing a Monte Carlo– based 756 Markov simulation model to project the course of the natural history of the disease and 757 the associated spending in both the Group 1-CGM and Group 2-SMBG 758

For all analyses, the effectiveness parameter will be expressed in terms of quality-adjusted life-759 years (QALY) and incremental cost effectiveness ratios (ICER). Cost accounting will vary 760 according to the time-frame and perspective of the analysis. The within-trial health system 761 perspective will include all the direct costs associated with the program and all direct and indirect 762 medical costs accrued by the subjects during the course of the trial. On the other hand, the 763 societal perspective for the within-trial analysis will also account for the time costs subjects 764 enrolled in the study. 765

For the lifetime analysis, investigators will use the Huang, O’Grady and Basu model that was 766 used in the JDRF CGM trial. The model will be modified to incorporate recent changes in our 767 understanding of the impact of glucose control on the development of complications, as well as 768 spending associated with the treatment of diabetes and its complications. 769

Data to be collected from study subjects at baseline and during the study will include utilities 770 information for current health, complication related to health states, treatment-related 771 experiences, medical care utilization and spending, household income, employment, and 772 caregiver time. 773

Utilities can be directly elicited using three standard methods: the time trade-off (TTO), standard 774 gamble (SG), and rating scale (RS) or visual-analog scale (VAS). TTO is the most commonly 775 used for both its ease of understanding and ease of administration. However, it also has drawn 776 some concern because it asks patients if they would be willing to trade off time at the end of their 777 lives to be disease free. 778

Further details will be provided in the detailed Statistical Analysis Plan. 779

17.4 Sample Size Justification 780

Phase 1 will be 90% powered to show a difference if the true population value is a difference of 781 0.4% between the two groups in Phase 1, using a SD of 0.7. 782



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Phase 2 there will be 80% power to show a difference if the true population value is a difference 783 of 7.5% in Time-in-Range between groups, assuming a standard deviation of 8.0% and a 784 minimum of 50 participants entering and completing phase 2. 785

A maximum of 338 subjects will be randomized. A sample size of 147 for each diabetes cohort 786 (total n=294) will allow for both study phases and cohorts to be powered to 90%. Assuming a 787 15% drop-rate a total of 169 subjects for each diabetes cohort is required in Phase 1 (T1DM 788 cohort: 113 subjects in Group 1-CGM, and 56 subjects in Group 2-SMBG; T2DM cohort: 85 in 789 Group1-CGM and 85 in Group 2-SMBG). To achieve randomization sample size, up to 500 790 subjects may be enrolled into the Run-in phase of the study. 791

A 2:1 CGM: SMBG unbalanced randomization scheme will be used in Phase 1 for the T1DM 792 cohort to ensure that an adequate sample size for Group 1a (CGM/MDI) and Group 1b 793 (CGM/CSII) will be available to enter Phase 2. 794

795 18. STUDY PROCEDURES (Run-in Period) 796

18.1 Visit S1 –Screening, Consenting, and Blinded CGM Initiated (Time = 0-14) 797

Potential subjects will be asked to voluntarily provide consent by signing an IRB-approved 798 informed consent document (Appendix A: Informed Consent). The investigator or designee will 799 explain the nature, purpose, expected duration, and risks associated with study participation. 800 Potential subjects will have the opportunity to ask questions and receive answers from study staff. 801 All subjects will be provided a copy of the signed informed consent document. 802

Subjects who have indicated willingness to participate by signing the informed consent document 803 and who meet the inclusion and exclusion criteria are eligible to participate in the study. Subjects 804 in each diabetes cohort (T1DM and T2DM) will be given different informed consent documents 805 to reflect that Phase 2 of the study is only applicable to subjects having T1DM. 806

All subjects will be considered enrolled in the screening phase of the study once subjects’ sign 807 the informed consent. Regarding study entry A1C confirmation, if the most recent historical A1C 808 is outside the 1 month window from study entry sites will need to draw a POC or local lab A1C 809 for eligibility confirmation (Sites that do not have a POC or on-site lab, may split this visit.) 810

Eligible subjects who sign the informed consent document will have the following tests/exams, 811 devices and training provided during this visit: 812

o Screening A1C (POC or local lab), confirm ≥7.7% and ≤10% (POC or local lab results 813 may be historical if results available 1 month prior to consent date.) If yes, then continue 814 collection of remaining visit labs and data. 815

o Pregnancy test (urine) will be completed for women of childbearing potential (test 816 conducted within 72 hours of sensor insertion). 817

o Labs: 818 o Central Lab – 819

• A1C; Note: via a method approved by the National Glycohemoglobin 820 Standardization Program (NGSP)29 821

o Local Labs – 822 • Complete Metabolic Panel (CMP) which includes liver and kidney function 823

fasting or non-fasting (if obtained within 3 months, may use historical) 824 • C-peptide, fasting or non-fasting (may use historical if obtained within the last 6 825

months) 826 • CBC (if obtained within 3 months may use historical) 827



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• Total cholesterol, fasting or non-fasting (if obtained within the last 12 months 828 may use historical) 829

o Vital Signs 830 o Basic demographic information 831 o Height & Weight (for BMI) 832 o Download current blood glucose meter(s) (if possible) to assess baseline SMBG 833

frequency. If the meter(s) is not available, it can be brought to the next visit. 834 o Study-assigned blood glucose meter, strips, and training as needed 835 o Initial CGM training/core tasks: 836

• Insertion steps 837 • Calibration 838 • Troubleshooting 839

o Blinded CGM insertion and initial calibration (CGM receiver blinded using SweetSpot. 840 Ensure receiver is blinded – receiver screen will read “Display Off” if properly blinded.) 841

o Home use instructions, such as CGM basic troubleshooting 842

Subjects will be provided a blood glucose meter and test strips to use for all SMBG testing. Test 843 strips will be allocated at each study visit. Instruction on blood glucose meter use will be 844 provided. 845

Subjects will be advised that MRIs, diathermy, and CT scans are not compatible with the CGM 846 sensor. In the event a subject needs to have an MRI or CT scan during course of the study, their 847 current sensor will to be discontinued prior to any of these tests per the IFU. 848

849

18.2 Visit S2 – Week 1 – Blinded CGM Use (Time = 0- 7 days; Window ± 2 days) 850

All subjects return after one week of initiation of the blinded-CGM wear to identify any 851 challenges with wearing or using the CGM device. Subjects will be guided how to self-deploy a 852 second device for a second week of data collection, or if preferred by the subject, study staff may 853 deploy at this visit. 854

Study staff will- 855

• Obtain CGM and Blood Glucose Meter (BGM) data, per usual practice 856 • Assess any AEs or device issues 857 • Upload devices to SweetSpot, and assess CGM and BGM compliance using the 858

utilization reports. Subjects will be terminated if non-compliant. The investigator and 859 team will assess subject’s eligibility to continue in the study based on adherence to CGM 860 and study procedures. Compliance definition for continuing on in the study is established 861 as: 862

o CGM Adherent - 85% of days with wearing CGM sensor , carrying the receiver 863 AND calibrating 2 times/ calendar day (approximating the 12-hour calibration 864 scheme) 865

o SMBG Adherent - Minimum of 3 or more fingersticks daily for BG monitoring 866 (inclusive of calibration measurements) for Type 1; minimum of 2 or more 867 fingersticks daily for BG monitoring (inclusive of calibration measurements) for 868 Type 2 869

o Medications: Avoidance of acetaminophen-containing medications 870 • Inform subject that they must be able to self-deploy sensor by Screening Visit 3 (required 871

if randomized to CGM group). 872

873



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18.3 Visit S3 – Week 2 - Run-In Completion, Subject Compliance Assessment, & 874 Randomization (Time = 0; Window ± 2 days) 875

