Conditions: Type1 Diabetes Mellitus
Keywords: bionic pancreas closed loop insulin continuous glucose monitor
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 36
Healthy volunteers: no

Brief summary:
The iLet is a closed-loop delivery system that can be used in insulin-only, bihormonal, or glucagon-only configurations. Previous studies have utilized a phone-based bionic pancreas. The iLet consists of a touchscreen-enabled, menu-driven user interface and an onboard microprocessor that provides a comprehensive and standalone platform, which allows the iLet to operate independently of smartphones or other devices and without the need for internet support during routine operation.

This is a multicenter study of adult participants with type 1 diabetes, who will manage their diabetes with the iLet bionic pancreas compared to usual care.

Detailed description:
This study will serve as a transitional study, bridging to larger and longer outpatient pivotal studies using the insulin-only configuration of the bionic pancreas.

The Adult RCT Period will consist of a multi-center, three-period, random-order, cross-over, feasibility study in 36 adult participants ≥ 18 years old with T1D. Insulin therapy for each participant will be administered (i) using the iLet in the insulin-only configuration and the insulin analog that they use for their usual care (either Humalog or Novolog) for 7 days, (ii) in another period using the iLet in the insulin-only configuration with faster insulin aspart (Fiasp) for 7 days (iii) in a third period using the participant's own usual care (UC) for 7 days. All three experimental periods will be followed by round-the-clock, remote, telemetric monitoring for hyperglycemia (\> 300 mg/dl for ≥ 90 minutes) and hypoglycemia (\< 50 mg/dl for ≥ 15 minutes). Half the subjects enrolled were expected to manage their diabetes with MDI and the other half with insulin pumps in their UC. An implantable Eversense CGM will also be placed in half the study participants for a CGM comparison.

Arms:
arm 1: Participants randomized to usual care first started the usual care arm (UC) managing their diabetes with either multiple daily injections or continuous subcutaneous insulin infusion (pump therapy) for 7 days. All subjects wore a Dexcom G5 continuous glucose monitor (CGM) and half of all subjects also were a senseonics CGM. The usual care period was followed by the other 2 arms according to each subject's randomization schedule arm 2: Participants randomized to the iLet with humalog/novolog first started the insulin-only iLet arm using the insulin analog that they use for their usual care (either Humalog or Novolog). All subjects wore a Dexcom G5 CGM and half of all subjects also wore a Senseonics Eversense CGM. The iLet period was followed by the other 2 arms according to each subject's randomization schedule arm 3: Participants randomized to the iLet with Fiasp first started the insulin-only iLet arm using faster insulin aspart (Fiasp) in PumpCart, where the pharmacokinetic (PK) parameter for tmax used by the insulin-dosing algorithm was set to the same value as is used for Humalog and Novolog (65 minutes). All subjects wore a Dexcom G5 CGM and half of all subjects also wore a Senseonics Eversense CGM. The iLet period was followed by the other 2 arms according to each subject's randomization schedule

Interventions: intervention 1: iLet Bionic Pancreas insulin-only configuration with Humalog or Novolog intervention 2: iLet Bionic Pancreas insulin-only configuration with Fiasp intervention 3: Usual care
Intervention descriptions: intervention 1: iLet Bionic Pancreas insulin-only configuration with Humalog or Novolog intervention 2: iLet Bionic Pancreas insulin-only configuration with Fiasp (faster insulin aspart) intervention 3: Usual care

Protocol document:
Prot_000.pdf: 
 
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The Insulin-Only Bionic Pancreas Bridging Study 
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Version 8.0 
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 June 26, 2018 
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Clinical Study Leadership 
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Steven Russell, M.D., Ph.D. (Director) 
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Courtney Balliro, BS, RN, CDE (Assistant Director) 
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Massachusetts General Hospital Diabetes Research Center 
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Boston, MA 
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Engineering and Technology Center 
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Edward Damiano, PhD (Project Principal Investigator) 
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Firas El-Khatib, PhD (Chief Technology Investigator) 
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Boston University, Biomedical Engineering Department 
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Boston, MA 
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National Coordinating Center 
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Roy W. Beck, M.D., Ph.D. 
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Katrina J. Ruedy, MSPH 
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Jaeb Center for Health Research 
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Tampa, FL 
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Table of Contents 
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CHAPTER 1:  INTRODUCTION ..................................................................................... 9 
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1.1. Background and Rationale ................................................................................. 9 
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1.2. Bihormonal BP System .................................................................................... 10 
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1.3. Insulin-Only BP System ................................................................................... 11 
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1.4. Glucagon-Only BP System .............................................................................. 11 
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1.5. Preliminary Studies .......................................................................................... 11 
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1.6. Fully Integrated Insulin-Only, Glucagon-Only, and Bihormonal BP .................. 15 
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1.7. Faster Insulin Aspart, an Ultra-rapid Insulin Analog Formulation ..................... 16 
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1.8. Senseonics Eversense Continuous Glucose Monitoring System ..................... 16 
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CHAPTER 2: SYNOPSIS OF INSULIN-ONLY BP BRIDGING STUDY ....................... 17 
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2.1. Study Objectives .............................................................................................. 17 
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2.2. Protocol Synopsis ............................................................................................ 17 
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2.3. Schedule of Study Visits and Procedures during the 7-day Adult Test-Run 
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Period and each of the 7-day Adult RCT Periods ...................................................... 25 
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2.4. Schedule of Study Visits and Procedures during the Senseonics Eversense 
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Test Run Period ......................................................................................................... 26 
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2.5. Schedule of Study Visits and Procedures during the 7-day Pediatric RCT 
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Periods ...................................................................................................................... 27 
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2.6. Schedule of Study Visits and Procedures during the 5-day Pediatric Transitional 
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Study Session ............................................................................................................ 28 
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2.7. General Considerations ................................................................................... 28 
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CHAPTER 3:  PARTICIPANT ENROLLMENT AND STUDY INITIATION ................... 29 
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3.1. Study Population .............................................................................................. 29 
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3.2. Eligibility and Exclusion Criteria ....................................................................... 29 
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3.3. Eligibility ........................................................................................................... 29 
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3.4. Exclusion .......................................................................................................... 30 
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3.5. Informed Consent ............................................................................................. 31 
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3.6. Eligibility Assessment and Baseline Data Collection ........................................ 31 
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3.7. Historical Information and Physical Exam ........................................................ 32 
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3.8. Screening Testing and Procedures .................................................................. 32 
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CHAPTER 4:  STARTUP VISITS.................................................................................. 33 
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4.1. Timing of Visits ................................................................................................. 33 
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4.2. Testing and Procedures ................................................................................... 33 
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4.3. Randomization ................................................................................................. 33 
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4.4. Senseonics Eversense CGM sensor insertion Visit (MGH Senseonics 
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Eversense Test Run and RCT Period only) ............................................................... 34 
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4.5. Initial Startup Visit ............................................................................................ 35 
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4.6. Subsequent Startup Visits ................................................................................ 36 
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CHAPTER 5:  PROTOCOLS FOR ADULT TEST-RUN PERIOD, PEDIATRIC 
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TRANSITIONAL STUDY SESSION, AND RCT PERIOD IN ADULTS AND PEDIATRIC 
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PARTICIPANTS ............................................................................................................ 38 
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5.1. Introduction ...................................................................................................... 38 
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5.2. Home Procedures and Study Policies for both UC and BP .............................. 38 
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5.3. Home Procedures specific to the UC Group .................................................... 40 
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5.4. Home Procedures specific to the Insulin-Only BP Group ................................. 41 
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5.5. Remote Monitoring ........................................................................................... 42 
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5.5.1. Remote Monitoring for Hypoglycemia ........................................................ 42 
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5.5.2. Remote Monitoring for Hyperglycemia....................................................... 43 
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5.6. Resources for Participants ............................................................................... 43 
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5.7. Daily At-Home Questionnaire ........................................................................... 43 
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5.8. Follow-Up Phone Contacts............................................................................... 43 
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5.9. Shutdown Visits ................................................................................................ 44 
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5.10. Final Shutdown Visit ......................................................................................... 44 
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5.10.1. 
Post-study Transition Period .................................................................. 44 
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5.11. Senseonics Eversense CGM sensor removal .................................................. 45 
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CHAPTER 6:  STUDY DRUGS AND DEVICES ........................................................... 46 
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6.1. Study Drugs ..................................................................................................... 46 
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6.2. Devices ............................................................................................................ 46 
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6.2.1. Infusion Sets .............................................................................................. 46 
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6.2.2. Continuous Glucose Monitors .................................................................... 46 
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6.2.3. Dexcom G5 CGM ...................................................................................... 46 
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6.2.4. Senseonics Eversense CGM ..................................................................... 46 
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6.2.5. BP Control Unit .......................................................................................... 47 
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CHAPTER 7:  QUESTIONNAIRES............................................................................... 49 
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7.1. Introduction ...................................................................................................... 49 
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7.2. Brief Description of Questionnaires .................................................................. 49 
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7.2.1. Diabetes Treatment Satisfaction Questionnaire - Status (DTSQs) ............ 49 
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7.2.2. Diabetes Treatment Satisfaction Questionnaire – Change (DTSQc) ......... 49 
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7.2.3. Diabetes Distress Scale (DDS) .................................................................. 49 
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7.2.4. Problem Areas in Diabetes Survey (PAID) ................................................ 49 
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7.2.5. Hypoglycemia Fear Survey (HFS) ............................................................. 49 
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7.2.6. Hypoglycemia Confidence Scale (HCS) .................................................... 50 
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7.2.7. INSPIRE Survey ........................................................................................ 50 
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7.2.8. Bionic Pancreas User Opinion Survey (BPUOS) ....................................... 50 
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CHAPTER 8: ADVERSE EVENTS, DEVICE ISSUES, AND STOPPING RULES ....... 51 
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8.1. Adverse Events ................................................................................................ 51 
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8.1.1. Definitions .................................................................................................. 51 
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8.1.2. Reportable Adverse Events ....................................................................... 52 
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8.1.3. Relationship of Adverse Event to Study Device and/or Study Drug ........... 53 
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8.1.4. Intensity of Adverse Event ......................................................................... 54 
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8.1.5. Coding of Adverse Events ......................................................................... 54 
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8.1.6. Outcome of Adverse Event ........................................................................ 54 
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8.2. Reportable Device Issues ................................................................................ 55 
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8.3. Pregnancy Reporting ....................................................................................... 55 
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8.4. Timing of Event Reporting ................................................................................ 55 
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8.5. Data and Safety Monitoring Board ................................................................... 56 
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8.6. Potential Risks and Side Effects ...................................................................... 56 
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8.6.1. Venipuncture Risks .................................................................................... 57 
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8.6.2. Fingerstick Risks ....................................................................................... 57 
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8.6.3. Subcutaneous Continuous Glucose Sensor and Subcutaneous Catheter 
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8.6.4. Risk of Hypoglycemia ................................................................................ 57 
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8.6.5. Risk of Hyperglycemia ............................................................................... 58 
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8.6.6. Psychosocial Questionnaires ..................................................................... 58 
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8.6.7. Other Risks ................................................................................................ 58 
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8.7. Study Stopping Criteria .................................................................................... 58 
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8.7.1. Criteria for Individual Participants .............................................................. 58 
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8.7.2. Criteria for Suspending/Stopping Overall Study ........................................ 59 
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CHAPTER 9:  MISCELLANEOUS CONSIDERATIONS .............................................. 60 
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9.1. Benefits ............................................................................................................ 60 
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9.2. Participant Compensation ................................................................................ 60 
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9.3. Participant Withdrawal ..................................................................................... 60 
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9.4. Confidentiality ................................................................................................... 60 
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CHAPTER 10:  STATISTICAL CONSIDERATIONS .................................................... 61 
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10.1. Sample sizes .................................................................................................... 61 
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10.2. Test-Run Period ............................................................................................... 61 
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10.2.1. 
Summary ................................................................................................ 61 
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10.2.2. 
Outcomes ............................................................................................... 61 
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10.3. Senseonics Eversense Test Run Period .......................................................... 62 
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10.3.1. 
Summary ................................................................................................ 62 
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10.3.2. 
Outcomes ............................................................................................... 62 
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10.4. Pediatric Transitional Study Session ................................................................ 63 
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Summary ................................................................................................ 63 
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10.4.2. 
Outcomes ............................................................................................... 63 
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10.5. Adult RCT Period ............................................................................................. 64 
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10.5.1. 
Summary ................................................................................................ 64 
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10.5.2. 
Outcomes ............................................................................................... 64 
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10.6. Pediatric RCT Period ....................................................................................... 67 
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10.6.1. 
Summary ................................................................................................ 67 
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10.6.2. 
Outcomes ............................................................................................... 67 
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10.7. Post-Study Transition to Usual Diabetes Management .................................... 67 
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10.7.1. 
Summary ................................................................................................ 67 
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10.7.2. 
Outcomes ............................................................................................... 67 
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CHAPTER 11: DATA COLLECTION AND MONITORING ........................................... 69 
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11.1. Case Report Forms and Device Data .............................................................. 69 
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11.2. Quality Assurance and Monitoring ................................................................... 69 
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TABLE OF ACRONYMS 
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Acronym 
Abbreviation For 
ADA 
American Diabetes Association 
ADE 
Adverse Device Effect 
AOC 
Area Over the Curve 
AUC 
Area Under the Curve 
BG 
Blood Glucose 
BP 
Bionic Pancreas 
BPMC 
Bionic Pancreas Multi-Center 
CRF 
Case Report Form 
CGM 
Continuous Glucose Monitoring 
CSII 
Continuous Subcutaneous Insulin Infusion 
CV 
Coefficient Variation 
DCCT 
Diabetes Control and Complications Trial 
DKA 
Diabetic Ketoacidosis 
DSMB 
Data and Safety Monitoring Board 
EKG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FDR 
False Discovery Rate 
GCP 
Good Clinical Practice 
GUI 
Graphical User Interface 
HbA1c 
Hemoglobin A1c 
HBGI 
High Blood Glucose Index 
HCG 
Human Chorionic Gonadotropin 
IDE 
Investigational Device Exemption 
IOB 
Insulin-on-Board 
IOBP 
Insulin-only Bionic Pancreas 
IQR 
Interquartile Range 
IRB 
Internal Review Board 
JCHR 
Jaeb Center for Health Research 
LBGI 
Low Blood Glucose Index 
MDI 
Multiple Daily Injections 
MODD 
Mode of Daily Difference 
NIDDK 
National Institute of Diabetes and Digestive and Kidney Diseases 
NYHA 
New York Heart Association 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
QC 
Quality Control 
RCT 
Randomized Controlled/Clinical Trial 
RBM 
Risk-Based Monitoring 
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Acronym 
Abbreviation For 
SD 
Standard Deviation 
TIA 
Transient Ischemic Attack 
T1D 
Type 1 Diabetes 
UC 
Usual Care 
UADE 
Unanticipated Adverse Device Effect 
UI 
User Interface 
 
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STATEMENT OF COMPLIANCE 
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The trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on 
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the Protection of Human Subjects (45 CFR Part 46), and the NIDDK Terms of Award. The 
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Principal Investigator will assure that no deviation from, or changes to the protocol will take 
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place without prior agreement from the sponsor and documented approval from the Institutional 
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Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial 
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participants. All personnel involved in the conduct of this study have completed Human 
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Subjects Protection Training. 
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I agree to ensure that all staff members involved in the conduct of this study are informed about 
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their obligations in meeting the above commitments.  
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Principal Investigator: ___________________________________________  
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Print/Type Name  
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Signed: _____________________________________ Date: ______________ 
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Signature
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CHAPTER 1:  INTRODUCTION 
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Maintaining near-normal blood glucose (BG) levels (70–120 mg/dl) is a challenging and critically 
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important task for people with type 1 diabetes (T1D). The Diabetes Control and Complications 
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Trial (DCCT) Research Group definitively demonstrated that tight BG control can reduce long-
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term complications. The likelihood and severity of nephropathy, retinopathy, neuropathy, 
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macrovascular disease, and skin disorders is reduced in proportion to reductions in glycated 
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hemoglobin (HbA1c), which is closely correlated with long-term average BG levels. Risks for such 
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complications are elevated by three- to five-fold with diabetes. On the other hand, tight BG control 
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through conventional intensive insulin therapy increases the likelihood of episodic hypoglycemia, 
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which carries acute risks, including convulsions, seizures, coma, and death. Conventional therapy 
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also requires a relentless daily effort to count carbohydrates, frequently monitor BG throughout 
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the day and night, and administer a daily insulin regimen. 
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A more reliable method for achieving consistent BG control consists of an integrated artificial or 
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bionic pancreas (BP) system, consisting of a continuous glucose monitor (CGM), an infusion 
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pump, and a control algorithm that actuates the pump based on CGM glucose data. Such a 
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system can automate and ease the burden of T1D management and vastly improve glycemic 
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control relative to the current standard of care. 
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Recent years have seen the development of several competing strategies for automated or semi-
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automated management of glycemia. One large difference between competing designs is whether 
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they use insulin alone (insulin-only) and rely on the user treating with carbohydrates if the blood 
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glucose falls too low, or insulin and glucagon (bihormonal) and use glucagon to automatically 
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prevent and treat hypoglycemia, with carbohydrate treatment used only if glucagon treatment is 
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not successful.  
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Glucagon is an endogenous hormone that binds with high affinity to its cognate receptor. 
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Glucagon is quantitatively the most important counter-regulatory hormone in normal glucose 
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control physiology. In healthy individuals without T1D, glucagon levels rise during exercise, and 
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in the late-postprandial period as glucose levels return to the normal range after a small 
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hyperglycemic excursion. The production of glucagon is dysregulated early in the course of T1D 
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and glucagon production in response to threatened hypoglycemia is lost. Therefore, people with 
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T1D are functionally glucagon deficient.  
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An important challenge for automated glucose control is that the physiologic need for insulin can 
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change rapidly, but insulin is slowly absorbed when delivered subcutaneously. Even “rapid-acting” 
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insulin analogs such as insulin lispro (Humalog) have a mean time-to-peak of ~70 minutes. This 
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means that if the need for insulin decreases rapidly, such as in the case of exercise, there is 
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already insulin-on-board that cannot be withdrawn. In contrast to insulin, glucagon is absorbed 
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quickly, with a time-to-peak of ~15-20 minutes. Therefore, small doses of glucagon can be given 
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to counter the effects of excess insulin that has already been delivered and cannot be withdrawn, 
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and can prevent hypoglycemic events that could not be prevented by suspending insulin delivery 
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alone.  
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The use of glucagon provides the BP with a powerful tool to automatically prevent and treat 
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hypoglycemia, but it does present two challenges. First, exogenous glucagon must be shown to 
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be safe when administered in micro-doses intermittently on a chronic basis. A second challenge 
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to the use of glucagon is that a form of glucagon that is stable near body temperature for at least 
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several days in a pump must be available. When we first began developing our BP, there was no 
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stable form of glucagon available; however, several companies have now developed stable 
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analogs (Zealand, Eli Lilly) and stable formulations (Xeris, Adocia). The clinical programs for the 
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Zealand analog are sufficiently advanced that we are now using it in the BP in preliminary studies, 
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and we expect it to be qualified for pivotal studies by the end of 2018. A third challenge is that, as 
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with subcutaneously administered insulin, replacement of glucagon by subcutaneous 
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administration cannot perfectly mimic normal physiology, and peripheral levels must be higher 
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than normal to generate adequate liver exposure for effectiveness. In our last inpatient study of 
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the BP in adults and adolescents during over 2,300 patient-hours of exposure, frequent blood 
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sampling showed that the aggregate mean glucagon levels were in the normal fasted range (<150 
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pg/ml by the Millipore radioimmunoassay) between 61% and 91% of the time. Based on these 
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results, we expect that the doses of glucagon used by the bihormonal BP will be safe. However, 
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a stable glucagon is not qualified for chronic use at this time and there will inevitably be additional 
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cost associated with use of a second drug.  
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Given the various advantages and disadvantages of using glucagon, we have developed a BP 
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system that can be used in either a bihormonal, insulin-only, or glucagon-only mode.  
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We have developed an autonomous, self-learning BP that requires only the participant's weight 
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for initialization, and then autonomously adapts, modestly or dramatically, as needed, to cope 
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with the wide range of insulin requirements of adults, adolescents, and pre-adolescents with T1D.  
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Our BP obviates the need for the patient to know, or even appreciate, their insulin requirements, 
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and renders obsolete any need for patients or caregivers to know carbohydrate-to-insulin ratios, 
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basal rates, or insulin correction factors. 
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Our core technology is our insulin controller, which orchestrates all subcutaneous (SC) insulin 
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dosing. At its centerpiece is a model-predictive control algorithm, which bases insulin doses  on 
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the glucose data and insulin absorption kinetics. We were the first to incorporate insulin 
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pharmacokinetics (PK) into our algorithm, by augmenting it with a mathematical formulation for 
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estimating the concentration of insulin in the blood and predicting its future concentration. It is 
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essential to compensate for the slow absorption rate of SC insulin analogs (peak time in blood of 
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30–90 min, clearance in 4–8 hr), and to enable the algorithm to refrain from stacking and 
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overdosing insulin.  Furthermore, our MPC algorithm automatically adjusts its insulin-doing 
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aggressiveness continuously and in real time to different insulin needs between individuals and 
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variable needs within the same individual.  Running in parallel with our MPC algorithm is an 
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algorithm that automatically modulates basal insulin delivery over multiple time scales, and 
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another algorithm that automatically adapts insulin doses in response to optional meal 
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announcements.  Unlike current insulin pumps, and all of the insulin-only control algorithms of 
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which we are aware, our adaptive basal insulin algorithm obviates the need for the user to set, or 
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even know, his or her “basal-rate profile”.  Instead, it is capable of automatically adapting to, and 
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compensating for, changes in an individual's basal insulin need, such as might occur over a period 
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of hours, days, or weeks (e.g. circadian hormonal fluctuations, intercurrent illness, physical 
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activity, or emotional state) or as might occur over a period of months or years due to 
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developmental changes (e.g. hormonal changes that occur during puberty or menopause). Our 
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adaptive meal dose controller obviates the need for the user to set, or even know, his or her 
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“carbohydrate-to-insulin ratios”, as it makes automatic adjustments based on dosing history for 
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similar meal announcements made on previous days, and customizes the dose for each individual 
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and for time of day. Our BP also includes a proportional-derivative algorithm governing SC micro-
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doses of glucagon to help prevent impending hypoglycemia. Glucagon dosing is based on the 
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glucose level and rate of descent. It could occur preemptively even if glucose is above range and 
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it includes a feedback term to account for the pending effects of recent glucagon doses. The 
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amount of glucagon dosed also feeds back on the insulin controller, so that large amounts of 
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glucagon dosing decrease the aggressiveness of the insulin controller. 
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Taken together, these mathematical algorithms provide a universal framework for a glycemic 
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control strategy that requires no quantitative input from, or participation by, the user (besides 
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entering body weight to initialize the system), but which automatically adapts insulin and glucagon 
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dosing to meet the individual needs of each user.  Another challenge we have met is enabling our 
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technology to remain completely autonomous in managing insulin and glucagon delivery even 
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when the CGM is offline. Specifically, when the CGM is offline, our BP invokes the high-resolution 
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“basal rate profile” that it had recently learned and stored when the CGM was online.  On the 
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basis of what the system learned and stored about meal announcements when the CGM was 
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online, it is able to respond to meal announcements in the same manner when the CGM is offline.  
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Finally, it automatically responds to user-entered BG values when the CGM is offline by issuing 
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a correction dose of insulin or glucagon based on what it learned about the user's insulin and 
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glucagon needs when the CGM was online. Thus, our BP never relies on, or burdens the user 
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with, the determination of dosing decisions, which inevitably vary in quality and reliability among 
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different users. The BP provides a turnkey solution for people with T1D that comprehensively 
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manages glycemia across a broad range of individual needs and a across a large spectrum of 
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circumstances and challenges to glycemic control.  
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The BP can also operate in an insulin-only mode. During operation in this mode, all of the other 
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features of the BP operate as usual except that glucagon is not given. In addition, the lowest 
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glucose target that can be chosen by the user (towards which the insulin controller drives down 
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the blood glucose levels) is increased from 100 mg/dl in the bihormonal system to 110 mg/dl in 
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the insulin-only system. This works to reducing the aggressiveness of insulin dosing in the insulin-
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only system relative to its bihormonal counterpart, with the aim of keeping the amount of 
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hypoglycemia low even at the potential cost of raising the mean glucose level achieved by the 
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insulin-only system.  The intended use for such a system would be to provide glycemic control for 
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people with type 2 diabetes who require insulin therapy, and early technology adopters with type 
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1 diabetes. 
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The BP can also operate in a glucagon-only mode. During operation in this mode, all of the other 
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features of the BP operate as usual except that insulin is not given. The intended use for such a 
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system would be to treat glycemic disorders associated with chronic hypoglycemia (such as 
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congenital hyperinsulinism, insulinoma syndrome, chronic hypoglycemia in post-bariatric surgery 
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patients, etc.). 
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Our BP hardware platform has evolved over the years from a laptop-driven system, which we 
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used in all of our inpatient studies (between 2008–2012), to the first truly mobile wearable iPhone-
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driven platform, which we have used in all of our outpatient studies thus far (between 2013–2016).  
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Using our iPhone-driven BP system, we have conducted >110 outpatient experiments of 5–11 
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days in duration in each participant (> 800 patient days or > 2 patient years of data), and across 
366 
participants ranging in age between 6 and 76 years old and in body mass between 21 and 133 
367 
kg.  The robust adaptation capabilities of our BP are evident in the fact that the average total daily 
368 
dose of insulin among these participants varied by over 13-fold (from 11 to 145 units/day).   
369 
 
370 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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All of our preclinical studies at BU testing our BP in a diabetic swine model of T1D (between 2005 
371 
and 2009), and all of our inpatient clinical trials in the Clinical Research Center at MGH testing 
372 
our BP in adults and adolescents with T1D (between 2008 and 2012) have set the stage for the 
373 
outpatient studies that followed.  In November 2012 we obtained FDA approval to conduct our 
374 
first outpatient study testing our bihormonal BP in adults 21 years or older with T1D. This study, 
375 
which we referred to as the Beacon Hill Study, followed a random-order cross-over design in 
376 
which 20 adults with T1D participated in 5 days on our iPhone-based BP and 5 days of usual 
377 
care. In the usual care control period the participants used conventional insulin pump therapy 
378 
(and their own CGM if they had one), and they wore a CGM with blinded display and muted 
379 
alarms.  In the BP period, participants kept to a three-square-mile geographic area centered 
380 
around the Beacon Hill neighborhood in Boston.  They ate as they chose at local restaurants, and 
381 
exercised at will with access to two gyms.  Analysis was pre-specified to focus on Days 2–5, since 
382 
glycemic control is more representative of BP performance after most of the adaptation by the BP 
383 
occurs on Day 1. Results are summarized in the plots and table of Figure 1.  
384 
 
385 
Mean CGMG (mg/dl)
90
120
154
180
210
240
1% <60 mg/dl
5% <60 mg/dl
10% >180 mg/dl
50% >180 mg/dl
Bionic
Pancreas
Control
Beacon Hill Study
Mean CGMG (mg/dl)
90
120
169
180
210
240
1% <60 mg/dl
5% <60 mg/dl
10% >180 mg/dl
50% >180 mg/dl
Bionic
Pancreas
Control
2013 Summer Camp Study
Mean CGMG (mg/dl)
90
120
150
169
180
210
240
1% <60 mg/dl
5% <60 mg/dl
10% >180 mg/dl
50% >180 mg/dl
Bionic
Pancreas
Control
2014 Summer Camp Study
Mean CGMG (mg/dl)
90
120
154
180
210
240
1% <60 mg/dl
5% <60 mg/dl
10% >180 mg/dl
50% >180 mg/dl
Bionic
Pancreas
Control
BP Multi-Center Study


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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386 
 
