The Insulin-Only Bionic Pancreas Pivotal Trial: Testing the iLet in Adults and Children With Type 1 Diabetes
Phase: NA
Conditions: Diabetes Mellitus, Type 1 Diabetes, Diabetes Mellitus, Type 1
Sponsor: Jaeb Center for Health Research

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
***CONFIDENTIAL*** 
The Insulin-Only Bionic Pancreas Pivotal Trial: 
Testing the iLet in Adults and Children with Type 1 Diabetes 
Version 10.0 
25 April 2021 
 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 2 OF 97 
Clinical Study Leadership 
Steven Russell, MD (Director) 
Courtney Balliro, BS, RN, CDE (Assistant Director) 
Massachusetts General Hospital Diabetes Research Center 
Boston, MA 
Engineering and Technology Center 
Edward Damiano, PhD (Director and Project Principal Investigator) 
Firas El-Khatib, PhD (Associate Director) 
Boston University, Biomedical Engineering Department 
Boston, MA 
National Coordinating Center 
Roy W. Beck, M.D., Ph.D. (Director) 
Katrina J. Ruedy, MSPH (Co-Director) 
Jaeb Center for Health Research 
Tampa, FL 
 
 
 
 
 
 
 
 
 
 
 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 3 OF 97 
SITE PRINCIPAL INVESTIGATOR STATEMENT OF COMPLIANCE 
Protocol Title: The Insulin-Only Bionic Pancreas Pivotal Trial: Testing the iLet in Adults and 
Children with Type 1 Diabetes 
Protocol Version/Date: Version 10.0/25 April 2021 
I have read the protocol specified above.  In my formal capacity as a Site Principal 
Investigator, my duties include ensuring the safety of the study participants enrolled under 
my supervision and providing the Jaeb Center for Health Research, which serves as the 
Coordinating Center for the protocol, with complete and timely information, as outlined in 
the protocol.  It is understood that all information pertaining to the study will be held strictly 
confidential and that this confidentiality requirement applies to all study staff at this site. 
This trial will be carried out in accordance with ICH E6 Good Clinical Practice (GCP) and as 
required by the following (use applicable regulations depending on study location and 
sponsor requirements; examples follow): United States (US) Code of Federal Regulations 
(CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 
CFR Part 312, and/or 21 CFR Part 812). 
As the Principal Investigator, I will assure that no deviation from, or changes to the protocol 
will take place without prior agreement from the sponsor and documented approval from the 
Institutional Review Board (IRB), or other approved Ethics Committee, except where 
necessary to eliminate an immediate hazard(s) to the trial participants. 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Participants Protection Training and Good Clinical Practice Training.  
Further, I agree to ensure that all staff members involved in the conduct of this study are 
informed about their obligations in meeting the above commitments. 
Investigator’s Signature _______________________________ Date: _____ / _____ / _____ 
 
dd 
mmm 
yyyy 
Investigator’s Name: ____________________________________ 
 
Site Name: ____________________________________________ 
 
 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 4 OF 97 
TABLE OF CONTENTS 
CHAPTER 1: INTRODUCTION ..................................................................................................................... 20 
1.1 Background and Rationale ................................................................................................................. 20 
1.2 Bihormonal BP System ..................................................................................................................... 21 
1.3 Insulin-Only BP System .................................................................................................................... 23 
1.3.1 iPhone-Based BP System ............................................................................................................ 23 
1.3.2 Fully Integrated iLet®  BP System (Beta Bionics) ....................................................................... 25 
1.3.3 Fiasp (Novo Nordisk) .................................................................................................................. 28 
1.4 Potential Risks and Benefits of the Investigational Device and Study Participation ........................ 28 
1.4.1 Known Potential Risks ................................................................................................................ 29 
1.4.1.1 Venipuncture Risks ............................................................................................................. 29 
1.4.1.2 Fingerstick Risks ................................................................................................................. 29 
1.4.1.3 Subcutaneous Catheter Risks (CGM) ................................................................................. 29 
1.4.1.4 Risk of Hypoglycemia ........................................................................................................ 29 
1.4.1.5 Risk of Hyperglycemia ....................................................................................................... 29 
1.4.1.6 Questionnaires ..................................................................................................................... 30 
1.4.1.7 Other Risks .......................................................................................................................... 30 
1.4.2 Known Potential Benefits ............................................................................................................ 30 
1.4.3 Risk Assessment .......................................................................................................................... 30 
1.5 General Considerations...................................................................................................................... 31 
CHAPTER 2: PARTICIPATION ENROLLMENT AND STUDY INITIATION ................................................... 32 
2.1 Participant Recruitment ..................................................................................................................... 32 
2.2 Informed Consent and Authorization Procedures .............................................................................. 33 
2.2.1 RCT Period .................................................................................................................................. 33 
2.2.2 Transition Phase .......................................................................................................................... 34 
2.3 Eligibility and Exclusion Criteria ...................................................................................................... 34 
2.3.1 Eligibility ..................................................................................................................................... 34 
2.4 Eligibility Assessment and Baseline Data Collection ....................................................................... 36 
2.5 Historical Information ....................................................................................................................... 37 
2.6 Screening Testing and Procedures ..................................................................................................... 37 
2.7 Baseline CGM Data Collection ......................................................................................................... 37 
2.8 Screen Failures .................................................................................................................................. 38 
CHAPTER 3: RCT RANDOMIZATION VISIT AND START UP .................................................................... 39 
3.1 Timing of Visit .................................................................................................................................. 39 
3.2 Testing and Procedures ...................................................................................................................... 39 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 5 OF 97 
3.3 Randomization ................................................................................................................................... 40 
3.4 Study Procedures for the Control Group ........................................................................................... 40 
3.5 Study Procedures for the BP Group .................................................................................................. 40 
CHAPTER 4: RCT OUTPATIENT STUDY PROCEDURES ............................................................................ 42 
4.1 Outpatient Procedures for Both Groups ............................................................................................ 42 
4.1.1 Resources for Participants ........................................................................................................... 42 
4.1.2 Weekly At-Home Questionnaire ................................................................................................. 42 
4.2 Outpatient Procedures for Control Group.......................................................................................... 42 
4.3 Outpatient Procedures for BP Group ................................................................................................. 43 
CHAPTER 5: RCT FOLLOW-UP STUDY VISITS ......................................................................................... 47 
5.1 Timing of Visits ................................................................................................................................. 47 
5.2 Procedures at Phone Contacts and Follow-up Visits ......................................................................... 47 
5.2.1 Phone Contacts ............................................................................................................................ 47 
5.2.2 Clinic Visits ................................................................................................................................. 47 
5.3 Evaluation of Control Group for Extension Study ............................................................................ 48 
5.4 Transition Phase ................................................................................................................................ 48 
CHAPTER 6: TRANSITION PHASE .............................................................................................................. 49 
6.1 Participants ........................................................................................................................................ 49 
6.2 Randomization ................................................................................................................................... 49 
6.3 iLet BP Guidance............................................................................................................................... 49 
6.4 Visits .................................................................................................................................................. 49 
CHAPTER 7: STUDY DRUGS AND DEVICES ............................................................................................... 50 
7.1 Study Drugs ....................................................................................................................................... 50 
7.2 Study Devices .................................................................................................................................... 50 
7.2.1 iLet Infusion Sets ......................................................................................................................... 50 
7.2.2 iLet Ready-to-Fill Insulin Cartridges .......................................................................................... 50 
7.2.3 Continuous Glucose Monitors ..................................................................................................... 50 
7.2.3.1 Dexcom G6 CGM ............................................................................................................... 51 
7.2.4 iLet Bionic Pancreas .................................................................................................................... 51 
7.2.5 Contour Next Glucometer ........................................................................................................... 52 
7.2.6 Precision Xtra Blood Ketone Meter ............................................................................................ 52 
7.3 Participant Access to Study Device at Study Closure ....................................................................... 52 
CHAPTER 8: LABORATORY TESTING, QUESTIONNAIRES AND FOCUS GROUP ...................................... 53 
8.1 Laboratory Testing ............................................................................................................................ 53 
8.2 Questionnaires ................................................................................................................................... 53 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 6 OF 97 
8.2.1 Introduction ................................................................................................................................. 53 
8.2.2 Brief Description of Questionnaires ............................................................................................ 53 
8.3 Focus Groups ..................................................................................................................................... 55 
Focus Groups ........................................................................................................................................ 55 
CHAPTER 9: UNANTICIPATED PROBLEMS, ADVERSE EVENTS, AND DEVICE ISSUE REPORTING ........ 57 
9.1 Unanticipated Problems ..................................................................................................................... 57 
9.2 Adverse Events .................................................................................................................................. 57 
9.2.1 Definitions ................................................................................................................................... 57 
9.2.2 Reportable Adverse Events ......................................................................................................... 58 
9.2.3 Hypoglycemic Events .................................................................................................................. 59 
9.2.4 Hyperglycemic/Ketotic Events .................................................................................................... 59 
9.2.5 Relationship of Adverse Event to Study Device ......................................................................... 60 
9.2.6 Severity (Intensity) of Adverse Events ........................................................................................ 60 
9.2.7 Expectedness ............................................................................................................................... 60 
9.2.8 Coding of Adverse Events ........................................................................................................... 60 
9.2.9 Outcome of Adverse Events ........................................................................................................ 61 
9.3 Reportable Device Issues ................................................................................................................... 61 
9.4 Timing of Event Reporting ................................................................................................................ 62 
9.5 Reporting to Novo Nordisk ............................................................................................................... 62 
9.6 Safety Oversight ................................................................................................................................ 63 
9.7 Stopping Criteria ............................................................................................................................... 63 
9.7.1 Criteria for Suspending or Stopping Overall Study ..................................................................... 64 
CHAPTER 10: MISCELLANEOUS CONSIDERATIONS ................................................................................. 65 
10.1 Collection of Medical Conditions and Medications ........................................................................ 65 
10.2 Prohibited Medications, Devices, Treatments and Procedures ........................................................ 65 
10.3 Rescue Medications ......................................................................................................................... 65 
10.4 Pregnancy Reporting ....................................................................................................................... 65 
10.5 Participant Compensation ................................................................................................................ 65 
10.6 Participant Withdrawal .................................................................................................................... 66 
10.7 Confidentiality ................................................................................................................................. 66 
CHAPTER 11: STATISTICAL CONSIDERATIONS ........................................................................................ 67 
11.1 Statistical and Analytical Plans ....................................................................................................... 67 
11.2 Statistical Hypotheses ...................................................................................................................... 67 
11.3 Sample Size ..................................................................................................................................... 67 
11.4 Efficacy Outcome Measures ............................................................................................................ 68 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 7 OF 97 
11.4.1 Primary and Key Secondary Efficacy Endpoints ...................................................................... 68 
11.4.2 Additional Secondary Efficacy Endpoints ................................................................................ 68 
11.4.2.1 Secondary Efficacy Endpoints Included in Hierarchical Analysis ................................... 68 
11.4.2.2 Other Secondary Efficacy Endpoints ................................................................................ 68 
11.5 CGM Metrics Calculations .............................................................................................................. 70 
11.6 Analysis of the Primary and Secondary Efficacy Endpoints ........................................................... 70 
11.6.1 HbA1c Analyses (Superiority) .................................................................................................. 70 
11.6.2 Time <54 mg/dL (Noninferiority) ............................................................................................. 71 
11.6.3 Secondary CGM Metrics (Superiority) ..................................................................................... 71 
11.6.4 Hierarchical Analyses ................................................................................................................ 71 
11.6.5 Questionnaires and Other Outcomes Analyses ......................................................................... 72 
11.7 Safety Analyses ............................................................................................................................... 72 
11.7.1 Safety Tabulations Specific to the BP Group ............................................................................ 73 
11.8 Additional Tabulations and Analyses .............................................................................................. 73 
11.8.1 Tabulations Specific to the BP Group ....................................................................................... 73 
11.9 Planned Interim Analyses ................................................................................................................ 73 
11.10 Subgroup Analyses ........................................................................................................................ 73 
11.11 Multiple Comparison/Multiplicity ................................................................................................. 74 
11.12 Additional Exploratory Analyses .................................................................................................. 74 
11.13 BP Fiasp Versus Control Group .................................................................................................... 74 
11.14 Comparison of Aspart/Lispro Group and Fiasp Group ................................................................. 75 
11.15 Transition Phase ............................................................................................................................ 75 
CHAPTER 12: DATA COLLECTION AND MONITORING ............................................................................ 76 
12.1 Case Report Forms and Other Data Collection ............................................................................... 76 
12.2 Study Records Retention ................................................................................................................. 76 
12.3 Quality Assurance and Monitoring .................................................................................................. 76 
12.4 Protocol Deviations ......................................................................................................................... 77 
CHAPTER 13: ETHICS/PROTECTION OF HUMAN PARTICIPANTS ............................................................ 78 
13.1 Ethical Standard ............................................................................................................................... 78 
13.2 Institutional Review Boards ............................................................................................................ 78 
13.3 Informed Consent Process ............................................................................................................... 78 
13.3.1 Consent Procedures and Documentation ................................................................................... 78 
13.3.2 Participant and Data Confidentiality ......................................................................................... 78 
13.3.3 Future Use of Data..................................................................................................................... 79 
13.3.4 Future Use of Biologic Samples ................................................................................................ 79 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 8 OF 97 
CHAPTER 14: ANCILLARY STUDY TO TEST THE ILET WITH INPUTTED BLOOD GLUCOSE 
MEASUREMENTS ........................................................................................................................................ 80 
14.1 Objective .......................................................................................................................................... 80 
14.2 Sample Size ..................................................................................................................................... 80 
14.3 Eligibility Criteria ............................................................................................................................ 80 
14.4 Study Protocol ................................................................................................................................. 80 
14.5 Outcomes and Analysis Plan ........................................................................................................... 81 
14.6 Safety Monitoring ............................................................................................................................ 81 
APPENDIX A: PRIOR STUDIES CONDUCTED USING THE BIONIC PANCREAS SYSTEM .......................... 82 
A.1 Studies Conducted with the iPhone-Based BP System..................................................................... 82 
A.1.1 The Beacon Hill Study, the 2013 and 2014 Summer Camp Studies, and the 
Bionic Pancreas Multi-Center Study .................................................................................................... 82 
A.1.2 The Bionic Pancreas Set Point Study ......................................................................................... 84 
A.1.3 The Stanford Insulin-Only Study ............................................................................................... 86 
A.1.4 The Bionic Pancreas Monitoring Study ...................................................................................... 87 
A.2 Studies Conducted with the Gen 3 iLet Bionic Pancreas System ..................................................... 89 
A.2.1 The iLet Insulin-Only Bionic Pancreas Bridging Study ............................................................. 89 
A.2.2 The iLet Day-Camp Transitional Study in Pediatrics ................................................................. 90 
A.2.3 The iLet Bihormonal Cross-Over Study ..................................................................................... 91 
 