Study staff will - 876 • Upload meter and CGM data to SweetSpot 877

Note: In the event the subject was unable to collect a minimum of 12 days of CGM 878 data during the 2 weeks of baseline blinded CGM data due to device issues, not 879 compliance issues (i.e., adhesive or sensor failures) they may have their Run-in 880 period extended for 1 additional week in order to collect this baseline data. This 881 extension would be at the discretion of the investigator. 882

• Assess any AEs or device issues that may have occurred since the last study visit 883 • Assess compliance using SweetSpot utilization report. Subjects will be terminated if non-884

compliant. The investigator and team will assess subject’s eligibility to continue in the 885 study based on adherence to CGM and study procedures. Compliance definition for 886 continuing on in the study is established as: 887

o CGM Adherent - 85% of days (e.g. 12 out of 14 days in a 2 week period). 888 Includes wearing CGM sensor ,carrying the receiver AND calibrating 2 889 times/calendar day (approximating the 12-hour calibration scheme) 890

o SMBG Adherent - Minimum of 3 or more fingersticks daily for BG monitoring 891 (inclusive of calibration measurements) for Type 1; minimum of 2 or more 892 fingersticks daily for BG monitoring (inclusive of calibration measurements) for 893 Type 2 894

o Medications: Avoidance of acetaminophen-containing medications 895

• Assess subject’s ability to self-deploy sensor (required if randomized to CGM group) 896

• Subjects are eligible to continue in the study if: 897 o Willing and compliant with CGM and BGM during the Run-in period 898

o Central lab A1C result is confirmed within eligibility range: ≥7.5% to ≤10% 899 Note: site is blinded to actual central lab result; however, site will be notified 900 whether subject’s central lab was within range for study eligibility. 901

• Obtain concomitant medications (not vitamins/minerals) including dose and frequency, 902 and if subject takes as needed (p.r.n.). Assess for addition or modification of any GLP-1 903 agonists, pramlintide, and SGLT-2 inhibitors. 904

• If these medications are added prior to randomization, the subjects will be 905 withdrawn from the study. Administer baseline PROs to all eligible subjects: 906

1. WHO-5 Well-Being Index 907 2. EQ-5D-5L 908 3. Health Service Utilization Form 909 4. Diabetes Distress Scale (DDS) 910 5. Hypoglycemic Fear Survey, Worry Subscale (HFS-W 911 6. Hypoglycemia Confidence 912 7. Bolus Insulin Questionnaire 913 8. Diabetes Numeracy Test (DNT5) 914 9. Clarke Hypoglycemia Scale 915 10. CGM Expectations Questionnaire 916

• Randomize per EDC procedures on the study website: 917

o RT-CGM (Group 1-CGM) 918



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o SMBG (Group 2-SMBG) 919

• Retrieve CGM Systems from subjects randomized to Group 2-SMBG and 920 maintain systems with proper identification for future study use with same 921 subject 922

• Un-blind CGM receiver for subjects in Group 1-CGM 923

o Train RT-CGM group on the use of the Dexcom G4 System in real-924 time mode, which includes: 925

Sensor insertion 926

CGM calibration 927

Focused instruction about alerts 928

Using the direction and rate of glucose change for diabetes 929 management 930

Troubleshooting 931

Provide and review the “Diabetes Management Guidelines 932 Using CGM” (Appendix F) 933

• Obtain abbreviated medical and diabetes history 934

• Schedule or provide general diabetes self-management education with 935 clinician (see Appendix C, Clinician Guidelines: General Diabetes 936 Education) 937

• Establish and review glucose targets with each subject (clinician) 938

• Inform each subject’s treating physician and/or primary care physician 939 regarding their patient’s involvement in the study 940

• Set initial alerts settings for subjects in the CGM group (clinician) 941

• Download CGM and Blood Glucose Meter (BGM) data, per usual practice 942 for diabetes management (clinician) 943

944 19. STUDY PROCEDURES (PHASE 1) 945

19.1 Visit 1 – Week 1 – CGM Troubleshooting - CGM Group Only (Window ± 2 days) 946

This visit is scheduled one week after randomization to perform the following: 947 948

• Upload meter and CGM data to SweetSpot 949

• Modify subject’s CGM alerts based on their experience (clinician) 950

• Assess for any AEs or device issues 951

• Subject will deploy a new CGM sensor, or staff will guide subject to deploy a new CGM 952 sensor (if the subject is unable to deploy on their own) 953

• Provide each subject with additional sensors to deploy at home until they return for Week 954 4 visit 955

• Teach and encourage subjects with home PCs to download their CGM devices (clinician) 956



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• Dispense test strips 957

• Provide and review the “Diabetes Management Guidelines Using CGM” (Appendix 958 F) (clinician) 959

• Download and review CGM with subjects to assess calibration, reinforce the need to 960 calibrate, and for diabetes management (clinician) 961

Study staff will train subjects who are willing and able to download CGM data on Dexcom CGM 962 software. From here, subjects can view their glucose trends which will give them their personal 963 data for review. If desired, subjects may send their data via email (PDF) or print their results to 964 share with their clinician. 965

Ad hoc follow-up phone calls and/or visits may be performed to address any questions on CGM 966 use from the subject. 967

19.2 Phone Visits (Week 2 Phone & Week 3 Phone): Window ± 2 days) 968 All subjects will receive a follow-up phone call at Week 2 and Week 3 to assess their overall 969 feedback, ability to deploy sensors and set-up system (for those in the CGM group), and to 970 answer any questions the subject may have. 971 Glucose data may be reviewed (if the subject is able to download at home) and therapy adjusted. 972 Ad hoc visits may be added as needed, that may include device downloads. 973 19.3 Visit 2 – Week 4 – Follow-Up (Window ± 4 days) 974

Study staff will - 975

• Upload meter and CGM data to SweetSpot database 976

• Troubleshoot CGM and/or SMBG issues 977

• Assess any AEs or device issues 978

• Obtain concomitant medications including dose and frequency (not vitamins/minerals), 979 and if subject takes as needed (p.r.n.). Assess for addition or modification of any GLP-1 980 agonists, pramlintide, and SGLT-2 inhibitors. 981

o In the event the subject begins GLP-1 agonists, pramlintide, or SGLT-2 982 inhibitors during the study, those subjects will still be allowed to participate in 983 future study visits. 984

• Provide additional education to either group if required per clinical assessment (clinician) 985

• Review and assess subject per Appendix D: Clinician Guidelines for Follow-Up Visits 986 (clinician) 987

• Make adjustments to diabetes therapy, if indicated (clinician) 988


• Download CGM and BGM data, per usual practice for diabetes management (clinician) 990

For the CGM group- 991

• Provide and review the “Diabetes Management Guidelines Using CGM” (Appendix F) 992 (clinician) 993

• Dispense additional sensors to deploy at home for weekly insertions until they return for 994 their Week 12 visit 995