387 
Figure 1. Outpatient results summarizing the distribution of mean CGM glucose levels and 
388 
hypoglycemia in the bihormonal BP and control periods. Mean CGM glucose levels for each 
389 
participant under usual care (shown as a red circle on the left) is connected with the participant's 
390 
mean CGM glucose level on the BP (shown as a black circle on the right). For each participant, 
391 
the circle diameter is proportional to the percentage of CGM glucose values < 60 mg/dl, and the 
392 
size of the triangle is proportional to the percentage of CGM glucose values > 180 mg/dl. The 
393 
heavy circles and lines represent the group means. The horizontal red dashed line refers to the 
394 
glucose level corresponding to the ADA therapy goal for each age group tested, which 
395 
corresponds to 154 mg/dl (HbA1c <7%) for adults and 169 mg/dl (HbA1c <7.5%) for children.  
396 
Results are summarized in the table below the plots, where the co-primary outcomes (mean CGM 
397 
glucose level and percentage of CGM glucose values < 60 mg/dl) for the BP are highlighted in 
398 
red for each of the four studies. 
399 
 
400 
In April 2013, we obtained FDA approval to conduct our first outpatient study testing our 
401 
bihormonal BP in adolescents 12–20 years old with T1D. This study, which we referred to as the 
402 
2013 Summer Camp Study, followed a random-order cross-over design in which 32 adolescents 
403 
with T1D participated in 5 days on our BP and 5 days of supervised camp care in the control 
404 
period. In the control period the participants used conventional insulin pump therapy (and their 
405 
own CGM if they had one), and they wore the BP without pumps and with blinded display and 
406 
muted alarms for remote monitoring. Participants were monitored remotely according to identical 
407 
criteria in all periods for proper device functioning and CGM glucose <70 mg/dl lasting more than 
408 
15 minutes, which would prompt study staff to call the participant and make sure they were 
409 
treated.  Participants were fully integrated into normal camp activities without restrictions on diet 
410 
or exercise. The study used the same iPhone-based BP that was used in our Beacon Hill Study.   
411 
The mean HbA1c of all 32 participants at baseline (pre-study) was 8.2%, which corresponds to a 
412 
mean BG of 189 mg/dl.  Results are summarized in the plots and table of Figure 1.   
413 
 
414 
In April 2014 we obtained FDA approval conduct our first outpatient study testing our bihormonal 
415 
BP in pre-adolescents 6–11 years old with T1D. This study, which we referred to as the 2014 
416 
Summer Camp Study, was similar in design to our 2013 Summer Camp Study.  Results are 
417 
summarized in the plots and table of Figure 1.  
418 
 
419 
In April 2014, we obtained FDA approval to conduct our first multi-center study, which was also 
420 
our first home study, to test our BP in adults 18 years or older with T1D. This study, which we 
421 
referred to as the Bionic Pancreas Multi-Center (BPMC) Study, followed a random-order cross-
422 
over design in which 39 adults participated in 11 days on our BP and 11 days of usual care. 
423 
Participants went to work as usual, and lived and slept at home, all without clinical supervision.  
424 
There were no restrictions placed on diet or exercise. The study included four medical centers 
425 
(10 participants per center), which included MGH, the University of Massachusetts Medical 
426 
School, Stanford University, and the University of North Carolina at Chapel Hill.  Results are 
427 
summarized in the plots and table of Figure 1. 
428 
 
429 
In July 2015 we obtained FDA approval to perform our first study testing the BP at different static 
430 
Study
Age
Mean CGM
Mean CGM
Mean CGM
(years)
glucose level
<"60"mg/dl
70–180"mg/dl glucose level
<"60"mg/dl
70–180"mg/dl glucose level
<"60"mg/dl
70–180"mg/dl
(mg/dl)
(%)
(%)
(mg/dl)
(%)
(%)
Beacon Hill (n=20, 5-day experiments)
≥*21
133
1.5
80
159
3.7
59
<*0.001
0.020
<*0.001
2013 Summer Camp (n=32, 5-day experiments)
12–20
142
1.3
76
158
2.2
65
0.004
0.192
<*0.001
2014 Summer Camp (n=19, 5-day experiments)
6–11
137
1.2
81
168
2.8
58
0.004
0.001
<*0.001
BP Multi-Center (n=39, 11-day experiments)
≥*18
141
0.6
78
162
1.9
62
<*0.001
<*0.001
<*0.001
Bionic Pancreas (BP)
Control
p-value (BP versus Control) for:
% of CGM glucose levels
% of CGM goucose values
% of CGM glucose values


 
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glucose targets (“set-points”), including in both the bihormonal and insulin-only configurations. In 
431 
this study, which we referred to as the MGH Set-point Study, 20 adults participated in 7 periods, 
432 
each lasting 3 days. This study was the first to explore modifying the glucose target towards which 
433 
the BP attempts to drive the glucose level. In all of our previous studies, the target glucose was 
434 
100 mg/dl. Since this was the first study to test the BP in a configuration without glucagon, the 
435 
insulin-only periods initially used significantly elevated glucose targets of 130 mg/dl and 145 mg/dl 
436 
(not shown). We subsequently obtained approval to test glucose targets of 120 mg/dl and 110 
437 
mg/dl in December 2015. Results for the insulin-only and control periods are summarized in 
438 
Figure 2. The conclusion of this study was that the insulin-only system was safe, with minimal 
439 
hypoglycemia, with the 120 mg/dl glucose target appearing to be a good compromise between 
440 
mean glucose, amount of hypoglycemia, and insulin utilization. 
441 
 
442 
 
443 
Figure 2 Outpatient results summarizing the distribution of mean CGM glucose levels and 
444 
hypoglycemia in the insulin-only BP (set-points 130, 120, and 110 mg/dl) and comparator periods. 
445 
Mean CGM glucose levels for each participant in each period (shown as a red circles) are 
446 
connected by black lines. For each participant, the circle diameter is proportional to the 
447 
percentage of CGM glucose values < 60 mg/dl.  The heavy circles and lines represent the group 
448 
means. The horizontal red dashed line refers to the glucose level corresponding to the ADA 
449 
therapy goal for each age group tested, which corresponds to 154 mg/dl (HbA1c <7%) for adults.   
450 
 
451 
In July 2015 we obtained FDA approval to perform our first study investigating a feature that 
452 
allowed the target glucose to be determined automatically by the BP, an additional level of 
453 
adaptation to the individual participant. In this study, which we call the Stanford Insulin-only Study, 
454 
16 adults participated in a week of usual care followed by another week on the insulin-only BP. 
455 
Participants were monitored remotely according to identical criteria in both periods for proper 
456 
device functioning and CGM glucose <50 mg/dl lasting more than 15 minutes, which would prompt 
457 
study staff to call the participant and make sure they were treated. The first week was a control 
458 
period in which participants managed their own conventional insulin pump therapy (using their 
459 
own CGM if they had one) and wore the BP without pumps and with blinded display and muted 
460 
alarms for remote monitoring. In the second week, the BP was initiated with target glucose of 130 
461 
mg/dl, which could be lowered to 115 mg/dl if certain criteria were met. All but one participant was 
462 


 
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kept at a target of 130 mg/dl, and one was lowered to 115 mg/dl, for an overall average target of 
463 
129 mg/dl. During this week the mean CGM glucose achieved was 159 mg/dl. There was only 
464 
0.8% time <60 mg/dl in the static set-point week. This was non-significantly lower than the 2.3% 
465 
observed in the usual care period. Results are summarized in Figure 3.  
466 
 
467 
Figure 3 Outpatient results summarizing the distribution of mean CGM glucose levels and 
468 
hypoglycemia in the insulin-only BP and control periods. Mean CGM glucose levels for each 
469 
participant under usual care (shown as a red circle on the left) is connected with the participant's 
470 
mean CGM glucose level on the BP (shown as a black circle on the right). For each participant, 
471 
the circle diameter is proportional to the percentage of CGM glucose values < 60 mg/dl.  The 
472 
heavy circles and lines represent the group means. The horizontal red dashed line refers to the 
473 
glucose level corresponding to the ADA therapy goal for each age group tested, which 
474 
corresponds to 154 mg/dl (HbA1c <7%) for adults.   
475 
 
476 
This provided further reassurance that the insulin-only configuration of the BP is safe and 
477 
effective.  
478 
 
479 
 
480 
We have designed, built, and tested our first-generation working prototype BP system, which we 
481 
refer to as the iLet, and which consists of a dual-chamber autonomous infusion pump. The iLet 
482 
has been built according to Class III medical device standards, adheres to a comprehensive and 
483 
robust quality system, and is fully compliant with ISO 13485 standards and document control 
484 
practices.  The bihormonal configuration of the iLet includes a dual motor and drivetrain assembly, 
485 
which independently actuates the delivery of insulin and/or glucagon from glass cartridges that 
486 
are separately loaded into the BP housing.  Each drivetrain utilizes a lead screw, which is driven 
487 
by a precision micromotor, a gear case assembly, and a motor controller unit, in a manner similar 
488 
to what is commonly found in most insulin infusion pumps on the market today. Our mathematical 
489 
control algorithms, the CGM glucose engine (Dexcom, originally G4 AP version with 505 algorithm 
490 
and now, the equivalent, G5 version), and the native user interface (UI) software, are all 
491 
interconnected through a host controller software module and reside as embedded systems on 
492 
printed circuit board assemblies contained within the device housing. Our touchscreen-enabled, 
493 
menu-driven UI and onboard microprocessor provide a comprehensive and standalone platform, 
494 
which allows the iLet to operate independently of smartphones or other devices and without the 
495 
need for internet support during routine operation. The iLet BP system has dosing accuracy that 
496 
is comparable to FDA-approved insulin pumps currently on the market.  
497 
 
498 
The iLet BP system is set to an insulin-only, bihormonal, or glucagon-only configuration by 
499 
Mean CGMG (mg/dl)
90
120
154
180
210
240
1% <60 mg/dl
5% <60 mg/dl
Control
Insulin Only
(n=16)
Mean: 151 +/- 26 mg/dl
1.9% <60,     26% >180
Mean: 160 +/-  9 mg/dl
0.9% <60,     30% >180
I: 0.57 U/kg


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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manually selecting the configuration in the user interface.  When in the bihormonal 
500 
configuration, the control algorithm would occasionally and automatically invoke the same 
501 
insulin-only dosing mode as in the insulin-only configuration during periods when the glucagon 
502 
cartridge has not been loaded, is empty, or becomes empty during use, or if there is a pump 
503 
occlusion detected in the glucagon fluid path.  Whenever the control algorithm is in the insulin-
504 
only mode, the minimum glucose target is 110 mg/dl.  The minimum glucose target in the 
505 
bihormonal or glucagon-only mode, when the glucagon cartridge is available for dosing and the 
506 
glucagon fluid path is patent, is 100 mg/dl. 
507 
 
508 
In addition to the iLet itself, the entire iLet BP system includes a glass insulin cartridge, a glass 
509 
glucagon cartridge, pigtail adapters that connect the drug cartridges to infusion sets, and a self-
510 
monitored blood-glucose (SMBG) meter.  The SMBG meter that we will use is the Contour Next 
511 
One (Ascensia).  This meter is the successor to the Contour Next SMBG meter (Bayer), which 
512 
was found to be the most accurate meter assessed in all three blood-glucose ranges tested (< 
513 
70, from 70 to 179, and ≥ 180 mg/dl) in a comparative accuracy study involving 17 point-of-care 
514 
glucose meters. 
515 
 
 
516 
The bionic pancreas will make recommendations for MDI dosing (for those on MDI therapy) AND 
517 
for CSII dosing (for those on CSII therapy).  We have shown in our previous outpatient and home-
518 
use studies in adult and pediatric participants with T1D that the total daily dose of insulin used by 
519 
the bionic pancreas is consistent with usual care.  The bionic pancreas has three insulin 
520 
controllers running in parallel: a basal insulin controller, which continually adapts to each 
521 
individual’s basal metabolic need for insulin, an MPC controller, which provides control doses that 
522 
are required above and beyond basal insulin, and a meal-announcement controller, which 
523 
continually adapts to the individual's prandial insulin needs.  The bionic pancreas provides a daily 
524 
readout with updated estimates of daily basal insulin (in terms of a daily long-acting dose for MDI 
525 
users and a basal rate regimen for CSII users), prandial insulin (for breakfast, lunch, and dinner) 
526 
and correction doses.  Thus, we hypothesize that the bionic pancreas can effectively provide a 
527 
recommendation of these quantities for both MDI and CSII users.  This bridging study will be the 
528 
first test of this hypothesis. 
529 
 
530 
 
531 
  
532 
Faster insulin aspart or Fiasp is a formulation of insulin aspart (sold as Fiasp in both the United 
533 
States and in Europe) that contains nicotinamide (also known as niacinamide or vitamin B3) and 
534 
L-arginine hydrochloride (an amino acid). The addition of nicotinamide is intended to result in a 
535 
faster initial absorption of insulin aspart following SC injection or infusion. The addition of L-
536 
arginine hydrochloride should support stabilization of the Fiasp formulation. The active substance 
537 
(i.e. insulin aspart) in Fiasp and Novolog is identical and therefore, once systemically absorbed, 
538 
it has the same biological action at the insulin receptor as that of Novolog.  
539 
 
540 
Since one of the important limitations of automated closed-loop glucose control is the delay in 
541 
absorption of insulin, the use of Fiasp may allow improved glycemic control with the bionic 
542 
pancreas. To date, there have been no published studies of the effect of an ultra-rapid insulin on 
543 
the performance of an artificial pancreas.  
544 
 
545 
 
546 
The Senseonics Eversense CGM is the first implantable CGM. The Senseonics Eversense CGM 
547 
is currently being marketed in select European countries, and the pre-market approval has been 
548 
submitted to the FDA in the US. As a part of the FDA review, an FDA Advisory Committee voted 
549 
8-0 that the system was safe, effective, and that the benefits outweighed the risk. The BP can 
550 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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operate using both the Dexcom G5 CGM system or the Senseonics Eversense CGM system as 
551 
the glucose value input to the algorithm. All functionality of the device and the algorithm remains 
552 
the same, regardless of which CGM is the driving system.  
553 
 
554 
We conducted a head-to-head comparison between the Dexcom G5 CGM and the Senseonics 
555 
Eversense CGM as an adjunctive study to a previous bionic pancreas study, and found 
556 
Senseonics Eversense to have modestly, but statistically significantly, better accuracy than the 
557 
Dexcom G5. From this, we concluded it would be safe to integrate this system with our bionic 
558 
pancreas in the same manner we have integrated the Dexcom.  
559 
 
560 
One of the limitations of the Dexcom CGM system is the short sensor life of 7 days, increased to 
561 
only 10 days with the new G6 system. The Senseonics Eversense CGM sensor is implanted in 
562 
the subcutaneous tissue of the upper arm and can operate for up to 90 days. The most recently 
563 
approved model of the Senseonics Eversense CGM system in Europe can operate for up to 180 
564 
days.  The option to use a longer lasting sensor of equivalent or superior accuracy would appeal 
565 
to many potential users of a closed loop system. To date, there have been no published studies 
566 
using the Senseonics Eversense CGM sensor in a closed loop system.  
567 
 
568 
 
569 
CHAPTER 2: SYNOPSIS OF INSULIN-ONLY BP BRIDGING STUDY 
570 
 
571 
 
572 
• 
To serve as a transitional study, bridging to larger and longer outpatient pivotal studies 
573 
using the insulin-only configuration of the bionic pancreas 
574 
• 
To assess the efficacy, safety, and reliability of the insulin-only configuration of the bionic 
575 
pancreas in regulating glycemia using Humalog, or Novolog, in adult and pediatric 
576 
participants and using Fiasp in adult participants in a short-term, outpatient study under 
577 
real-world conditions; 
578 
• 
To assess safety of the insulin-only configuration of the bionic pancreas using Humalog, 
579 
Novolog, and Fiasp (adults only), particularly with respect to severe hyperglycemia and 
580 
hypoglycemia; 
581 
• 
To assess the impact of the insulin-only configuration of the bionic pancreas on quality of 
582 
life and treatment satisfaction among study participants, their caregivers and/or family 
583 
members; 
584 
• 
To document the interaction of the participants with the insulin-only configuration of the 
585 
bionic pancreas device for human factors analysis, with the goals of identifying any 
586 
problems with the user interface or instruction manual for the device that could lead to 
587 
unsafe use of the device or an adverse event. 
588 
• 
To assess the efficacy, safety, and reliability of the insulin-only configuration of the bionic 
589 
pancreas in the transition from autonomous glycemic control to either multiple daily 
590 
injection therapy or insulin pump therapy. 
591 
• 
To assess the efficacy, safety, and reliability of the insulin-only configuration of the bionic 
592 
pancreas using the Senseonics Eversense CGM as the input CGM in adult participants in 
593 
a short-term outpatient study under real-world conditions.  
594 
 
595 
 
596 
 
597 
Study Design 
598 
Test-Run Period: Prior to beginning the Adult RCT Period, 8 adults ≥ 18 years old with T1D will 
599 
participate in the Test-Run Period.  The Test-Run Period will consist of an uncontrolled, 7-day 
600 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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pilot study (at MGH) testing the iLet in the insulin-only configuration using the iLet pigtail adapter 
601 
and iLet ready-to-fill insulin cartridge, the Contact Detach infusion set, the Dexcom G5 CGM, and 
602 
the insulin analog that they use for their usual care (either Humalog or Novolog).  Participants will 
603 
be followed with round-the-clock, remote, telemetric monitoring for hyperglycemia (> 300 mg/dl 
604 
for ≥ 90 minutes) and hypoglycemia (< 50 mg/dl for ≥ 15 minutes). All 8 adult participants will have 
605 
a designated contact, who will serve as an emergency contact person in the event study staff are 
606 
unable to reach the participant. The Test-Run Period will be completed before the Adult RCT 
607 
Period starts. If any events described in the study stopping criteria (section 8.7) occur during the 
608 
Test-Run Period, the data for the Test-Run Period will be reviewed by the DSMB to determine if 
609 
the RCT Period will commence. If there are no events for DSMB review during the Test-Run 
610 
Period, the RCT Period will proceed prior to review of the data by the DSMB.  
611 
 
612 
 
613 
Pediatric Transitional Study Session: Prior to beginning the Pediatric RCT Period, 20 pediatric 
614 
participants from three clinical sites (Colorado, Nemours, and Stanford) will take part in the 
615 
Pediatric Transitional Study Session to assess the efficacy, safety, and reliability of the insulin-
616 
only configuration of the bionic pancreas in regulating glycemia in pediatric subjects in a more 
617 
supervised setting prior to beginning the true outpatient study.  The Pediatric Transitional Study 
618 
Session will consist of a multi-center, two-period, random-order, cross-over, pilot study in 20 
619 
pediatric participants 6–17 years old with T1D (~ 6 adolescent participants at Colorado 12–17 
620 
years old, ~ 6 pre-adolescent participants at Nemours 6–11 years old, and ~ 8 pediatrics subjects 
621 
at Stanford 6-17 years old).  Insulin therapy for each participant will be administered (i) in one 
622 
period using the iLet in the insulin-only configuration with the iLet pigtail adapter and the iLet 
623 
ready-to-fill insulin cartridge, the Contact Detach infusion set, the Dexcom G5 CGM, and the 
624 
insulin analog that they use for their usual care (either Humalog or Novolog), and (ii) in the other 
625 
period using the participant’s own usual care (UC), where each participant will wear a Dexcom 
626 
G5 CGM.  Both experimental periods will be followed by round-the-clock, remote, telemetric 
627 
monitoring for hyperglycemia (> 300 mg/dl for ≥ 90 minutes) and hypoglycemia (< 50 mg/dl for ≥ 
628 
15 minutes). The two experimental periods will each span 5 days, including 4 nights (e.g. 
629 
Monday–Friday). A washout period of ~ 3 days in duration will separate the two experimental 
630 
periods of the Pediatric Transitional Study Session.   
631 
 
 
632 
Both study periods will be conducted in the same clinically supervised setting during each of the 
633 
5 days and at home under parental supervision or other overnight companion who is available to 
634 
serve as an emergency contact during each of the 4 nights.  Parents/guardians must be present 
635 
(i.e. in the house or building) while the participant is home and sleeping and will serve as the 
636 
contact person for overnight alerts. During the daytime in the Pediatric Transitional Study Session, 
637 
participants of each cohort will be with the clinical study staff at each of the three clinical sites and 
638 
will engage in common activities such that meals and activities can be well-characterized and 
639 
supervised.  For further quantification of stress due to exercise, activity monitors will be worn by 
640 
all of the participants in both periods of the study.  In terms of physical activity, diet, and remote 
641 
monitoring for hypo- and hyperglycemia, parity will be maintained between both study periods.   
642 
All 20 pediatric participants in the Pediatric Transitional Study Session will use insulin pump 
643 
therapy for their usual diabetes management. The Dexcom G5 CGM will serve as the input CGM 
644 
to the iLet for all 20 pediatric participants. The cohort of 6 adolescent participants at Colorado and 
645 
6 pre-adolescent participants at Nemours, and 8 participants at Stanford might overlap or might 
646 
not overlap in time. The Pediatric Transitional Study Session will be completed before the 
647 
Pediatric RCT Period starts. If any events described in the study stopping criteria (section 8.7) 
648 
occur during the Pediatric Transitional Study Session, the data for the Pediatric Transitional Study 
649 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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Session will be reviewed by the DSMB to determine if the RCT Period will commence. If there are 
650 
no events for DSMB review during the Pediatric Transitional Study Session, the RCT Period will 
651 
proceed prior to review of the data by the DSMB. 
652 
 
653 
Adult RCT Period:  The Test-Run Period will be completed and the data will be reviewed to verify 
654 
safety prior to beginning the Adult RCT Period.  The Adult RCT Period will consist of a multi-
655 
center, three-period, random-order, cross-over, feasibility study in 36 adult participants ≥ 18 years 
656 
old with T1D (18 participants at MGH and 18 participants at Stanford).  
657 
 
658 
Four adult participants at MGH will have a Senseonics Eversense CGM sensor implanted and 
659 
will participate in a 3-day supervised Test Run. All 4 adult participants will have a designated 
660 
contact, who will serve as an emergency contact person in the event study staff are unable to 
661 
reach the participant. This Senseonics Eversense Test Run Period will be completed and data 
662 
will be reviewed to verify safety prior to beginning the Adult RCT Period at MGH using the 
663 
Senseonics Eversense CGM sensor as the input to the iLet. All 18 adult participants at MGH will 
664 
have a Senseonics Eversense CGM sensor implanted prior to the initiation of the Adult RCT 
665 
Period by the clinical PI at MGH (Dr. Steven Russell) or by a study physician under his 
666 
supervision.  These subjects will use the Senseonics Eversense CGM as the input to the bionic 
667 
pancreas instead of the Dexcom G5.  
668 
 
669 
All 18 adult participants at Stanford will use the Dexcom G5 CGM as the input to the bionic 
670 
pancreas. All other aspects of the Adult RCT Period will remain the same across the two sites.  
671 
 
672 
Insulin therapy for each participant will be administered (i) in one period using the iLet in the 
673 
insulin-only configuration with the iLet pigtail adapter and the iLet ready-to-fill insulin cartridge, 
674 
the Contact Detach infusion set, and the insulin analog that they use for their usual care (either 
675 
Humalog or Novolog), (ii) in another period using the iLet in the insulin-only configuration using 
676 
the iLet pigtail adapter, the Contact Detach infusion set, and faster insulin aspart (Fiasp) in 
677 
PumpCart, where the pharmacokinetic (PK) parameter for tmax used by the insulin-dosing 
678 
algorithm will be set to the same value as is used for Humalog and Novolog (65 minutes), and (iii) 
679 
in a third period using the participant’s own usual care (UC), where each participant will wear a 
680 
CGM.  All three experimental periods will be followed by round-the-clock, remote, telemetric 
681 
monitoring for hyperglycemia (> 300 mg/dl for ≥ 90 minutes) and hypoglycemia (< 50 mg/dl for ≥ 
682 
15 minutes).  The three experimental periods will each have a duration of 7 days.  Washout 
683 
periods of approximately 7 days in duration will follow the first and second experimental periods 
684 
of the Adult RCT Period. The washout period could be as short as 5 days or as long as 9 days, 
685 
depending on scheduling of study visits. Of the 36 adult participants, 9 at MGH and 9 at Stanford 
686 
will use MDI therapy for their usual diabetes management; the remaining 18 will use insulin pump 
687 
therapy.  The participants in Stanford Adult RCT Period will wear the Dexcom G5 CGM and the 
688 
participants in the MGH Adult RCT Period will wear the Senseonics Eversense CGM.  This will 
689 
allow us to collect further comparative accuracy data on both the Senseonics Eversense and the 
690 
Dexcom G5 in the outpatient setting using the Ascensia Contour Next One meter as the reference. 
691 
The cohort of 18 participants at MGH and 18 participants at Stanford might run simultaneously, 
692 
might overlap, or might not overlap in time.  The Adult RCT Period may take place weeks or 
693 
months after the Test-Run Period, so the cohort for the Adult RCT Period may include all, some, 
694 
or none of the participants from the cohort of the Test-Run Period. 
695 
 
 
696 
Pediatric RCT Period:  The Pediatric Transitional Study Session will be completed and the data 
697 
will be reviewed to verify safety prior to beginning the Pediatric RCT Period.  The Pediatric RCT 
698 
Period will consist of a multi-center, two-period, random-order, cross-over, feasibility study in 20 
699 
pediatric participants 6–17 years old with T1D (10 participants at Colorado and 10 participants at 
700 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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Nemours).  Insulin therapy for each participant will be administered (i) in one period using the iLet 
701 
in the insulin-only configuration with the iLet pigtail adapter and the iLet ready-to-fill insulin 
702 
cartridge, the Contact Detach infusion set, the Dexcom G5 CGM, and the insulin analog that they 
703 
use for their usual care (either Humalog or Novolog), and (ii) in the other period using the 
704 
participant’s own usual care (UC), where each participant will wear a Dexcom G5 CGM.  Both 
705 
experimental periods will be followed by round-the-clock, remote, telemetric monitoring for 
706 
hyperglycemia (> 300 mg/dl for ≥ 90 minutes) and hypoglycemia (< 50 mg/dl for ≥ 15 minutes).  
707 
The two experimental periods will each have a duration of 7 days. A washout period of 
708 
approximately 7 days in duration will separate the two experimental periods of the Pediatric RCT 
709 
Period. The washout period could be as short as 5 days or as long as 9 days depending on 
710 
scheduling of study visits. Of the 20 pediatric participants, 5 at Colorado and 5 at Nemours will 
711 
use MDI therapy for their usual diabetes management; the remaining 10 will use insulin pump 
712 
therapy. The Dexcom G5 CGM will serve as the input CGM to the iLet for all 20 pediatric 
713 
participants. The cohort of 10 participants at Colorado and 10 participants at Nemours might run 
714 
simultaneously, might overlap, or might not overlap in time.  The Pediatric RCT Period may take 
715 
place weeks or months after the Pediatric Transitional Study Session, so the cohort for the 
716 
Pediatric RCT Period may include all, some, or none of the participants from the cohort of the 
717 
Pediatric Transitional Study Session. 
718 
 
719 
Post-Study Transition to Usual Diabetes Management:  For 48 hours after the last period of the 
720 
RCT Period in both adults and pediatric participants is completed, there will be a small Post-Study 
721 
Transition period.  All adult and pediatric participants who complete the RCT Period on an 
722 
intervention period will transition to their usual care (CSII or MDI) regimen following the 
723 
recommendations of the bionic pancreas for 48 hours.  
724 
 
725 
Insulin Usage During Usual Diabetes Management:  Those who use Humalog (CSII or MDI) for 
726 
their usual diabetes management will use Humalog in the iLet during the RCT Period, and those 
727 
who use Novolog (CSII or MDI) or Fiasp (adults, MDI only) for their usual diabetes management 
728 
will use Novolog in the iLet during the RCT Period except for the period in the adult RCT Period 
729 
for which Fiasp is specified. Those who use glulisine for their usual diabetes management will be 
730 
excluded from participating in the study. 
731 
 