 
 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 9 OF 97 
TABLE OF ACRONYMS 
Acronym 
Abbreviation For 
ADA 
American Diabetes Association 
AP 
Artificial Pancreas 
BG 
Blood Glucose 
BP 
Bionic Pancreas 
BPMC 
Bionic Pancreas Multicenter Study 
CRF 
Case Report Form 
CGM 
Continuous Glucose Monitoring 
CSII 
Continuous Subcutaneous Insulin Infusion 
DCCT 
Diabetes Control and Complications Trial 
DKA 
Diabetic Ketoacidosis 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP1 
Glucagon-Like Peptide 1 
GUI 
Graphical User Interface 
HbA1c 
Hemoglobin A1c 
IDE 
Investigational Device Exemption 
MDI 
Multiple Daily Injections 
MGH 
Massachusetts General Hospital 
MPC 
Model predictive controller 
NIH 
National Institutes of Health 
NYHA 
New York Heart Association 
PD 
Proportional derivative 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
QC 
Quality Control 
RCT 
Randomized Controlled/Clinical Trial 
SADE 
Serious Adverse Device Event 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard Deviation 
SGLT2 
Sodium Glucose Cotransporter 2 
SH 
Severe Hypoglycemia 
SMBG 
Self-Monitoring of Blood Glucose 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 10 OF 97 
Acronym 
Abbreviation For 
T1D 
Type 1 Diabetes 
TDD 
Total Daily Dose 
UADE 
Unanticipated Adverse Device Effect 
UI 
User Interface 
 
 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 11 OF 97 
PROTOCOL SUMMARY 
 
Description 
Title 
The Insulin-Only Bionic Pancreas Pivotal Trial: Testing the iLet in Adults and 
Children with Type 1 Diabetes
Précis 
This multi-center randomized control trial (RCT) will compare efficacy and 
safety endpoints using the insulin-only configuration of the iLet Bionic 
Pancreas (BP) System versus a control group using CGM during a 13-week 
study period. Participants may be enrolled initially into a screening protocol 
and then transfer into the RCT protocol, or they may enter directly into the 
RCT protocol. At the completion of use of the BP system (end of RCT for BP 
Group), participants will enter a 2–4 day Transition Phase and be randomly 
assigned to either transition back to their usual mode of therapy (MDI or pump 
therapy) based on therapeutic guidance from the iLet BP System or transition 
back to their usual mode of therapy based on what their own insulin regimens 
were prior to enrolling in the RCT. 
Investigational Device 
iLet Bionic Pancreas System, which consists of an integrated infusion pump, 
touchscreen display, Bluetooth radio, and insulin dosing algorithms, that 
automatically controls insulin delivery based on glucose values obtained by 
communicating with a Dexcom G6 sensor. 
Objectives 
Primary Objective 
• To compare the efficacy and safety of the insulin-only configuration of 
the iLet BP System using insulin lispro, insulin aspart, and Fiasp (adults 
only) in maintaining near-normal glycemia relative to usual care in a 
home-use study in adults and children with T1D. 
Secondary Objectives 
• To assess the impact of the insulin-only configuration of the iLet BP 
System on quality of life and treatment satisfaction. 
Study Design 
Randomized clinical trial followed by a Transition Phase for those using the 
iLet BP System 
Number of Sites 
~16 
Endpoints for RCT 
The primary analysis will include both the pediatric and adult participants in a 
single analysis.  BP aspart/lispro Group and BP Fiasp Group will be compared 
separately with the Control Group. 
Superiority for HbA1c at 13 weeks will be considered the primary endpoint. 
Non-inferiority for time <54 mg/dL measured with CGM at intervals over the 
13 weeks (pooled for analysis) will be considered a key secondary endpoint. 
To preserve the overall type 1 error, a hierarchical gatekeeping testing 
procedure will be used. If a comparison results in a statistically significant 
result (p < 0.05 for superiority testing and <0.025 for one-sided non-inferiority 
testing), then testing will proceed to the next one on the list. 
The order of testing will be as follows: 
1. HbA1c at 13 weeks (superiority) 
2. CGM time < 54 mg/dl (non-inferiority) 
Superiority for the following CGM metrics 
3. Mean glucose 
4. Time 70-180 mg/dL 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 12 OF 97 
 