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19.4 Visit 3 – Week 11 – Blinded CGM - SMBG Group only (Window ± 5 days) 996

The purpose of this visit is to have subjects wear blinded CGM for one sensor session. Subjects 997 will return the CGM at Week 12 Visit. 998

At this visit the following will be done: 999


• A CGM sensor will be inserted in blinded mode (self-deployed or assisted by study staff) 1001 and subjects will be provided CGM training and core tasks to include calibration, and 1002 troubleshooting. (Subjects are asked to contact the site if any sensor/adhesive issues arise 1003 within the first 3 days of wear for sensor replacement.) 1004

19.5 Visit 4 – Week 12 – (Month 3) – Mid Phase 1 Assessment (Window ± 1 days – SMBG; 1005 ± 7 days – CGM) 1006



• Troubleshoot CGM and/or SMBG issues 1009


• Obtain concomitant medications (not vitamins/minerals). Assess if subject takes as 1011 needed (p.r.n). Assess for addition or modification of any GLP-1 agonists, pramlintide, 1012 and SGLT-2 inhibitors. 1013


• Provide additional education to either group, if required per clinical assessment 1017 (clinician) 1018

• Review and assess subject per Appendix D: Clinician Guidelines and Follow-Up Visits 1019 (clinician) 1020



• Complete POC A1C (via POC or local lab); these results may be shared with the subject 1023

• Draw blood for A1C assessment. Note: Results of central lab A1C will not be shared 1024 with the subject 1025

• Record Height and weight (for BMI) 1026

• Retrieve blinded-CGM from Group 2-SMBG. (NOTE: If subject’s sensor/adhesive failed 1027 within the first 3 days during this one week of blinded wear, they were instructed to 1028 contact the site for a new sensor to be inserted.) 1029

• CGM group subjects, provide additional sensors to self-deploy weekly until they return 1030 for Week 24 visit 1031

• CGM group subjects, provide and review Appendix F: Diabetes Management Guidelines 1032 Using CGM (clinician) 1033




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19.6 Visit 5 – Week 23 – Blinded CGM - SMBG Group Only (Window ± 5 days) 1035

The purpose of this visit is to have subjects wear blinded CGM for one sensor session. Subjects 1036 will return their blinded-CGM at Week 24 Visit. 1037

At this visit the following will be done: 1038


• A CGM sensor will be inserted in blinded mode (self-deployed or assisted by study staff) 1040 and subjects will be provided CGM training on core tasks to include calibration, and 1041 troubleshooting. (Subjects are asked to contact the site if any sensor/adhesive issues 1042 occur within the first 3 days of wear for sensor replacement.) 1043

19.7 Visit 6 -- Week 24 (Month 6) – Phase 1 Final Assessments (Window ± 1 days – 1044 SMBG; ± 7 days – CGM) & Commencement of Phase 2 1045

Follow-up assessments for eligibility to continue onto Phase 2 for Group 1-CGM, and end-of-1046 study tasks will occur during this visit. The following subjects complete the study at the end 1047 of Phase 1: 1048

• Subjects who have T2DM 1049 • Group 1-CGM subjects who are using ≥100 units/day of insulin 1050 • Group 2-SMBG subjects 1051

1052 Study staff will - 1053





• Provide additional education to either group if required per clinical assessment (clinician) 1062


• Complete POC A1C (via POC or local lab); these results may be shared with the subject 1065

• Record height and weight (for BMI) 1066

• CGM group subjects, provide and review Appendix F: Diabetes Management Guidelines 1067 Using CGM (clinician) 1068

• Administer PROs: 1069

1. WHO-5 1070 2. EQ-5D-5L 1071 3. Health Service Utilization Form 1072 4. Diabetes Distress Scale (DDS) 1073 5. Hypoglycemic Fear Survey – Worry subscale (HFS-W) 1074 6. Hypoglycemia Confidence 1075



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7. Bolus Insulin Questionnaire 1076 8. Clarke Hypoglycemia Scale 1077 9. CGM Attitudes* 1078 10. CGM Satisfaction Scale* 1079 *NOTE: CGM Satisfaction and CGM Attitudes are administered only to Group 1- CGM. 1080

• Retrieve blinded-CGM from Group 2-SMBG (NOTE: If subject’s sensor/adhesive failed 1081 within the first 3 days during this one week of blinded wear, they were instructed to 1082 contact the site for a new sensor to be inserted.) 1083


• Complete Care Management Form to assess clinic visits unrelated to study visits (See 1085 Section 10) 1086

For subjects not continuing on to Phase 2: 1087 Subjects in Group 2-SMBG will be offered a trial of real-time CGM (using a FDA-approved 1088 CGM System) and, if interested, will be trained on basic RT-CGM. Follow-up will be provided 1089 after the 2-week trial is complete, according to site’s standard-of-care with CGM follow-up. 1090 If the subject desires to continue with CGM and the investigator believes CGM is clinically 1091 warranted for the particular subject, a prescription will be written for sensors and follow-up 1092 communication with their treating physician will be made. Their prescription will be 1093 communicated with the subject’s treating physician. 1094 Subjects in Group 1-CGM not continuing onto Phase 2 will have a review of Diabetes 1095 Management Guidelines. They will be provided a prescription for CGM, if desired and the 1096 investigator believes CGM is clinically warranted for the particular subject. Their prescription 1097 will be communicated with the subject’s treating physician. 1098

For subjects continuing on to Phase 2: 1099

Eligible subjects with T1DM in Group 1-CGM, using <100 units/day of insulin and who used 1100 CGM 21 out of 28 days within the last month, will be asked if they are willing to participate in 1101 Phase 2. If eligible and willing to continue, subjects will be randomized to one of the following 1102 groups: 1103

• MDI with CGM (Group 1a-CGM/MDI) 1104 • CSII with CGM (Group 1b-CGM/CSII) 1105

For all subjects who enter Phase 2: 1106

• Offer carbohydrate counting instruction (individual or group training) 1107 • Group 1a-CGM/MDI subjects will meet with a clinician to discuss any further questions 1108

they have regarding diabetes management 1109 • Group 1b-CGM/CSII subjects will be provided a study-assigned pump, PDM, and will 1110

receive insulin pump-related training on device set-up and use 1111 o Initial pump settings will be determined and discussed 1112 o Additional visits for pump training can be scheduled as needed 1113

• Subjects will be provided sensors and strips to cover the weeks between visits. 1114 • Insulin pods are provided to subjects randomized to Group 1b-CGM/CSII 1115

Randomization in this phase will be stratified between Groups 1a and 1b to ensure even 1116 distribution for subjects with A1C result ≤ 7%, >7% to <7.5% and ≥7.5% 1117

1118 20. STUDY PROCEDURES (PHASE 2 – Follow-up Study) 1119



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1120 20.1 Visit 1 - Week 26 – Follow-up – CGM/CSII Group Only (Window ± 4 days) 1121 Study staff will- 1122

• Upload CGM and BGM to SweetSpot database 1123 • Download OmniPod data onto a centrally-located computer 1124 • Troubleshoot any pump/device issues 1125 • Assess any AEs or device issues, specifically related to the pump 1126



• Provide and review Appendix D Clinical Guidelines for Follow-up Visits; and Appendix 1133 F: Diabetes Management Guidelines Using CGM (clinician) 1134

• Make pump adjustments. Note: pump adjustments may require frequent visits, and 1135 follow-up phone calls. These ad hoc visits will be documented as part of pump training. 1136 (clinician) 1137