732 
Participant Training: Training on the use of the iLet BP system will be provided to all participants 
733 
(and caregivers) prior to initiating the Test-Run Period at MGH, the Pediatric Transitional Study 
734 
Session at all three sites, and the RCT Period at all four clinical sites.  In particular, these skills 
735 
sets will include (1) replacement of batteries, (2) installing the iLet ready-to-fill insulin cartridge or 
736 
PumpCart, (3) priming the fluid path, (4) priming and inserting the Contact Detach infusion set, 
737 
(5) replacement and calibration of a sensor, (6) entering an SMBG value into the bionic pancreas, 
738 
(7) use of the meal-announcement feature, (8) use of temporary and recurring set points, (9) 
739 
general use of the graphical user interface, and (10) troubleshooting the bionic pancreas (for 
740 
occlusions, sensor drop-outs, alarms and alerts, etc.).  Additional time will be allocated for training 
741 
on the use of the iLet BP system for all participants who normally use MDI therapy for their usual 
742 
care or are otherwise naïve to the use of sensor-augmented, insulin-pump therapy.  It is 
743 
noteworthy that whether or not the CGM is communicating with the iLet, there are no basal rates 
744 
to adjust, carb-to-insulin ratios to know, or correction factors to calculate when the iLet is dosing 
745 
insulin, so training of these particular skill sets will not be necessary for any of our participants. 
746 
 
747 
Sites 
748 
The Test-Run Period in adults will be conducted by one site in the U.S. (MGH), the Pediatric 
749 
Transitional Study Session will be conducted by three sites in the U.S. (Colorado, Nemours, and 
750 
Stanford), and the RCT Period in adults and pediatrics will be conducted by all four sites (MGH, 
751 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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Stanford, Nemours, and Colorado). 
752 
 
753 
Major Eligibility Criteria  
754 
• 
Clinical diagnosis of type 1 diabetes for at least 12 months 
755 
• 
HbA1c level < 11.0% 
756 
o At least 13 adult participants and 6 pediatric participants in the RCT Period must have 
757 
an HbA1c level of 8–11% 
758 
o At least 13 adult participants and 6 pediatric participants in the RCT Period must have 
759 
an HbA1c level < 8% 
760 
• 
Using an FDA-approved insulin therapy (including Fiasp on MDI therapy for adults, Humalog 
761 
or Novolog with CSII or MDI therapy; glulisine users will be excluded) 
762 
o 18 adult participants and 10 pediatric participants must use MDI therapy to manage 
763 
their diabetes 
764 
o 18 adult participants and 10 pediatric participants must use CSII therapy to manage 
765 
their diabetes 
766 
• 
The Adult RCT Period will enroll participants ≥ 18 years old  
767 
o Approximately 9 participants in a young adult group (18–24 years old)  
768 
o Approximately 27 participants in an adult group (≥ 25 years old) 
769 
• 
The Pediatric RCT Period will enroll participants 6–17 years old 
770 
o 10 participants in a pre-adolescent group (< 12 years old) 
771 
o 10 participants in an adolescent group (12–17 years old) 
772 
 
773 
Additional eligibility and exclusion criteria are listed in section 3.2 
774 
 
775 
Sample Size  
776 
• 
The Test-Run Period: 8 participants (age ≥ 18 years, MGH only) 
777 
• 
The Pediatric Transitional Study Session: 20 participants (~ 6 participants age 6–11 years at 
778 
Nemours, ~ 6 participants age 12–17 years at Colorado, and ~ 8 participants age 12–17 years 
779 
at Stanford) 
780 
• 
Adult RCT Period: 36 participants (age ≥ 18 years, 18 participants at MGH, 18 participants at 
781 
Stanford) 
782 
• 
Pediatric RCT Period: 20 participants (age 6–17 years, 10 participants at Nemours, 10 
783 
participants at Colorado) 
784 
 
785 
Treatment Groups 
786 
• 
The Test-Run Period: All participants will use the iLet in the insulin-only configuration with 
787 
Humalog or Novolog (using the iLet pigtail adapter, the iLet ready-to-fill insulin cartridge, the 
788 
Contact Detach infusion set, and the Dexcom G5 CGM) in one uncontrolled 7 day period. 
789 
• 
The Pediatric Transitional Study Session: All participants will use the iLet in the insulin-only 
790 
configuration with Humalog or Novolog (using the iLet pigtail adapter, the iLet ready-to-fill 
791 
insulin cartridge, the Contact Detach infusion set, and the Dexcom G5 CGM) 
792 
• 
Senseonics Eversense Test Run (MGH only): 4 adults will use the iLet in the insulin-only 
793 
configuration using Humalog or Novolog with the iLet pigtail adapter, the iLet ready-to-fill 
794 
insulin cartridge, the Contact Detach infusion set, and the Senseonics Eversense CGM as the 
795 
input to the iLet in an uncontrolled 3-day period.  
796 
• 
Adult RCT Period: Three-period, random-order, cross-over study into the following study 
797 
periods:  
798 
o (1) the iLet in the insulin-only configuration using Humalog or Novolog with the iLet 
799 
pigtail adapter, the iLet ready-to-fill insulin cartridge, the Contact Detach infusion set, 
800 
and either the Dexcom G5 or Senseonics Eversense CGM as the input depending on 
801 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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the site 
802 
o (2) the iLet in the insulin-only configuration using faster insulin aspart (Fiasp) in 
803 
PumpCart with the iLet pigtail adapter, the Contact Detach infusion set, and either the 
804 
Dexcom G5 or Senseonics Eversense CGM) as the input, depending on the site, 
805 
where the pharmacokinetic (PK) parameter for tmax used by the insulin-dosing 
806 
algorithm will be set to the same value for Fiasp as is used for Humalog and Novolog 
807 
(65 minutes)  
808 
o (3) UC (with the Dexcom G5 or the Senseonics Senseonics Eversense CGM 
809 
depending on the site). 
810 
• 
 Pediatric RCT Period: Two-period, random-order, cross-over study where assignment of 
811 
study period order follows either (1) the iLet in the insulin-only configuration using Humalog 
812 
or Novolog with the iLet pigtail adapter, the iLet ready-to-fill insulin cartridge, the Contact 
813 
Detach infusion set, and the Dexcom G5 CGM) in period 1 and UC (with the Dexcom G5 
814 
CGM) in period 2 or (2) UC (with the Dexcom G5 CGM) in period 1 and the iLet in the insulin-
815 
only configuration using Humalog or Novolog with the iLet pigtail adapter, the iLet ready-to-fill 
816 
insulin cartridge, the Contact Detach infusion set, and the Dexcom G5 CGM) in period 2. 
817 
 
818 
Visit and Phone Contact Schedule 
819 
1. Screening Visit  
820 
• 
Eligibility assessed, informed consent, and bloodwork including point-of-care/local 
821 
HbA1c and eGFR. 
822 
1.5. Senseonics Eversense CGM sensor placement visit (MGH site only, prior to Senseonics 
823 
Eversense Test Run and RCT Period only) 
824 
• 
The procedures of this visit will take place at least 24 hours before the first Startup 
825 
visit, to allow the Senseonics Eversense sensor to complete its 24-hour warm up 
826 
period after insertion. In order to test the performance of the full life of the Senseonics 
827 
Eversense sensor the study team will endeavor to schedule these visits such that 
828 
subjects have the sensor placed in a roughly even distribution (approximately 3 
829 
insertions per week) over the 6 weeks prior to the Startup Visit of the RCT Period 
830 
Each study period will follow the schedule below: 
831 
2. Startup visit (day 0) 
832 
• 
The first start up period will include the completion of the baseline psychosocial 
833 
questionnaires. See Chapter 7 for more details. 
834 
• 
Every start up visit will include a review of medical history since the last study visit to 
835 
ensure continued eligibility, and adverse event querying.  
836 
• 
Test-Run Period:  Reassess eligibility, place the Dexcom G5 CGM sensor, train, and 
837 
initiate automated glycemic management with the iLet in the insulin-only configuration 
838 
(using the iLet pigtail adapter, the iLet ready-to-fill insulin cartridge, the Contact Detach 
839 
infusion set, and the Dexcom G5 CGM) 
840 
• 
Transitional Study Session: Reassess eligibility, place the Dexcom G5 CGM sensor, 
841 
train, and initiate automated glycemic management with the iLet in the insulin-only 
842 
configuration (using the iLet pigtail adapter, the iLet ready-to-fill insulin cartridge, the 
843 
Contact Detach infusion set, and the Dexcom G5 CGM) 
844 
• 
Eversense Test Run: Reassess eligibility, assess sensor insertion site, train, and 
845 
initiate automated glycemic management with the iLet in the insulin-only configuration 
846 
(using the iLet pigtail adapter, the iLet ready-to-fill insulin cartridge, the Contact Detach 
847 
infusion set, and the Senseonics Eversense CGM) 
848 
• 
Adult RCT Period: Reassess eligibility prior to randomization, place the Dexcom G5 
849 
CGM sensor where applicable, train and: 
850 
• 
BP periods: Initiate automated glycemic management for the BP Periods with the 
851 


 
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iLet in the insulin-only configuration (with the iLet pigtail adapter, the Contact 
852 
Detach infusion set) using Humalog, Novolog (with the iLet ready-to-fill insulin 
853 
cartridge), or Fiasp (in PumpCart) 
854 
• 
Pediatric RCT Period: Reassess eligibility prior to randomization, place the Dexcom 
855 
G5 CGM sensor, training and: 
856 
• 
BP periods: Initiate automated glycemic management for the BP Period with the 
857 
iLet in the insulin-only configuration (with the iLet pigtail adapter, the iLet ready-to-
858 
fill insulin cartridge, the Contact Detach infusion set, and the Dexcom G5 CGM) 
859 
using Humalog or Novolog  
860 
3. Phone contacts to query for adverse events and proper device functioning will occur on: 
861 
• 
Days 3 or 4 for each 7-day Adult and Pediatric RCT Periods and the 7-Day Test-Run 
862 
Period 
863 
• 
No phone contact during the Pediatric Transitional Study Session or the Senseonics 
864 
Eversense Test Run since clinical study staff will be with the entire cohort every day 
865 
of the study 
866 
4. Shutdown visits (Day 7 for the Test-Run Period in adults and for each period of the RCT 
867 
Period in both adults and pediatric participants, Day 5 for the Transitional Study Session in 
868 
pediatrics, Day 3 for the Senseonics Eversense Test Run) 
869 
• 
Download data from study devices as follows: 
870 
• 
Usual care: Dexcom G5 CGM, glucose meter, ketone meter, participant’s 
871 
personal insulin pump if applicable, and Senseonics Eversense CGM 
872 
where applicable 
873 
• 
BP: iLet BP, glucose meter, ketone meter, and Senseonics Eversense 
874 
CGM where applicable 
875 
• 
Psychosocial questionnaires will be completed at the end of each period. See 
876 
Chapter 7 for more details.  
877 
4.5 Senseonics Eversense CGM sensor removal visits (MGH site of RCT Period only) 
878 
The Senseonics Eversense CGM may be removed on the final shutdown visit, after the Post-
879 
Study Transition Period is complete, or on a subsequent visit as schedules allow. The 
880 
Senseonics Eversense CGM will be removed within the required 90 day window.  
881 
 
882 
The Startup and Shutdown visit are repeated for each study period in the RCT period. There is 
883 
only one Startup and Shutdown visit in the Test Run, the Senseonics Eversense Test Run and 
884 
the Pediatric Transitional Study Session.  
885 
 
886 
 
887 
Participants randomized to a BP period using Humalog or Novolog for the final period of the RCT 
888 
period will be discharged to their usual care following the dosing recommendations of the iLet for 
889 
48 hours in the Post-Study Transition Period. Remote monitoring will continue per the same 
890 
protocol as the RCT Period. At the end of this period, participants will return to the research clinic 
891 
and the CGM data will be analyzed for the safety and efficacy of the iLet dosing recommendations.  
892 
 
893 
Outcomes 
894 
Primary Efficacy Outcomes 
895 
• 
Mean CGM glucose (Days 3–7 for the Adult Test-Run Period, Days 2–5 for the Pediatric 
896 
Transitional Study Session, Days 3–7 for the RCT Period, Days 2-3 for the Senseonics 
897 
Eversense Test Run)  
898 
• 
Time < 54 mg/dl according to CGM (Days 3–7 for the Adult Test-Run Period, Days 2–5 
899 
for the Pediatric Transitional Study Session, Days 3–7 for the RCT Period, Days 2-3 for 
900 
the Senseonics Eversense Test Run)  
901 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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902 
 
903 
Main Safety Outcomes 
904 
• 
Number of episodes of severe hypoglycemia 
905 
• 
Number of episodes of diabetic ketoacidosis (DKA) 
906 
• 
Other serious adverse events 
907 
 
908 
The two primary outcome metrics (mean glucose and time <54 mg/dl) and three treatment 
909 
group comparisons in the adult RCT Period [(2) BP with rapid insulin vs. (3) UC, (1) BP with 
910 
analog insulin vs. (3) UC, and (2) BP with rapid insulin vs. (1) BP with analog insulin], combine 
911 
for a total of six statistical comparisons.  
912 
 
913 
To preserve the overall type 1 error, a hierarchical gatekeeping testing procedure will be used. If 
914 
a comparison results in a statistically significant result (p < 0.05), then testing will proceed to the 
915 
next one on the list. See Chapter 10 for additional information.  
916 
 
 
917 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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918 
919 
 
920 
Each Period of the Test-Run Period and the Adult RCT Period 
 
Screening 
Senseonics 
Eversense 
Sensor 
Insertion 
Day 0 
Day 3   
or  
Day 4 
Day 7  
Senseonics 
Eversense 
Sensor 
Removal 
Informed Consent  
X 
 
 
 
 
 
Eligibility assessment 
X 
 
X 
 
 
 
Bloodwork: eGFR and 
HbA1c  
X 
 
 
 
 
 
EKG1 
X 
 
 
 
 
 
Body weight 
X 
 
X 
 
X 
 
Urine pregnancy test2 
X 
 
 
 
 
 
Physical exam  
X 
 
 
 
 
 
Insertion of Dexcom 
CGM sensor3 
 
 
X 
 
 
 
Insertion 
of 
Senseonics Eversense 
CGM sensor4 
 
X 
 
 
 
 
Removal 
of 
Senseonics Eversense 
CGM sensor5 
 
 
 
 
 
X 
Psychosocial 
questionnaires6 
 
 
X 
 
X 
 
Data download 
 
 
 
 
X 
 
Adverse 
event 
querying7 
 
X 
X 
X 
X 
X 
 
921 
1 – An EKG is required for participants ≥ 50 years old and/or with a diabetes duration of ≥ 20 years 
922 
2 -- A urine pregnancy test will be conducted for women post-menarche and pre-menopause who are not surgically 
923 
sterile. 
924 
3 –At Stanford during the RCT Period, a new Dexcom CGM sensor will be inserted at each day 0. 
925 
4 – At MGH during the RCT Period, Senseonics Eversense CGM sensor will be inserted during the period between 
926 
Screening and Day 0, at least 24 hours before Day 0. 
927 
5 – At MGH during the RCT Period, Senseonics Eversense CGM sensor will be removed at the Final Shutdown visit, 
928 
after the Post-Study Transition Period, or a later date, up to 90 days after insertion 
929 
6 – Questionnaires (see Chapter 7) 
930 
• 
Baseline questionnaires include: Diabetes Treatment Satisfaction Questionnaire - Status (DTSQs), Diabetes 
931 
Distress Scale (DDS), Hypoglycemia Fear Survey (HFS), Hypoglycemia Confidence, INSPIRE Survey. These 
932 
will be completed by the participant on the first Startup visit only.  
933 
• 
Day 7 of each experimental period: Diabetes Treatment Satisfaction Questionnaire - Change (DTSQc), 
934 


 
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Diabetes Distress Scale (DDS), Hypoglycemia Fear Survey (HFS), Hypoglycemia Confidence, INSPIRE 
935 
survey, Bionic Pancreas User Opinion Survey (BPUOS) – BP period only 
936 
7-- Study physicians will follow up with subjects and query about any adverse events within 48 hours following 
937 
Senseonics Eversense insertion and removal. 
938 
 
939 
 
940 
941 
 
942 
Senseonics Eversense Test Run Period 
 
Screening 
Senseonics 
Eversense 
Sensor 
Insertion 
Day 0 
Days 
1-3  
Day 3 
Senseonics 
Eversense 
Sensor 
Removal 
Informed Consent  
X 
 
 
 
 
 
Eligibility 
assessment 
X 
 
X 
 
 
 
Bloodwork: eGFR 
and HbA1c  
X 
 
 
 
 
 
EKG1 
X 
 
 
 
 
 
Body weight 
X 
 
X 
 
X 
 
Urine pregnancy 
test2 
X 
 
 
 
 
 
Physical exam  
X 
 
 
 
 
 
Insertion of 
Senseonics 
Eversense CGM 
sensor3 
 
X 
 
 
 
 
Daytime supervision 
by study staff 
 
 
X 
X 
X 
 
Removal of 
Senseonics 
Eversense CGM 
sensor4 
 
 
 
 
 
X 
Data download 
 
 
 
 
X 
 
Adverse event 
querying5 
 
X 
X 
X 
X 
X 
 
943 
1 – An EKG is required for participants ≥ 50 years old and/or with a diabetes duration of ≥ 20 years 
944 
2 -- A urine pregnancy test will be conducted for women post-menarche and pre-menopause who are not surgically 
945 
sterile. 
946 
3 –Senseonics Eversense CGM sensor will be inserted during the period between Screening and Day 1, at least 24 
947 
hours before day 1. 
948 
4 –Senseonics Eversense CGM sensor will be removed at the Final Shutdown visit or a later date, up to 90 days after 
949 
insertion. Subjects who participate in the Eversense Test Run may also participate in the Adult RCT. They may use the 
950 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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same sensor for the RCT Period, as long as it will not expire.  
951 
5 – Study physicians will follow up with subjects and query about any adverse events within 48 hours following 
952 
Senseonics Eversense insertion and removal. 
953 
 
954 
 
955 
 
 
956 
Experimental Periods of Pediatric RCT Period 
 
Screening 
Day 0 
Day 3    
or 4 
Day 7 
Informed Consent  
X 
 
 
 
Eligibility assessment 
X 
X 
 
 
Bloodwork: 
eGFR 
and 
HbA1c 
X 
 
 
 
Body weight 
X 
X 
 
X 
Urine pregnancy test1 
X 
 
 
 
Physical exam  
X 
 
 
 
Insertion of Dexcom CGM 
sensor 
 
X 
 
 
Psychosocial 
questionnaires2 
 
X 
 
X 
Data download 
 
 
 
X 
Adverse event querying 
 
X 
X 
X 
 
957 
1 -- A urine pregnancy test will be conducted for women post-menarche and pre-menopause who are not surgically 
958 
sterile. 
959 
2 – Questionnaires (see Chapter 7) 
960 
Baseline questionnaires include: Diabetes Treatment Satisfaction Questionnaire - Status (DTSQs), Diabetes 
961 
Distress Scale (DDS), Problem Areas in Diabetes Survey (PAID), Hypoglycemia Fear Survey (HFS), 
962 
Hypoglycemia Confidence, INSPIRE Survey. These will be completed by the participant on the first Startup visit 
963 
only.  
964 
Day 7 of each experimental period of the Pediatric RCT Period: Diabetes Treatment Satisfaction Questionnaire - 
965 
Change (DTSQc), Diabetes Distress Scale (DDS), Problem Areas in Diabetes Survey (PAID), Hypoglycemia Fear 
966 
Survey (HFS), Hypoglycemia Confidence, INSPIRE survey, Bionic Pancreas User Opinion Survey (BPUOS) – BP 
967 
period only 
968 
 
 
969 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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970 
 
971 
972 
 
 
973 
Pediatric Transitional Study Session 
 
Screening 
Day 0 
Days 
1-5 
Day 5 
Informed Consent  
X 
 
 
 
Eligibility assessment 
X 
X 
 
 
Bloodwork: 
eGFR 
and 
HbA1c 
X 
 
 
 
Body weight 
X 
X 
 
X 
Urine pregnancy test1 
X 
 
 
 
Physical exam  
X 
 
 
 
Insertion of CGM sensor 
 
X 
 
 
Psychosocial 
questionnaires2 
 
X 
 
X 
Data download 
 
 
 
X 
Adverse event querying 
 
X 
X 
X 
 
974 
1 -- A urine pregnancy test will be conducted for women post-menarche and pre-menopause who are not surgically 
975 
sterile. 
976 
2 – Questionnaires (see Chapter 7) 
977 
• 
Baseline questionnaires include: Diabetes Treatment Satisfaction Questionnaire - Status (DTSQs), Diabetes 
978 
Distress Scale (DDS), Problem Areas in Diabetes Survey (PAID), Hypoglycemia Fear Survey (HFS), 
979 
Hypoglycemia Confidence, INSPIRE Survey 
980 
• 
Day 5: Diabetes Treatment Satisfaction Questionnaire - Change (DTSQc), Diabetes Distress Scale (DDS), 
981 
Problem Areas in Diabetes Survey (PAID), Hypoglycemia Fear Survey (HFS), Hypoglycemia Confidence, 
982 
INSPIRE survey, Bionic Pancreas User Opinion Survey (BPUOS) – BP period only 
983 
 
984 
 
985 
The study is being conducted in compliance with the policies described in the study policies 
986 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with the 
987 
protocol described herein, and with the standards of Good Clinical Practice. 
988 
 
989 
Data will be directly collected in electronic case report forms, which will be considered the source 
990 
data.   
991 
 
992 
A risk-based monitoring approach will be followed, consistent with the FDA “Guidance for Industry 
993 
Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 2013). 
994 
 
995 
The protocol is considered a significant risk device study, due to the fact that the iLet BP system 
996 
is experimental.  Therefore, an IDE from the FDA is required to conduct the study. 
997 


 
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CHAPTER 3:  PARTICIPANT ENROLLMENT AND STUDY INITIATION 
998 
 
999 
Up to 240 individuals with type 1 diabetes may be screened and sign the informed consent form 
1000 
for the study so that a minimum of 8 will enter the Test-Run Period in adults, 20 will enter the 
1001 
Transitional Study Period in pediatrics, 4 will enter the Senseonics Eversense Test Run and a 
1002 
total of 56 will enter the RCT Periods between adults (36 subjects) and pediatrics (20 subjects). 
1003 
Screening will continue until the required number is reached. Adult participants in the Test Run 
1004 
and the Senseonics Eversense Test Run may also participate in the RCT Period. 
1005 
 
1006 
No individuals will be excluded on the basis of gender or race.   An equal gender distribution 
1007 
between males and females is anticipated.   
1008 
 
1009 
The Test-Run Period will be conducted at a single site (MGH) and the Transitional Study Session 
1010 
will take place at three sites (Stanford, Nemours and Colorado). It is anticipated that 8 adult 
1011 
participants will be in the Test-Run Period and 20 pediatric participants in the Transitional Study 
1012 
Session.  The Senseonics Eversense Test Run will include 4 adult participants at MGH only. The 
1013 
Adult and Pediatric RCT Period will be conducted at four sites in the United States.  It is 
1014 
anticipated that each adult site (MGH and Stanford) will randomize approximately 18 participants 
1015 
into the Adult RCT Period and each pediatric site (Nemours and Colorado) will randomize 
1016 
approximately 10 participants into the Pediatric RCT Period. The maximum number of 
1017 
randomized participants at a site will be 40. 
1018 
 
 
1019 
Individuals generally will be recruited from each site’s existing patient population.  Direct 
1020 
contacting of patients and advertisements including website postings may be used subject to 
1021 
Institutional Review Board approval. 
1022 
 
1023 
 
1024 
Eligibility and exclusion criteria will be the same for both the adult and pediatric patient 
1025 
populations, and the same for the Test Run Period, the Pediatric Transitional Study Session, the 
1026 
Senseonics Eversense Test Run, and the Adult and Pediatric RCT Period. Exceptions to this are 
1027 
noted below. 
1028 
 
1029 
 
1030 
To be eligible for the study, a participant must meet the following criteria: 
1031 
1. Clinical diagnosis of type 1 diabetes for at least one year and using insulin for at least 1 year  
1032 
2. Diabetes managed using an insulin pump for ≥ 3 months or with multiple daily injections 
1033 
(approximately 1/2 of participants should use a pump and approximately 1/2 should use MDI) 
1034 
• 
The Test Run Period, the Pediatric Transitional Study and the Senseonics 
1035 
Eversense Test Run Period will only enroll participants using an insulin pump. 
1036 
3. Age ≥18 years (for Test-Run Period and Adult RCT Period); >6 years, up to 17 years (for 
1037 
Pediatric Transitional Study and Pediatric RCT Period) 
1038 
• 
There is no upper age limit in the Adult RCT Period (instead the exclusion criteria are used 
1039 
to restrict the participants to those healthy enough to participate in the trial) 
1040 
4. HbA1c level <11.0% 
1041 
• 
A point of care or local lab measurement is used to assess eligibility for screening.  
1042 
5. At least 3 SMBG meter tests daily on average or use of a CGM and 2 or more SMBG meter 
1043 
tests daily on average by history 
1044 
6. For females, not currently known to be pregnant 
1045 
• 
If female, sexually active, and at risk for pregnancy, must agree to use a highly effective 
1046 
form of contraception to prevent pregnancy while a participant in the study.  A negative 
1047 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
Page 30 of 69  
urine pregnancy test will be required for all women who are post-menarche and pre-
1048 
menopause who are not surgically sterile.  Participants who become pregnant will be 
1049 
discontinued from the study. 
1050 
7. An understanding of and willingness to follow the protocol and sign the informed consent and 
1051 
assent where applicable 
1052 
8. Pediatric Transitional Study Session, Adult Test Run, and Senseonics Eversense Test Run 
1053 
only:  an adult (≥ 18 years of age) willing to serve as an emergency contact person throughout 
1054 
the study 
1055 
   
1056 
 
1057 
Note: any laboratory testing needed to assess for eligibility is considered part of standard care as 
1058 
it is necessary as part of a participant’s general medical management. 
1059 
 
1060 
The presence of any of the following is an exclusion for the study: 
1061 
1. Unable to provide informed consent (e.g. impaired cognition or judgment) 
1062 
2. Unable to safely comply with study procedures and reporting requirements (e.g. impairment 
1063 
of vision or dexterity that prevents safe operation of the BP, impaired memory) 
1064 
3. Unable to speak and read English 
1065 
4. Currently using for the first time a real-time CGM for < 1 month (Individuals who have been 
1066 
using CGM for 1 or more months are eligible) 
 