Description 
5. Time >180 mg/dL 
6. Time >250 mg/dL 
7. Standard deviation 
8. Time <70 mg/dL 
9. Time <54 mg/dL 
10. Coefficient of variation 
Key Safety Outcomes: 
• severe hypoglycemia 
• diabetic ketoacidosis 
• other serious adverse events 
Other Key Outcomes: 
• quality of life questionnaires 
Eligibility Criteria 
Eligibility may be assessed initially in a separate screening protocol or at a 
screening visit in the RCT protocol. To be eligible for all phases of the study, 
a participant must meet all of the following inclusion criteria and none of the 
exclusion criteria: 
Inclusion 
1. Clinical diagnosis of T1D for at least one year and using insulin for at 
least 1 year 
2. Diabetes managed using the same regimen (either pump or MDI, 
with or without CGM) for ≥ 3 months prior to collection of CGM 
data (either from personal Dexcom G6 device or blinded G6 device) 
3. Age ≥ 6 years old 
 
4. Current use of a CGM, or if not a CGM user, at least 3 blood glucose 
meter tests daily on average over the last 4 weeks (according to 
judgment of investigator if meter is not available). 
5. Willingness not to start any new non-insulin glucose-lowering agent 
during the course of the trial 
6. For participants <18 years old, living with one or more parent/legal 
guardian knowledgeable about emergency procedures for severe 
hypoglycemia.  
7. For participants >18 years old who live alone, participant has a 
relative or acquaintance who lives within 30 minutes of participant 
and is willing to be contacted to check on participant if study staff 
feel that participant may be experiencing a medical emergency and 
can’t be reached. 
8. Investigator believes that the participant can safely use the iLet and 
will follow the protocol 
• 
The investigator will take into account the participant’s 
HbA1c level, compliance with current diabetes management, 
and prior acute diabetic complications. For this reason, 
there is no upper limit on HbA1c specified for eligibility. 
9. If a GLP-1 agonist or pramlintide is being used, participant must be 
willing to discontinue use while the iLet BP system is being used. 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 13 OF 97 
 
Description 
Exclusion 
1. Unable to provide informed consent (e.g. impaired cognition or 
judgment) 
2. Unable to safely comply with study procedures and reporting 
requirements (e.g. impairment of vision or dexterity that prevents 
safe operation of the bionic pancreas, impaired memory) 
3. Unable to speak and read English 
• 
 For pediatric participants, both caregivers and participants 
must be able to speak and read English 
4. Plan to change usual diabetes regimen in the next 3 months 
• 
This would include changing from MDI to pump.  pump to MDI, 
change in insulin automation delivery system, starting a CGM if 
not previously used, changes in drug therapy specifically for 
glucose control except for changes in one insulin analog to 
another.  
o 
Changes in insulin dose, carb ratio, sensitivity factor and 
basal rate profile are allowed. 
5. Current use of non-FDA approved closed-loop or hybrid closed-loop 
insulin delivery system 
6. Use of Apidra as the pre-study rapid-acting insulin analog and 
unwilling to switch to lispro or aspart for the duration of the study 
7. Known hemoglobinopathy (sickle cell trait is not an exclusion) 
8. Current participation in another diabetes-related clinical trial 
9. History of cystic fibrosis, pancreatitis, or other pancreatic disease, 
including pancreatic tumor or insulinoma, or history of complete 
pancreatectomy 
10. Electrically powered implants (e.g. cochlear implants, 
neurostimulators) that might be susceptible to RF interference 
11. Established history of allergy or severe reaction to adhesive or tape 
that must be used in the study 
12. Current use of SGLT2 inhibitors or a sulfonylurea drug (use more 
than 3 months prior to enrollment is acceptable) 
• 
If using GLP1 agonist, pramlintide, or metformin drugs must be 
on a stable dose for 3 months prior to enrollment (and as per 
inclusion criterion #8, must be willing to discontinue use of 
GLP-1 agonist or pramlintide while using the iLet BP system 
during the RCT).  
13. Pregnant (positive urine hCG), breast feeding, plan to become 
pregnant in the next 3 months, or sexually active without use of 
contraception  
• 
If the visit is conducted virtually, a pregnancy test will be 
provided to the participant and verbal report of the result will be 
acceptable 
14. For adults >18 years old, most recent (must be within the last 2 years) 
eGFR <30 ml/min; OR currently in renal failure on dialysis  
• 
If no eGFR is available for an adult participant during the last 2 
years, one must be obtained to confirm eligibility 
15. Presence of a medical condition or use of a medication that, in the 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 14 OF 97 
 
Description 
judgment of the investigator, clinical protocol chair, or medical 
monitor, could compromise the results of the study or the safety of 
the participant.  Conditions to be considered by the investigator may 
include the following: 
• 
Alcohol or drug abuse 
• 
Use of prescription drugs that may dull the sensorium, reduce 
sensitivity to symptoms of hypoglycemia, or hinder decision 
making during the period of participation in the study  
• 
Coronary artery disease that is not stable with medical 
management, including unstable angina, angina that prevents 
moderate exercise (e.g. climbing a flight of stairs) despite 
medical management, or within the last 12 months before 
screening a history of myocardial infarction, percutaneous 
coronary intervention, enzymatic lysis of a presumed coronary 
occlusion, or coronary artery bypass grafting  
• 
Congestive heart failure with New York Heart Association 
(NYHA) Functional Classification III or IV  
• 
History of TIA or stroke in the last 12 months 
• 
Untreated or inadequately treated mental illness  
• 
History of eating disorder within the last 2 years, such as 
anorexia, bulimia, or diabulemia or omission of insulin to 
manipulate weight 
• 
History of intentional, inappropriate administration of insulin 
leading to severe hypoglycemia requiring treatment 
16. Employed by, or having immediate family members employed by 
Beta Bionics, or being directly involved in conducting the clinical 
trial, or having a direct supervisor at place of employment who is also 
directly involved in conducting the clinical trial (as a study 
investigator, coordinator, etc.); or having a first-degree relative who 
is directly involved in conducting the clinical trial 
 
Sample Size 
RCT Period: ~ 440 participants (165 participants 6–<18 years and 275 
participants  ≥18 years) 
Transition Phase for All Participants on Completion of BP Use: up to 
~440 participants  (up to ~165 pediatric participants and ~275 adult 
participants) 
Treatment Groups 
Pediatric (6-<18 years old) RCT Period: Random assignment in a 2:1 ratio 
to the BP Group (with lispro or aspart) or the Control Group (~110 and ~55 
participants, respectively) for a period of 13 weeks, such that a minimum of 
100 in the BP Group will complete the 13-week RCT. 
Adult (≥18 years) RCT Period: Random assignment in a 2:2:1 ratio to the 
BP Group (with lispro or aspart), the BP Fiasp Group, or the Control Group 
(~110, 110, and 55 participants, respectively) for a period of 13 weeks such 
that a minimum of 100 in each BP Group complete the 13-week RCT. 
Transition Phase (all adult and pediatric participants at end of RCT [BP 
Group]: random assignment in a 1:1 ratio to transition back to either 
participant’s usual therapy or the dosing recommendations from the iLet BP. 
Participant Duration 
~3 months 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 15 OF 97 
 
Description 
Protocol Overview/Synopsis 
The study has two major parts: (1) the RCT Period, and (2) the Transition 
Phase. These parts are described below and detailed in the main part of the 
protocol.  
The 13-week, parallel-group, multi-center RCT Period is designed to compare 
the insulin-only iLet BP Group using insulin lispro, insulin aspart, or Fiasp 
(adults only); and a control group using CGM (Control Group).  Upon 
completion of the RCT Period, the BP Group will enter the 2–4 day Transition 
Phase and eligible participants in the Control Group will be offered 
participation in a separate Extension Study. 
A 2–4 day Transition Phase will be conducted for all participants who 
complete BP use at the end of the RCT Period (BP Group).  Participants will 
be randomly assigned (1:1) to either transition back to their usual mode of 
therapy (MDI or pump therapy) based on therapeutic guidance from the iLet 
BP system or transition back to their usual mode of therapy based on what 
their own insulin regimens were prior to enrolling in the RCT Period. For 
those randomized to using their pre-study regimens, the dosing can be 
adjusted by the investigator to mitigate safety issues but should follow pre-
study regimen as closely as possible.  
 