• Dispense diabetes supplies – pods (Group 1b only), test strips, sensors to deploy at home 1138 until they return for their Week 30 visit 1139

• Download CGM and BGM data, per usual practice for diabetes management (clinician) 1140 1141

20.2 Visit 2 – Week 30 - Follow-Up (Window ± 4 days) 1142


• Upload meter, CGM, to SweetSpot database 1144 • Download OmniPod data onto a centrally-located computer 1145 • Troubleshoot any CGM, BGM or pump issues 1146 • Assess any AEs or device issues 1147 • Provide additional education to either group if required per clinical assessment (clinician) 1148 • Make adjustments to diabetes therapy, if indicated (clinician) 1149 • Provide and review Appendix D Clinical Guidelines for Follow-up Visits; and Appendix 1150

F: Diabetes Management Guidelines Using CGM Dispense diabetes supplies – pods 1151 (Group 1b only), strips and additional sensors to deploy at home until they return for their 1152 Week 38 visit (clinician) 1153

• Download CGM, BGM and pump data, per usual practice for diabetes management 1154 (clinician) 1155

1156

20.3 Visit 3 – Week 38 (Month 9) –Follow-Up (Window ± 7 days) 1157

Study staff will- 1158

• Upload BGM, CGM, and OmniPod PDM data to SweetSpot database 1159

• Download OmniPod data onto a centrally-located computer 1160 • Troubleshoot any CGM, BGM or pump issue 1161 • Assess any AEs or device issues 1162



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• Obtain CGM, BGM and pump data, per usual practice Provide additional education to 1169 either group if required per clinical assessment (clinician) 1170


• Provide and review Appendix D Clinical Guidelines for Follow-up Visits; and Appendix 1172 F: Diabetes Management Guidelines Using CGM (clinician) 1173


• Complete POC A1C (via POC or local lab); these results may be shared with the subject 1176 • Dispense diabetes supplies – pods (Group 1b only), strips and additional sensors to 1177

deploy at home until they return for their Week 52 visit 1178 • Download CGM, BGM and pump data, per usual practice for diabetes management 1179

(clinician) 1180 1181

20.4 Visit 4 – Week 52 (Month 12) – Final Assessment (Window ± 7 days) 1182

This visit signifies Phase 2 completion. 1183 1184 Study staff will - 1185

• Upload meter, and CGM, to SweetSpot database 1186

• Download OmniPod data onto a centrally-located computer 1187 • Assess any AEs or device issues 1188 • Obtain concomitant medications including dose and frequency (not vitamins/minerals), 1189

and if subject takes as needed (p.r.n.). Assess for addition or modification of any GLP-1 1190 agonists, pramlintide, and SGLT-2 inhibitors. 1191

• Assess compliance (SC), and make final evaluation of subjects’ diabetes management 1192 decisions (clinician). 1193

• Draw final blood for A1C assessment. Note: Results of central lab A1C will not be 1194 shared with the subject. 1195

• Complete POC A1C (via POC or local lab); these results may be shared with the subject 1196 • Administer PRO surveys 1197 • Collect OmniPod PDM, collect CGM if not clinically warranted/desired. . Note: Subject 1198

may be prescribed the CGM System and pump per Investigator’s assessment, if requested 1199 by the subject. 1200

• Download CGM, BGM and pump data, per usual practice for diabetes management 1201 (clinician) 1202

• Complete Care Management Form to assess clinic visits unrelated to study visits (See 1203 Section 10) 1204

1205



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PROs to be administered at Month 12 include: 1206 1. WHO-5 1207 2. EQ-5D-5L 1208 3. Health Service Utilization Form 1209 4. Diabetes Distress Scale (DDS) 1210 5. Hypoglycemic Fear Survey – Worry subscale (HFS-W) 1211 6. Hypoglycemia Confidence 1212 7. Bolus Insulin Questionnaire 1213 8. Clarke Hypoglycemia Scale 1214 9. CGM Satisfaction Scale 1215 10. CGM Attitudes 1216 20.5 Device Replacements 1217 Dexcom G4 PLATINUM components that malfunction or are lost during the course of the study 1218 may be replaced at any time at the discretion of the Investigator and Sponsor. 1219

1220 21. RISKS 1221

21.1 Sensor Insertion/Use/Removal 1222

Insertion of the sensors into the skin may result in pain, erythema, and/or edema at the insertion 1223 sites. Infection, excessive bleeding, or hematoma are also possible side effects of device use; 1224 however, the expected frequency of these events is low based on data obtained from similar 1225 devices and adverse event information from more than five previous Dexcom studies where the 1226 device was inserted from 12 hours to 15 days. 1227

After removal of the sensors, subjects may experience irritation due to the medical adhesive used 1228 to apply the sensor pod and any bandages that may be placed over the device. This reaction is 1229 self-limiting and should resolve within hours and not more than a week post-removal. Subjects 1230 may experience some itching in the area during the healing process, which is normal. 1231

Rarely, subjects may develop an allergic reaction to one or more of the components of the sensor 1232 and/or transmitter. This is similar to allergies that can occur due to contact with medical tape. 1233

Sensors may fracture in situ on rare occasions. In these rare instances when this has occurred in 1234 the past, consulting physicians and surgeons have recommended not to remove the wire fragment 1235 from beneath the skin as long as there are no symptoms of infection or inflammation. In the event 1236 that signs and/or symptoms of infection or inflammation arise such as redness, swelling, and pain 1237 subjects should consult with the investigator or prescribing physician for the best course of 1238 action. If there is no portion of the broken sensor wire fragment visible above the skin, attempts 1239 to remove it without medical guidance are not advised. 1240

A thermal burn due to the electrical components of the device is not a risk as the circuit designed 1241 and verified to limit the intra-electrode current to a maximum of 20 µAmps. Given that any level 1242 less than 1 µAmp is considered safe, per ISO 14708-1 and EN45502-1, the device’s maximum 1243 current output is 2 percent of the 1 µAmp limit. 1244

21.2 Hypoglycemia 1245

Treatment of diabetes is associated with increased risk of severe hypoglycemia. Hypoglycemia 1246 may be associated with reduced cognitive function, diaphoresis, tachycardia, coma, and seizure. 1247 These complications are an inherent risk of having diabetes. Subjects will be required to use 1248 blood glucose meter (not CGM) values to guide all diabetes-related therapeutic decisions (e.g. 1249 insulin dosing modifications) to minimize the risk of treatment errors. 1250



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Severe hypoglycemia will be captured as a serious adverse event if the event required assistance 1251 of another person due to altered consciousness to actively administer carbohydrate, glucagon, or 1252 other resuscitative actions. This means that the participant was impaired cognitively to the point 1253 that the subject was unable to treat his or herself, was unable to verbalize his or her needs, was 1254 incoherent, disoriented, and/or combative, or experienced seizure or coma. If these criteria are 1255 not met but emergency evaluation or treatment was obtained from a health care provider the event 1256 will be captured as an Adverse Event and not a Serious Adverse Event unless one of the criteria 1257 for SAE is met. 1258