 
1067 
5. Current use of non-FDA approved closed-loop or hybrid closed-loop insulin delivery system 
1068 
6. Current use of insulin glulisine (Apidra) as part of usual diabetes home regimen 
1069 
7. Current off-label use of faster-acting insulin aspart (Fiasp) in CSII therapy as part of usual 
1070 
diabetes home regimen 
1071 
8. Current participation in another diabetes-related clinical trial that, in the judgment of the 
1072 
principal investigator, will compromise the results of this study or the safety of the participant 
1073 
9. Pregnant (positive urine HCG), breast feeding, plan to become pregnant in the next 12 
1074 
months, or sexually active and at risk for pregnancy without use of contraception 
1075 
10. Current alcohol abuse (intake averaging >4 drinks daily in last 30 days) or other substance 
1076 
abuse (use within the last 3 months of controlled substances other than marijuana without a 
1077 
prescription)  
1078 
11. Unwilling or unable or to avoid use of drugs that may dull the sensorium, reduce sensitivity to 
1079 
symptoms of hypoglycemia, or hinder decision making during the period of participation in the 
1080 
study (use of benzodiazepines or narcotics, even if by prescription, may be excluded 
1081 
according to the judgment of the principal investigator) 
1082 
12. Stage 4 renal failure (eGFR <30) or Stage 5 renal failure on dialysis (hemodialysis or 
1083 
peritoneal dialysis) 
1084 
13. History of cystic fibrosis, pancreatitis, or other pancreatic disease, including pancreatic tumor 
1085 
or insulinoma, or history of complete pancreatectomy 
1086 
14. Coronary artery disease that is not stable with medical management, including unstable 
1087 
angina, angina that prevents moderate exercise (e.g. exercise of intensity up to 6 METS) 
1088 
despite medical management, or within the last 12 months before screening a history of 
1089 
myocardial infarction, percutaneous coronary intervention, enzymatic lysis of a presumed 
1090 
coronary occlusion, or coronary artery bypass grafting  
1091 
15. Abnormal EKG consistent with increased risk of malignant arrhythmia including, but not limited 
1092 
to, evidence of active ischemia, proximal LAD critical stenosis (Wellen’s sign), or prolonged 
1093 
QT interval (> 440 ms). Other EKG findings, including stable Q waves, are not grounds for 
1094 
exclusion as long as the participant is not excluded according to other criteria. A reassuring 
1095 
evaluation by a cardiologist after an abnormal EKG finding may allow participation. 
1096 
• EKG is only required for participants ≥50 years old or with diabetes duration ≥20 years 
1097 
16. For participants < 50 years of age and < 20 years since diagnosis: History of prolonged QT 
1098 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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interval, malignant arrhythmia, or congenital heart disease 
1099 
17. Congestive heart failure with New York Heart Association (NYHA) Functional Classification III 
1100 
or IV  
1101 
18. History of TIA or stroke in the last 12 months 
1102 
19. Recent history of diabetic ketoacidosis (DKA) or severe hypoglycemia in the last 6 months. 
1103 
Severe hypoglycemia is defined as an event that required assistance of another person due 
1104 
to altered consciousness, and required another person to actively administer carbohydrate, 
1105 
glucagon, or other resuscitative actions.  This means that the participant was impaired 
1106 
cognitively to the point that he/she was unable to treat himself/herself, was unable to verbalize 
1107 
his/ her needs, was incoherent, disoriented, and/or combative, or experienced seizure or 
1108 
coma.   
1109 
20. History of more than 1 episode of DKA requiring hospitalization in the last 2 years  
1110 
21. History of more than 1 episode of severe hypoglycemia in the last year. 
1111 
22. Untreated or inadequately treated mental illness (indicators would include symptoms such as 
1112 
psychosis, hallucinations, mania, and any psychiatric hospitalization in the last year), or 
1113 
treatment with anti-psychotic medications that are known to affect glucose regulation. 
1114 
23. Electrically powered implants (e.g. cochlear implants, neurostimulators) that might be 
1115 
susceptible to RF interference 
1116 
24. Unable or unwilling to completely avoid acetaminophen for duration of study. Participants 
1117 
wearing the Senseonics Eversense CGM must also be willing and able to avoid tetracycline, 
1118 
sorbitol and mannitol for the duration of the study.  
1119 
25. Established history of allergy or severe reaction to adhesive or tape that must be used in the 
1120 
study 
1121 
26. History of eating disorder within the last 2 years, such as anorexia, bulimia, or diabulemia or 
1122 
omission of insulin to manipulate weight 
1123 
27. Current or planned use of SGLT2 inhibitors (prior use more than 3 months prior to enrollment 
1124 
is acceptable; SGLT2 inhibitors should not be initiated during the trial) 
1125 
28. If using GLP1, pramlintide, or metformin must be on a stable dose for 3 months prior to 
1126 
enrollment (these agents should not be initiated during the trial) 
1127 
29. Required use of 2 or more steroid bursts in the 6 months prior to the trial 
1128 
30. Participants wearing the Senseonics Eversense CGM cannot be currently using systemic 
1129 
glucocorticoids at baseline or throughout the study.  
1130 
31. History of intentional, inappropriate administration of insulin leading to severe hypoglycemia 
1131 
requiring treatment 
1132 
32. Any factors that, in the opinion of the site principal investigator or clinical protocol chair, would 
1133 
interfere with the safe completion of the study, including medical conditions that may require 
1134 
hospitalization during the trial  
1135 
 
1136 
 
1137 
Informed consent, and assent where applicable, and an authorization for release of personal 
1138 
information will be obtained according to IRB requirements prior to any data collection or study-
1139 
specific procedures that are not part of the participant’s routine care. The principal investigator at 
1140 
each site will be responsible for assuring that the informed consent and assent process is properly 
1141 
followed and that each study participant is well informed about the study and the participant’s 
1142 
responsibilities. 
1143 
 
1144 
 
1145 
Potential participants will be evaluated for study eligibility through the elicitation of a medical 
1146 
history, performance of a physical examination by study personnel and local laboratory testing to 
1147 
screen for exclusionary medical conditions.  Participant exclusion will be at the discretion of the 
1148 
investigator based on study inclusion/exclusion criteria and lab results.     
1149 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
Page 32 of 69  
 
1150 
 
1151 
A history will be elicited from the participant (and parents/guardians if applicable) and extracted 
1152 
from available medical records with regard to the participant’s diabetes history, current diabetes 
1153 
management, other past and current medical problems, past and current medications, and drug 
1154 
allergies.  A standard physical exam (including vital signs and height and weight measurements) 
1155 
will be performed by the study investigator or designee (a physician, fellow, nurse practitioner or 
1156 
a physician assistant).   
1157 
 
1158 
 
1159 
At the Screening Visit the following procedures will be performed:  
1160 
• Informed consent/assent process 
1161 
• Assessment of eligibility 
1162 
• The following labs will be required:  
1163 
• 
eGFR  
1164 
• 
HbA1c assessment via fingerstick using DCA2000 or equivalent NGSP-certified 
1165 
point-of-care method or via venous blood sample at a local laboratory (value within 
1166 
2 weeks prior to enrollment acceptable) 
1167 
• Physical examination to include:  
1168 
• 
Height/weight and vital signs including measurement of blood pressure and pulse  
1169 
• 
Tanner staging for participants <18 years 
1170 
• EKG (for participants ≥50 years old or diabetes duration ≥20 years) 
1171 
• Urine pregnancy test for all premenopausal women who are not surgically sterile 
1172 
 
1173 
Screening for the Adult RCT Period may start while the Test-Run Period is being conducted.  
1174 
However, the crossover phase of the Adult RCT Period cannot begin until the Test-Run Period 
1175 
and the subsequent review of the data for safety and feasibility has been completed.  The 
1176 
crossover phase of the Adult RCT Period at MGH using the Senseonics Eversense CGM 
1177 
cannot begin until the Senseonics Eversense Test Run and the subsequent review of the data 
1178 
for safety and feasibility has been completed.  
1179 
 
1180 
Similarly, screening for the Pediatric RCT Period may start while the Transitional Study 
1181 
Session is being conducted, however the crossover phase of the Pediatric RCT Period cannot 
1182 
begin until the Transitional Study Session and the subsequent review of the data for safety 
1183 
and feasibility has been completed.  
1184 
 
1185 
Participants in the Test Run, the Senseonics Eversense Test Run, and the Pediatric 
1186 
Transitional Study Session may also participate in the RCT Period. Study staff will confirm 
1187 
they are still eligible to participate prior to enrolling them in the RCT Period.  
1188 
 
1189 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
Page 33 of 69  
CHAPTER 4:  STARTUP VISITS 
1190 
 
1191 
The Initial Startup Visit, or Senseonics Eversense Insertion visit where applicable, should occur 
1192 
within 30 days after the screening visit. Participants in the Test Run, the Senseonics Eversense 
1193 
Test Run, and the Pediatric Transitional Study Session may also participate in the RCT Period. 
1194 
Study staff will confirm they are still eligible to participate prior to enrolling them in the RCT Period. 
1195 
 
1196 
In the three-period Adult RCT Period, there should be a minimum of 5 days, but no more than 9 
1197 
days, between a Shutdown Visit and a subsequent Startup Visit.  In the two-period Pediatric RCT 
1198 
Period, there should be a minimum of 5 days, but no more than 9 days, between a Shutdown Visit 
1199 
and a subsequent Startup Visit. 
1200 
 
1201 
 
1202 
The following will be completed at each Startup Visit: 
1203 
• 
Review medical history since screening visit to verify that there have been no events that 
1204 
affect participant eligibility 
1205 
• 
Verify that participant understands the protocol   
1206 
 
1207 
 
1208 
Test-Run Period 
1209 
In the Test-Run Period, adult participants will all use the iLet in the insulin-only configuration and 
1210 
the iLet pigtail adapter, the iLet ready-to-fill insulin cartridge, and the Contact Detach infusion set 
1211 
for 7 days.  The Dexcom G5 CGM will serve as the input CGM to the iLet. 
1212 
 
1213 
Pediatric Transitional Study Session  
1214 
In the Pediatric Transitional Study Period, pediatric participants will all use the iLet in the insulin-
1215 
only configuration and the iLet pigtail adapter, iLet ready-to-fill insulin cartridge, and the Contact 
1216 
Detach infusion set across ~ 5 days.  The Dexcom G5 CGM will serve as the input CGM to the 
1217 
iLet. 
1218 
 
1219 
Senseonics Eversense Test Run Period 
1220 
In the Senseonics Eversense Test Run Period, adult participants will all use the iLet in the insulin-
1221 
only configuration and the iLet pigtail adapter, the iLet ready-to-fill insulin cartridge, and the 
1222 
Contact Detach infusion set for 3 days.  The Senseonics Eversense CGM will serve as the input 
1223 
CGM to the iLet. 
1224 
 
1225 
RCT Period 
1226 
In the RCT Period, participants for whom eligibility has been verified will complete each of the 
1227 
following phases with the order randomly assigned:  
1228 
• 
Adult RCT Period: (i) the iLet in the insulin-only configuration with the iLet pigtail adapter and 
1229 
the iLet ready-to-fill insulin cartridge, the Contact Detach infusion set, and the insulin analog 
1230 
that they use for their usual care (either Humalog or Novolog), (ii) the iLet in the insulin-only 
1231 
configuration using the iLet pigtail adapter, the Contact Detach infusion set, and faster insulin 
1232 
aspart (Fiasp) in PumpCart, where the pharmacokinetic (PK) parameter for tmax used by the 
1233 
insulin-dosing algorithm will be set to the same value as is used for Humalog and Novolog (65 
1234 
minutes), and (iii) the participant’s own usual care (UC), where each participant will wear a 
1235 
CGM. 
1236 
o 18 adults at Stanford will use the Dexcom G5 CGM as the input to the iLet and as the 
1237 
CGM during usual care. 18 adults at MGH will use the Senseonics Eversense CGM 
1238 
as the input to the iLet and as the CGM during usual care. All 36 adults will participate 
1239 
in the same three arms, regardless of CGM.  
1240 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
Page 34 of 69  
• 
Pediatric RCT Period: (i) the iLet in the insulin-only configuration with the iLet pigtail adapter 
1241 
and the iLet ready-to-fill insulin cartridge, the Contact Detach infusion set, the Dexcom G5 
1242 
CGM, and the insulin analog that they use for their usual care (either Humalog or Novolog), 
1243 
and (ii) the participant’s own usual care (UC), where each participant will wear a Dexcom G5 
1244 
CGM. 
1245 
 
1246 
The participant’s randomization group assignment is determined by entering the Randomization 
1247 
Visit data on the study website.  The Jaeb Center will construct a Master Randomization List using 
1248 
a block design. 
1249 
 
1250 
 
1251 
1252 
• 
The Senseonics Eversense sensor insertion will take place after participants have been 
1253 
confirmed as eligible to participate but before they start their first study period. In order to 
1254 
test the performance of the full life of the sensor, the study team will endeavor to schedule 
1255 
these visits so subjects have the sensor placed in a roughly even distribution over the six 
1256 
weeks prior to the Initial Startup Visit, averaging 3 sensor insertions per week.  
1257 
• 
A urine pregnancy test will be performed in female volunteers prior to the sensor insertion. 
1258 
If the test is positive, the volunteer will be informed of the result, the visit will be ended and 
1259 
the sensor will not be inserted.  
1260 
• 
The temperature of the subject will be documented. Study staff will ask about any recent 
1261 
fever or vomiting, in addition to other adverse events or changes to medications. If the 
1262 
subject has a temperature greater than 100.4 degrees F, or has had one in the previous 
1263 
24 hours, the visit will be ended and the sensor will not be inserted.  
1264 
• 
The subject’s skin will be numbed using a local anesthetic (i.e. lidocaine without 
1265 
epinephrine). The study physician will make a small incision in the skin between the 
1266 
shoulder and the elbow using the Insertion Templates provided by Senseonics to mark in 
1267 
the incision site.  
1268 
• 
Senseonics will provide sterile, one-time use tools for placing the sensor. The Blunt 
1269 
Dissector is used to create the subcutaneous pocket for insertion of the sensor, and has 
1270 
guide marks to assist in determining the correct pocket length. The Insertion Tool is used 
1271 
in combination with the Sensor Holder to transfer the sensor, and has guide marks on the 
1272 
cannula to assist in proper placement in the subcutaneous pocket. See the Investigator 
1273 
Brochure for details on sensor insertion.  
1274 
• 
The sensor will be inserted at least three inches away from any infusion or injection sites.  
1275 
• 
Once the sensor is inserted, the incision will be closed using surgical tapes or a suture 
1276 
and a bandage. Blood loss during the procedure is expected to be minimal (less than 3 
1277 
ml) 
1278 
• 
Subjects will be instructed to leave the bandage on for approximately 24 hours. They will 
1279 
be instructed to monitor for any discharge, excessive bleeding, redness, warmth, or 
1280 
swelling at the insertion site and to contact study staff if this occurs. 
1281 
• 
A study physician will follow up with a phone call within 48 hours of insertion to assess 
1282 
appropriate healing and query for any adverse events.  
1283 
• 
During this visit, subjects will be trained on how to use the Senseonics Eversense 
1284 
transmitter and mobile app, as well as the study glucose meter. Subjects will be instructed 
1285 
to put their transmitter on approximately 24 hours after sensor insertion to begin the Initial 
1286 
Calibration phase. Subjects will be instructed to then calibrate twice daily and continue to 
1287 
wear the transmitter in the weeks before their start of the RCT Period.  
1288 
• 
Subjects will be told that their sensor must be removed within 90 days of the insertion date 
1289 
at the insertion visit. Study staff will add all insertion visits to a log, for tracking removal 
1290 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
Page 35 of 69  
visit dates and deadlines.  
1291 
• 
The procedures for this visit will be the same, regardless of if the subject is participating 
1292 
in the Senseonics Eversense Test Run, the RCT Period or both.  
1293 
 
1294 
 
1295 
The same procedures for the initial startup visit will be followed in the Test Run, Transitional Study 
1296 
Session, the Senseonics Eversense Test Run and the Adult and Pediatric RCT Period. 
1297 
 
1298 
Participants may be trained on the operation of the all study devices in a group setting or may be 
1299 
trained one-on-one. Both the participant and the study staff must be satisfied that the participant 
1300 
is comfortable with the operation of all study devices before he/she begins the study. Additional 
1301 
training sessions may be arranged as needed.  
1302 
 
1303 
• 
Participants will complete their baseline psychosocial questionnaires 
1304 
• 
Senseonics Eversense Test Run has no questionnaires 
1305 
• 
Their body weight will be documented 
1306 
• 
Study staff will review any changes in the participant’s medical history or medications to 
1307 
ensure continued eligibility, and any adverse events that may have occurred since their 
1308 
screening visit. 
1309 
• 
All participants will be given additional Dexcom G5 CGM sensors where applicable, an 
1310 
Ascensia Contour Next One SMBG meter with test strips, a ketone meter and ketone test 
1311 
strips, insulin, and a glucagon emergency kit.   
1312 
• 
Participants at Nemours, Colorado and Stanford will be trained on the insertion and use 
1313 
of the Dexcom G5 CGM. Participants will insert their own CGM sensor and study staff will 
1314 
confirm they are doing it correctly. Study staff will remind participants to only use FDA 
1315 
approved insertion sites (abdomen only for > 17 years old, abdomen or upper buttocks for 
1316 
ages 6-17 years old) for their CGM sensor.  
1317 
• 
Study staff will review all study procedures and policies (including the use of the Dexcom 
1318 
G5 or Senseonics Eversense, the Contour Next One, the blood ketone meter and the iLet 
1319 
BP) and the upcoming visit schedule.  
1320 
• 
MGH site only: For the adult subjects at the MGH site, the Senseonics Eversense CGM 
1321 
sensor will serve as the input to the iLet. This sensor may be placed any time after the 
1322 
participant has screened into the study before the start of their first study period. It must 
1323 
be placed in advance to allow for the 24 hour warm up period of the sensor prior to the 
1324 
startup visit.  Instructions will be given for calibration and use of the sensor. The 
1325 
Senseonics Eversense sensor will only be in place for up to 90 days. It will be removed 
1326 
by a study provider after the completion of the study, or before the 90th day.  
1327 
• 
The Dexcom G5 or Senseonics Eversense CGM will be calibrated by the participant using 
1328 
the Ascensia Contour Next One SMBG glucometer, and study staff will confirm they are 
1329 
doing it properly. 
1330 
Usual Care period (RCT period and Pediatric Transitional Study Session only) 
1331 
• 
Participants will be instructed to follow their usual diabetes management (see section 5.1). 
1332 
Bionic Pancreas periods (all study phases) 
1333 
• 
The control algorithm will be initialized with the participant’s current weight 
1334 
• 
The participant will remove his/her own insulin infusion pump (if used) and the participant 
1335 
will set up and start the BP under the supervision of study staff. Participants will be 
1336 
instructed to not take any further insulin outside of the BP throughout the study. A study 
1337 
provider will specifically address the transition of participants off of their MDI therapy as 
1338 
needed.  
1339 
• 
The staff will confirm that the BP is functioning properly prior to discharging the participant.   
1340 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
Page 36 of 69  
• 
Study staff will provide the following additional supplies: the iLet BP, iLet ready-to-fill 
1341 
insulin cartridges along with iLet pigtail adapters or Fiasp in PumpCart along with iLet 
1342 
pigtail adapters and Contact Detach infusion sets.  
1343 
• 
Due to the adaptive nature of the BP, patients on multiple daily injections will be started 
1344 
on the BP without a need for active management of the transition period by study staff, 
1345 
but the new equilibrium will not be reached until all of the insulin glargine (the most 
1346 
common insulin used by this group of patients) has completely cleared their system, which 
1347 
may take approximately 48 hours. Participants will be trained to expect escalating dosing 
1348 
by the BP during this period.  
1349 
 
1350 
 
1351 
 
1352 
The Test Run, Senseonics Eversense Test Run and the Transitional Study Session each only 
1353 
have one startup visit. 
1354 
 
1355 
The Adult RCT Period will have two subsequent startup visits after the initial visit. The 
1356 
procedures at this visit will be as follows: 
1357 
• 
The participants body weight will be documented 
1358 
• 
Study staff will review any changes in the participant’s medical history or medications to 
1359 
ensure continued eligibility, and any adverse events that may have occurred since their 
1360 
last study visit. 
1361 
• 
All participants will be given additional supplies as needed.   
1362 
• 
Participants at Stanford will insert their own Dexcom G5 CGM sensor and study staff will 
1363 
confirm they are doing it correctly. Study staff will remind participants to only use FDA 
1364 
approved insertion sites (abdomen only for > 17 years old, abdomen or upper buttocks for 
1365 
ages 6-17 years old) for their CGM sensor. 
1366 
• 
Study staff will review all study procedures and policies (including the use of the CGM, the 
1367 
Contour Next One, the blood ketone meter and the iLet BP) and the upcoming visit 
1368 
schedule.  
1369 
• 
Study staff will assess the site of the Senseonics Eversense CGM sensor for any signs of 
1370 
infection or other adverse signs. (MGH site only) 
1371 
• 
The Dexcom G5 or Senseonics Eversense CGM will be calibrated by the participant using 
1372 
the Ascensia Contour Next One SMBG glucometer, and study staff will confirm they are 
1373 
doing it properly. 
1374 
Usual Care period  
1375 
• 
Participants will be instructed to follow their usual diabetes management (see section 5.1). 
1376 
Bionic Pancreas periods 
1377 
• 
The control algorithm will be initialized with the participant’s current weight 
1378 
• 
The participant will remove his/her own insulin infusion pump (if used) and the participant 
1379 
will set up and start the BP under the supervision of study staff. Participants will be 
1380 
instructed to not take any further insulin outside of the BP throughout the study. A study 
1381 
provider will specifically address the transition of participants off of their MDI therapy as 
1382 
needed.  
1383 
• 
The staff will confirm that the BP is functioning properly prior to discharging the participant.   
1384 
• 
Study staff will provide the following additional supplies: the iLet BP, iLet ready-to-fill 
1385 
insulin cartridges along with iLet pigtail adapters or Fiasp in PumpCart along with iLet 
1386 
pigtail adapters and Contact Detach infusion sets.  
1387 
• 
Due the adaptive nature of the BP, patients on multiple daily injections will be started on 
1388 
the BP without a need for active management of the transition period by study staff, but 
1389 
the new equilibrium will not be reached until all of the insulin glargine (the most common 
1390 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
Page 37 of 69  
insulin used by this group of patients) has completely cleared their system, which may 
1391 
take approximately 48 hours. Participants will be trained to expect escalating dosing by 
1392 
the BP during this period.  
1393 
 
1394 
The Pediatric RCT Period will have one subsequent startup visit after the initial visit. The 
1395 
procedures for this visit will be as follows: 
1396 
• 
The participants body weight will be documented 
1397 
• 
Study staff will review any changes in the participant’s medical history or medications to 
1398 
ensure continued eligibility, and any adverse events that may have occurred since their 
1399 
last study visit. 
1400 
• 
All participants will be given additional supplies as needed.   
1401 
• 
Participants will insert their own CGM sensor and study staff will confirm they are doing it 
1402 
correctly. Study staff will remind participants to only use FDA approved insertion sites 
1403 
(abdomen only for > 17 years old, abdomen or upper buttocks for ages 6-17 years old) for 
1404 
their CGM sensor. 
1405 
• 
Study staff will review all study procedures and policies (including the use of the Dexcom 
1406 
G5, the Contour Next One, the blood ketone meter and the iLet BP) and the upcoming 
1407 
visit schedule.  
1408 
• 
The Dexcom G5 will be calibrated by the participant using the Ascensia Contour Next One 
1409 
SMBG glucometer, and study staff will confirm they are doing it properly. 
1410 
Usual Care period  
1411 
• 
Participants will be instructed to follow their usual diabetes management (see section 5.1). 
1412 
Bionic Pancreas period 
1413 
• 
The control algorithm will be initialized with the participant’s current weight 
1414 
• 
The participant will remove his/her own insulin infusion pump (if used) and the participant 
1415 
will start the BP. Participants will be instructed to not take any further insulin outside of the 
1416 
BP throughout the study.  
1417 
• 
Due the adaptive nature of the BP, patients on multiple daily injections will be 
1418 
started on the BP without a need for active management of the transition period by 
1419 
study staff, but the new equilibrium will not be reached until all of the insulin 
1420 
glargine (the most common insulin used by this group of patients) has completely 
1421 
cleared their system, which may take approximately 48 hours. Participants will be 
1422 
trained to expect escalating dosing by the BP during this period.  
1423 
• 
The staff will confirm that the BP is functioning properly prior to discharging the participant.   
1424 
• 
Study staff will provide the following additional supplies: the iLet BP, iLet ready-to-fill 
1425 
insulin cartridges along with iLet pigtail adapters and Contact Detach infusion sets.  
1426 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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CHAPTER 5:  PROTOCOLS FOR ADULT TEST-RUN PERIOD, PEDIATRIC 
1427 
TRANSITIONAL STUDY SESSION, AND RCT PERIOD IN ADULTS AND PEDIATRIC 
1428 
PARTICIPANTS 
1429 
 
1430 
 
1431 
The Test-Run Period will include 8 adult participants who use the BP who will follow the protocol 
1432 
as described in this chapter for the BP period in the RCT Period.  Any exceptions will be noted.  
1433 
 
1434 
The Transitional Study Session will include 20 adolescent and pre-adolescent participants who use 
1435 
the BP and who follow the protocol as described in this chapter for the BP period in the RCT period. 
1436 
Any exceptions will be noted. 
1437 
 
1438 
The Test-Run Period will be completed before the Adult RCT Period starts. If any events described 
1439 
in the study stopping criteria (section 8.7) occur during the Test-Run Period, the data for the Test-
1440 
Run Period will be reviewed by the DSMB to determine if the RCT Period will commence. If there 
1441 
are no events for DSMB review during the Test-Run Period, the RCT Period will proceed prior to 
1442 
review of the data by the DSMB. A similar approach will be applied between the Transitional Study 
1443 
Session and the RCT Period in pediatric subjects, and between the Senseonics Eversense Test 
1444 
Run and the Adult RCT Period at MGH.  
1445 
 