Protocol Overview/Synopsis 
(continued) 
RCT Period Visit and Phone Contact Schedule 
• 
Screening Visit (which may be completed as part of a separate 
screening protocol) 
 – Eligibility assessed, informed consent signed, point-of-care/local 
HbA1c, psychosocial questionnaires completed, baseline Dexcom G6 
CGM data collection. 
o 
For baseline data collection, participants using a personal 
Dexcom G6 who have at least 85% of possible glucose data 
in last 14 days can skip the CGM data collection 
o 
Participants using a personal Dexcom G6 with <85% of data 
will use their personal Dexcom G6. 
o 
Participants using a personal Dexcom G5 will be provided 
with an unblinded Dexcom G6 for CGM data collection. 
o 
Participants who do not use a Dexcom G5 or G6 will be 
provided with a blinded Dexcom G6 for CGM data 
collection.  
o 
For participants who completed the separate screening 
protocol, eligibility will be reassessed.  Participants will not 
need to repeat the point-of-care/local HbA1c, psychosocial 
questionnaires or CGM data collection.   
• If the separate screening protocol was completed or CGM data collection 
is not needed, randomization can proceed immediately.  If CGM data 
collection was performed as part of this protocol, randomization visit 
will occur14-21 days after screening.  
• Prior to randomization, eligibility will be reassessed and blood collected 
for central lab HbA1c 
• BP study start/Control study start on day of Randomization Visit 
• Phone contacts after 1-2 days and 7 (±2) days 
• Visits at 2 weeks (±4 days), 6 weeks (±4 days), 10 weeks (±4 days), and 
~13 weeks (91–98 days from randomization): 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 16 OF 97 
 
Description 
o 
Participants in the Control Group will be trained on use of 
the unblinded Dexcom G6 unless they are current users of 
the Dexcom G6 CGM. All participants in the Control Group 
will be provided with Dexcom G6 supplies to use the CGM 
unblinded for the duration of the RCT phase.  
o 
At the 6-week and 13-week visits, central lab HbA1c 
determination and psychosocial questionnaires 
Transition Phase Visit Schedule 
• Randomization and transition to usual care regimen at 13-week visit for 
BP Group, for a period of 2–4 days in duration. 
• Visit 2-4 days later for end of study 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 17 OF 97 
SCHEMATIC OF STUDY DESIGN 
 
 
 
 
Numbers in cells are approximations and assume no dropouts and exact randomization 
distributions
RCT Period
Transition Phase
Peds < 18 yo
2 equal age groups
N=165
BP
N=110
Adults ≥ 18
N=275
Control
N=55
Control
N=55
BP-F
N=110
BP-LA
N=110
Transition Phase
N=330 (max)
iLet
Recommendations
N=165
Usual Care Transition
N=165

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 18 OF 97 
SCHEDULE OF STUDY VISITS AND PROCEDURES 
Table 1. Schedule of Study Visits8 and Procedures During 13-Week RCT Period 
 
Screening 
Randomization/ 
Study Start (0w)  
1-2d 
(phone 
call) 
1w 
(phone 
call) 
2w 
6w 
10w 
13w 
Informed Consent 
X 
 
 
 
 
 
 
 
Eligibility 
assessment 
X 
X 
 
 
 
 
 
 
Hypoglycemia 
Unawareness 
Assessment 
X 
 
 
 
 
 
 
X 
HbA1c point of 
care/local lab9 
X7 
 
 
 
 
 
 
 
HbA1c 
central lab 
 
X 
 
 
 
X 
 
X 
C-peptide and 
glucose central 
lab9 
 
X 
 
 
 
 
 
 
Blood collection 
for storage1, 9 
 
X 
 
 
 
 
 
X 
Urine 
pregnancy test2 
X 
X 6 
 
 
X 
X 
X 
 
Height/Weight 
X 
X6  
 
 
 
X 
 
X 
Psychosocial 
questionnaires3 
X7 
 
 
 
 
X 
 
X 
Placement of 
CGM sensor  
X4 
 
 
 
X4 
X4 
X4 
 
Data download 
X5 
 
 
 
X 
X 
X 
X 
Adverse event 
querying 
 
X 
X 
X 
X 
X 
X 
X 
1Optional for participants 
2Pregnancy test for post-menarche and pre-menopausal women with child-bearing potential 
3Questionnaires (See Chapter 8) 
4At screening, CGM wear can be skipped for the purpose of collection of baseline data by current users of Dexcom G6 sensor 
with at least 85% usage in last 14 days. Current users of a Dexcom G5 will be provided with an unblinded G6 device for 
baseline data collection. Participants who do not use a Dexcom G5 or G6 will be provided with a blinded Dexcom G6 device. 
During follow-up, a sensor will be placed for participants in the Control Group if they are not already wearing one. An 
unblinded sensor will be placed for those in the BP Group who have stopped using the iLet BP system and Dexcom G6 CGM 
and agree to wear a Dexcom G6 sensor. 
5For participants who use a Dexcom G6 CGM 
6 If randomization date is different from screening date 
7 If not completed as part of separate screening protocol 
8 Study visits can occur in clinic or virtually 
9 Will be skipped if visit is conducted virtually 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 19 OF 97 
Table 2. Schedule of Study Visits2 and Procedures During the Transition Phase 
 
Randomization/ 
Study Start (0d) 
 