21.3 Diabetic Ketoacidosis (DKA) 1259 Subjects may also be randomized to use a currently-marketed insulin pump during Phase 2. Due 1260 to the use of insulin, there are risks of hypoglycemia and associated symptoms related to the 1261 infusion of insulin. 1262 Diabetic ketoacidosis is a serious complication of diabetes that occurs when the liver produces 1263 high levels of ketones, which are an acid. Diabetic ketoacidosis develops when there is insulin 1264 deficiency; in response the body switches to burning fatty acids and producing acidic ketone 1265 bodies that cause most of the symptoms and complications. Vomiting, dehydration, tachypnea, 1266 confusion and occasionally coma are symptoms. 1267

DKA will be captured as a serious adverse event if confirmed and treated. Hyperglycemia that 1268 does not meet criteria for definite or probable DKA is reported as an Adverse Event if emergency 1269 evaluation or treatment was obtained from a health care provider; these events are considered 1270 Adverse Events and not Serious Adverse Events unless one of the criteria for SAE is met. 1271

Subjects may also be randomized to use a currently-marketed insulin pump during Phase 2. Due 1272 to the use of insulin, there are risks of hyperglycemia and associated symptoms related to 1273 potential interruptions of insulin delivery. 1274

22. Non-Significant Risk Rationale 1275 The Dexcom Continuous Glucose Monitoring System described in this protocol is considered by 1276 the Sponsor to be of non-significant risk as it does not meet the definition of a significant risk 1277 device per 21 CFR 812.3(m), in that: 1278

• It is not an implant nor presents a potential for serious risk to the health, safety or welfare 1279 of a subject; 1280

• CGM devices are not purported or represented to be for use in supporting or sustaining 1281 human life and thus do not present a potential for serious risk to the health, safety, or 1282 welfare of a subject; or 1283

• Use of CGM devices does not present a potential for serious risk to the health, safety or 1284 welfare of a subject. 1285

The following information supports a non-significant risk determination for the device that will 1286 be used in this protocol: 1287

• FDA-approved Dexcom CGM Systems have been considered a non-significant risk 1288 device; 1289

• The CGM device and insulin pump used in this study are being used on label in intended 1290 population; 1291

• The Medtronic-Minimed Guardian RT® CGMS, a FDA approved device using similar 1292 technology, has been considered a non-significant risk device; 1293

• The FreeStyle Navigator® CGMS, a FDA-approved device using similar technology, has 1294 been considered a non-significant risk device; 1295



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• The insertion needle thickness used in the device is not significantly thicker than the 1296 needles used in syringes for insulin injection and the needle insertion depth is less than 1297 0.5 inches; 1298

• None of the expected device-related adverse events as defined in the protocol and 1299 associated documents (e.g. Instructions for Use) would be life-threatening or would 1300 result in any permanent impairment of a body function or permanent damage to a body 1301 structure; 1302

• There are no expected electrical safety risks as the device has passed the electrical safety 1303 tests as per EN45502-1 and EN60601; 1304

• If the subject feels any discomfort during the course of the study, he/she will be able to 1305 remove the device immediately (the device is not permanent); 1306

• The device is being used to complement, not replace, self-monitoring of blood glucose 1307 meter information and readings are not intended to be used alone to make diabetes self-1308 management decisions. As with the currently approved device and per intended use of 1309 similar technologies, subjects in the study will be instructed not to use the device for 1310 diabetes therapy or management; 1311

• Subjects will be instructed to monitor their blood glucose levels as per their usual 1312 practice. 1313

• A recently completed Dexcom-sponsored study, conducted for regulatory purposes 1314 (FDA), concluded that the safety profile of the System is comparable to the initial 1315 Dexcom G4 Platinum CGM System for adults. 1316

1317 23. ADVERSE EVENTS 1318

At all study visits, study staff will determine if any device or study-related adverse events (AEs) have 1319 occurred. Disease related events that are chronic in nature and occur as part of the progression of the 1320 diabetes disease state (i.e. diagnoses of retinopathy, nephropathy, neuropathy) will not be captured as 1321 adverse events in this study. 1322

Confirmed DKA and severe hypoglycemic events will be captured as adverse events, as well as 1323 captured on separate event CRFs - a DKA Event Form, or a Severe Hypoglycemic Event Form, 1324 respectively. These event-specific forms will be utilized to capture additional details surrounding each 1325 event, if known. All confirmed DKA and severe hypoglycemic events, per protocol definition (see 1326 Section 1. Abbreviations and Definitions), will be considered Serious Adverse Events (SAEs). 1327 Therefore, a SAE form will always be completed for any confirmed DKAs and severe hypoglycemic 1328 events which occur during the course of this study. 1329

Hypoglycemic events are also considered reportable adverse events if the criteria for severe 1330 hypoglycemia are not met but emergency evaluation or treatment was obtained from a health care 1331 provider; these events are considered Adverse Events and not Serious Adverse Events unless one of 1332 the criteria for SAE is met. 1333

Hyperglycemia that does not meet criteria for definite or probable DKA is reported as an Adverse 1334 Event if emergency evaluation or treatment was obtained from a health care provider; these events are 1335 considered Adverse Events and not Serious Adverse Events unless one of the criteria for SAE is met. 1336

All study or device-related AEs will be monitored until adequately resolved or stable. 1337

For purpose of this protocol, AEs will be captured on the AE CRF form if causality is related to the 1338 study, or device. AEs are categorized as follows: 1339

23.1 Adverse Event (AE) 1340



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Any clinically significant undesirable experience (sign, symptom, illness, or other medical event) 1341 meeting the causality definition above that appears or worsens in a subject during a clinical study. 1342 A clinically significant event is any event (sign, symptom, lab/imaging abnormality, or diagnosis) 1343 that is noteworthy enough to merit documentation in standard medical records (e.g. history and 1344 physical, progress notes, clinic visit notes, etc.). Other non-clinically significant events (e.g. 1345 colds, minor headaches, etc.) may be documented on source documents only. 1346 23.2 Serious Adverse Event (SAE) 1347

A serious adverse event (SAE) is defined as any AE that is fatal, life-threatening, results in 1348 persistent or significant disability or incapacity, requires medical or surgical intervention to 1349 prevent permanent impairment or damage, or results in initial (in-patient) hospitalization or 1350 prolongation of hospitalization. Life-threatening is defined as the substantial risk of dying at the 1351 time of the adverse event or suspicion that continued use of the device would result in a subject’s 1352 death. 1353

Any SAE, including death, due to any cause (related or unrelated to the device), that may occur 1354 during a clinical study must be reported immediately (within 2 working days of learning of the 1355 event). Details of the SAE submitted via eCRF will result in an automatic email generated and 1356 forwarded to the Sponsor. The Sponsor contact for SAE review: 1357

David Price, MD 1358 Vice President, Medical Affairs 1359 Dexcom, Inc. 1360 6340 Sequence Drive 1361 San Diego, CA 92121 1362 Telephone: (858) 875-9525 1363 Fax: (858) 332-0200 1364 Email: [email protected] 1365

Dexcom Clinical Affairs personnel will document SAE details and assessment by Clinical Affairs 1366 management in a timely manner. 1367 23.3 Severity of Adverse Events 1368 The following definitions may be used to rate severity of AEs: 1369

23.3.1 Mild 1370 Awareness of signs or symptoms, but easily tolerated; are of minor irritant type; 1371 causing no loss of time from normal activities; symptoms would not require 1372 medication or a medical evaluation; signs and symptoms are transient. 1373 Example: hypoglycemia with at home treatment by subject or friend/family member. 1374