1446 
 
1447 
 
1448 
• 
The protocol outlined below is the same for all study participants in all study periods.  
1449 
• 
Study participants will use the Contour Next One glucometer for all glucose measurements 
1450 
in the study.  
1451 
• 
Study participants will keep the study glucometer easily accessible at all times in 
1452 
case a calibration is needed. They will keep fast-acting carbohydrates and a 
1453 
glucagon emergency kit easily accessible in case they are needed.  
1454 
• 
Participants are encouraged to check their BG at least four times a day, before 
1455 
meals and before bedtime. They will also be encouraged to check before driving, 
1456 
before exercise and at intervals during exercise, and for any symptoms of 
1457 
hypoglycemia or hyperglycemia.  
1458 
• 
Participants will use the study provided blood ketone meter for all ketone 
1459 
measurements in the study.  
1460 
• 
The participants will calibrate the Dexcom G5 or Senseonics Eversense CGM before 
1461 
breakfast and supper (approximately every 12 hours) daily using the study glucometer. 
1462 
• 
Participants may perform additional calibrations if the Dexcom G5 (or Senseonics 
1463 
Eversense CGM) is inaccurate relative to a BG measurement. 
1464 
• 
Participants will be reminded not to perform a calibration if they have eaten 
1465 
carbohydrates within the last 30 minutes, or there is a steep rise or fall in their 
1466 
glucose.  
1467 
• 
Participants in the Pediatric Transitional Study Session will be required to check a 
1468 
fingerstick BG between 2:00 and 3:00 AM on the first two nights of each study arm. 
1469 
Participants and their overnight companions will be instructed to contact study staff if they 
1470 
have any concerns with the result of this fingerstick BG. The same remote monitoring 
1471 
protocols will be in place for hypoglycemia and hyperglycemia on these two nights.  
1472 
• 
Participants may not take acetaminophen during all study periods due to potential 
1473 
interference with CGM sensing.   
1474 
• 
Participants will not be allowed to travel by airplane throughout the study, due to our inability 
1475 
to remotely monitor for hypoglycemia and hyperglycemia.  
1476 
• 
Participants will complete a brief daily e-mailed survey during all study periods including 
1477 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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questions about hypoglycemia, carbohydrate interventions, and any other adverse events. 
1478 
They will be reminded that a portion of their reimbursement is dependent on completing at 
1479 
least 90% of these surveys.  
1480 
• 
Participants will not tamper with or alter the iLet BP device in any way, including changing 
1481 
their weight in the iLet. Participants will be instructed not to change their weight in the iLet 
1482 
during a study period, even if their weight changes. They will not edit any of the alarm 
1483 
settings of the CGM.  
1484 
• 
Participants will be asked to change their insulin reservoir and infusion set every 2 days in 
1485 
both the BP and UC periods (for CSII users). 
1486 
• 
Participants will be asked to replace the batteries in the iLet every 2 days to ensure optimal 
1487 
performance of the device.  
1488 
• 
A new Dexcom G5 CGM sensor will be placed every 7 days if no replacement was required 
1489 
before this time. The Dexcom G5 app will generate an alarm when replacement is required. 
1490 
Participants will be reminded to only use FDA approved insertion sites for the G5 CGM 
1491 
sensor.  
1492 
• 
Alarms will sound and a visual alert will appear at the lowest threshold allowed for each 
1493 
CGM system: on the G5 mobile app when the CGM glucose is ≤ 55 mg/dl, or on the 
1494 
Senseonics Eversense app for CGM glucose ≤ 60 mg/dl. 
1495 
• 
Participants will be trained to test their BG with the study glucometer in response 
1496 
to such an alarm and take any necessary measures to treat hypoglycemia. 
1497 
• 
Participants will be trained on troubleshooting for various scenarios that could lead 
1498 
to low threshold alarms. For instance, a threshold alarm could be due to true 
1499 
hypoglycemia, inaccurate CGM readings, or a compression artifact at the site of 
1500 
the sensor.  
1501 
• 
The first step for all glucose-related alarms will be to perform a fingerstick BG 
1502 
measurement.  
1503 
▪ 
If the BG measurement is not consistent with the fact that a threshold alarm 
1504 
has occurred, then the participant will assess the possibility of a compression 
1505 
artifact (they will be trained in the causes and recognition of these events). 
1506 
If a compression artifact is suspected, they will take steps to relieve the 
1507 
pressure on the transmitter. If no compression is suspected, the participant 
1508 
will calibrate the CGM. 
1509 
▪ 
If the BG measurement is consistent with a low threshold alarm, the 
1510 
participant will treat hypoglycemia with carbohydrate ingestion according to 
1511 
their usual practice. Study staff will recommend the standard of care, 15 
1512 
grams of rapid acting carbohydrates and re-testing BG in 15 minutes. Study 
1513 
staff will recommend the participant continue to monitor their BG until it 
1514 
returns to normoglycemia, and to contact study staff with any questions or 
1515 
concerns. 
1516 
• 
Alarms will sound and a visual alert will appear on the CGM app (Dexcom or Senseonics 
1517 
Eversense) if CGM glucose is > 300 mg/dl.  
1518 
• 
Participants will be trained to test their BG with the study glucometer (provided) 
1519 
and the ketone level with the study ketone meter (provided) in response to such 
1520 
an alarm and take necessary measures to treat the hyperglycemia.  
1521 
• 
Participants will be trained on troubleshooting for various scenarios that could lead 
1522 
to persistent or severe hyperglycemia. For instance, hyperglycemia could be due 
1523 
to true hyperglycemia (caused by a missed insulin dose or a failed infusion set for 
1524 
example) or inaccurate CGM readings.  
1525 
• 
The first step in responding to severe or persistent hyperglycemia according to the 
1526 
CGM will be to perform a fingerstick BG and ketone measurement.  
1527 
▪ 
If the BG measurement is not consistent with the CGM readings, the 
1528 
participant will calibrate the CGM.  
1529 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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▪ 
If the BG measurement is consistent with the CGM readings: 
1530 
• 
CSII or BP users will be asked to investigate their insulin infusion set 
1531 
and consider replacing it, check for any occlusions along the insulin 
1532 
fluid path, and check to make sure that the insulin cartridge is not 
1533 
empty.  
1534 
• 
MDI participants on UC will be asked to review their previous insulin 
1535 
doses, and consider correction insulin per their home regimen.  
1536 
• 
Study staff will recommend the participant continue to monitor their 
1537 
BG until it returns to normoglycemia, and to contact study staff with 
1538 
any questions or concerns.  
1539 
• 
If ketones >0.6 mmol/L are present: 
1540 
▪ 
CSII participants on UC will be advised to change their pump infusion set 
1541 
and take correction insulin per their home regimen. 
1542 
▪ 
MDI participants on UC will be advised to take correction insulin per their 
1543 
home regimen. 
1544 
▪ 
BP users will be advised to change their pump infusion set, and will be 
1545 
reminded that the BP should dose insulin accordingly. 
1546 
▪ 
Study staff will recommend the participant continue to monitor their ketone 
1547 
levels and BG every 60 minutes until ketones return to < 0.6 mmol/L and BG 
1548 
is < 180 mg/dl, and to contact study staff with any questions.  
1549 
• 
If participants experience persistent hyperglycemia lasting more than 2 hours, they 
1550 
will be instructed to contact study staff for consideration of infusion set 
1551 
replacement and/or correction insulin according to the above protocol.  
1552 
• 
There are no restrictions of any kind on diet, exercise, or other activities. Participants will 
1553 
be asked to keep their diet and activity as similar as possible throughout the study.  
1554 
• 
The BP is not water resistant and therefore must be removed for showering and swimming 
1555 
and must be kept dry during exercise. Participants are urged to take appropriate precautions 
1556 
when they are disconnected from the BP, including frequent BG checks and having 
1557 
carbohydrate readily available. They are urged to limit the amount of time they are 
1558 
disconnected from the iLet to ensure optimal glucose control.  
1559 
• 
Any medical advice needed by the participants during their participation that is not directly 
1560 
related to the study protocol should be obtained by them in the usual manner with their own 
1561 
physician.  
1562 
• 
If a participant develops an illness during the study he/she can seek medical care 
1563 
as usual. As long as the participant is not hospitalized, the study can be continued. 
1564 
If the participant is unable to eat for a period exceeding one day, they must notify 
1565 
study staff so that the medical staff can assess the safety of continuing to use the 
1566 
BP.  BP use may be temporarily discontinued if study staff believes this is 
1567 
warranted. 
1568 
 
1569 
 
1570 
• 
The protocol outlined below is the same for the entire RCT period. The only modifications 
1571 
for the Transitional Study Session are as follows: 
1572 
• 
Participants will spend the daytime hours under the supervision of study staff 
1573 
participating in group activities and meals 
1574 
• 
Participants will wear an activity monitor 
1575 
• 
Participants will be required to use CSII as their usual care 
1576 
• 
The Test-Run Period and Senseonics Eversense Test Run have no usual care group.  
1577 
• 
The UC group will continue its pre-study diabetes management, including their approach to 
1578 
insulin delivery and monitoring.  The study will provide the CGM supplies and glucometer 
1579 
for use by this group.  Diabetes management will be handled by the participant’s diabetes 
1580 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
Page 41 of 69  
health care provider. If participants use a continuous glucose monitor as a part of usual care 
1581 
they are specifically encouraged to continue use of the CGM during the study period.  
1582 
 
1583 
 
1584 
• 
The protocol outlined below are the same protocol for the Test-Run Period, and the entire 
1585 
RCT Period.  
1586 
o The only modification for the Transitional Study Session are as follows: 
1587 
▪ 
Participants will spend the daytime hours under the supervision of study staff 
1588 
participating in group activities and meals 
1589 
▪ 
Participants will wear an activity monitor 
1590 
o The only modifications for the Senseonics Eversense Test Run are as follows: 
1591 
▪ 
Participants will spend the daytime hours under the supervision of clinically 
1592 
licensed study staff, in a limited area surrounding MGH.  
1593 
• 
All functionality of the BP will remain the same regardless of which CGM system is driving 
1594 
the iLet.  
1595 
• 
The BP will alarm if the CGM glucose is ≤ 50 mg/dl. Participants will follow the same 
1596 
hypoglycemia protocol outlined above.  
1597 
• 
If there is a technical fault with the BP, the participant will call the technical support line 
1598 
immediately. If necessary, a staff member will meet the participant to assist with 
1599 
troubleshooting. This meeting may be delayed until morning if the problem occurs overnight 
1600 
- in this case, the participant will use their own pump or use injectable insulin until a meeting 
1601 
is possible. A member of the study staff (within their scope of practice and under the 
1602 
supervision of the site principal investigator) may advise them on how to manage their 
1603 
diabetes in the interim. If necessary, the BP device may be replaced.   
1604 
o If there is a complete failure of BP operation and it is anticipated that restarting it will 
1605 
take more than an hour, participants may revert to usual care using their own insulin 
1606 
pump or with insulin injections until the BP can be brought back online with the help 
1607 
of study staff. Every effort should be made to correct the problem as soon as 
1608 
possible, which should almost always be possible within 12 hours. 
1609 
• 
If the CGM sensor fails during the course of an experiment, the system will provide 
1610 
automated basal insulin based on past requirements, and will allow announcement of meals 
1611 
(with 75% of predicted insulin delivered based on past requirements), and entry of 
1612 
fingerstick BG measurements (which will be treated as CGM data and may result in 
1613 
administration of insulin or temporary suspension of basal insulin). The system will alarm 
1614 
and request a BG measurement every 120 minutes when the CGM signal is not available, 
1615 
but the system will remain in closed-loop mode even if CGM data are not available. 
1616 
Participants will be encouraged to enter a fingerstick BG measurement into the BP as 
1617 
frequently as they wish to achieve optimal control during CGM downtime. The CGM sensor 
1618 
will be replaced as soon as possible and normal (online) BP control will resume when the 
1619 
new sensor is calibrated.  
1620 
• 
Participants will be encouraged to announce the three major meals of the day to the BP. 
1621 
The meal announcement will consist of choosing the timing of the meal relative to one’s 
1622 
regular sleep period (first of the day, middle of the day, end of the day, or during what would 
1623 
be regular sleep hours if one occasionally happens to be up) and the size of the meal 
1624 
relative to typical meals for that participant (snack, smaller than typical, typical, larger than 
1625 
typical). Participants will be trained not to announce snacks that occur between major 
1626 
meals.  
1627 
• 
The iLet ready-to-fill insulin cartridge or Fiasp in PumpCart, insulin cartridge connectors, 
1628 
and tubing will be replaced as needed, but at least every 2 days.  
1629 
• 
Once the BP is initialized on day 0, participants who use MDI therapy will stop taking insulin 
1630 
by injection. If they take their long-acting insulin in the evening, then they will take their last 
1631 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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dose of long-acting insulin in the evening of day -1. If they take their long-acting insulin in 
1632 
the morning before the scheduled time of the day 0 visit, then they will take their last dose 
1633 
on the morning of day 0. The bionic pancreas will ramp up insulin dosing automatically as 
1634 
needed as the levels of long-acting insulin fall.  
1635 
 
1636 
 
1637 
• 
All remote monitoring protocols will be the same for the Test-Run Period, the Transitional 
1638 
Study Session, the Senseonics Eversense Test Run and the RCT Period. They will also be 
1639 
the same regardless of if the participant is using the BP or is under usual care. They will 
1640 
also be the same regardless of which CGM system is serving as the input to the iLet.  
1641 
• 
Real-time remote telemetric monitoring for biochemically severe hypoglycemia or persistent 
1642 
hyperglycemia will be performed by the study staff 24 hours a day. There will be at least 
1643 
one provider (MD, NP, or PA) and at least one additional study staff member on call in 
1644 
addition to the staff member monitoring for alarms. A staff member will make contact with 
1645 
participants as necessary and help them troubleshoot any issues that may arise.  
1646 
• 
When an alert comes in, a study staff member will call the participant. Depending on the 
1647 
circumstances, they may call locations the participant is known to frequent (e.g. usual work 
1648 
location) or they may be dispatched to make contact with the participant (if the location is 
1649 
nearby and reaching the location would be no risk to the safety of staff member or violate 
1650 
employment rules). 
1651 
• 
Remote monitoring is only possible when the participant has Verizon network coverage and 
1652 
data can be transmitted to the cloud service.  There may be times when a participant enters 
1653 
an area where Verizon coverage is not available.  We may provide participants with WiFi 
1654 
boosters for their homes or WiFi hot spots to carry with them in order to improve data 
1655 
throughput.  We may also encourage participants to connect to public but secure wireless 
1656 
networks if they are having trouble connecting to cellular service. 
1657 
• 
An alert will be generated if remote monitoring indicates that a participant is offline.  We will 
1658 
call the participant every 2 hours to check on safety and device function until remote 
1659 
monitoring is restored. If there are no indications of device malfunction as the cause for lost 
1660 
connectivity, the glucose level is in safe range, and a participant chooses to remain in an 
1661 
area with poor network coverage, we will instruct the participant to check the BP display or 
1662 
CGM at least every 20 minutes for alert icons and to be aware that we are unable to monitor 
1663 
for severe lows or highs at this time.  The same rules will be used for checking in when the 
1664 
participant in in the UC and BP periods. 
1665 
• 
Participants in the Adult Test Run and Senseonics Eversense Test Run will have 
1666 
designated contacts who will serve as an emergency contact person in the event the study 
1667 
staff is unable to get in touch with the participant in response to such an alarm. These 
1668 
designated contacts should have access to where the participant may be sleeping if 
1669 
necessary.  
1670 
• 
Participants in the Pediatric Transitional Study Session will be supervised by study staff 
1671 
during the day, and discharged to a parent or guardian at the end of the day until they return 
1672 
to the study site the following morning. This parent or guardian must be at home when the 
1673 
participant is home and/or sleeping and will serve as the contact for overnight alarms.  
1674 
• 
Participants in the Senseonics Eversense Test Run will be supervised by study staff during 
1675 
the day, and discharged to home at night. Remote monitoring will be continuous regardless 
1676 
of if the subject is with the staff or at home.  
1677 
 
1678 
 
1679 
• 
The remote monitoring system will generate an alarm if the CGM glucose is < 50 mg/dl for 
1680 
15 minutes.  
1681 
• 
Study staff will verify the participants are aware of the hypoglycemia and taking action to 
1682 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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treat it. Participants will be reminded of the protocol for hypoglycemia, and the study 
1683 
provider will ensure they understand and will follow study procedures. Participants will be 
1684 
encouraged to follow up with any questions or concerns. All contact with the participants in 
1685 
response to hypoglycemia alarms will be documented.  
1686 
• 
In the case of a low threshold alarm with no response from the participant and no success 
1687 
in locating them, the site principal investigator will be immediately informed. If remote 
1688 
monitoring shows ongoing hypoglycemia, a decision may be made to dispatch emergency 
1689 
medical services to the locations the participant is known to frequent. 
1690 
• 
Remote monitoring for hypoglycemia will be applied in the Test-Run Period, the Transitional 
1691 
Study Session, the Senseonics Eversense Test Run, and the RCT Period. Monitoring will 
1692 
be identical if participants are on the BP or UC.  
1693 
 
1694 
 
1695 
 
1696 
• 
The remote monitoring system will generate an alarm if the CGM glucose is > 300 mg/dl for 
1697 
90 minutes. Participants will be reminded of the protocol for prolonged hyperglycemia, and 
1698 
the study provider will ensure they understand and will follow study procedures. Participants 
1699 
will be encouraged to follow up with any questions or concerns. All contact with the 
1700 
participants in response to hyperglycemia alarms will be documented. 
1701 
• 
Remote monitoring for hyperglycemia will be applied in the Test-Run Period, the 
1702 
Transitional Study Session, the Senseonics Eversense Test Run, and the RCT Period. 
1703 
Monitoring will be identical if the participants are on the BP or UC.  
1704 
 
1705 
 
1706 
• 
Questions relating to study protocol will be dealt with by a study staff member on call. 
1707 
Participants will be referred to their own medical providers for issues not directly related to 
1708 
the study and to local Emergency Medical Services for medical emergencies.  
1709 
• 
A central technical support line for the BP will be staffed 24 hours a day. An engineer will 
1710 
be on call to deal with non-routine matters.  
1711 
• 
If there is a technical problem with the BP that cannot be resolved over the phone, the 
1712 
participant may be asked to come to the local study site or the study staff may meet them 
1713 
at another location. If this is not possible or would be too disruptive (i.e. in the middle of the 
1714 
night) the participant will be asked to take over his/her own glycemic control using his/her 
1715 
insulin pump (if on CSII) or by giving subcutaneous insulin injections (if on MDI) until such 
1716 
time as a meeting can be arranged for in-person inspection of the device. This should occur 
1717 
in most cases within 12 hours.  
1718 
 
1719 
 
1720 
Participants in all study periods will complete a web-based questionnaire daily.  Participants will be 
1721 
asked to report certain events occurring during the prior day such as hypoglycemia, other medical 
1722 
conditions, alcohol use, exercise, and use of a personal CGM as a part of usual care. In addition, 
1723 
events during the prior 24 hours including nausea and/or vomiting will be solicited. 
1724 
 
1725 
Participants will complete this questionnaire during all study periods (with the assistance of a 
1726 
parent/guardian as needed in the Pediatric periods).   
1727 
 
1728 
 
1729 
The schedule for follow-up visits and phone contacts is the same for both BP and UC. In all groups, 
1730 
study staff will ask participants about any adverse events  
1731 
 
1732 
• 
Test-Run Period: Phone contacts will occur on days 3 or 4 out of the 7-day period. 
1733 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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• 
Transitional Study Session: there will be no phone contact, as the participants are with the 
1734 
study staff daily 
1735 
• 
Senseonics Eversense Test Run: there will be no phone contact, as the participants are 
1736 
with the study staff daily 
1737 
• 
Pediatric RCT Period: Phone contacts will occur on days 3 or 4 out of the 7-day period.  
1738 
• 
Adult RCT Period: Phone contacts will occur on days 3 or 4 out of the 7-day period.  
1739 
 
1740 
 
1741 
The protocol below describes visit shut down procedures for the Test-Run Period, the Transitional 
1742 
Study Session, the Senseonics Eversense Test Run, and the RCT Period. The Test Run, the 
1743 
Transitional Study Session, and the Senseonics Eversense Test Run each only have one 
1744 
shutdown visit. The Adult RCT Period will have three shutdown visits. The Pediatric RCT Period 
1745 
will have two shutdown visits. Shutdown visits occur at the end of each study period. 
1746 
 
1747 
The following procedures will be performed during each shutdown visit: 
1748 
• 
The body weight of the participant will be documented. 
1749 
• 
All study devices, including the iLet BP, the CGM system, the ketone meter and the study 
1750 
glucometer will be downloaded. The subject’s personal insulin pump will be downloaded as 
1751 
needed. The Dexcom G5 transmitter will be cleaned and disinfected per the validated 
1752 
protocol provided by the manufacturer.  
1753 
• 
Any changes to medications or medical history will be documented. 
1754 
• 
The participant will be queried regarding the occurrence of any adverse events 
1755 
• 
Participants will complete psychosocial questionnaires at the end of each period. The Bionic 
1756 
Pancreas User Opinion Survey (BPUOS) will be completed after each BP study period. See 
1757 
chapter 7 for more details.  
1758 
• 
The Senseonics Eversense Test Run will not include questionnaires. 
1759 
• 
A study provider will review the last few hours of glucose trend data and insulin on board 
1760 
from the BP, and assist the participants in resuming their usual diabetes management if 
1761 
they are transitioning off of the BP to their usual care.  
1762 
 
1763 
 
1764 
The Final shutdown visit will occur at the end of the last study period. The following procedures will 
1765 
be performed at the Final Shutdown Visit: 
1766 
• 
The body weight of the participant will be documented. 
1767 
• 
All study devices, including the iLet BP, the CGM system, the ketone meter and the study 
1768 
glucometer will be downloaded. The subject’s personal insulin pump will be downloaded as 
1769 
needed. The Dexcom G5 transmitter will be cleaned and disinfected per the validated 
1770 
protocol provided by the manufacturer. 
1771 
• 
Any changes to medications or medical history will be documented. 
1772 
• 
The participant will be queried regarding the occurrence of any adverse events 
1773 
• 
Participants will complete psychosocial questionnaires. The Bionic Pancreas User Opinion 
1774 
Survey (BPUOS) will be completed after each BP study period. See chapter 7 for more 
1775 
details.  
1776 
• 
A study provider will review the last few hours of glucose trend data and insulin on board 
1777 
from the BP, and assist the participants in resuming their usual diabetes management if 
1778 
they are transitioning off of the BP to their usual care.  
1779 
 
1780 
 
1781 
• 
Adult and pediatric participants randomized to a BP period for their final study period will be 
1782 
discharged to a usual care regimen following the dosing recommendations calculated by 
1783 
the iLet for 48 hours.  
1784 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
Page 45 of 69  
• 
The iLet will recommend doses to be used as basal, for meals, and for corrections. This is 
1785 
intended to provide future consumers of the iLet with a regimen to follow in the event their 
1786 
iLet breaks and it will take a few days to get a replacement.  
1787 
• 
All participants will use either Humalog or Novolog. They will use whichever insulin they 
1788 
used during the BP period.  
1789 
• 
Adult participants will only follow the iLet recommendations based on their iLet BP 
1790 
period using either Humalog or Novolog. If the completed the Fiasp BP period as 
1791 
their last period, they will still be discharged to the Post-Study Transition Period, but 
1792 
will be following the recommendations from the previous period where they used 
1793 
Humalog or Novolog in the iLet.  
1794 
• 
During this time, participants will continue to wear the CGM used during the RCT Period. 
1795 
They will be monitored remotely for severe hypoglycemia and prolonged hyperglycemia 
1796 
according to the same protocol during the study. They will be required to follow all of the 
1797 
same study policies and procedures, including completion of the daily e-mail survey.  
1798 
• 
At the end of this 48-hour period, participants will return to the research clinic for an 
1799 
additional study visit. The CGM data and their insulin pump data where applicable will be 
1800 
collected and analyzed for safety and efficacy of the iLet’s recommendations.  
1801 
• 
Participants will then return to their usual CSII or MDI diabetes regimen.   
1802 
 
1803 
 
1804 
• 
Senseonics Eversense CGM sensor removals will be scheduled for immediately after the 
1805 
RCT Period (or Post-Study Transition Period where appropriate) is finished. This may be 
1806 
on the same day as the Final Shutdown Visit, or in the next few days after as schedules 
1807 
allow, on the condition that no sensor remains in place for 90 days or more.  
1808 
• 
This procedure is similar to the sensor insertion. The skin near the sensor is numbed using 
1809 
a local anesthetic, a small incision is made in the skin using the Removal Template provided 
1810 
by the sponsor, and the sensor is removed. The incision will be closed using surgical tape 
1811 
or a suture, and covered with a bandage.  
1812 
• 
Subjects will be instructed to leave the bandage on for approximately 24 hours. They will 
1813 
be instructed to monitor for any discharge, excessive bleeding, redness, warmth or swelling 
1814 
at the removal site and to contact study staff if this occurs. 
1815 
• 
A study physician will follow up with a phone call within 48 hours of removal to assess 
1816 
appropriate healing and query for any adverse events.  
1817 
 
1818 
 
1819 
 
1820 
 
1821 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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CHAPTER 6:  STUDY DRUGS AND DEVICES 
1822 
 
1823 
The study involves subcutaneous administration of insulin lispro (Humalog, Eli Lilly), insulin aspart 
1824 
(Novolog, Novo Nordisk), or faster-acting insulin aspart (Fiasp, Novo Nordisk). Humalog and 
1825 
Novolog are commercially available by prescription and are indicated for patients with type 1 
1826 
diabetes, but not for use in a BP. Fiasp is approved for use in an MDI regimen, but not in PumpCart 
1827 
or for use in a BP. The current version of the package insert for Fiasp will be used for this protocol. 
1828 
Participants will use their usual rapid-acting insulin analog during the UC period of the study and 
1829 
during the Humalog/Novolog BP period. Adults in the Fiasp BP period will use Fiasp as pre-
1830 
specified.  
1831 
 
1832 
The control system can administer bolus doses of each drug up to every five minutes. A single 
1833 
autonomous bolus of insulin will not exceed 3 units per 5-minute dose [30 µl] (except when it is in 
1834 
response to an isolated BG entry, where the dose will not exceed 12 units [120 µl]) and a single 
1835 
meal-priming dose, which is triggered by the user but automatically determined by the control 
1836 
system, will not exceed 18 units [180 µl]. The dual pump can administer as little as 0.10 µl (0.01 
1837 
units of U-100 insulin) in single programmable bolus doses. Insulin exposure is expected to be 
1838 
comparable to that of participants when not participating in the study.  
1839 
 
1840 
 
1841 
 
1842 
 
1843 
Participants will be provided with infusion sets (Contact Detach infusion sets, Unomedical) for the 
1844 
Test-Run Period, Transitional Study Period and BP periods of the RCT Period. These infusion sets 
1845 
utilize a 6 mm 29 G steel cannula and 23 inch tubing with a leur-lock connection. Participants will 
1846 
be instructed to replace their infusion set every 2 days at least. If the infusion set fails for any reason 
1847 
during the experiment it will be replaced promptly.  
1848 
 
1849 
 
1850 
 
1851 
 
1852 
One transcutaneous glucose sensor for the Dexcom G5 will be inserted in the subcutaneous tissue 
1853 
and will provide input to the controller. The sensor is powered by the battery within the transmitter 
1854 
that clips to the sensor and the whole assembly is held to the skin with an adhesive patch and 
1855 
communicates wirelessly with the BP. If the Dexcom G5 CGM sensor fails for any reason during 
1856 
the experiment it will be replaced promptly.  
1857 
 
1858 
All participants in the Test-Run Period, the Transitional Study Session and the Stanford site of the 
1859 
RCT Period will wear a Dexcom G5 CGM sensor. In these cohorts, the Dexcom G5 CGM will serve 
1860 
as the input to the iLet.  
1861 
 
1862 
 
1863 
 
1864 
One subcutaneous glucose sensor for the Senseonics Eversense Continuous Glucose Monitor 
1865 
System will be inserted in the subcutaneous tissue of the upper arm. The insertion is an office 
1866 
procedure that takes approximately 5 minutes. The insertion requires local anesthesia and a sterile 
1867 
field. After up to 90 days, the sensor is removed in a brief office procedure under local anesthesia. 
1868 
The sensor is approximately 3.3 mm in diameter and 15.7 mm long. It contains a ring that elutes 
1869 
the steroid dexamethasone and core electronics that are potted in epoxy within a poly-
1870 
methylmethacrylate (PMMA) encasement. The glucose indicating copolymer, which is grafted onto 
1871 
the PMMA surface, is fluorescent and changes in intensity in response to changes in glucose 
1872 
concentrations. That intensity data is transmitted to a battery-powered transmitter that is worn on 
1873 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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the upper arm over the insertion site of the sensor. The transmitter is a reusable device that powers 
1874 
the sensor and collects information about glucose levels. It is secured over the sensor insertion site 
1875 
with a transmitter strap or adhesive patch.  The transmitter communicates via Bluetooth Low 
1876 
Energy (BTLE) to a Mobile Medical Application (MMA) installed on a smartphone or other handheld 
1877 
device. This MMA displays glucose information and allows for calibration of the sensor. 
1878 
 
1879 
Only participants at the MGH site of the Senseonics Eversense Test Run and adult RCT Period 
1880 
will wear a Senseonics Eversense CGM. The Senseonics Eversense CGM will act as the input to 
1881 
the iLet in this cohort.  
1882 
 
1883 
 
 
1884 
 
1885 
The iLet bionic pancreas is compatible with both the Dexcom G5 CGM and the Senseonics 
1886 
Eversense CGM. It has an integrated graphical user interface (GUI) and touchscreen display that 
1887 
displays the current CGM glucose, a graphical history of the CGM glucose, and doses of insulin 
1888 
delivered by the control algorithm. The GUI can also be used to input optional meal 
1889 
announcements, designating the size of the meal as “Large for Me” “Typical for Me”, “Small for 
1890 
Me”, or “Tiny for Me”, and the mealtime as the “Start”, “Middle”, “End”, or “Sleeping” periods of the 
1891 
day. This will trigger a partial meal-priming bolus, the size of which will adapt during the course of 
1892 
the trial to meet a target of 75% of the insulin needs for that size and mealtime. Participants will be 
1893 
instructed to announce meals in the same way when using the BP with Humalog or Novolog, or 
1894 
with Fiasp.  
1895 
 
 
1896 
The default “usual” glucose target level for the bionic pancreas in the insulin-only mode is 120 
1897 
mg/dl. This default will be the same when using Humalog or Novolog, or Fiasp.  A higher (130 
1898 
mg/dl) or lower glucose target (110 mg/dl) can be set indefinitely as the “usual” target, or as 
1899 
“temporary” for a limited time with automatic expiration, or as “recurring” with automatic renewal 
1900 
and expiration times. When a temporary target is set, or when a recurring target period is on, upon 
1901 
expiration the target will revert to the currently chosen usual glucose target.  Although our previous 
1902 
studies showed that the bionic pancreas decreased hypoglycemia and the need for carbohydrate 
1903 
interventions relative to usual care, this will allow participants to raise the glucose target for 
1904 
additional safety, particularly temporarily during periods when hypoglycemia may become 
1905 
problematic, such as when driving or otherwise unable to check or attend to their BG for a period 
1906 
of time, or during periods when hypoglycemia is more likely, such as during exercise. It may also 
1907 
be used to raise the mean BG if the mean is unnecessarily low and the user prefers to further 
1908 
reduce the risk of hypoglycemia. The use of this feature will be entirely optional – it will be presented 
1909 
to participants as an option that they may use or not, as they wish. Participants will be allowed to 
1910 
modify the target of the BP according to the same protocol in the Humalog or Novolog periods and 
1911 
the Fiasp period.  
1912 
 
1913 
During periods when the CGM is offline, such as after a sensor is replaced and before the new 
1914 
sensor has been calibrated, the control algorithm will determine and direct the administration of 
1915 
insulin basal rates either based on the participant's weight in the first 24 hours of the experiment, 
1916 
or on the average of adaptively determined basal rates for that time of day once sufficient 
1917 
experience has been accumulated (i.e. 24 hours or more) by the control algorithm. The user will 
1918 
also be able to enter meal announcements in the GUI, in order to trigger automatically calculated 
1919 
meal boluses, in the same way as when the CGM was online. Finally, the user can trigger an 
1920 
automated correction bolus during such periods by entering a BG value in the GUI. The controller 
1921 
will administer insulin or decrease basal insulin as appropriate, in response to entered BG values 
1922 
during such CGM-offline periods, to a large extent as if the BG values were CGM values. 
1923 
 
1924 
The device also displays visual alarms, sounds audible alarms, and generates vibration alarms for 
1925 


 
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problems with the functioning of the bionic pancreas.   
 