2-4d 
Questionnaire1 
 
 
X 
Placement of CGM sensor  (if not 
already wearing one) 
X 
 
 
Data download 
 
 
X 
Adverse event querying 
 
 
X 
1Customized questionnaire (See Section 8.2.1) 
2Study visits can occur in clinic or virtually 
 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 20 OF 97 
Chapter 1: Introduction 
1 
1.1 Background and Rationale 
2 
Maintaining near-normal blood glucose (BG) levels (70–120 mg/dl) is a challenging and 
3 
critically important task for people with type 1 diabetes (T1D).  The Diabetes Control and 
4 
Complications Trial (DCCT) Research Group definitively demonstrated that tight BG control 
5 
can reduce long-term complications.  The likelihood and severity of nephropathy, retinopathy, 
6 
neuropathy, macrovascular disease, and skin disorders is reduced in proportion to reductions in 
7 
glycated hemoglobin (HbA1c), which is closely correlated with long-term average BG levels.  
8 
Risks for such complications are elevated by three- to five-fold with diabetes.  On the other hand, 
9 
tight BG control through conventional intensive insulin therapy increases the likelihood of 
10 
episodic hypoglycemia, which carries acute risks, including convulsions, seizures, coma, and 
11 
death. Conventional therapy also requires a relentless daily effort to count carbohydrates, 
12 
frequently monitor BG throughout the day and night, and administer a daily insulin regimen. 
13 
A more reliable method for achieving consistent BG control consists of an integrated artificial 
14 
or bionic pancreas (BP) system, consisting of a continuous glucose monitor (CGM), an infusion 
15 
pump, and a control algorithm that actuates the pump based on CGM glucose data.  Such a 
16 
system can automate and ease the burden of T1D management and vastly improve glycemic 
17 
control relative to the current standard of care. 
18 
Recent years have seen the development of several competing strategies for automated or semi-
19 
automated management of glycemia. One large difference between competing designs is whether 
20 
they use insulin alone (insulin-only) and rely on the user treating with carbohydrates if the blood 
21 
glucose falls too low, or insulin and glucagon (bihormonal) and use glucagon to automatically 
22 
prevent and treat hypoglycemia, with carbohydrate treatment used only if glucagon treatment is 
23 
not successful. 
24 
Glucagon is an endogenous hormone that binds with high affinity to its cognate receptor. 
25 
Glucagon is quantitatively the most important counter-regulatory hormone in normal glucose 
26 
control physiology.  In healthy individuals without T1D, glucagon levels rise during exercise, 
27 
and in the late-postprandial period as glucose levels return to the normal range after a small 
28 
hyperglycemic excursion.  The production of glucagon is dysregulated early in the course of 
29 
T1D and glucagon production in response to threatened hypoglycemia is lost.  Therefore, 
30 
people with T1D are functionally glucagon deficient. 
31 
An important challenge for automated glucose control is that the physiologic need for 
32 
insulin can change rapidly, but insulin is slowly absorbed when delivered subcutaneously.  
33 
Even “rapid-acting” insulin analogs such as insulin lispro (Humalog) have a mean time-to-peak 
34 
of ~70 minutes.  This means that if the need for insulin decreases rapidly, such as in the case of 
35 
exercise, there is already insulin-on-board that cannot be withdrawn.  In contrast to insulin, 
36 
glucagon is absorbed quickly, with a time-to-peak of ~15-20 minutes.  Therefore, small doses of 
37 
glucagon can be given to counter the effects of excess insulin that has already been delivered and 
38 
cannot be withdrawn, and can prevent hypoglycemic events that could not be prevented by 
39 
suspending insulin delivery alone.  This allows the BP to ask less of the user (less need to 
40 
respond to alarms, take carbohydrates to treat hypoglycemia) and allows the user to be more 
41 
spontaneous (no need to announce exercise in advance). 
42 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 21 OF 97 
The use of glucagon provides the BP with a powerful tool to automatically prevent and treat 
43 
hypoglycemia, but it does present several challenges.  First, exogenous glucagon must be shown 
44 
to be safe when administered in micro-doses intermittently on a chronic basis.  This means that 
45 
clinical trials must be longer to allow adequate exposure to demonstrate safety.  A second 
46 
challenge to the use of glucagon is that a form of glucagon that is stable near body temperature 
47 
for at least several days in a pump must be available.  When we first began developing our BP, 
48 
there were no stable glucagon formulations or glucagon analogs available.  However, Zealand 
49 
Pharma’s development program for its glucagon analog (dasiglucagon) is now sufficiently 
50 
advanced to meet our timeline for pivotal studies.  A third challenge is that, as with 
51 
subcutaneously administered insulin, replacement of glucagon by subcutaneous administration 
52 
cannot perfectly mimic normal physiology, and peripheral levels must be higher than normal to 
53 
generate adequate liver exposure for effectiveness.  However, in our last inpatient study of the 
54 
BP in adults and adolescents during over 2,300 patient-hours of exposure, frequent blood 
55 
sampling showed that the aggregate mean glucagon levels were in the normal fasted range 
56 
(<150 pg/ml by the Millipore radioimmunoassay) between 61% and 91% of the time and 
57 
exceeded 400 pg/ml on only 4 occasions, all of which were transient.  In the glucagonoma 
58 
syndrome, clinically evident cases are associated with glucagon levels chronically in excess of 
59 
1,000 pg/ml. A review of case series suggests that glucagonomas and other neuroendocrine 
60 
tumors producing chronic glucagon levels <400 pg/ml are usually discovered incidentally on 
61 
imaging, suggesting that unless glucagon levels are chronically above this threshold, the tumors 
62 
are asymptomatic.  In previous studies, the doses of glucagon administered by the BP are vastly 
63 
lower than levels that have been shown to be safe in pre-clinical studies.  In our home use Bionic 
64 
Pancreas Multi-Center Study (BPMC), mean glucagon usage on the BP was 7 mcg/kg/day.  
65 
Doses of glucagon up to 9 mg/kg/day (1,286-fold higher) have been administered to rats, rabbits, 
66 
cats, and dogs for 6 months without any toxic effects or weight loss.  In rats and beagle dogs 
67 
given up to 4 mg/kg/day and 0.2 mg/kg, respectively (571-fold and 29-fold higher than our BP 
68 
doses, respectively), the only changes were increases in serum glucose and a small increase in 
69 
liver weight without adverse histopathologic changes.  Based on these results, we expect that the 
70 
doses of glucagon used by the BP will be safe.  Finally, there will inevitably be additional cost 
71 
associated with use of a second drug, but this may be balanced by the advantages associated with 
72 
the improvement in glycemic control that is possible with a bihormonal BP. 
73 
In consideration of the potential for automated glucagon delivery, we have developed a bionic 
74 
pancreas system that can be used in either the bihormonal, insulin-only, and glucagon-only 
75 
configurations. 
76 
1.2 Bihormonal BP System 
77 
We have developed an autonomous, self-learning BP that requires only the participant's weight 
78 
for initialization, and then autonomously adapts, modestly or dramatically, as needed, to cope 
79 
with the wide range of insulin requirements of adults, adolescents, and pre-adolescents with 
80 
T1D.  Our BP obviates the need for the patient to know, or even appreciate, their insulin 
81 
requirements, and renders obsolete any need for patients or caregivers to know 
82 
carbohydrate-to-insulin ratios, basal rates, or insulin correction factors. 
83 
Our core technology is our suite of three mathematical dosing algorithms for insulin infusion, 
84 
which orchestrates all subcutaneous (SC) insulin dosing.  At its centerpiece is a model-predictive 
85 
control (MPC) algorithm, which bases insulin doses on the glucose data and insulin absorption 
86 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 22 OF 97 
kinetics.  We were the first to incorporate insulin pharmacokinetics (PK) into our algorithm, by 
87 
augmenting it with a mathematical formulation for estimating the concentration of insulin in the 
88 
blood and predicting its future concentration.  It is essential to compensate for the slow 
89 
absorption rate of SC insulin analogs (peak time in blood of 30–90 min, clearance in 4–8 hr), and 
90 
to enable the algorithm to refrain from stacking and overdosing insulin.  Furthermore, our MPC 
91 
algorithm automatically adjusts its insulin-doing aggressiveness continuously and in real time to 
92 
different insulin needs between individuals and variable needs within the same individual.  
93 
Running in parallel with our MPC algorithm is an algorithm that automatically modulates basal 
94 
insulin delivery over multiple time scales, and another algorithm that automatically adapts 
95 
insulin doses in response to optional meal announcements.  Unlike current insulin pumps, and 
96 
all of the insulin-only control algorithms of which we are aware, our adaptive basal insulin 
97 
algorithm obviates the need for the user to set, or even know, his or her “basal-rate profile”.  
98 
Instead, it is capable of automatically adapting to, and compensating for, changes in an 
99 
individual's basal insulin need, such as might occur over a period of hours, days, or weeks 
100 
(e.g. circadian hormonal fluctuations, intercurrent illness, physical activity, or emotional state) 
101 
or as might occur over a period of months or years due to developmental changes (e.g. hormonal 
102 
changes that occur during puberty or menopause).  Our adaptive meal dose controller obviates 
103 
the need for the user to set, or even know, his or her “carbohydrate-to-insulin ratios,” as it 
104 
makes automatic adjustments based on dosing history for similar meal announcements made on 
105 
previous days, and customizes the dose for each individual and for time of day.  Our BP also 
106 
includes a proportional-derivative (PD) algorithm governing SC micro-doses of glucagon to help 
107 
prevent impending hypoglycemia.  Glucagon dosing is based on the glucose level and rate of 
108 
descent. It could occur preemptively even if glucose is above range and it includes a feedback 
109 
term to account for the pending effects of recent glucagon doses.  The amount of glucagon dosed 
110 
also feeds back on the insulin controller, so that large amounts of glucagon dosing decrease the 
111 
aggressiveness of the insulin controller. 
112 
Taken together, these mathematical algorithms provide a universal framework for a glycemic 
113 
control strategy that requires no quantitative input from, or participation by, the user (besides 
114 
entering body weight to initialize the system), but which automatically adapts insulin and 
115 
glucagon dosing to meet the individual needs of each user.  Another challenge we have met is 
116 
enabling our technology to remain completely autonomous in managing insulin and glucagon 
117 
delivery even when the CGM is offline.  Specifically, when the CGM is offline, our BP invokes 
118 
the high-resolution “basal rate profile” that it had recently learned and stored when the CGM was 
119 
online.  On the basis of what the system learned and stored about meal announcements when the 
120 
CGM was online, it is able to respond to meal announcements in the same manner when the 
121 
CGM is offline.  Finally, it automatically responds to user-entered BG values when the CGM is 
122 
offline by issuing a correction dose of insulin or glucagon based on what it learned about the 
123 
user's insulin and glucagon needs when the CGM was online.  Thus, our BP never relies on, or 
124 
burdens the user with, the determination of dosing decisions, which inevitably vary in quality 
125 
and reliability among different users.  The BP provides a turnkey solution for people with T1D 
126 
that comprehensively manages glycemia across a broad range of individual needs and a across a 
127 
large spectrum of circumstances and challenges to glycemic control. 
128 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 23 OF 97 
1.3 Insulin-Only BP System 
129 
The BP can also operate in an insulin-only mode.  During operation in this mode, all of the other 
130 
features of the BP operate as usual except that glucagon is not given.  In addition, the lowest 
131 
glucose target that can be chosen by the user (towards which the insulin controller drives down 
132 
the blood glucose levels) is increased from 100 mg/dl in the bihormonal system to 110 mg/dl in 
133 
the insulin-only system.  This works to reducing the aggressiveness of insulin dosing in the 
134 
insulin-only system relative to its bihormonal counterpart, with the aim of keeping the amount of 
135 
hypoglycemia low even at the potential cost of raising the mean glucose level achieved by the 
136 
insulin-only system.   
137 
In the insulin-only configuration the BP keeps track of the glucagon that would have been given 
138 
had it been in the bihormonal configuration. In both configurations, use of glucagon has the 
139 
effect of reducing the aggressiveness of the insulin controller. In the insulin-only configuration 
140 
glucagon doses cannot actually be given so the CGM glucose does not rise in response. 
141 
Therefore, more virtual glucagon is given by the insulin-only configuration compared to the 
142 
amount of actual glucagon that would have been given by the bihormonal configuration. This has 
143 
the effect of reducing insulin dosing more in the insulin-only configuration than in the 
144 
bihormonal configuration and leads to a higher average glucose achieved by the insulin-only 
145 
configuration than the bihormonal configuration for the same glucose target.    
146 
The intended use for the insulin-only configuration of the BP system is to provide automated 
147 
glucose control prior to commercial availability of a stable glucagon analog. It may also be used 
148 
for people for whom goals for therapy can be achieved with minimal hypoglycemia and/or use of 
149 
oral carbohydrates without the use of glucagon. This may include people with type 2 diabetes or 
150 
cystic fibrosis-related diabetes. 
151 
1.3.1 iPhone-Based BP System 
152 
Our BP hardware platform began as a laptop-driven system, which we used in all of our inpatient 
153 
studies (between 2008–2012) at MGH.  In late 2012, we received FDA approval to conduct our 
154 
first outpatient study using our new mobile wearable iPhone-Based BP System, which we used 
155 
in all of our outpatient and home-use studies between 2013 and 2017.  The system consisted of 
156 
one or two (depending on the configuration of the system) t:slim infusion pumps (Tandem), a 
157 
G4 Platinum AP CGM (Dexcom), and the BP insulin-dosing and glucagon-dosing control 
158 
algorithms.  The control algorithms were encoded in an app together with a simple graphical user 
159 
interface (GUI) that ran on an iPhone 4S (Apple).  The iPhone and the Dexcom CGM receiver 
160 
were connected through their external communication ports with a custom hardware interface 
161 
and were housed together in a custom enclosure.  The iPhone, CGM, and enclosure together 
162 
comprised our BP Control Unit.  The BP app ran the insulin-dosing and glucagon-dosing control 
163 
algorithms, managed connectivity between the iPhone and the Dexcom receiver, and controlled 
164 
the Bluetooth radio, which effectuated communication between the iPhone and the t:slim pump.  
165 
The GUI displayed the current CGM glucose, the CGM trend, and the insulin and glucagon 
166 
doses.  The BP app also provided the interface to input meal announcements.  Meal announce-
167 
ments (1) specified a type of meal (as “breakfast,” “lunch,” or “dinner”) (2) designated the size 
168 
of the meal (as “larger than typical,” “typical,” “smaller than typical,” or “just a bite”), and 
169 
(3) triggered a partial meal-priming bolus, the size of which automatically adapts during the 
170 
course of the trial to meet a target of 75% of the insulin required for that size and type of meal. 
171 
The BP managed all insulin and glucagon dose calculations when the CGM was online and 
172 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 24 OF 97 
offline.  When the CGM was offline, the control algorithm administered correction boluses of 
173 
insulin or glucagon as appropriate in response to any entered BG value, just as if they were CGM 
174 
values.  The GUI also displayed visual alarms associated with an audio signal if communication 
175 
was dropped between the BP app and the t:slim pump, or if the CGM glucose was below a low 
176 
threshold.  The BP Control Unit communicated to a server that allowed the BP to support remote 
177 
telemetry of CGM data. 
178 
Using our iPhone-based BP, we have conducted over 110 outpatient experiments of 5–11 days 
179 
in duration in each participant with T1D (> 800 patient days or > 2 patient years of data), and 
180 
across participants ranging in age between 6 and 76 years old and in body mass between 21 and 
181 
133 kg.  The robust adaptation capabilities of our BP are evident from the fact that the average 
182 
total daily dose of insulin among these participants varied by over 13-fold (from 11 to 145 
183 
units/day) among children and adults with T1D. 
184 
Using the iPhone-based BP we have also performed a study with the bihormonal configuration 
185 
in children and adolescents with congenital hyperinsulinism after subtotal pancreatectomy. 
186 
We have performed studies using the glucagon-only configuration as an adjunct to 
187 
patient-controlled insulin dosing in adults with T1D and a study using the glucagon-only 
188 
configuration as an adjunct to usual therapy in adults with post-bariatric hypoglycemia. 
189 
In addition, we have performed pilot studies with both the insulin-only and bihormonal 
190 
configurations in adults with cystic fibrosis-related diabetes and adults with insulin-dependent 
191 
type 2 diabetes with inadequate glycemic control despite multiple daily injections or use of an 
192 
insulin pump. 
193 
Studies that have utilized the iPhone-based BP system are summarized in the table below and 
194 
described in more detail in Appendix A. 
195 
Table 3. iPhone BP System Studies 
196 
 