23.3.2 Moderate 1375 Discomfort severe enough to cause interference with usual activities, requiring 1376 treatment but not extended hospitalization or intensive care for the subject. 1377 Example: hypoglycemia with seizure involvement, requiring treatment with 1378 glucagon and/or an emergency room visit. 1379

23.3.3 Severe 1380 Incapacitating, causing inability to do work or usual activities; signs and symptoms 1381 may be of systemic nature or require medical evaluation and/or treatment, requiring 1382 additional hospitalization or intensive care (prolonged hospitalization). 1383 Example: hypoglycemia with seizure involvement, requiring hospitalization. 1384

23.4 Relationship of Adverse Event to the Study, Disease, or Device 1385



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The investigator will categorize the relationship of the event to the study, disease, or study device 1386 as follows: 1387

23.4.1 Not Related 1388 AE is due to an underlying disease state or concomitant medication or therapy not 1389 related to the device, disease or study. 1390

23.4.2 Probably Not Related 1391 AE has minimum or no temporal relationship to the device, disease or study 1392 participation and/or a more likely alternative etiology exists. 1393

23.4.3 Possibly Related 1394 AE has a strong temporal relationship to the device, disease or study procedures and 1395 alternative etiology is equally or less likely compared to the potential relationship to 1396 the device, disease or study. 1397

23.4.4 Probably Related 1398 AE has a strong temporal relationship to the device, disease or study and another 1399 etiology is unlikely. 1400

23.5 Anticipated Adverse Device Effects 1401 The following events have been identified as possible device-related adverse events of sensor 1402 insertion and wear: 1403

• Excessive pain or discomfort from system deployment (8 or greater on a 10-point 1404 Likert scale) 1405

• Excessive bleeding 1406 • Hematoma (slight ecchymosis is a known consequence of needle skin puncture and 1407

will not be captured as an AE) 1408 • Excessive edema from sensor and/or adhesive tape that is significant and non-1409

resolving within 48 hours of sensor pod removal 1410 • Excessive erythema from sensor and/or adhesive tape that is significant and non-1411

resolving within 48 hours of sensor pod removal 1412 • Local infection 1413 • Sensor or introducer needle fracture during insertion/wear/removal 1414

Degrees of edema, erythema, or infection that may occur at the sensor insertion or adhesive tape 1415 site will be assessed by the subject and documented for review by study staff. An AE will be 1416 recorded as severe in intensity if skin appearance indicates significant edema or erythema (per 1417 definition above) and/or if infection, defined as the presence of pus, at the sensor insertion or 1418 adhesive tape site occurs. 1419

The following events have been identified as possible device-related AEs of insulin pump use, 1420 infusion of insulin and potential interruptions of insulin delivery: 1421

• Localized infection 1422 • Skin irritation/erythema /rash (slight irritation/ erythema will not be captured as an 1423

AE) 1424 • Hematoma (Slight ecchymosis is a known consequence of needle skin puncture and 1425

will not be captured as an AE) 1426 • Discomfort/pain deployment (8 or greater on a 10-point Likert scale) 1427 • Bleeding, excessive 1428 • Diabetic Ketoacidosis (DKA) 1429 • Severe hypoglycemia 1430



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Information regarding device-related AEs that occur during the study will be entered into 1431 appropriate CRFs. Such information will include, at a minimum: 1432

• Date of event 1433 • Severity 1434 • Outcome 1435 • Resolution of event 1436 • Causality to study devices and procedures 1437

1438 23.6 Unanticipated Adverse Device Effects 1439

An unanticipated adverse device effect (UADE) is not expected to occur. An UADE is defined as 1440 any serious adverse effect on health or safety or any life-threatening problem or death caused by – 1441 or associated with – the device, if that effect, problem, or death was not previously identified in 1442 nature, severity, or degree of incidence in the investigational plan (including documents such as 1443 the protocol, the informed consent document, other study-related documents), or any other 1444 unanticipated serious problem associated with the device that relates to the rights, safety, or 1445 welfare of subjects. 1446

During the review of a reported SAE, if Clinical Affairs management with the Investigator input 1447 determines the severity or extent of the event was not cited in this protocol or associated protocol 1448 materials, and the event was classified as, ‘possibly related’ to the device, the event will be 1449 documented as an UADE. If the event is classified as an UADE, the Investigator must notify the 1450 IRB and Dexcom will notify the FDA within ten (10) working days of the original SAE 1451 notification. 1452

If determined that the UADE presents an unreasonable risk to subjects, Dexcom will terminate all 1453 investigations or parts of investigations presenting that risk as soon as possible, but not later than 1454 5 working days after such determination is made and not later than 15 working days after 1455 Dexcom first receives notice of the original SAE. Dexcom will not resume a terminated study 1456 without IRB and FDA approval. 1457

23.7 MDR Reportable Events/MDR Reporting 1458

For purposes of this protocol, the CGM devices are either currently marketed or similar to devices 1459 currently marketed in the US. Therefore, the sponsor will follow the required reporting 1460 regulations if a MDR reportable event were to occur according to Sponsor SOP and FDA 1461 guidelines. (SOP-300024 US MDR Reporting; Code of Federal Regulations Title 21 Part 803; 1462 Medical Device Reporting; Draft Guidance for Industry and Food and Drug Administration Staff 1463 Medical Device Reporting for Manufacturers: July 9, 2013, 19-21). 1464

MDR reportable events are events that manufacturers become aware of that reasonably suggest 1465 one of their marketed devices may have caused or contributed to a death or serious injury, or has 1466 malfunctioned and the malfunction of the device would likely cause or contribute to a death or 1467 serious injury if the malfunction were to recur (21 CFR 803.3). 1468

1469 24. ETHICAL CONSIDERATIONS 1470

24.1 Informed Consent 1471

Informed consent will be obtained in accordance with the Code of Federal Regulations (CFR) 1472 Title 21, Part 50. Subjects will be asked to sign state specific forms, such as Subject’s Bill of 1473 Rights, or equivalent, (if applicable) and HIPAA authorization form, if not included in the site’s 1474 consent template. Subjects will be provided the opportunity to review these documents prior to 1475



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coming to the clinical site. The Investigator or designee will explain the purpose and duration of 1476 the study, the study procedures and subject requirements, and the potential risks and benefits. 1477 Study staff will attempt to answer all questions the subject may have. Consenting process will be 1478 documented in the subject’s source documents. A copy of the consent will be provided to the 1479 subject. 1480

The study will be conducted in accordance with the Declaration of Helsinki (1964) including all 1481 amendments up to and including the 1983 amendment per FDA’s Guidance for Industry: 1482 Acceptance of Foreign Clinical Studies written in March, 2001. 1483

Subjects will receive a stipend for their participation in the study and a CGM system at the end of 1484 Phase 1 if clinically warranted, subject was compliant with study protocol and requested by 1485 subject. 1486

24.2 Institutional Review Board 1487

The protocol, informed consent document, and subject training materials for this study will be 1488 reviewed and approved by a duly constituted Institutional Review Board (IRB) before subjects 1489 are screened. 1490

The Investigator will ensure that all aspects of the IRB review are conducted in accordance with 1491 current institutional, local, and national regulations. An IRB approval letter will be provided to 1492 the Sponsor prior to study initiation. Protocol amendments must adhere to the same requirements 1493 as the original protocol. The Investigator will submit all IRB-required reports and updates, 1494 including any continuing review and/or final closeout reports. The Investigator will inform the 1495 IRB of any reportable AEs as per the IRB reporting rules. 1496