1926 
1927 


 
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CHAPTER 7:  QUESTIONNAIRES 
1928 
 
1929 
 
1930 
Questionnaires are completed by all participants at the Initial Startup Visit and each Shutdown Visit. 
1931 
Each questionnaire is described briefly below.  The procedures for administration are described in 
1932 
the study procedures manual. Age appropriate versions of each questionnaire will be administered 
1933 
wherever possible. Parents/guardians of pediatric subjects and designated contacts in the Adult 
1934 
Test Run may complete parent or partner versions of these questionnaires where applicable.  
1935 
Questionnaires will not be administered in the Adult Senseonics Eversense Test Run.  
1936 
 
1937 
 
1938 
 
1939 
 
1940 
The DTSQs measures patient satisfaction with diabetes treatment. It consists of a 6 item scale for 
1941 
assessing treatment satisfaction and two additional items assessing perceived frequency of 
1942 
hyperglycemia and hypoglycemia. The DTSQs is meant for adults and older children. Dr. Clare 
1943 
Bradley has produced a version that is appropriate for BP studies for our use, along with a version 
1944 
for younger children. It is administered at the Initial Startup Visit. The DTSQs is valid and reliable. 
1945 
Administration time is less than 5 minutes. 
1946 
 
1947 
 
1948 
Although the DTSQ is responsive to treatment changes, ceiling effects are often seen with this 
1949 
instrument, where maximum or close-to-maximum scores at baseline provide little opportunity for 
1950 
registering improvement. The DTSQc contains the same items as the DTSQs version but asks 
1951 
patients to consider their satisfaction with their current treatment compared with their previous 
1952 
treatment. The DTSQc is meant for adults and older children. Dr. Clare Bradley has produced a 
1953 
version that is appropriate for BP studies for our use, along with a version for younger children. It 
1954 
is administered at each Shutdown Visit. The DTSQc is valid and reliable. Administration time is less 
1955 
than 5 minutes. 
1956 
 
1957 
 
1958 
There are two versions of the DDS which we will be using; Adult and Partners of Adults. The DDS 
1959 
is a 28-item survey that assesses seven sources of diabetes distress for type 1 adults. It captures 
1960 
feelings of powerlessness; management distress; hypoglycemia distress; negative social 
1961 
perceptions by others; eating distress; physician (health care) distress; and friend/family distress. 
1962 
Items are scored on a 6-point scale from not a problem to a very serious problem. It is administered 
1963 
at the Initial Startup Visit and each Shutdown Visit. The scale is valid and reliable, and has been 
1964 
shown to be sensitive to change over time. Administration time is 5 minutes. 
1965 
 
1966 
 
1967 
There are four versions of the PAID which we will be using; Teen (PAID-T), Parents of Children 
1968 
(PAID-C), Parents of Teens (PAID-T) and Child (PAID-C) versions. This measure of diabetes-
1969 
specific emotional distress in youth with diabetes and their parents is 26 items. A total score is 
1970 
generated. It is administered at the Initial Startup Visit and each Shutdown Visit. The PAID-T and 
1971 
PAID-P are valid and reliable. Psychometric analysis of the PAID-C is in progress. Administration 
1972 
time is 5 minutes. 
1973 
 
1974 
 
1975 
There are three versions of the HFS, Adult (HFS), Youth (HFS-Y) and Parent (HFS-P). The HFS 
1976 
measures several dimensions of fear of hypoglycemia among adults with type 1 diabetes. It 
1977 
consists of 23 items and produces two sub-scale scores; a Behavior sub-scale that measures 
1978 
behaviors involved in avoidance and/or over-treatment of hypoglycemia and a Worry sub-scale that 
1979 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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measures anxiety and fear surrounding hypoglycemia. The HFS-Y consists of 25 items and the 
1980 
HFS-P consists of 26 items; both produce sub-scale scores similar to the Adult HFS. It is 
1981 
administered at the Initial Startup Visit and each Shutdown Visit. All versions of the HFS are valid 
1982 
and reliable. Administration time is 5-10 minutes. 
1983 
 
1984 
 
1985 
The HCS (20) is a 9-item self-report scale that examines the degree to which people with diabetes 
1986 
feel able, secure, and comfortable regarding their ability to stay safe from hypoglycemic-related 
1987 
problems. It has been validated for use in adults with type 1 diabetes and insulin-using type 2 
1988 
diabetes. It is administered at the Initial Startup Visit and each Shutdown Visit. Administration time 
1989 
is approximately 5 minutes. 
1990 
 
1991 
 
1992 
There are five versions of the INSPIRE; Adolescent, Adult, Child, Parent and Partner. The INSPIRE 
1993 
(Insulin Delivery Systems: Perceptions, Ideas, Reflections and Expectations) survey was 
1994 
developed to assess various aspects of a user’s experience regarding automated insulin delivery 
1995 
for both patients and family members. The surveys include various topics important to patients with 
1996 
type 1 diabetes and their family members based upon >200 hours of qualitative interviews and 
1997 
focus groups. The adult survey includes 31 items; the adolescent survey includes 28 items; and 
1998 
the parent survey includes 30 items. Response options for all surveys include a 5-point Likert scale 
1999 
from strongly agree to strongly disagree, along with an N/A option. It is administered at the Initial 
2000 
Startup Visit and each Shutdown Visit. Administration time is approximately 5 minutes. 
2001 
 
2002 
 
2003 
 
2004 
The BPUOS is a 38 item measure that assesses both the benefits from, and difficulties with, use 
2005 
of the BPA total score is generated. It is administered at the end of each BP intervention only. 
2006 
Administration time is 10 minutes. 
2007 
 
 
2008 
 
2009 


 
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51 of 69  
CHAPTER 8: ADVERSE EVENTS, DEVICE ISSUES, AND STOPPING RULES  
2010 
 
2011 
 
2012 
Adverse Event (AE): Any untoward medical occurrence in a patient or clinical investigation subject 
2013 
administered/using a Product and which does not necessarily have a causal relationship with this 
2014 
treatment. An Adverse Event can therefore be any unfavorable and unintended sign (including an 
2015 
abnormal laboratory finding), symptom or disease temporarily associated with the use of a Product, 
2016 
whether or not considered related to the Product. For clarity, an adverse event can occur any time 
2017 
during the course of the study from the time of screening through the final study visit, irrespective of 
2018 
whether a study device or drug is being used at the time of the untoward medical occurrence. 
2019 
 
2020 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
2021 
Results in death. 
2022 
Is life-threatening; (a non-life-threatening event which, had it been more severe, might have become 
2023 
life-threatening, is not necessarily considered a serious adverse event). 
2024 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
2025 
Results in persistent or significant disability/incapacity or substantial disruption of the ability to 
2026 
conduct normal life functions (sight threatening). 
2027 
Is a congenital anomaly or birth defect. 
2028 
Is considered a significant medical event by the investigator based on medical judgment (e.g., may 
2029 
jeopardize the participant or may require medical/surgical intervention to prevent one of the 
2030 
outcomes listed above). 
2031 
Suspicion of transmission of an infectious agent will also be considered an SAE 
2032 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or any life-
2033 
threatening problem or death caused by, or associated with, a device, if that effect, problem, or death 
2034 
was not previously identified in nature, severity, or degree of incidence in the investigational plan or 
2035 
application (including a supplementary plan or application), or any other unanticipated serious problem 
2036 
associated with a device that relates to the rights, safety, or welfare of participants (21 CFR 812.3(s)). 
2037 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which the device 
2038 
may have caused or to which the device may have contributed (Note that an Adverse Event Form is to 
2039 
be completed in addition to a Device Deficiency or Issue Form). 
2040 
Device Complaints: A device complication or complaint is something that happens to a device or related 
2041 
to device performance, whereas an adverse event happens to a participant.  A device complaint may 
2042 
occur independently from an AE, or along with an AE.  An AE may occur without a device complaint or 
2043 
there may be an AE related to a device complaint. 
2044 
Device Malfunction: Any failure of a device to meet its performance specifications or otherwise perform 
2045 
as intended.  Performance specifications include all claims made in the labeling for the device.  The 
2046 
intended performance of a device refers to the intended use for which the device is labeled or marketed. 
2047 
(21 CFR 803.3) 
2048 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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2049 
For this protocol, a reportable adverse event includes any untoward medical occurrence that meets one 
2050 
of the following criteria: 
2051 
1) Non-serious adverse events 
2052 
2) A serious adverse event 
2053 
3) An Adverse Device Effect as defined in section 8.1.1, unless excluded from reporting in 
2054 
section 8.2 
2055 
4) An Adverse Event occurring in association with a study procedure  
2056 
5) Hypoglycemia meeting the definition of severe hypoglycemia as defined below  
2057 
6) Diabetic ketoacidosis (DKA) as defined below 
2058 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse events 
2059 
unless associated with an Adverse Device Effect.  Skin reactions from sensor placement are only 
2060 
reportable if severe and/or required treatment.   
2061 
Pregnancy occurring during the study will be recorded. 
2062 
Reporting to Novo Nordisk 
2063 
For NovoLog: Copies of reports submitted to the FDA.   
2064 
For Fiasp PumpCart: 
2065 
• 
Copies of reports submitted to the FDA. 
2066 
• 
All non-serious adverse events  
2067 
• 
All Serious adverse events 
2068 
• 
All events of pregnancy 
2069 
• 
All technical issues with the product alone, all technical issues with the combined system 
2070 
(pump and PumpCart®) and all issues with the packaging material and labelling” 
2071 
 
2072 
8.1.2.1 Hypoglycemic Events 
2073 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as an adverse event 
2074 
when the following definition for severe hypoglycemia is met:  the event required assistance of another 
2075 
person due to altered consciousness, and required another person to actively administer carbohydrate, 
2076 
glucagon, or other resuscitative actions.  This means that the participant was impaired cognitively to the 
2077 
point that he/she was unable to treat himself/herself, was unable to verbalize his/ her needs, was 
2078 
incoherent, disoriented, and/or combative, or experienced seizure or coma.  These episodes may be 
2079 
associated with sufficient neuroglycopenia to induce seizure or coma.  If plasma glucose measurements 
2080 
are not available during such an event, neurological recovery attributable to the restoration of plasma 
2081 
glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose 
2082 
concentration. 
2083 
8.1.2.2 Hyperglycemic Events/Diabetic Ketoacidosis 
2084 
Hyperglycemia not associated with an Adverse Device Effect is only reportable as an adverse event 
2085 
when one of the following criteria is met:  (1) the event involved DKA, as defined by the Diabetes Control 
2086 
and Complications Trial (DCCT) and described below, or (2) in the absence of DKA if evaluation or 
2087 
treatment was obtained at a health care provider facility for an acute event involving hyperglycemia or 
2088 
ketosis. 
2089 


 
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Hyperglycemic events are classified as DKA if the following are present: 
2090 
• 
Symptoms such as polyuria, polydipsia, nausea, or vomiting; 
2091 
• 
Serum ketones >1.5 mmol/L or large/moderate urine ketones; 
2092 
• 
Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and 
2093 
• 
Treatment provided in a health care facility 
2094 
All reportable Adverse Events—whether volunteered by the participant, discovered by study personnel 
2095 
during questioning, or detected through physical examination, laboratory test, or other means—will be 
2096 
reported on an adverse event form online.  Each adverse event form is reviewed by the Medical Monitor 
2097 
to verify the coding and the reporting that is required. 
2098 
 
2099 
The study investigator will assess the relationship of any adverse event to be related or unrelated by 
2100 
determining if there is a reasonable possibility that the adverse event may have been caused by the 
2101 
study device and/or study drug. 
2102 
Relationship between an AE/SAE and the relevant trial product(s) should be assessed as:  
2103 
Unrelated: The AE is clearly not related to a study drug/device and a likely alternative etiology exists 
2104 
such as an underlying disease, environmental or toxic factors or other therapy. 
2105 
Unlikely Related: The AE does not follow a reasonable temporal sequence during or after use of 
2106 
study drug/device and a more likely alternative etiology exists such as an underlying disease, 
2107 
environmental or toxic factors, or other therapy.  
2108 
Possibly Related: The AE occurred in a reasonable time during or after use of study drug/device; but 
2109 
could be related to another factor such as an underlying disease, environmental or toxic factors, or 
2110 
other therapy; and there is a possible, though weak, scientific basis for establishing a causal 
2111 
association between the AE and the study drug/device. 
2112 
Probably Related: The AE occurred in a reasonable time during or after use of study drug/device; is 
2113 
unlikely to be related to another factor such as an underlying disease, environmental or toxic factors, 
2114 
or other therapy; and there is a plausible, though not strong, scientific basis for establishing a causal 
2115 
association between the AE and the study drug/device.  
2116 
Definitely Related: The AE occurred in a reasonable time during or after use of study drug/device; 
2117 
cannot be explained by another factor such as an underlying disease, environmental or toxic factors, 
2118 
or therapy; and there is a strong scientific basis for establishing a causal association between the AE 
2119 
and the study drug/device.  
2120 
Not Assessable: Causality of an adverse event cannot be judged because information is insufficient 
2121 
or contradictory, and which cannot be supplemented or verified. 
2122 
Alternative etiology, such as underlying disease(s), concomitant medication, and other risk factors, as 
2123 
well as the temporal relationship of the event to trial product administration will be considered and 
2124 
investigated. 
2125 
The investigator should use the investigator’s brochure for the assessment. For each AE/SAE, the 
2126 
investigator must document in the medical records that he/she has reviewed the AE/SAE and has 
2127 
provided an assessment of causality. 
2128 


 
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There may be situations in which an SAE has occurred and the investigator has minimal information to 
2129 
include in the initial report. However, it is important that the investigator always makes an assessment 
2130 
of causality for every event before the initial transmission of the SAE data. 
2131 
The investigator may change his/her opinion of causality in light of follow-up information and updated 
2132 
causality assessment on the electronic CRF completed for the AE/SAE. 
2133 
 
2134 
The causality assessment is one of the criteria used when determining regulatory reporting 
2135 
requirements. 
2136 
 
2137 
The intensity of an adverse event will be rated on a three point scale: (1) mild, (2) moderate, or (3) 
2138 
severe.  It is emphasized that the term severe is a measure of intensity: thus a severe adverse event is 
2139 
not necessarily serious. For example, itching for several days may be rated as severe, but may not be 
2140 
clinically serious. 
2141 
MILD: Usually transient, requires no special treatment, and does not interfere with the participant’s 
2142 
daily activities. 
2143 
MODERATE: Usually causes a low level of inconvenience or concern to the participant and may 
2144 
interfere with daily activities, but is usually ameliorated by simple therapeutic measures. 
2145 
SEVERE: Interrupts a participant’s usual daily activities and generally requires systemic drug 
2146 
therapy or other treatment. 
2147 
 
2148 
Adverse events will be coded using the MedDRA dictionary.  The Medical Monitor will review the 
2149 
investigator’s assessment of causality and may agree or disagree.  Both the investigator’s and Medical 
2150 
Monitor’s assessments will be recorded.  The Medical Monitor will have the final say in determining the 
2151 
causality. 
2152 
Adverse events that continue after the participant’s discontinuation or completion of the study will be 
2153 
followed until their medical outcome is determined or until no further change in the condition is expected. 
2154 
 
2155 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
2156 
RESOLVED – The participant recovered from the AE/SAE without sequelae.  Record the AE/SAE 
2157 
stop date. 
2158 
RESOLVED WITH SEQUELAE – The event persisted and had stabilized without change in the 
2159 
event anticipated.  Record the AE/SAE stop date. 
2160 
FATAL – A fatal outcome is defined as the SAE that resulted in death.  Only the event that was the 
2161 
cause of death should be reported as fatal.  AEs/SAEs that were ongoing at the time of death; 
2162 
however, were not the cause of death, will be recorded as “resolved” at the time of death. 
2163 
UNKNOWN – An unknown outcome is defined as an inability to access the participant or the 
2164 
participant’s records to determine the outcome (for example, a participant that was lost to follow-
2165 
up). 
2166 
ONGOING – An ongoing AE/SAE is defined as the event was ongoing with an undetermined 
2167 
outcome. 
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An ongoing outcome will require follow-up by the site in order to determine the final outcome of 
2169 
the AE/SAE. 
2170 
The outcome of an ongoing event at the time of death that was not the cause of death, will be 
2171 
updated and recorded as “resolved” with the date of death recorded as the stop date. 
2172 
All clinically significant abnormalities of clinical laboratory measurements or adverse events occurring 
2173 
during the study and continuing at study termination should be followed by the participant’s physician 
2174 
and evaluated with additional tests (if necessary) until diagnosis of the underlying cause, or resolution.  
2175 
Follow-up information should be recorded on source documents.  
2176 
If any reported adverse events are present when a participant completes the study, or if a participant is 
2177 
withdrawn from the study due to an adverse event, the participant will be contacted for re-evaluation 
2178 
within 2 weeks.  If the adverse event has not resolved, additional follow-up will be performed as 
2179 
appropriate.  Every effort should be made by the Investigator or delegate to contact the participant until 
2180 
the adverse event has resolved or stabilized. 
2181 
 
2182 
All UADEs, ADEs, device complaints, and device malfunctions will be reported irrespective of whether 
2183 
an adverse event occurred, except in the following circumstances. 
2184 
The following device issues are anticipated and will not be reported on a Device Issue Form but will 
2185 
reported as an Adverse Event if the criteria for AE reporting described above are met: 
2186 
Component disconnections 
2187 
Dexcom G5 CGM sensors lasting fewer than 7 days 
2188 
CGM tape adherence issues 
2189 
Pump infusion set occlusion not leading to ketosis 
2190 
Battery lifespan deficiency due to inadequate charging or extensive wireless communication 
2191 
Intermittent device component disconnections/communication failures not leading to system 
2192 
replacement 
2193 
Device issues clearly addressed in the user guide manual that do not require additional 
2194 
troubleshooting 
2195 
Skin reactions from CGM sensor placement or pump infusion set placement that don’t meet criteria 
2196 
for AE reporting 
2197 
 
2198 
If pregnancy occurs, the participant will be discontinued from the study.  The occurrence of pregnancy 
2199 
will be reported on an AE Form. 
2200 
 
2201 
Serious or unexpected device-related or drug-related adverse events must be reported to the 
2202 
Coordinating Center within 24 hours via completion of the online serious adverse event form. 
2203 
Other reportable adverse events and device malfunctions (with or without an adverse event) will be 
2204 
reported within 3 days of the investigator becoming aware of the event by completion of an electronic 
2205 
case report form. 
2206 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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Device complaints not associated with device malfunction or an adverse event must be reported within 
2207 
7 days of the investigator becoming aware of the event. 
2208 
The Coordinating Center will notify all participating investigators of any adverse event that is serious, 
2209 
related, and unexpected. Notification will be made within 10 days after the Coordinating Center 
2210 
becomes aware of the event. 
2211 
Each principal investigator is responsible for reporting serious study-related adverse events and abiding 
2212 
by any other reporting requirements specific to his/her Institutional Review Board or Ethics Committee. 
2213 
Upon receipt of a UADE report, the Sponsor will investigate the UADE and if indicated, report the results 
2214 
of the investigation to the sites’ IRBs, and the FDA within 10 working days of the Sponsor becoming 
2215 
aware of the UADE per 21CFR 812.46(b) (2).  The Medical Monitor must determine if the UADE 
2216 
presents an unreasonable risk to participants.  If so, the Medical Monitor must ensure that all 
2217 
investigations, or parts of investigations presenting that risk, are terminated as soon as possible but no 
2218 
later than 5 working days after the Medical Monitor makes this determination and no later than 15 
2219 
working days after first receipt notice of the UADE. 
2220 
Device malfunctions will be handled by the Sponsor or designee as described below.  In the case of a 
2221 
CGM transmitter or sensor device malfunction, information will be forwarded to Dexcom by the site 
2222 
personnel, to be handled by their complaint management system. 
2223 
Beta Bionics will notify the Investigator of trial product-related suspected unexpected serious adverse 
2224 
reactions (SUSARs) in accordance with local requirements and GCP. In addition, the Investigator will 
2225 
be informed of any trial-related SAEs that may warrant a change in any trial procedure. 
2226 
In accordance with regulatory requirements, Beta Bionics will inform the regulatory authorities of trial 
2227 
product-related SUSARs. In addition, Beta Bionics will inform the Institutional Review 
2228 
Boards/Independent Ethics Committees (IRBs/IECs) of trial product-related SUSARs in accordance 
2229 
with local requirement and GCP, unless locally this is an obligation of the Investigator. 
2230 
Prompt notification to Novo Nordisk of a SAE is essential so that legal obligations and ethical 
2231 
responsibilities towards the safety of subjects and the safety of a trial product under clinical investigation 
2232 
are met. Novo Nordisk has a legal responsibility to notify both the local regulatory authority and other 
2233 
regulatory agencies about the safety of a trial product under clinical investigation. Novo Nordisk will 
2234 
comply with country-specific regulatory requirements relating to safety reporting to the regulatory 
2235 
authority, institution review board (IRB), independent ethics committee (IEC), and investigators. 
2236 
Drug related UADEs will also be reported to Novo Nordisk within 15 days of the investigator’s first 
2237 
knowledge of the event. At a minimum, the following should be reported: Study name, Patient 
2238 
identification (e.g. subject number, initials, sex, age), Event (Preferably diagnosis), Trial drug, Reporter, 
2239 
Causality, and Outcome.  
2240 
 
2241 
An independent Data and Safety Monitoring Board (DSMB) will be informed of all serious adverse 
2242 
events and any unanticipated adverse device events that occur during the study and will review 
2243 
compiled safety data at periodic intervals.  Details regarding review will be documented in standalone 
2244 
DSMB procedural documentation.   
2245 
 
2246 
 
2247 
Loss of confidentiality is a potential risk; however, data are handled to minimize this risk.  Hypoglycemia 
2248 
is always a risk in participants with type 1 diabetes and participants will be closely monitored for this. 
2249 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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Hyperglycemia and ketone formation are always a risk in participants with type 1 diabetes and 
2250 
participants will be closely monitored for this.  
2251 
 
2252 
 
2253 
A hollow needle/plastic tube will be placed in the arm for taking blood samples. Blood draws can cause 
2254 
some common reactions like pain, bruising, or redness at the sampling site.  Less common reactions 
2255 
include bleeding from the sampling site, formation of a small blood clot or swelling of the vein and 
2256 
surrounding tissues, and fainting. 
2257 
 
2258 
 
2259 
About 1 drop of blood will be removed by finger stick for measuring blood sugars and sometimes HbA1c 
2260 
or other tests. This is a standard method used to obtain blood for routine hospital laboratory tests.  Pain 
2261 
is common at the time of lancing.  In about 1 in 10 cases, a small amount of bleeding under the skin will 
2262 
produce a bruise.  A small scar may persist for several weeks.  The risk of local infection is less than 1 
2263 
in 1000.  This should not be a significant contributor to risks in this study as finger pokes are part of the 
2264 
usual care for people with diabetes. 
2265 
 
2266 
 
2267 
Participants using the Dexcom continuous glucose sensor will be at low risk for developing a local 
2268 
skin infection at the site of the sensor needle placement. On rare occasions, the Dexcom continuous 
2269 
glucose sensor may break and leave a small portion of the sensor under the skin that may cause 
2270 
redness, swelling or pain at the insertion site.  The participant should be further instructed to notify the 
2271 
study coordinator immediately if this occurs.  
2272 
 
2273 
There are additional risks associated with the Senseonics Eversense CGM sensor insertion, removal, 
2274 
and/or use of the CGM system. The risks are greater than in the lives of people with diabetes outside this 
2275 
trial, as the Senseonics Eversense system is not approved for consumer use in the United States. In 
2276 
studies using the Senseonics Eversense CGM system to date, no device related serious adverse events 
2277 
have been reported, and only a few device related averse events have been reported. Of those, most 
2278 
were predominately expected local skin reactions to the insertion and/or the local anesthesia provided 
2279 
during this procedure, which all recovered without residual damage after short time periods. In our own 
2280 
experience with the Senseonics Eversense sensor, 27 sensors were implanted and removed without any 
2281 
unexpected or serious adverse events. Study staff will examine the insertion site at each study visit and 
2282 
make appropriate notes that will be relayed back to the sponsor. Subjects will be instructed to contact 
2283 
study staff immediately upon any sign of extreme irritation or discomfort.  
2284 
 
2285 
If a subcutaneous infusion set catheter is left under the skin for more than 24 hours it is possible to get 
2286 
an infection where it goes into the skin, with swelling, redness and pain.  There may be bleeding where 
2287 
the catheter is put in and bleeding under the skin causing a bruise (1 in 10 risk).  When wearing sensors 
2288 
and insulin infusion sets there is always a risk of skin rashes, allergic reactions to the tape, or infections 
2289 
at the insertion site. Infections occur very infrequently, but, if an infection was to occur, oral and/or 
2290 
topical antibiotics can be used.   
2291 
 
2292 
 
2293 
Hypoglycemia could occur if the system delivers an inappropriate amount of insulin given the 
2294 
participant’s underlying glycemic state.  This could occur if, for example, a sensor is functioning poorly 
2295 
and significantly over-reading glucose values.  Over-delivery may be minimized if the sensor’s trend 
2296 
data remains accurate despite inaccurate level values, or by the safety constraints of the closed loop 
2297 
system.  However, there is a risk of having a low blood sugar (hypoglycemia) that may exceed the risk 
2298 
present as part of normal daily living.  Symptoms of hypoglycemia can include sweating, jitteriness, and 
2299 
not feeling well.  Just as with normal daily living, there is the possibility of fainting or seizures 
2300 
(convulsions) and that for a few days the participant may not be as aware of symptoms of low blood 
2301 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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58 of 69  
sugar. 
2302 
 
2303 
 
2304 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an extended 
2305 
period or if the pump or infusion set is not working properly.  A sensor which was functioning poorly and 
2306 
significantly under-reading glucose values could lead to inappropriate reduction of insulin delivery. 
2307 
 
2308 
 
2309 
As part of the study, participants will complete psychosocial questionnaires which include questions 
2310 
about their private attitudes, feelings and behavior related to diabetes.  It is possible that some people 
2311 
may find these questionnaires to be mildly upsetting. Similar questionnaires have been used in previous 
2312 
research and these types of reactions have been uncommon. 
2313 
2314 
 
2315 
Some participants may develop skin irritation or allergic reactions to the adhesives used to secure the 
2316 
CGM, the activity monitor, or the insulin infusion sets.  If these reactions occur, different adhesives or 
2317 
“under-taping” (such as with IV 3000, Tegaderm, etc.) will be tried, sites will be rotated frequently, and 
2318 
a mild topical steroid cream or other medication may be required. 
2319 
 
2320 
Data downloaded from the BP, the SMBG meter, and the ketone meter, and the activity monitor will be 
2321 
collected for the study as measures of diabetes self-management behaviors.  Some people may be 
2322 
uncomfortable with the researchers' having such detailed information about their daily diabetes habits. 
2323 
 
2324 
 
2325 
In general, once a participant is randomized, he/she will remain in the study through Shutdown Visit 
2326 
unless the investigator believes it is not safe for the participant to continue.  However, the criteria below 
2327 
will be used to determine whether use of the BP should be discontinued for a participant. 
2328 
 