Year 
Name of 
Study 
Setting 
N 
Duration 
of Use 
BP 
Configuration 
Monitoring 
Protocol Description 
1 
2013 
Beacon Hill 
Study 
Supervised 
hotel stay 
20 
5 days 
Bihormonal 
Direct 
supervision 
Adults 21 and older, 
randomized crossover 
with usual care 
(at home)  
2 
2013 
2013 
Summer 
Camp Study 
Supervised 
summer camp 
setting 
32 
5 days 
Bihormonal 
Remote 
telemetric 
monitoring 
Adolescents aged 12 
to 20, randomized 
crossover with usual 
care at camp 
3 
2014 
2014 
Summer 
Camp Study 
Supervised 
summer camp 
setting 
19 
5 days 
Bihormonal 
Remote 
telemetric 
monitoring 
Pre-adolescents aged 
6 to 11, randomized 
crossover with usual 
care at camp 
4 
2014 
BP 
Multi-center 
Study 
Outpatient, 
unsupervised at 
home, 4 study 
centers 
39 
11 days 
Bihormonal 
Remote 
telemetric 
monitoring 
Adults 18 and older, 
randomized crossover 
with usual care 
5 
2015-
2016 
BP Set 
Point Study 
Outpatient, 
unsupervised 
at home 
20 
8 arms, 
4 days 
each 
Bihormonal 
and 
Insulin-only 
Remote 
telemetric 
monitoring 
Adults aged 18 and 
older, randomized 
crossover with usual 
care and 8 different 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 25 OF 97 
 
Year 
Name of 
Study 
Setting 
N 
Duration 
of Use 
BP 
Configuration 
Monitoring 
Protocol Description 
BP configurations 
testing different 
glucose target set 
points in addition to 
insulin only for the 
first time 
6 
2015 
Stanford 
Insulin-
only Study 
Outpatient, 
unsupervised 
at home 
16 
2 arms, 
7 days 
each 
Insulin-only 
Remote 
telemetric 
monitoring 
Adults aged 18 and 
older, compared 
with usual care 
7 
2017 
Monitoring 
Study 
Outpatient, 
unsupervised 
at home 
23 
4 arms, 
7 days 
each 
Bihormonal 
and Insulin-
only 
Each arm 
repeated 
with and 
without 
remote 
telemetric 
monitoring  
Adults aged 18 and 
older, compared 
with usual care with 
and without remote 
monitoring 
8 
2017 
Zealand 
Feasibility 
Study 
Supervised, 
in clinic 
12 
2 arms, 
8 hours 
each 
Bihormonal 
N/A 
Adults aged 18 and 
older, randomized 
crossover comparing 
Eli Lilly glucagon 
with dasiglucagon in 
structured clinic 
setting 
1.3.2 Fully Integrated iLet®  BP System (Beta Bionics) 
197 
The iLet® Bionic Pancreas System (iLet), developed by Beta Bionics, Inc., is a wearable device 
198 
that autonomously manages glycemia in people with diabetes and other conditions of glycemic 
199 
dysregulation.  The iLet integrates CGM technology (choice of either Dexcom G6 or Senseonics 
200 
Eversense) via its built-in Bluetooth radio.  It includes two independent motor–drivetrain 
201 
pumping mechanisms, which independently actuate the delivery of insulin and glucagon from 
202 
cartridges that are separately loaded into the iLet.  The iLet is capable of functioning in an 
203 
insulin-only, glucagon-only, or bihormonal configuration.  The iLet is compatible with three 
204 
insulin analog formulations (insulin lispro, Lilly; insulin aspart and Fiasp, Novo Nordisk) and 
205 
one glucagon analog (dasiglucagon, Zealand Pharma).  The iLet also includes a touchscreen 
206 
display that enables user interactions through a custom graphical user interface with smartphone 
207 
simplicity.  Finally, the iLet contains embedded software that includes adaptive control 
208 
algorithms that autonomously and continually adapt to the ever-changing insulin requirements of 
209 
each individual to enable lifelong adaptive learning.  The control algorithms used by the iLet 
210 
only require initialization with the user’s body mass and are the very same algorithms that were 
211 
developed for the Boston University iPhone-Based BP and were tested and refined in all of the 
212 
clinical trials described above (i.e. the Beacon Hill Study, the 2013 and 2014 Summer Camp 
213 
Studies, the Bionic Pancreas Multi-Center Study the Stanford Insulin-Only Study, the Bionic 
214 
Pancreas Set-Point Study, and the Bionic Pancreas Monitoring Study).  As such, the iLet requires 
215 
only the patient’s body weight for initialization.  It does not require carbohydrate counting, nor 
216 
does it require any information about the patient’s total daily dose of insulin, basal or long-acting 
217 
insulin requirements, carbohydrate-to-insulin ratios, or insulin correction factors for managing 
218 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 26 OF 97 
hyperglycemia.  It is a fully autonomous glycemic control system that requires very little 
219 
management on the part of the patient or provider.  Figure 1 illustrates the iLet’s features and 
220 
drug-delivery configurations and is shown together with its compatible CGM devices. 
221 
 