1497 25. DATA COLLECTION 1498

This study will use electronic data capture (EDC). The Investigator or designee is responsible for 1499 completing the CRFs. Good Documentation Practices principles will be required. 1500 1501

26. DEVICE ACCOUNTABILITY 1502 The Investigator(s) will store devices in a secure location at the clinical site. An accurate and 1503 current accounting of the dispensing for the Dexcom and other device components will be 1504 maintained by a member of the study site staff on the “Device Accountability Log”. All used and 1505 unused devices must be returned to the Dexcom Clinical Affairs department (or accounted for if 1506 lost) upon completion of enrollment or upon request of the Sponsor. 1507 1508

27. MONITORING 1509 Monitoring will be conducted by trained and experienced Clinical Research Associates (CRAs) in 1510 accordance with Dexcom’s standard operating procedures. CRAs will evaluate study conduct and 1511 documentation on an ongoing basis. Assessment of site performance will be reviewed with 1512 Clinical Affairs management to determine the level of monitoring required. All informed consent 1513 documents will be source verified along with key data fields related to safety and performance 1514 indicators. All CRF data will be collected via the EDC system designated for the study for 1515 analysis. A risk-based monitoring plan will be developed consistent with the Food and Drug 1516 Administration (FDA) Guidance for Industry: Oversight of Clinical Investigations—A Risk-1517 based Approach to Monitoring (August 2013). This approach focuses on critical study parameters 1518 and relies on a combination of monitoring activities to oversee a study. Monitoring is separated 1519 into Central (remote) monitoring and On-Site monitoring (site visits). Considerable focus is 1520 placed on real-time centralized monitoring methods. 1521



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1522 28. STUDY TERMINATION 1523

Subject participation in the clinical study will be terminated following the last visit or when all 1524 AEs have been resolved or considered ongoing but stable. Prior to this time, subjects may 1525 voluntarily withdraw at any point in the study or the Investigator and/or Sponsor may determine 1526 that it is in the best interest of the subject to be terminated from the study. Reasons for withdrawal 1527 of subject from the study include, but are not limited, to the following: 1528

a) In the opinion of the Investigator, the subject’s health or safety would be compromised by 1529 continuing in the study 1530

b) In the opinion of the Investigator, it is in the subject’s best interest to discontinue 1531 participation in the study 1532

c) During the study, (female) subject becomes pregnant. 1533

However, discontinuation of the study intervention (CGM) does not equate with discontinuation 1534 from the study and every effort will be made to retain subjects in the study for the primary 1535 outcome assessment, even if CGM is discontinued. 1536

The clinical study in its entirety will be considered complete upon receipt of reports from study 1537 monitoring activities, completion of site closeout visits, and issuance of a clinical study report. 1538 The clinical study report will include all safety and efficacy data. 1539

Any early termination of the study will be reported to the IRB. 1540

1541 29. INVESTIGATOR RESPONSIBILITIES 1542

The Investigator’s signature(s) on this protocol confirms that the Investigator is familiar with all 1543 sections of the protocol and agrees to conduct this study in accordance with the provisions of the 1544 protocol and applicable regulations. The Investigator(s) must sign this protocol prior to 1545 commencement of any study-related activities (e.g. screening). 1546

The Investigator(s) are responsible for protecting the rights, safety, and welfare of subjects under 1547 their care. The Investigator(s) are also responsible for obtaining IRB approval prior to study start 1548 and the written informed consent of each subject before participation in this study. The informed 1549 consent must comply with FDA regulations (21 CFR 50) and be approved by the IRB. 1550

The Investigator(s) are responsible for ensuring completion of the CRFs per the study timelines 1551 discussed in the site initiation visit and subsequent monitoring visits. 1552

Dexcom and/or the IRB retain the right to disqualify an Investigational Site and remove all study 1553 materials at any time. Specific instances, which may precipitate clinical site disqualification, 1554 include but are not limited to: 1555

a) Unsatisfactory subject enrollment with regard to quality and quantity. 1556 b) Persistent non-compliance related to protocol procedures by the Investigator/Investigational 1557

Center. 1558 c) Inaccurate, incomplete, and/or untimely data recording on a recurrent basis. 1559 d) The incidence and/or severity of adverse experiences in this or other studies indicating 1560

inadequate oversight 1561 e) Unsatisfactory accountability of study devices. 1562 1563

30. SPONSOR RESPONSIBILITIES 1564



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The Sponsor is responsible for selecting qualified Investigators and providing them with the 1565 information needed to properly conduct the study. The Sponsor will ensure proper monitoring of 1566 the study and that IRB approval has been obtained prior to the Investigator commencing study-1567 related activities. The Sponsor is also responsible for ensuring that the reviewing IRB(s) and 1568 FDA, if applicable, are promptly informed of significant new information. 1569 1570

31. CONFIDENTIALITY OF RECORDS 1571

All records and documents pertaining to this study will be retained for a period of no less than 2 1572 years by Dexcom, Inc. and will be available for inspection by FDA or other regulatory agencies at 1573 any time. All records containing personal identification or information that identifies a study 1574 subject will be handled confidentially within the law. These records will be coded and kept in 1575 locked files. No individual identities will be used in any reports or publications resulting from this 1576 study. 1577

Neither the site nor subjects will disclose, share, or use any information gathered during the 1578 course of the clinical study. All information about the study, including the study product and 1579 study procedures, is confidential. Any publication about the products or the study by print or 1580 electronic format (e.g. blogging) is strictly prohibited. 1581

1582



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32. REFERENCES 1583

1. Gale E. Declassifying diabetes. Diabetologia. 2006;49:1989-1995. 1584

2. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates 1585 and general information on diabetes and prediabetes in the United States. 2011. Available at: 1586 http://www.cdc.gov/diabetes/pubs/factsheet11.htm. 1587

3. Zimmet P, et al. Preventing type 2 diabetes and the dysmetabolic syndrome in the real world: 1588 a realistic view. Diábêt Med. 2003;20:693-702. 1589

4. The Diabetes Control and Complications Trial Research Group. The effect of intensive 1590 treatment of diabetes on the development and progression of long-term complications of 1591 insulin-dependent diabetes mellitus. N Eng J Med. 1993;329:977-986. 1592

5. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents progression of 1593 diabetic microvascular complications in Japanese patients with non-insulin-dependent 1594 diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1595 1995;28:103-117. 1596

6. The Diabetes Control and Complications Research Group. –The DCCT Research Group: 1597 Effect of intensive diabetes treatment on the development and progression of long-term 1598 complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and 1599 Complications Trial. J Ped 1994; 125:177-188. 1600

7. Bolinder J, Ungerstedt U, Hagstrom-Toft E, Arner P. Self-monitoring of blood glucose in 1601 Type 1 diabetic patients: comparison with continuous micro dialysis measurements of 1602 glucose in subcutaneous adipose tissue during ordinary life conditions. Diabetes Care. 1997; 1603 20:64-70. 1604

8. Bode, Bruce W., et al. Glycemic Characteristics in Continuously Monitored Patients with 1605 Type 1 and Type 2 Diabetes. Diabetes Care. 2005: 28: 2361-2366. 1606