2329 
 
2330 
Rules for discontinuing study device are described below. 
2331 
1. The investigator believes it is unsafe for the participant to continue on the intervention.  This 
2332 
could be due to the development of a new medical condition or worsening of an existing 
2333 
condition; or participant behavior contrary to the indications for use of the device that imposes 
2334 
on the participant’s safety. 
2335 
2. The participant requests that the treatment be stopped 
2336 
3. Developing >1.0 mmol/L ketones on more than 3 days total due to prolonged periods of 
2337 
inadequate insulin delivery recommendation. 
2338 
4. Participant Pregnancy 
2339 
5. One episode of DKA (as defined in section 8.1.2.2), unrelated to infusion site failure, related to 
2340 
automated attenuation of insulin delivery  
2341 
6. One severe hypoglycemia event (as defined in section 8.1.2.1) related to automated insulin 
2342 
delivery  
2343 
 
2344 
If BP use is stopped according to the above criteria, but the participant is willing, he/she will remain in 
2345 
the trial and will continue to make all of the scheduled visits and participate in all monitoring. The primary 
2346 
analysis will be intention to treat.  Since participants in the UC period are following their normal diabetes 
2347 
care regimen, there will be no change in their participation in the trial if they experience one of the 
2348 
events that would trigger stopping in the BP period. 
2349 
 
2350 
Study participation is voluntary, and participants may withdraw at any time.  
2351 
 
2352 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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59 of 69  
 
2353 
The DSMB will have the responsibility of determining if the overall study should be stopped.  If there 
2354 
are no events for DSMB review during the pilot study for the first 8 participants in the Test Run, then 
2355 
the Adult RCT crossover study will be initiated prior to review of the data from the pilot study. Similarly 
2356 
for the pediatric population, if there are no events for DSMB review during the pilot study for the first 20 
2357 
participants in the Transitional Study Session, then the Pediatric RCT crossover study will be initiated 
2358 
prior to review of the data from the pilot study.  
2359 
 
2360 
In case of a recurring system malfunction or participant safety issue observed with multiple participants, 
2361 
the overall study will be suspended while the problem is diagnosed.  The study may resume if the 
2362 
underlying problem can be corrected by a protocol or system modification that will not invalidate the 
2363 
results obtained prior to suspension. 
2364 
 
2365 
An instance of severe hypoglycemia or hyperglycemia as defined in section 8.1 in the BP group will 
2366 
result in temporarily stopping additional enrollment of participants until DSMB review of the data to 
2367 
determine whether the event was triggered by the system or not and whether it is safe to proceed.  The 
2368 
currently-enrolled participants will continue use of the system during this time unless the DSMB 
2369 
determines it is unsafe for them to do so.  
2370 
 
2371 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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CHAPTER 9:  MISCELLANEOUS CONSIDERATIONS 
2372 
 
2373 
 
2374 
It is expected that this protocol will yield increased knowledge about using an automated closed-loop to 
2375 
control the glucose level.  This research is one step on the path towards development of a fully closed-
2376 
loop system.  The individual participant may not benefit from study participation. 
2377 
 
2378 
 
2379 
Participants will be compensated $50 for each pre-specified clinic visit during the study and $50 for 
2380 
completing at least 90% of the daily questionnaires. 
2381 
 
2382 
 
2383 
Participation in the study is voluntary, and a participant may withdraw at any time.  The investigator may 
2384 
withdraw a participant who is not complying with the protocol. Withdrawal of a participant will be 
2385 
considered for the reasons listed in section 8.7.  For participants who withdraw, their data will be used 
2386 
up until the time of withdrawal. 
2387 
 
2388 
For participants using the BP who withdraw, a study provider will help them transition to their own CSII 
2389 
or MDI therapy safely. 
2390 
 
2391 
 
2392 
For security and confidentiality purposes, participants will be assigned an identifier that will be used 
2393 
instead of their name.  Protected health information gathered for this study will be shared with the 
2394 
coordinating center, the Jaeb Center for Health Research in Tampa, FL. De-identified participant 
2395 
information may also be provided to research sites involved in the study. 
2396 


 
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CHAPTER 10:  STATISTICAL CONSIDERATIONS 
2397 
 
2398 
 
2399 
The approach to sample size and statistical analyses are summarized below. A detailed statistical 
2400 
analysis plan will be written and finalized prior to the start of the study.   
2401 
 
2402 
 
2403 
Eight adult participants are expected to complete the Test-Run Period, 4 adults are expected to 
2404 
complete the Senseonics Eversense Test Run, and 36 adult participants will be enrolled in the RCT 
2405 
Period. 20 pediatric participants are expected to complete the Transitional Study Session and 20 
2406 
pediatric participants will be enrolled in the Pediatric RCT Period. These are convenience samples not 
2407 
based on statistical principles. 
2408 
 
2409 
 
2410 
 
2411 
 
2412 
Eight adult participants (age ≥18 years) will use the iLet in the insulin-only configuration with Humalog 
2413 
or Novolog (using the iLet pigtail adapter, the iLet ready-to-fill insulin cartridge, the Contact Detach 
2414 
infusion set, and the Dexcom G5 CGM) for 7 days at a single site. The uncontrolled Test-Run Period 
2415 
will be completed and data reviewed to verify safety before proceeding with Transitional Study and with 
2416 
Adult RCT Period. 
2417 
 
2418 
 
2419 
No formal statistical comparisons will be done for Test-Run Period. This period has no control period 
2420 
and is primarily intended to verify that the iLet is operating as expected (based on its design and on 
2421 
bench testing) in the outpatient setting.   
2422 
 
2423 
Since the main aim for Test-Run Period is to verify safety and feasibility, plus some trends in efficacy, 
2424 
the following outcomes will be considered: 
2425 
• 
Safety: 
2426 
o Episodes of severe hypoglycemia as defined in section 8.1.2.1 
2427 
o Episodes of diabetic ketoacidosis (DKA) as defined in section 8.1.2.2 
2428 
o Other serious adverse events 
2429 
• 
Questionnaires (treatment satisfaction): 
2430 
o For each questionnaire completed at 0 and 7 days, mean (standard deviation [SD]) 
2431 
values or medians (interquartile range [IQR]) appropriate to the distribution will be given 
2432 
for the total score and where indicated for each subscale  
2433 
• 
Sensor: 
2434 
o Hypoglycemia: 
2435 
▪ 
time <70, 60, and 54 mg/dl  
2436 
▪ 
low blood glucose index (LBGI) 
2437 
▪ 
hypoglycemic events per 24 hours - defined as ≥15 consecutive minutes with a 
2438 
sensor glucose <50 mg/dL 
2439 
o Overall Control: 
2440 
▪ 
mean glucose  
2441 
▪ 
time in the target ranges of 70-180 and 70-120 mg/dl  
2442 
▪ 
glucose variability measured with coefficient of variation (CV) 
2443 
o Hyperglycemia: 
2444 
▪ 
time >180 and 250mg/dl  
2445 
▪ 
High blood glucose index (HBGI) 
2446 
▪ 
hyperglycemic events per 24 hours - defined as ≥90 consecutive minutes with a 
2447 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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62 of 69  
sensor glucose >300 mg/dL 
2448 
• 
Sensor accuracy: 
2449 
o The following will be calculated using the Ascensia Contour Next One point-of care 
2450 
glucose meter: 
2451 
▪ 
MARD for the Dexcom G5 overall and in the following SMBG ranges: < 70, 70–
2452 
180, > 180, > 250 
2453 
 
2454 
• 
System and remote monitoring: 
2455 
o percentage of time IOBP was in use 
2456 
o number and rates of different errors or malfunctions 
2457 
• 
Daily at-home questionnaire: 
2458 
o symptomatic hypoglycemia 
2459 
o hypoglycemia requiring carbohydrate intervention 
2460 
o alcohol use 
2461 
o exercise 
2462 
o nausea and/or vomiting 
2463 
o use of a personal CGM as a part of usual care 
2464 
2465 
Sensor metrics will be calculated using data from days 3-7. The Test Run will be completed and the 
2466 
data will be reviewed to verify safety prior to beginning the Adult RCT Period.  
2467 
 
2468 
 
2469 
 
2470 
 
2471 
Four adult participants (age ≥18 years) will use the iLet in the insulin-only configuration with Humalog 
2472 
or Novolog (using the iLet pigtail adapter, the iLet ready-to-fill insulin cartridge, the Contact Detach 
2473 
infusion set, and the Senseonics Eversense CGM) for 3 days at a single site. This uncontrolled study 
2474 
period will be completed and data reviewed to verify safety before proceeding with the Adult RCT Period 
2475 
at MGH using the Senseonics Eversense CGM as the input to the iLet. 
2476 
 
2477 
 
2478 
No formal statistical comparisons will be done for Senseonics Eversense test run period. This period 
2479 
has no control period and is primarily intended to verify that the iLet is operating as expected (based on 
2480 
its design and on bench testing) in the outpatient setting using this alternative CGM that has not been 
2481 
tested with the iLet before.   
2482 
 
2483 
Since the main aim for this period is to verify safety and feasibility, plus some trends in efficacy, the 
2484 
following outcomes will be considered: 
2485 
• 
Safety: 
2486 
o Episodes of severe hypoglycemia as defined in section 8.1.2.1 
2487 
o Episodes of diabetic ketoacidosis (DKA) as defined in section 8.1.2.2 
2488 
o Other serious adverse events 
2489 
o distribution will be given for the total score and where indicated for each subscale  
2490 
• 
Sensor: 
2491 
o Hypoglycemia: 
2492 
▪ 
time <70, 60, and 54 mg/dl  
2493 
▪ 
low blood glucose index (LBGI) 
2494 
▪ 
hypoglycemic events per 24 hours - defined as ≥15 consecutive minutes with a 
2495 
sensor glucose <50 mg/dL 
2496 
o Overall Control: 
2497 
▪ 
mean glucose  
2498 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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63 of 69  
▪ 
time in the target ranges of 70-180 and 70-120 mg/dl  
2499 
▪ 
glucose variability measured with coefficient of variation (CV) 
2500 
o Hyperglycemia: 
2501 
▪ 
time >180 and 250mg/dl  
2502 
▪ 
High blood glucose index (HBGI) 
2503 
▪ 
hyperglycemic events per 24 hours - defined as ≥90 consecutive minutes with a 
2504 
sensor glucose >300 mg/dL 
2505 
• 
Sensor accuracy: 
2506 
o The following will be calculated using the Ascensia Contour Next One point-of care 
2507 
glucose meter: 
2508 
▪ 
MARD for the Senseonics Eversense CGM overall and in the following SMBG 
2509 
ranges: < 70, 70–180, > 180, > 250 
2510 
• 
System and remote monitoring: 
2511 
o percentage of time IOBP was in use 
2512 
o number and rates of different errors or malfunctions 
2513 
• 
Daily at-home questionnaire: 
2514 
o symptomatic hypoglycemia 
2515 
o hypoglycemia requiring carbohydrate intervention 
2516 
o alcohol use 
2517 
o exercise 
2518 
o nausea and/or vomiting 
2519 
o use of a personal CGM as a part of usual care 
2520 
2521 
Sensor metrics will be calculated using data from days 2-3. The Senseonics Eversense Test Run will 
2522 
be completed and the data will be reviewed to verify safety prior to beginning the Adult RCT Period 
2523 
with the Senseonics Eversense CGM as the input to the iLet.  
2524 
 
2525 
 
2526 
 
2527 
 
2528 
20 pediatric participants (~ 6 participants age 6–11 years at Nemours, ~ 6 participants age 12–17 
2529 
years at Colorado, and ~ 8 participants age 6–17 years at Stanford) will be randomly assigned to the 
2530 
following study periods: (1) use of iLet in the insulin-only configuration with the iLet pigtail adapter and 
2531 
the iLet ready-to-fill insulin cartridge, the Contact Detach infusion set, the Dexcom G5 CGM, and the 
2532 
insulin analog that they use for their usual care (either Humalog or Novolog), and (2) participant’s own 
2533 
usual care (UC) where each participant will wear a Dexcom G5 CGM. The two experimental periods 
2534 
will each span approximately 5 days with a washout period of ~ 3 days in between.  The Pediatric 
2535 
Transitional Study Sessions will be completed and the data will be reviewed to verify safety prior to 
2536 
beginning the Pediatric RCT Period.  
2537 
 
2538 
 
2539 
• 
The outcomes and analyses will parallel the ones mentioned above for Test-Run Period (i.e, 
2540 
Section 10.2.2) with the exceptions: 
2541 
o Sensor metrics will be calculated using data from days 2–5 from each experimental 
2542 
period.  
2543 
o The results will be presented by both experimental periods without any formal statistical 
2544 
comparison. Summary statistics appropriate to the distribution will be given separately 
2545 
for the two experimental periods.  
2546 
o Questionnaires will be completed at baseline and day 5 of each experimental period.  
2547 
 
2548 
 
2549 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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2550 
2551 
 
2552 
Forty adult participants (age ≥18 years) will be enrolled at two sites and will be randomly assigned to 
2553 
the following study periods: (1) the iLet in the insulin-only configuration (with the iLet pigtail adapter, the 
2554 
iLet ready-to-fill insulin cartridge, and the Contact Detach infusion set) using insulin analog that they 
2555 
use for their usual care (either Humalog or Novolog), (2) the iLet in the insulin-only configuration (with 
2556 
the iLet pigtail adapter, and the Contact Detach infusion set) using faster insulin aspart (Fiasp), where 
2557 
the pharmacokinetic (PK) parameter for tmax used by the insulin-dosing algorithm will be set to the same 
2558 
value as is used for Humalog and Novolog (65 minutes), and (3) UC (with CGM). Each treatment period 
2559 
will last 7 days and there will be approximately 7 days of wash-out in between them. 
2560 
 
2561 
 
2562 
 
2563 
10.5.2.1 Main Efficacy Outcomes 
2564 
 
2565 
All pre-specified main efficacy outcomes in adult subjects will be calculated by pooling data from 
2566 
subjects enrolled at the MGH and Stanford sites (and therefore using the Senseonics Eversense and 
2567 
Dexcom G5 CGMs, respectively). All reference to CGM data below refers to the CGM system that is 
2568 
serving as the input to the iLet.  
2569 
 
2570 
There are two primary outcome metrics (mean glucose and time <54 mg/dl) and three treatment 
2571 
group comparisons [(2) BP with rapid insulin vs. (3) UC, (1) BP with analog insulin vs. (3) UC, and (2) 
2572 
BP with rapid insulin vs. (1) BP with analog insulin], for a total of six statistical comparisons.  
2573 
 
2574 
To preserve the overall type 1 error, a hierarchical gatekeeping testing procedure will be used. If a 
2575 
comparison results in a statistically significant result (p < 0.05), then testing will proceed to the next 
2576 
one on the list in the following order: 
2577 
1. Mean glucose for (2) BP with rapid insulin vs. (3) UC 
2578 
2. Time <54 mg/dl for (2) BP with rapid insulin vs. (3) UC 
2579 
3. Mean glucose for (1) BP with analog insulin vs. (3) UC 
2580 
4. Time <54 mg/dl for (1) BP with analog insulin vs. (3) UC 
2581 
5. Mean glucose for (2) BP with rapid vs. (1) BP with analog insulin 
2582 
6. Time <54 mg/dl for (2) BP with rapid vs. (1) BP with analog insulin 
2583 
 
2584 
This process continues iteratively moving to the next combination down on the list until a non-
2585 
significant result (p ≥ 0.05) is observed, or all six tests are performed.   
2586 
 
2587 
Regardless of the results of the hierarchical testing, summary statistics appropriate to the distribution 
2588 
will be tabulated by treatment period for each metric.   
2589 
 
2590 
Time <54 mg/dl and mean glucose will be computed from all available CGM data during days 3-7 for 
2591 
each one of the three treatment periods in the Adult RCT Period. The performance in the iLet periods 
2592 
and the difference between the iLet periods and the usual care periods can be compared with historical 
2593 
data from previous bionic pancreas trials using previous generations of hardware. If the performance of 
2594 
the iLet in this study is comparable to our previous data from trials using the iPhone-based bionic 
2595 
pancreas that will support the hypothesis that the iLet is an effective and safe implementation of the 
2596 
bionic pancreas. All participants with at least 24 hours of CGM data during days 3-7 of any two of the 
2597 
three treatments periods will be included in these analyses. Summary statistics appropriate to the 
2598 
distribution for time <54 mg/dl and mean glucose will be reported for all periods; while a linear model 
2599 
that accounts for correlated data from the same subject will be used to compare the treatment periods 
2600 
for the Adult RCT Period as described above. From prior experience, the values for time <54 mg/dl will 
2601 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
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have a skewed distribution and for mean glucose a bell-shaped distribution, but the paired differences 
2602 
may follow an approximate bell-shaped curve. Residual values for the paired differences will be 
2603 
examined for an approximate normal distribution. If values are highly skewed then a rank test will be 
2604 
used instead. Additional models will be run to test for any carry-over effects, by adding a treatment by 
2605 
order interaction term. 
2606 
 
2607 
Scatter plots for time <54 mg/dl and for mean glucose by the three randomized treatment periods in the 
2608 
Adult RCT Period will be generated. Additionally, boxplots for all three periods will be generated for both 
2609 
outcomes. 
2610 
 
2611 
Assuming an effective SD of 1.0% for the pair differences between any one of the three pairwise 
2612 
comparisons for time <54 mg/dl, the half width of the associated 95% confidence interval are 
2613 
approximately ±0.4% for N=36 and ±0.6% for N=18. Similarly, assuming an effective SD of 25 mg/dl for 
2614 
mean glucose, the half width of the associated 95% confidence interval are approximately ±10 mg/dl 
2615 
for N=36 and ±15 mg/dl for N=18. Results from the Medtronic 670G Pivotal Trial were used to estimate 
2616 
SD for time <54 mg/dl and data from the control period of the JDRF CGM RCT were used to estimate 
2617 
SD for mean glucose in the proposed study. 
2618 
 
2619 
All other analyses discussed below will be considered exploratory and the overall type I error will not be 
2620 
controlled. The models for these exploratory outcomes will parallel the above primary models (including 
2621 
residuals diagnostics and alternative non-parametric models).  
2622 
 
2623 
 
2624 
10.5.2.2 Secondary Efficacy Outcomes 
2625 
The following CGM outcomes will be analyzed for the 24-hour period, daytime (6am-12mn) and 
2626 
overnight (12mn-6am): 
2627 
 
 
2628 
Hypoglycemia 
2629 
time <60 and <70 mg/dl 
2630 
• 
low blood glucose index (LBGI) 
2631 
• 
hypoglycemic events per 24 hours - defined as ≥15 consecutive minutes with a sensor glucose 
2632 
<50 mg/dl 
2633 
 
2634 
Overall Control 
2635 
• 
time in the target ranges of 70-180 and 70-120 mg/dl  
2636 
• 
glucose variability measured with coefficient of variation (CV) and with mean of daily difference 
2637 
(MODD) 
2638 
 
2639 
Hyperglycemia 
2640 
• 
Time >180 and >250 mg/dl 
2641 
• 
High blood glucose index (HBGI) 
2642 
• 
hyperglycemic events per 24 hours - defined as ≥90 consecutive minutes with a sensor glucose 
2643 
>300 mg/dL 
2644 
 
2645 
For all secondary analyses (including subgroup analyses), the false discovery rate (FDR) will be 
2646 
controlled using the adaptive Benjamini-Hochberg procedure.   
2647 
 
2648 
10.5.2.3 Other Secondary Outcomes 
2649 
The following additional outcomes will be included in secondary analyses:  
2650 
• 
Total daily dose of insulin 
2651 
• 
Sensor accuracy: 
2652 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
Page 
66 of 69  
o The following will be calculated using the Ascensia Contour Next One point-of care 
2653 
glucose meter: 
2654 
▪ 
MARD for the Dexcom G5 and Senseonics Eversense overall and in the following 
2655 
SMBG ranges: < 70, 70–180, > 180, > 250 
2656 
• 
Daily at-home questionnaire: 
2657 
o symptomatic hypoglycemia 
2658 
o hypoglycemia requiring carbohydrate intervention 
2659 
o alcohol use 
2660 
o exercise 
2661 
o nausea and/or vomiting 
2662 
o use of a personal CGM as a part of usual care 
2663 
• 
All glycemic CGM outcomes will be calculated for the first 24 hour period separately as a 
2664 
secondary analysis of the BP as participants transition off of an MDI regimen onto closed loop 
2665 
control.  
2666 
 
2667 
10.5.2.4 Safety Outcomes 
2668 
All adverse events will be tabulated. Additionally, the following outcomes will be tabulated by treatment 
2669 
period: 
2670 
• 
Episodes of severe hypoglycemia per participant 
2671 
• 
Episodes of diabetic ketoacidosis (DKA) per participant 
2672 
• 
Other serious adverse events per participant 
2673 
 
2674 
Due to the relatively short follow-up duration for this study, it is unlikely there will be enough such events 
2675 
for a formal statistical comparison. However, if there are enough events, a Poisson regression that 
2676 
accounts for correlated data from the same subject will be used to compare the number of events 
2677 
between the three treatment periods. The amount of follow up will be included as an offset covariate to 
2678 
compare the rates. Influence diagnostics will be reviewed and if outliers are present then the model will 
2679 
be run without them and the results compared. 
2680 
 
2681 
10.5.2.5 Questionnaires 
2682 
For each questionnaire completed at screening and the end of each one of the three 7-day treatment 
2683 
periods, mean (SD) values or median (IQR) appropriate to the distribution will be given for the total 
2684 
score and where indicated for each subscale.  
2685 
 
2686 
10.5.3 Subgroup Analyses 
2687 
Subgroup analyses/assessments of effect modification (interaction) will be conducted for each of the 
2688 
two main outcomes (time <54 mg/dl and mean glucose). These analyses will include, but will not be 
2689 
limited to, evaluating potential differences between sites, including differences between the RCT Period 
2690 
at the MGH site using the Senseonics Eversense as the input to the iLet and the RCT Period at the 
2691 
Stanford site using the Dexcom G5 CGM as the input to the iLet. The general approach for these 
2692 
analyses will be to add an interaction term for the subgroup factor by treatment into the models used 
2693 
for the primary analyses. Moreover, the continuous variables will be used in the models, while for 
2694 
presentation purposes, a binary variable will be created.  
2695 
 
2696 
Summary statistics appropriate to the distribution will be tabulates in each subgroup by treatment period. 
2697 
The study is not expected to have sufficient statistical power for definitive conclusions in subgroups and 
2698 
statistical power will be low to formally assess for the presence of interaction. Interpretation of subgroup 
2699 
analyses will depend on whether the overall analysis demonstrates a significant treatment group 
2700 
difference. In the absence of such an overall difference and if performed, subgroup analyses will be 
2701 
interpreted with caution and used to suggest hypotheses for further investigation in future studies.  
2702 
 
2703 
The following baseline factors will be assessed: 
2704 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
Page 
67 of 69  
• 
Age 
2705 
• 
Baseline HbA1c 
2706 
• 
Study center 
2707 
• 
Insulin method: pump versus injection (participants will be recruited with a 1:1 ratio) 
2708 
• 
T1D duration 
2709 
 
2710 
10.5.4 Analyses for the Two BP Treatment Periods Only 
2711 
The amount of time the system is active and CGM data available to the system, and the frequencies of 
2712 
different system errors during the two BP treatment periods only will be reported.  
2713 
 
2714 
10.5.5 Additional Tabulations and Plots 
2715 
The following tabulations will be performed: 
2716 
- 
Baseline demographics and clinical characteristics 
2717 
- 
Flowchart accounting for all subjects and both phases 
2718 
- 
Visits and phone contacts as scheduled 
2719 
Number and reasons for unscheduled visits and phone contacts  
2720 
- 
Protocol deviations 
2721 
- 
Twenty-four hour plots with median line and IQR bands for % CGM <54 mg/dl, >180 mg/dl, 
2722 
mean, 70-180 mg/dl, and coefficient of variation by the three periods.  
2723 
 
2724 
 
2725 
2726 
 
2727 
Twenty pediatric participants (age 6–17 years) will be enrolled at two sites and will be randomly 
2728 
assigned to the following study periods: (1) the iLet in the insulin-only configuration (with the iLet pigtail 
2729 
adapter and iLet ready-to-fill insulin cartridge, the Contact Detach infusion set, and the Dexcom G5 
2730 
CGM) using insulin analog that they use for their usual care (either Humalog or Novolog)and (2) UC 
2731 
(with Dexcom G5 CGM).  
2732 
 
2733 
 
2734 
All the above Adult RCT Period outcomes and analyses will be replicated here with the exceptions that, 
2735 
since there are only 2 treatment periods here (instead of 3 above). For the primary outcomes, a similar 
2736 
hierarchical gatekeeping procedure as the one described above for Adult RCT Period will be used; the 
2737 
list will include only two outcomes in this order: 
2738 
1. Mean glucose for (1) BP with analog insulin vs. (2) UC 
2739 
2. Time <54 mg/dl for (1) BP with analog insulin vs. (2) UC 
2740 
 
2741 
 
2742 
 
2743 
All adult and pediatric participants randomized to complete a BP period as their final study period in 
2744 
the RCT period will participate in this post-study transition period. For 48 hours immediately after the 
2745 
RCT period, they will be discharged to their usual care using the iLet’s dosing recommendations. 
2746 
They will be monitored remotely and continue to follow all study procedures.  
2747 
 
2748 
 
2749 
No formal statistical comparisons will be done for the Post-Study Transition Period.  
2750 
 
2751 
Since the main aim of the Post-Study Transition Period is to verify safety and feasibility, plus some 
2752 
trends in efficacy; the following outcomes will be considered: 
2753 
• 
Safety: 
2754 
o Episodes of severe hypoglycemia as defined in section 8.1.2.1 
2755 
o Episodes of diabetic ketoacidosis (DKA) as defined in section 8.1.2.2 
2756 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
Page 
68 of 69  
o Other serious adverse events 
2757 
• 
Hypoglycemia: time < 54 mg/dl 
2758 
• 
Mean CGM glucose 
2759 
• 
Daily at-home questionnaire: 
2760 
o symptomatic hypoglycemia 
2761 
o hypoglycemia requiring carbohydrate intervention 
2762 
o alcohol use 
2763 
o exercise 
2764 
o nausea and/or vomiting 
2765 
 
2766 
 
2767 
 
2768 
 
 
2769 


 
IOBP_Bridging Protocol_V8.0 26June2018_CLEAN 
 
Page 
69 of 69  
CHAPTER 11: DATA COLLECTION AND MONITORING 
2770 
 
2771 
 
2772 
The main study data are collected through a combination of electronic case report forms (CRFs) and 
2773 
electronic device datafiles obtained from the study software and individual hardware components (BP, 
2774 
CGM, SMBG meter, and blood ketone meter).  These electronic device files and electronic CRFs from 
2775 
the study website are considered the primary source documentation. 
2776 
 
2777 
 
2778 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
2779 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
2780 
conducted and data are generated, documented and reported in compliance with the protocol, GCP 
2781 
and the applicable regulatory requirements. Adverse events will be prioritized for monitoring. 
2782 
 
2783 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course of the 
2784 
study.  The data of most importance for monitoring at the site are participant eligibility and adverse 
2785 
events.  Therefore, the RBM plan will focus on these areas.  As much as possible, remote monitoring 
2786 
will be performed in real-time with on-site monitoring performed to evaluate the verity and completeness 
2787 
of the key site data.  Elements of the RBM may include: 
2788 
• 
Qualification assessment, training, and certification for sites and site personnel 
2789 
• 
Oversight of Institutional Review Board (IRB) coverage and informed consent procedures 
2790 
• 
Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol review 
2791 
of entered data and edits, statistical monitoring, study closeout 
2792 
• 
On-site monitoring (site visits): source data verification, site visit report 
2793 
• 
Device accountability 
2794 
• 
Communications with site staff 
2795 
• 
Patient retention and visit completion 
2796 
• 
Quality control reports 
2797 
• 
Management of noncompliance 
2798 
• 
Documenting monitoring activities 
2799 
• 
Adverse event reporting and monitoring 
2800 
 