222 
Figure 1 The commercial version of the iLet bionic pancreas system (Beta Bionics, Inc.) 
223 
uses adaptive control algorithms that autonomously and continuously adapt to the patient’s ever-
224 
changing insulin needs to enable lifelong adaptive learning.  The control algorithms in the iLet 
225 
only require initialization with the user’s body mass, have been tested, refined, and improved 
226 
through over 10 years of clinical research.  The iLet can be configured in the insulin-only, 
227 
glucagon-only, or bihormonal configurations.  It is interoperable with one of two CGM devices 
228 
and is compatible with three insulin analog formulations and one glucagon analog. 
229 
The iLet is set to either the insulin-only, bihormonal, or glucagon-only configuration by 
230 
manually selecting the desired configuration in the user interface.  When in the bihormonal 
231 
configuration, the control algorithm may occasionally and automatically invoke the same insulin-
232 
only dosing mode as in the insulin-only configuration during periods when the glucagon 
233 
cartridge has not been loaded, is empty, or becomes empty during use, or if there is an occlusion 
234 
detected in the glucagon fluid path.  Whenever the iLet is in an insulin-only mode, the minimum 
235 
glucose target is 110 mg/dl.  Whenever the iLet is in a bihormonal or glucagon-only mode, and 
236 
the glucagon fluid path is patent and primed, the minimum glucose target is 100 mg/dl. 
237 
In addition to the iLet ready-to-fill glass insulin cartridge and the prefilled glass dasiglucagon 
238 
cartridge, the iLet uses separate insulin and glucagon administration sets, which each have their 
239 
own proprietary connectors to the insulin and glucagon cartridges in the iLet and to the infusion 
240 
site on the patient.   
241 
The iLet BP will make recommendations for multiple daily injection (MDI) dosing (for those on 
242 
MDI therapy) AND for continuous subcutaneous insulin infusion (CSII) dosing via an insulin 
243 
pump (for those on CSII therapy).  We have shown in our previous outpatient and home-use 
244 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 27 OF 97 
studies in adult and pediatric participants with T1D that the total daily dose (TDD) of insulin 
245 
used by the BP is consistent with usual care.  The iLet has three insulin controllers running in 
246 
parallel: a basal insulin controller, which continually adapts to each individual’s basal metabolic 
247 
need for insulin, an MPC controller, which provides control doses that are required above and 
248 
beyond basal insulin, and a meal-announcement controller, which continually adapts to the 
249 
individual's prandial insulin needs.  The iLet provides a daily readout with updated estimates of 
250 
daily basal insulin (in terms of a daily long-acting insulin dose for MDI users and a 24-hour, 
251 
four-segment basal rate dose for CSII users), prandial insulin (for breakfast, lunch, and dinner) 
252 
and correction doses.  Thus, the iLet is designed to provide an up-to-date recommendation of 
253 
these quantities for both MDI and CSII users if, for any reason, the iLet may be temporarily 
254 
unavailable to the user. 
255 
Studies conducted using the iLet are summarized in the table below and described in Appendix 
256 
A. 
257 
Table 4. iLet BP System Studies 
258 
 
Year 
Name of 
Study 
Setting 
N 
Duration 
of use 
BP 
Configuration 
Monitoring 
Protocol 
Description 
1 
2018 
Adult 
Bridging 
Study 
Outpatient, 
unsupervised 
at home, 
2 centers 
34 
2 arms, 
7 days each 
Insulin-only 
Remote 
telemetric 
monitoring 
Adults aged 18 
and older, 
compared with 
usual care. One 
arm used insulin 
aspart/lispro, the 
other arm used 
Fiasp. 
MGH used 
Senseonics 
Eversense CGM, 
Stanford used 
Dexcom G5 
CGM 
2 
2018 
Day-Camp 
Transitional 
Study 
Supervised 
day camp 
setting 
followed by 
unsupervised 
at home 
nightly, 
2 centers 
20 
5 days 
Insulin-only 
Remote 
telemetric 
monitoring 
Children aged 
6-17, randomized 
crossover with 
usual care 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 28 OF 97 
 
Year 
Name of 
Study 
Setting 
N 
Duration 
of use 
BP 
Configuration 
Monitoring 
Protocol 
Description 
3 
2019 
Fiasp 
Exploratory 
Study 
48 hour 
supervised 
hotel stay, 
followed by 
5 days 
unsupervised 
at home 
24 
2 arms, 
7 days each 
Insulin-only 
Remote 
telemetric 
monitoring 
Adults aged 18 
and older, 
randomized to 
compare default 
insulin PK 
settings with 
faster PK 
settings.  Faster 
PK setting was 
escalated over 
three cohorts of 
8 subjects 
4 
2019 
Bihormonal 
Crossover 
Study 
Outpatient, 
unsupervised 
at home 
10 
2 arms, 
7 days each 
Bihormonal 
and Insulin-
only 
Remote 
telemetric 
monitoring 
Adults aged 18 
and older, 
randomized to 
compare insulin-
only with 
bihormonal using 
dasiglucagon, 
testing 
bihormonal iLet 
for the first time 
5 
2019 
MultiPK 
BP Study 
Outpatient, 
unsupervised 
at home 
Ongoing 
3 arms, 
7 days each 
Insulin-only 
Remote 
telemetric 
monitoring 
Adults aged 18 
and older, 
randomized to 
compare one 
week each on 
insulin lispro, 
insulin aspart and 
BioChaperone 
lispro 
1.3.3 Fiasp (Novo Nordisk) 
259 
Faster insulin aspart or Fiasp is a formulation of insulin aspart (sold as Fiasp in both the United 
260 
States and in Europe) that contains nicotinamide (also known as niacinamide or vitamin B3) and 
261 
L-arginine hydrochloride (an amino acid).  The addition of nicotinamide is intended to result in a 
262 
faster initial absorption of insulin aspart following SC injection or infusion.  The addition of L-
263 
arginine hydrochloride stabilizes the Fiasp formulation.  The active substance (i.e. insulin aspart) 
264 
in Fiasp and Novolog is identical and therefore, once systemically absorbed, it has the same 
265 
biological action at the insulin receptor as that of Novolog.  Since one of the important 
266 
limitations of automated closed-loop glucose control is the delay in absorption of insulin, the use 
267 
of Fiasp with the bionic pancreas in some individuals may provide improved glycemic control 
268 
relative to lispro or aspart. 
269 
1.4 Potential Risks and Benefits of the Investigational Device and Study 
270 
Participation 
271 
Risks and benefits are detailed below. Loss of confidentiality is a potential risk; however, data 
272 
are handled to minimize this risk.  Hypoglycemia, hyperglycemia and ketone formation are 
273 
always a risk in participants with type 1 diabetes and participants will be monitored for this. 
274 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 29 OF 97 
1.4.1 Known Potential Risks 
275 
1.4.1.1 Venipuncture Risks 
276 
A hollow needle/plastic tube may be placed in the arm for taking blood samples. Blood draws 
277 
can cause some common reactions like pain, bruising, or redness at the sampling site.  Less 
278 
common reactions include bleeding from the sampling site, formation of a small blood clot or 
279 
swelling of the vein and surrounding tissues, and fainting. 
280 
1.4.1.2 Fingerstick Risks 
281 
About 1 drop of blood will be removed by fingerstick for measuring blood sugars and sometimes 
282 
HbA1c or other tests. This is a standard method used to obtain blood for routine hospital 
283 
laboratory tests.  Pain is common at the time of lancing.  In about 1 in 10 cases, a small amount 
284 
of bleeding under the skin will produce a bruise.  A small scar may persist for several weeks.  
285 
The risk of local infection is less than 1 in 1000.  This should not be a significant contributor to 
286 
risks in this study as fingersticks are part of the usual care for people with diabetes. 
287 
1.4.1.3 Subcutaneous Catheter Risks (CGM) 
288 
Participants using the CGM will be at low risk for developing a local skin infection at the site 
289 
of the sensor needle placement.  If a catheter is left under the skin for more than 24 hours it is 
290 
possible to get an infection where it goes into the skin, with swelling, redness and pain.  
291 
There may be bleeding where the catheter is put in and bleeding under the skin causes a bruise 
292 
(1 in 10 risk). 
293 
Study staff should verbally alert the participant that on rare occasions, the CGM may break and 
294 
leave a small portion of the sensor under the skin that may cause redness, swelling or pain at the 
295 
insertion site.  The participant should be further instructed to notify the study coordinator 
296 
immediately if this occurs. 
297 
1.4.1.4 Risk of Hypoglycemia 
298 
As with any person having type 1 diabetes and using insulin, there is always a risk of having a 
299 
low blood sugar (hypoglycemia).  The frequency of hypoglycemia should be no more and 
300 
possibly less than it would be as part of daily living.  Symptoms of hypoglycemia can include 
301 
sweating, jitteriness, and not feeling well.  Just as at home, there is the possibility of fainting or 
302 
seizures (convulsions) and that for a few days the participant may not be as aware of symptoms 
303 
of hypoglycemia.  A CGM functioning poorly and significantly over-reading glucose values 
304 
could lead to inappropriate insulin delivery. 
305 
1.4.1.5 Risk of Hyperglycemia 
306 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
307 
extended period or if the pump or infusion set is not working properly.  A CGM functioning 
308 
poorly and significantly under-reading glucose values could lead to inappropriate suspension of 
309 
insulin delivery. 
310 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 30 OF 97 
1.4.1.6 Questionnaires 
311 
As part of the study, participants will complete questionnaires, which include questions about 
312 
their private attitudes, feelings and behavior related to the investigational equipment as well as 
313 
managing diabetes.  It is possible that some people may find these questionnaires to be mildly 
314 
upsetting. Similar questionnaires have been used in previous research and these types of 
315 
reactions have been uncommon. 
316 
1.4.1.7 Other Risks 
317 
Some participants may develop skin irritation or allergic reactions to the adhesives used to secure 
318 
the CGM, or to secure the insulin infusion sets for the continuous subcutaneous insulin infusion.  
319 
If these reactions occur, different adhesives or “under-taping” (such as with IV 3000, Tegaderm, 
320 
etc.) will be tried, sites will be rotated frequently, and a mild topical steroid cream or other 
321 
medication may be required. 
322 
Whenever the skin is broken there is the possibility of an infection.  The CGM and pump 
323 
infusion sites are inserted under the skin.  It is possible that any part that is inserted under the 
324 
skin may cause an infection.  These occur very infrequently, but, if an infection was to occur, 
325 
oral and/or topical antibiotics can be used.  The risk of skin problems could be greater if you use 
326 
a sensor for longer than it is supposed to be used.  Therefore, participants will be carefully 
327 
instructed about proper use of the sensor. 
328 
Data downloaded from the CGM, pump, and the home glucose and ketone meter will be 
329 
collected for the study as measures of diabetes self-management behaviors.  Some people may be 
330 
uncomfortable with the researchers' having such detailed information about their daily diabetes 
331 
habits. 
332 
1.4.2 Known Potential Benefits 
333 
One purpose of this research is to reduce the frequency of hypoglycemia and severe 
334 
hypoglycemic events.  Hypoglycemia is the number one fear of many individuals and families 
335 
with someone who has type 1 diabetes and this fear often prevents optimal glycemic control. 
336 
It is expected that this protocol will yield increased knowledge about using an automated closed 
337 
loop to control the glucose level and is intended to develop data to support a future PMA 
338 
application for approval from the FDA to commercially distribute the iLet bionic pancreas in the 
339 
United States.  The individual participant may not benefit from study participation. 
340 
1.4.3 Risk Assessment 
341 
Based on the facts that (1) adults and adolescents with diabetes experience mild hypoglycemia 
342 
and hyperglycemia frequently as a consequence of the disease and its management, (2) the study 
343 
intervention involves periodic automated insulin dosing that may increase the likelihood of 
344 
hypoglycemia, and periodic automated attenuation of insulin delivery that may increase the 
345 
likelihood of hyperglycemia, (3) mitigations are in place, and have been tested in prior studies 
346 
using the investigational device system in the home setting, that limit the likelihood of excessive 
347 
insulin dosing or prolonged withdrawal of insulin, and (4) rapid reversal of hypoglycemia and 
348 
hyperglycemia can be achieved, it is the assessment of the investigators that this protocol falls 
349 
under DHHS 46.405 which is a minor increase over minimal risk.  In addition, it is the belief of 
350 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 31 OF 97 
the investigators that this study also presents prospect of direct benefit to the participants and 
351 
general benefit to others with diabetes. 
352 
1.5 General Considerations 
353 
The study is being conducted in compliance with the policies described in the study policies 
354 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
355 
the protocol described herein, and with the standards of Good Clinical Practice (GCP). 
356 
When feasible, data will be directly collected in electronic case report forms, which will be 
357 
considered the source data. 
358 
The protocol is considered a significant risk device study, due to the fact that the bionic pancreas 
359 
system is experimental.  Therefore, an IDE approval from the FDA is required to conduct the 
360 
study. 
361 
 