9. Pickup J. Are insulin pumps underutilized in type 1 diabetes? Yes. Diabetes Care. 1607 2006;29:1449-1452. 1608

10. Raccah, D., et al. Incremental Value of Continuous Glucose Monitoring When Starting Pump 1609 Therapy in Patients with Poorly Controlled Type 1 Diabetes. Diabetes Care. 2009, 32:12: 1610 2245-2250. 1611

11. The Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. 1612 Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Eng J Med. 1613 2008;359:1464-1476. 1614

12. Battelino T, et al. Effect of continuous glucose monitoring on hypoglycemia in type 1 1615 diabetes. Diabetes Care. 2011;34:795-800. 1616

13. Riveline J, et al. Assessment of patient-led or physician-led continuous glucose monitoring in 1617 patients with poorly controlled type 1 diabetes using basal-bolus insulin regimens. Diabetes 1618 Care. 2012;35:965-971. 1619

14. Garg S, et al. Use of continuous glucose monitoring in subjects with type 1 diabetes on 1620 multiple daily injections versus continuous subcutaneous insulin infusion therapy. Diabetes 1621 Care. 2011;34:574-579. 1622

15. Rodbard D, et al. Responses to continuous glucose monitoring in subjects with type 1 1623 diabetes using continuous subcutaneous insulin infusion or multiple daily injections. Diabetes 1624 Technol Ther. 2009;11:757-765. 1625



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16. Deiss D, et al. Improved glycemic control in poorly controlled patients with type 1 diabetes 1626 using real-time continuous glucose monitoring. Diabetes Care. 2006;29:2730-2732. 1627

17. Langendam M, et al. Continuous glucose monitoring systems for type 1 diabetes mellitus 1628 (review). Cochrane Database of Systematic Reviews. 2012;1. 1629

a. doi: 10.1002/14651858.CD008101.pub2. 1630

18. Bech P, Olsen LR, Kjoller M, Rasmussen NK. Measuring well-being rather than the absence 1631 of distress symptoms: a comparison of the SF-36 Mental Health subscale and the WHO-Five 1632 Well-Being Scale. Int J Methods Psychiatr Res 2003; 12: 8591. 1633

19. Szende et al. Self-reported population health: an international perspective based on EQ-5D. 1634 2014. XV. 196p. 1635

20. Polonsky WH, Fisher L, Earles J, Dudl RJ, Lees J, Mullan J, Jackson RA (2005).Assessing 1636 psychosocial distress in diabetes: Development of the Diabetes Distress Scale. Diabetes Care, 1637 28, 626-631. 1638

21. Cox DJ, Irvine A, Gonder-Frederick L, Nowacek G, Butterfield J: Fear of hypoglycemia: 1639 quantification, validation, and utilization. Diabetes Care 10:617-621, 1987. 1640

22. Polonsky WH, Hypoglycemia Confidence Scale, Behavioral Diabetes Institute. 1641

23. Polonsky WH, Bolus Insulin Questionnaire, Behavioral Diabetes Institute. 1642

24. Huizinga, MM, et al, “Development and Validation of the Diabetes Numeracy Test (DNT)” 1643 Diabetes Numeracy Test; copyright 2007 by Vanderbilt University. 1644

25. Clarke, WL, Cox DJ, Gonder-Frederick, LA, Julian D, Schlundt, D, Polonsky WH; Reduced 1645 Awareness of Hypoglycemia in Adults with IDDM. Diabetes Care 18:4 517-522, 1995. 1646

26. Polonsky, WH; CGM Expectations Questionnaire, Behavioral Diabetes Institute. 1647

27. Polonsky WH, Hessler D (2013). What are the quality of life-related benefits and losses 1648 associated with real-time continuous glucose monitoring? A survey of current users. Diabetes 1649 Technol Ther, 15, 295-301. 1650

28. Tansy M, et al, Satisfaction with continuous glucose monitoring in adults and youths with 1651 Type 1 diabetes. Diabet Med 2011 Sep: 28(9): 1118-22 doi: 10. 1111/j. 1464-5491. 2011. 1652 03368.x. 1653

29. National Glycohaemoglobin Standardization Program (NGSP). Harmonizing hemoglobin 1654 A1C testing. Division of Laboratory Sciences and the Centers for Disease Control and 1655 Prevention. 2010. 22 Jun 2011. http://www.ngsp.org/index.asp. 1656

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33. APPENDICES 1658

Appendix A: Informed Consent 1659

Appendix B: Study Flowchart 1660

Appendix C: Clinician Guidelines: General Diabetes Education 1661

Appendix D: Clinician Guidelines for Follow-Up Visits 1662

Appendix E: Visit Flowchart 1663

Appendix F: Diabetes Management Guidelines Using CGM 1664

Appendix G: Patient Reported Outcome (PRO) Measures 1665

Appendix H: Test and Exam Table 1666

Appendix I: Sample CGM Information Guide 1667

Appendix J: OmniPod Guidance Documents 1668

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1670 Appendix A: Informed Consent 671

1672

ICF_T1DM_20May15.docx 1673

ICF_T2DM_20May15.doc 1674

1675 1676 1677 1678 1679 1680 1681 1682 1683 1684 1685 1686 1687 1688 1689 1690 1691 1692 1693 1694


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1695 Appendix B: Overall Study Flowchart 696

697

Appendix B_Overall Study Flowchart_v3. 1698 1699 1700 1701 1702

1703 1704 1705 1706 1707 1708 1709 1710


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1711 Appendix C: Clinician Guidelines: General Diabetes Education 1712

1713 1714

Appendix C_Clinician Guidelin 1715 1716


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1717 Appendix D: Clinician Guidelines for Follow-Up Visits 718

719

Appendix D_Dexcom PTL90114720 1721 1722

1723


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1724 Appendix E: Visit Flowchart 1725

1726

Appendix E_Visit Flowchart_rev3.docx 1727 1728 1729

1730


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1731 Appendix F: Diabetes Management Guidelines Using CGM 1732

1733

Diabetes Management Guide 1734 1735 1736 1737


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1738 Appendix G: Patient Reported Outcome (PRO) Measures 1739

1740

Appendix G_BolusInsulinQues

Appendix G_Care Management Time F

Appendix G_CGM Attitudes_v3.0.docx

Appendix G_CGM Expectations_v3.0.do

Appendix G_CGM Satisfaction_v3.0.do

Appendix G_Clarke Hypo_v3.0.docx1741

Appendix G_DDS_v3.0.docx

Appendix G_DNT5_v3.0.docx

Appendix G_EQ_5D_5L_v3.pdf

Appendix G_Health Service Form_v3.doc

Appendix G_HFS-W_v3.0.docx

Appendix G_Hypo Confidence_v3.0.doc1742

Appendix G_WHO-5_v3.0.docx 1743 1744


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-1745 1746

Appendix H: Test and Exam Table 1747

1748

Appendix H_Test&Exam Table_ 1749 1750

1751


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1752 Appendix I: Sample CGM Information Guide 1753

1754 This is a sample of CGM information and training that may be used by clinicians at the study site: 1755 1756

Appendix I_Joslin's Guide to Real Time Co

1757

1758

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1760 Appendix J: OmniPod Guidance Documents 1761

1762

1763

Appendix J_OmniPod Training Checklist.pdf

Ten Tips for Better Podding.pdf 1764