2801 
JCHR representatives or their designees may visit the study facilities at any time in order to maintain 
2802 
current and personal knowledge of the study through review of the records, comparison with source 
2803 
documents, observation and discussion of the conduct and progress of the study.  
2804 
 
  
2805 

SAP_001.pdf: 
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Insulin Only Bionic Pancreas 
Bridging Trial 
Adult RCT Phase 
 
 
 
Statistical Analyses Plan 
 
Version 0.4 
 
 
 
September 21, 2018 
 
Based on Protocol Version 8.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The table shells are included in a separate document


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Page 2 of 14 
 
Version History 
1 
 
2 
Version 
Author 
Approvers 
Effective 
Date 
Revision 
Description 
Study Stage 
1.0 
Dan 
Raghinaru/ 
Tonya 
Riddlesworth 
Craig Kollman 
Katrina Ruedy 
Edward Damiano 
Steven Russell 
9/xx/2018 
Original 
Version 
The Adult RCT Phase started 
the enrollment on 7/xx/2018. 
Still enrolling 
 
3 
Lead Statistician and Author: 
4 
              
 
 ___________________________________________ 
5 
 
6 
Senior Statistician Approver: 
7 
              
 
 ___________________________________________ 
8 
 
9 
JAEB PI Approver: 
10 
              
 
 ___________________________________________ 
11 
 
12 
Sponsor Approver: 
13 
              
 
 ___________________________________________ 
14 
 
15 
Study PI Approver: 
16 
              
 
 ___________________________________________ 
17 
 
 
18 


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Page 3 of 14 
 
1. Study Overview 
19 
This document outlines the statistical analyses to be performed for the IOBP Bridging Trial – Adult RCT 
20 
Period - to be presented to DSMB and maybe published.  
21 
 
22 
The IOBP Bridging Trial consists of four different periods in this order: 
23 
- 
Test Run, 
24 
- 
Adult RCT, 
25 
- 
Pediatric Transitional, 
26 
- 
Pediatric RCT. 
27 
 
28 
The Test-Run Period will be completed and the data will be reviewed to verify safety prior to beginning 
29 
the Adult RCT Period. 
30 
 
31 
The Adult RCT Period will consist of a multi-center, three-period, random-order, cross-over, feasibility 
32 
study in 36 adult participants ≥ 18 years old with T1D (18 participants at MGH and 18 participants at 
33 
Stanford).  All 18 adult participants at MGH will have a Senseonics Eversense CGM sensor implanted prior 
34 
to the initiation of the Adult RCT Period by the clinical PI at MGH (Dr. Steven Russell) or by a study 
35 
physician under his supervision. These subjects will use the Senseonics Eversense CGM as the input to the 
36 
bionic pancreas instead of the Dexcom G5. All 18 adult participants at Stanford will use the Dexcom G5 
37 
CGM as the input to the bionic pancreas. All other aspects will remain the same across the two sites.  
38 
Insulin therapy for each participant will be administered (i) in one period using the iLet in the insulin-only 
39 
configuration with the iLet pigtail adapter and the iLet ready-to-fill insulin cartridge, the Contact Detach 
40 
infusion set, and the insulin analog that they use for their usual care (either Humalog or Novolog), (ii) in 
41 
another period using the iLet in the insulin-only configuration using the iLet pigtail adapter, the Contact 
42 
Detach infusion set, and faster insulin aspart (Fiasp) in PumpCart, where the pharmacokinetic (PK) 
43 
parameter for tmax used by the insulin-dosing algorithm will be set to the same value as is used for Humalog 
44 
and Novolog (65 minutes), and (iii) in a third period using the participant’s own usual care (UC), where 
45 
each participant will wear a CGM.  All three experimental periods will be followed by round-the-clock, 
46 
remote, telemetric monitoring for hyperglycemia (> 300 mg/dl for ≥ 90 minutes) and hypoglycemia (< 50 
47 
mg/dl for ≥ 15 minutes).  The three experimental periods will each have a duration of 7 days. Washout 
48 
periods of approximately 7 days in duration will follow the first and second experimental periods. The 
49 
washout period could be as short as 5 days or as long as 9 days, depending on scheduling of study visits. 
50 
Of the 36 participants, 9 at MGH and 9 at Stanford will use MDI therapy for their usual diabetes 
51 
management; the remaining 18 will use insulin pump therapy.  The participants at Stanford will wear the 
52 
Dexcom G5 CGM and the participants at MGH will wear the Senseonics Eversense CGM.  This will allow 
53 
us to collect further comparative accuracy data on both the Senseonics Eversense and the Dexcom G5 in 
54 
the outpatient setting using the Ascensia Contour Next One meter as the reference. Four participants at 
55 
MGH will have a Senseonics Eversense CGM sensor implanted and will participate in a 3-day supervised 
56 
Test Run. This Senseonics Eversense Test Run Period will be completed and data will be reviewed to verify 
57 
safety prior to beginning the Adult RCT Period at MGH using the Senseonics Eversense CGM sensor as 
58 
the input to the iLet. The cohort of 18 participants at MGH and 18 participants at Stanford might run 
59 
simultaneously, might overlap, or might not overlap in time.   
60 
 
61 


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Page 4 of 14 
 
Major eligibility criteria include:  
62 
• 
Clinical diagnosis of type 1 diabetes for at least 12 months 
63 
• 
HbA1c level < 11.0% 
64 
o At least 13 participants must have an HbA1c level of 8–11% 
65 
o At least 13 participants must have an HbA1c level < 8% 
66 
• 
Using an FDA-approved insulin therapy (including Fiasp on MDI therapy for adults, Humalog or 
67 
Novolog with CSII or MDI therapy; glulisine users will be excluded) 
68 
o 18 participants must use MDI therapy to manage their diabetes 
69 
o 18 participants must use CSII therapy to manage their diabetes 
70 
• 
Age ≥ 18 years old  
71 
o Approximately 9 participants in a young adult group (18–24 years old)  
72 
o Approximately 27 participants in an adult group (≥ 25 years old) 
73 
• 
At least 3 daily SMBG or 2 if used with a CGM 
74 
 
 
75 


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The following table gives an overview of the schedule of study visits and key procedures during each one 
76 
of the three 7-day randomized treatment periods [BP with analog insulin (1), BP with rapid insulin (2), 
77 
and UC (3)]: 
78 
 
 
 
Each Treatment Period 
 
 
Screening 
Senseonics 
Eversense 
Sensor 
Insertion 
0 
Day 3    
or  
Day 4 
Day 7   
Senseonics 
Eversense 
Sensor 
Removal 
Informed Consent  
X 
 
 
 
 
 
Eligibility assessment 
X 
 
X 
 
 
 
Bloodwork: eGFR and 
HbA1c  
X 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
Body weight 
X 
 
X 
 
X 
 
Urine pregnancy test 
X 
 
 
 
 
 
Physical exam  
X 
 
 
 
 
 
Insertion 
of 
Dexcom 
CGM sensor 
 
 
X 
 
 
 
Insertion of Senseonics 
Eversense CGM sensor 
 
X 
 
 
 
 
Removal of Senseonics 
Eversense CGM sensor 
 
 
 
 
 
X 
Psychosocial 
questionnaires 
 
 
X 
 
X 
 
Data download 
 
 
 
 
X 
 
Adverse event querying 
 
 
X 
X 
X 
 
 
 
79 


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Page 6 of 14 
 
2. Statistical Hypotheses 
80 
The primary outcome for this study is CGM-measured mean glucose when compared during (2) BP with 
81 
rapid insulin and UC (3) treatment periods. 
82 
The hypotheses are: 
83 
1. Null Hypothesis: There is no difference in mean CGM-measured glucose during UC and BP with 
84 
rapid insulin treatment periods  
85 
2. Alternative Hypothesis: The mean CGM-measured glucose is different during UC and BP with 
86 
rapid insulin treatment periods. 
87 
 
88 
The intervention will be considered effective if the above null hypothesis is rejected using a significance 
89 
level of 0.05 (i.e. p<0.05). 
90 
 
91 
3. Sample Size 
92 
Thirty-six subjects will be enrolled and randomized at two sites. This is a convenience sample; however 
93 
assuming an effective SD of 25 mg/dl for mean glucose, the half width of the associated 95% confidence 
94 
interval are approximately ±10 mg/dl for N=36 and ±15 mg/dl for N=18. Results from the control period 
95 
of the JDRF CGM RCT were used to estimate SD for mean glucose in the proposed study. 
96 
 
97 
4. Outcome Measures 
98 
4.1 Primary Efficacy Outcome 
99 
• 
CGM-measured mean glucose 
100 
 
101 
4.2 Secondary Efficacy Outcome 
102 
 
103 
4.2.1 Secondary Efficacy Endpoint Included in Hierarchical Analysis 
104 
• 
CGM-measured time <54 mg/dl 
105 
 
106 
4.2.2 Other Secondary Efficacy Outcomes 
107 
The following endpoints are considered exploratory.  
108 
• 
CGM metrics related to hypoglycemia  
109 
o % <70 mg/dL 
110 
o % <60 mg/dL 
111 
o low blood glucose index 
112 
• 
CGM metrics related to overall control 
113 
o % time in target range 70-180 mg/dL 
114 
o % time in target range 70-120 mg/dL 
115 
o glucose variability measured with CV (coefficient of variation) 
116 
o glucose variability measured with MODD (mean of daily difference) 
117 
• 
 CGM metrics related to hyperglycemia  
118 
o % >180 mg/dL 
119 
o % >250 mg/dL  
120 
o high blood glucose index   
121 


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Page 7 of 14 
 
 
122 
• 
Total daily dose of insulin 
123 
 
124 
• 
Questionnaires - The following table provides a description of the questionnaires to be 
125 
administered during each one of the three 7-day randomized treatment periods [BP with analog 
126 
insulin (1), BP with rapid insulin (2), and UC (3)]: 
127 
Questionnaire’s 
Name 
Day 0 
Day 7 
Description 
Diabetes Treatment 
Satisfaction 
Questionnaire - Status  
X 
 
Measures patient satisfaction with diabetes treatment. 
 
8 items (6 for assessing treatment satisfaction and two for 
frequency of hypoglycemia and hyperglycemia). Scale 0-6.  
 
Higher scores denote higher satisfaction or higher frequency of 
hypoglycemia/hyperglycemia.  
Diabetes Treatment 
Satisfaction 
Questionnaire - 
Change 
 
X 
Similar with the above (Status); except scale -3 to 3.  
Diabetes Distress 
Scale 
X 
X 
Measures Adult and Partner of Adult diabetes distress. 
Adult: 17 items (4 subscales and total score) and scale 1-6.  
Partner: 21 items (4 subscales and total score) and scale 0-4.  
Higher score denotes more of a problem or more distress. 
Hypoglycemia Fear 
Survey  
X 
X 
23 items (2 subscales and total score). Scale 0-4.  
Higher score denotes more fear.  
Hypoglycemia 
Confidence Scale - 
Status 
X 
X 
Measures confidence status.  
8 items and a 4-level scale.  
Hypoglycemia 
Confidence Scale - 
Change 
 
X 
Measures confidence change.  
8 items and a 5-level scale. 
INSPIRE Survey 
X 
X 
Measures experience with automated insulin delivery systems.  
Adult and partner versions.  
31 items. 5-point Likert scale.   
Bionic Pancreas User 
Opinion Survey* 
 
X 
Measures user’s experience with BP.  
43 items. Two subscales (benefits and difficulties) and total 
score. 5-point Likert scale. 
Daily At-Home 
Questionnaires 
 
 
Administered at the end of each day – expected 6 times for 
each subject and randomized period combination.  
17 items – most of them with sub-items (depending on the 
subject’s answer).  
*to be administered only during the two BP periods  
128 
4.3 Calculation of CGM Metrics: 
129 
• 
All sensor data excluding the first 48 hours will be included in the calculation of glycemic 
130 
metrics.  
131 
• 
Only subjects with at least 24hr of CGM data in any two of the three treatments periods will be 
132 
included in CGM analyses. It is considered that 24hr of data is the minimum and a representative 
133 
amount of data for any treatment period.  
134 
• 
If there are 12-<24hr of CGM data from days 3-7 in each one of the three treatment periods and 
135 
there are more CGM data during days 1-2, then the data from days 3-7 will be supplemented with 
136 


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Page 8 of 14 
 
data from days 1-2 (going backwards) until 24hr of data is reached. Otherwise the data are 
137 
considered missing for that treatment period.  
138 
• 
Metrics will be calculated giving equal weight to each CGM point from each treatment period.  
139 
 
140 
5. Description of Statistical Methods 
141 
5.1. General Approach 
142 
Analyses will involve pairwise comparisons of the three treatment arms: 
143 
1. Bionic Pancreas (BP) with analog insulin 
144 
2. Bionic Pancreas (BP) with rapid insulin 
145 
3. Usual Care (UC) 
146 
 
147 
All primary, hierarchical, and secondary analyses comparing the three treatment periods will follow the 
148 
intention-to-treat (ITT) principle with each period analyzed according to the treatment assigned by 
149 
randomization. All randomized participants with at least 24hr of CGM readings during at least two of the 
150 
three treatment periods will be included in the primary, hierarchical, and secondary analyses of CGM 
151 
metrics. There will be no imputation of missing data.  
152 
All p-values will be two-sided.  
153 
Standard residual diagnostics will be performed for all analyses. If values are highly skewed, then a rank 
154 
transformation will be used instead for the primary and secondary outcomes. From prior experience, the 
155 
values for time <54 mg/dl will have a skewed distribution and for mean glucose a bell-shaped 
156 
distribution.  
157 
 
158 
5.2. Analyses Cohorts 
159 
Primary and Secondary Analyses: 
160 
• 
For CGM-based and insulin outcomes, all randomized participants and treatment periods will be 
161 
analyzed according to the ITT principle and the 24hr rule as described above.  
162 
• 
For questionnaires, all questionnaires with at least one item answered will be included in 
163 
analyses. Total and subscale score may be calculated or not depending on specific instructions or 
164 
rules (see section 7.2).  
165 
 
166 
Safety Analyses: 
167 
• 
Safety outcomes will be reported for all enrolled participants, irrespective of whether the safety 
168 
event happened during the randomized treatment periods or in between (i.e. during wash-out 
169 
periods).  
170 
 
171 
Sensitivity Analyses: 
172 
• 
Primary and secondary CGM-based outcomes will be replicated using: 
173 
o all CGM data during the randomized treatment periods (i.e. days 1-7), and  
174 
o only the first 24hr of CGM data from each treatment period following randomization.  
175 
• 
Additional models for primary and secondary outcomes will be run to test for any carry-over 
176 
effects, by adding a treatment by order interaction term. 
177 
 
178 


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179 
6. Primary Analysis 
180 
The primary analysis will be a comparison of CGM-measured mean glucose between (2) BP with rapid 
181 
insulin versus (3) UC treatment periods. 
182 
 
183 
Plots and summary statistics appropriate to the distribution for mean glucose will be reported.  
184 
 
185 
A repeated measures linear model with mean glucose as the dependent variable will be fit to the data 
186 
including all three treatment periods.  The model will adjust for treatment period and account for 
187 
correlated data from the same subject using an unstructured covariance matrix.  
188 
 
189 
The p-value for the primary analysis will be calculated using a contrast in the model described above 
190 
between the (2) BP with rapid insulin (3) UC treatment arms. From prior experience, the values for mean 
191 
glucose will follow a bell-shaped distribution. Residual values will be examined for an approximate normal 
192 
distribution. If values are highly skewed then rank transformation will be used instead. 
193 
 
194 
7. Secondary Analyses 
195 
Plots and summary statistics appropriate to the distribution will be given for both mean glucose and time 
196 
below 54 mg/dl for all three treatment arms.   
197 
 
198 
For mean glucose, contrasts from the same model described above will also be used to compare: 
199 
• 
(2) BP with analog insulin versus (3) UC, and 
200 
• 
(2) BP with rapid versus (1) BP with analog insulin  
201 
Both of these are considered secondary analyses.   
202 
 
203 
A similar model will be fit with time below 54 mg/dl as the dependent variable with contrasts for all 
204 
three pairwise comparisons of the treatment arms.  It is anticipated that the distribution of this metric will 
205 
be skewed.  In this case, a transformation will be used as described above. 
206 
 
207 
7.1 Hierarchical Analyses 
208 
To preserve the overall type 1 error for the 6 comparisons (2 selected key secondary endpoints times 3 
209 
treatment arm pairs), a hierarchical testing procedure will be used. If the primary analysis described above 
210 
results in a statistically significant outcome (p < 0.05), then testing will proceed to the next comparison in 
211 
the following order: 
212 
• Mean glucose for (2) BP with rapid insulin vs. (3) UC  (primary analysis) 
213 
• Time <54 mg/dl for (2) BP with rapid insulin vs. (3) UC 
214 
• Mean glucose for (1) BP with analog insulin vs. (3) UC 
215 
• Time <54 mg/dl for (1) BP with analog insulin vs. (3) UC 
216 
• Mean glucose for (2) BP with rapid vs. (1) BP with analog insulin 
217 
• Time <54 mg/dl for (2) BP with rapid vs. (1) BP with analog insulin 
218 
 
219 
This process continues iteratively moving to the next variable down on the list until a non-significant 
220 
result (p ≥ 0.05) is observed, or all six comparisons have been tested.  If a non-significant result is 
221 


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encountered, then formal statistical hypothesis testing is terminated and any comparisons below on the list 
222 
are not formally tested. 
223 
For example, in the hypothetical scenario depicted in the table below, the first three comparisons both 
224 
have a significant result so testing continues to the fourth row [Time <54 mg/dl for (1) BP with analog 
225 
insulin vs. (3) UC].  The result is not significant for that fourth row (p = 0.06) so testing stops.  No formal 
226 
hypothesis test is conducted for the fifth and sixth comparisons on the list in this example scenario. 
227 
 
228 
Table 1. Example application of the hierarchical procedure to control type 1 error. 
229 
HIERARCHICA
L ORDER 
 
COMPARISON 
CONTRAST 
 P-VALUE 
SIGNIFICANT? 
ACTION 
1st 
Mean glucose for (2) 
BP with rapid insulin 
vs. (3) UC  (primary 
outcome) 
0.001 
Yes 
Test next 
comparison 
2nd 
Time <54 mg/dl for (2) 
BP with rapid insulin 
vs. (3) UC 
0.02 
Yes 
Test next 
comparison 
3rd 
Mean glucose for (1) 
BP with analog insulin 
vs. (3) UC 
0.007 
Yes 
Test next 
comparison 
4th 
Time <54 mg/dl for (1) 
BP with analog insulin 
vs. (3) UC 
0.06 
No 
Stop formal testing 
5th 
Mean glucose for (2) 
BP with rapid vs. (1) 
BP with analog insulin 
Not tested 
Unknown 
N/A 
6th 
Time <54 mg/dl for (2) 
BP with rapid vs. (1) 
BP with analog insulin 
Not tested 
Unknown 
N/A 
 
230 
Regardless of the results of the hierarchical testing, summary statistics appropriate to the distribution will 
231 
be tabulated.   
232 
 
233 
7.2 Other Endpoint Analyses 
234 
CGM-Measured Outcomes 
235 
The analyses for the secondary CGM-measured outcomes will parallel the descriptive statistics and 
236 
regression model mentioned above for the primary outcome without the hierarchical procedure. 
237 
Analyses will also be done limiting to daytime (6am-12mn) and nighttime (12mn-6am) data. Only 
238 
subjects with at least 12hr of CGM data in any two of the three treatments periods will be included in 
239 
daytime/nighttime CGM analyses. 
240 
 
241 
Questionnaires  
242 


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For each question, the percent of all answers will be reported across all subjects by treatment periods; and 
243 
if applicable, by beginning and ending of each treatment period. For questions with additional numeric or 
244 
ordinal scales, mean score will be reported in addition to the percent.  
245 
 
246 
Some questionnaires will be administered at the beginning and ending of each treatment period, and the 
247 
results presented as such. If a subject completed the beginning but not the ending questionnaires, the 
248 
results will be presented as such (i.e. with different underlying number of subjects).  
249 
 
250 
For some questionnaires total and subscale scores will be calculated and mean ± SD values or percentiles 
251 
appropriate to the distribution will be reported across all subjects by treatment periods.  
252 
 
253 
All questionnaires will be administered online (through REDCap) and subjects can skip specific 
254 
questionnaires or questions within a questionnaire. All questionnaires will be scored according to the 
255 
instructions given in the manual.  In case no manual exists for a given questionnaire or the manual does 
256 
not provide guidance on how to handle missing questions, then the following “75% rule” will be used.  
257 
For all questionnaires, at least 75% of the questions must be completed to be included in the 
258 
analysis.  This 75% rule will be applied separately for the total score and each subscale so it is possible 
259 
the sample size will be different for some subscales. The score used for analysis will be based on the 
260 
average among the questions that were answered and then scaled accordingly in order to a corresponding 
261 
total or subscale score.  
262 
 
263 
The Daily At-Home Questionnaire will be administered at the end of each day (for a maximum of 6 times 
264 
for each one of the three treatment periods). Each question in this questionnaire will be first summarized 
265 
(percent or mean) and presented at period level and then summarized across all subjects by treatment 
266 
period as mentioned above.  
267 
 
268 
No formal hypothesis tests will be done for questionnaires.  
269 
 
270 
Sensor Accuracy 
271 
Each reference glucose measurement from the blood glucose meter will be paired with the closest sensor 
272 
reading within ± 5 minutes (choosing the CGM that immediately precedes the BGM value, rather than the 
273 
other way around).  Each reference measurement will be paired with only reading from sensor and each 
274 
sensor reading will only be paired with one meter reference value.  Any meter measurements used to 
275 
calibrate the sensor will be excluded from the accuracy analysis.  Any data available during the wash-out 
276 
periods will also be included. 
277 
 
278 
Difference, absolute relative difference, and International Organization for Standardization criteria (ISO) 
279 
will be calculated for each sensor-reference pair.  Descriptive summary statistics will be reported separately 
280 
for Eversence and DexCom according to their distribution overall and by different meter ranges: 
281 
• 
<70 mg/dl 
282 
• 
70-180 mg/dl 
283 
• 
>180 mg/dl 
284 
• 
>250 mg/dl 
285 
 
286 


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Insulin Outcomes 
287 
Total daily insulin analyses  during the BP treatment period will include data from days 3-7 (i.e. exclude 
288 
the first 48 hours of data)  and will be displayed using boxplots for each day.  Summary statistics for the 
289 
total daily insulin reported on the CRF on Days 0 and 7 will also be given for both treatment periods. 
290 
 
291 
8. Safety Analyses 
292 
All subjects will be included in these analyses and all their safety events will be reported.    
293 
The circumstances of all reportable cases of the following will be summarized and tabulated by 
294 
randomized treatment periods and wash-out intervals: 
295 
• 
Severe hypoglycemia (as defined in Section 8.1 of the protocol) 
296 
• 
Diabetic ketoacidosis (as defined in Section 8.1 of the protocol) 
297 
• 
All other adverse events 
298 
• 
Ketone events defined as ketone level >1.0 mmol/l 
299 
• 
CGM-measured hypo- and hyperglycemia events  
300 
 
301 
Due to the relatively short follow-up duration for this study, it is unlikely there will be enough such 
302 
events for a formal statistical comparison. However, if there are enough events, a Poisson regression that 
303 
accounts for correlated data from the same subject will be used to compare the number of events between 
304 
the three treatment periods. The amount of follow up will be included as an offset covariate to compare 
305 
the rates. Influence diagnostics will be reviewed and if outliers are present then the model will be run 
306 
without them and the results compared. 
307 
 
308 
The CGM-measured (days 1-7) hypo- and hyperglycemia events will use all available CGM data and are 
309 
defined as follows: 
310 
• 
hypoglycemia - defined as at least 15 consecutive minutes <50 mg/dl 
311 
• 
hyperglycemia - defined as at least 90 consecutive minutes >300 mg/dl 
312 
 
313 
9. Intervention Adherence  
314 
A listing of the following outcomes as well as summary statistics appropriate to the distribution will be 
315 
given to assess intervention adherence for the study: 
316 
• 
The daily frequency of downloaded SMBG use  
317 
• 
BP use (using days 3-7 and days 1-7), # hours BP was “on”, # hours BP was in Closed Loop 
318 
mode and % of time BP was in Closed Loop mode. 
319 
 
320 
10. Adherence and Retention Analyses 
321 
The following tabulations and analyses will be performed by treatment period to assess protocol 
322 
adherence for the study: 
323 
• 
Flow chart accounting for all subjects at all scheduled visits  
324 
• 
A listing of protocol deviations  
325 
• 
A listing of unscheduled visits  
326 
• 
A listing of subjects who dropped out of the study and reasons 
327 


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328 
11. Baseline Descriptive Statistics 
329 
Baseline demographic and clinical characteristics of all participants will be summarized in a table using 
330 
summary statistics appropriate to the distribution of each variable. Descriptive statistics will be displayed 
331 
overall and will include:  
332 
• 
Age  
333 
• 
HbA1c  
334 
• 
Gender  
335 
• 
Race/ethnicity  
336 
• 
Income, education, and insurance status 
337 
• 
Clinical Center 
338 
• 
Diabetes duration  
339 
• 
BMI  
340 
• 
Total daily insulin  
341 
• 
Previous Pump and CGM use 
342 
 
343 
12. Device Issues 
344 
Device issues reported on the CRF by the sites will be tabulated according to treatment period.   
345 
13. Planned Interim Analyses 
346 
No formal interim analyses are planned for this study.  
347 
The DSMB will review data collected. 
348 
 
349 
14. Subgroup Analyses 
350 
This study was not powered for subgroup analyses.  These are considered exploratory and results will be 
351 
interpreted with caution.  Subgroup analyses will only be performed for those pairwise treatment 
352 
comparisons (see above) that were statistically significant at p < 0.05. 
353 
 
354 
These analyses will include, but will not be limited to, evaluating potential differences between sites, 
355 
including differences between the RCT Period at the MGH site using the Senseonics Eversense as the 
356 
input to the iLet and the RCT Period at the Stanford site using the Dexcom G5 CGM as the input to the 
357 
iLet. The general approach for these analyses will be to add an interaction term for the subgroup factor by 
358 
treatment into the models used for the analyses described above. Continuous variables will be modelled as 
359 
such in the subgroup analyses to calculate p-values for interaction, but summary statistics will be 
360 
displayed as discrete subgroups in tables. 
361 
 
362 
Summary statistics appropriate to the distribution will be tabulated in each subgroup by treatment period.  
363 
 
364 
The following baseline factors will be assessed: 
365 
• 
Age 
366 


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• 
Baseline HbA1c 
367 
• 
Study Center/Sensor 
368 
• 
Insulin method: pump versus injection  
369 
• 
T1D duration 
370 
 
371 
15. Multiple Comparison/Multiplicity  
372 
For the 6 key comparisons listed in Section 7.1, strong control of the familywise error rate (FWER) will 
373 
be accomplished using the hierarchical procedure described above. 
374 
 
375 
For all other secondary analyses which are considered exploratory, the false discovery rate will be 
376 
controlled using the adaptive Benjamini-Hochberg procedure. The method will be applied separately for 
377 
the following four categories:  
378 
• 
Secondary CGM-measured and insulin for BP-rapid vs. UC comparisons, 
379 
• 
Secondary CGM-measured and insulin for BP-analog vs. UC comparisons, 
380 
• 
Secondary CGM-measured and insulin for BP-rapid vs. BP-analog comparisons, Subgroup 
381 
analyses mentioned in section 14 (if applicable) 
382 
No multiple comparisons adjustment will be made for sensitivity analyses or safety analyses.  
383 
 
384 
16. Additional Analyses   
385 
Twenty-four hour boxplots by the three treatment periods will be generated for the following CGM-based 
386 
outcomes: 
387 
• 
% <54 mg/dl 
388 
• 
Mean glucose 
389 
• 
 %  >180 mg/dl  
390 
• 
% 70-180 mg/dl  
391 
• 
Coefficient of variation  
392 
 
393 
The purpose of the above boxplots will be to see the trend of each outcome within a 24-hour day for each 
394 
treatment period and across all subjects.   
395 
 
396