362 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 32 OF 97 
Chapter 2: Participation Enrollment and Study Initiation 
363 
2.1 Participant Recruitment 
364 
Study participants will be recruited from ~16 clinical centers in the United States.  The 
365 
recruitment target for the RCT is 440 (165 participants 6–<18 years and 275 participants ≥18 
366 
years) in the 13-week randomized trial  such that a minimum of 100 in the pediatric BP group 
367 
and at least 100 in each of the two adult BP groups will complete the 13-week RCT.  Up to 600 
368 
may be screened to achieve the RCT recruitment targets. 
369 
The study is expected to be conducted at ~ 8 sites that will enroll pediatric participants and ~ 8 
370 
sites that will enroll adult participants in the United States, although there may be crossing over 
371 
of the age groups of participants that sites enroll.  It is anticipated that each pediatric site will 
372 
randomize ~15-20 participants and each adult site will randomize ~ 30-35 participants.  The 
373 
maximum number of randomized participants at a pediatric site will be 40 and at an adult site 
374 
will be 66; and the maximum number enrolled into screening at each site will be 60 and 80, 
375 
respectively. 
376 
No individuals will be excluded on the basis of gender or race.  An approximately equal gender 
377 
distribution between males and females is anticipated.  A study goal will be to include 15% of 
378 
participants of minority race/ethnicity in the study overall. The percentage of minority 
379 
race/ethnicity participants is expected to vary by site. 
380 
Individuals generally will be recruited from each site’s existing patient population or from a pool 
381 
of individuals who contact the site. Central and local IRB requirements regarding recruitment 
382 
materials and policies will be adhered to. Study recruitment methods may consist of the 
383 
following: 
384 
• Culling of pre-existing databases (held by one of the 16 clinical sites, Boston University, 
385 
or Beta Bionics, Inc.) of patients who have expressed interest in the bionic pancreas or 
386 
research participation. Those identified will be contacted via IRB-approved mailing sent 
387 
through post, email blast, or via phone and will be provided information about how to 
388 
complete the consent process and demographics survey; 
389 
• IRB-approved press release announcing study and study fact sheet; 
390 
• Support groups, patient education classes, and not-for-profit community support groups 
391 
(e.g., Children with Diabetes, College Diabetes Network, etc.); 
392 
• IRB-approved paper and digital advertisements, brochures, postcards, flyers, and/or 
393 
newsprint advertisements; 
394 
• IRB-approved digital advertisements posted on social media sites like LinkedIn, Twitter, 
395 
YouTube, Instagram, Facebook, and other public forums managed by a clinical trial site 
396 
or Beta Bionics, Inc.; 
397 
• In-person recruitment and telephone recruitment by individual clinical sites; and 
398 
• An IRB-approved website dedicated to clinical trial recruitment. 
399 
All recruitment methods and specific advertising materials will be approved by the Central 
400 
and/or local IRB prior to their implementation. 
401 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 33 OF 97 
Participants may be included who completed a separate screening protocol which determined 
402 
eligibility for this protocol (with eligibility verified prior to randomization). 
403 
2.2 Informed Consent and Authorization Procedures 
404 
Potential eligibility may be assessed as part of a routine-care examination or as part of a separate 
405 
IRB-approved screening protocol.  Before completing any procedures or collecting any data that 
406 
are not part of usual care, informed consent will be provided and the participant’s electronic 
407 
signatures will be obtained (and assent from minors as indicated). 
408 
For potential study participants ≥18 years old, the study protocol will be discussed with the 
409 
potential study participant by study staff.  The potential study participant will be given the 
410 
Informed Consent Form to read.  Potential study participants will be encouraged to discuss the 
411 
study with family members and their personal physicians(s) before deciding whether to 
412 
participate in the study. If the study participant decides to participate their electronic signature 
413 
will be obtained. 
414 
For potential participants under 18 years of age, a parent/legal guardian (referred to subsequently 
415 
as “parent”) will be provided with the Informed Consent Form to read and will be given the 
416 
opportunity to ask questions.  Potential participants meeting the IRB’s minimum age of assent 
417 
will be given a Child Assent Form to read and discuss with his/her parents and study personnel.  
418 
If the parent and child agree to participate, the minor will verbally provide their assent, and the 
419 
parent/legal guardian’s electronic signature will be obtained.  A copy of the consent form will be 
420 
provided to the participant and his/her parent and another copy will be added to the participant’s 
421 
study record. 
422 
As part of the informed consent process, each participant will be asked to sign an authorization 
423 
for release of personal information.  The investigator, or his or her designee, will review the 
424 
study-specific information that will be collected and to whom that information will be disclosed.  
425 
After speaking with the participant, questions will be answered about the details regarding 
426 
authorization. 
427 
A participant is considered enrolled when informed consent has been obtained. 
428 
The principal investigator at each site will be responsible for assuring that the informed consent 
429 
process is properly followed and that each study participant is well informed about the study and 
430 
the participant’s responsibilities. 
431 
2.2.1 RCT Period 
432 
Participants who have signed consent and started the screening process may be permitted to 
433 
continue into the trial, if eligible, even if the randomization goal has been reached.  Participants 
434 
who turn 18 during the course of the study will need to review the adult Informed Consent Form 
435 
and re-consent by providing their electronic signature. Participants who turn 7 during the course 
436 
of the study will need to review the Child Assent Form and provide assent verbally that they still 
437 
want to participate, the parent/LAR will need to re-consent by providing their electronic 
438 
signature. 
439 
For the pediatric cohort, there will be a goal to have ~50% aged 6-<12 years and 50% aged 12-
440 
<18 years old. For the adult cohort, there will be a goal to have at least 33% of the cohort ≥ 50 
441 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 34 OF 97 
years old.  There also will be approximate goals within each of the 3 age strata (6–<12, 12–<18, 
442 
and ≥18 years old) for the following: 
443 
Pump/multiple daily injection users: at least 33% of each 
444 
HbA1c: at least 33% < 8.0% and 33% ≥ 8.0%; and no more than 20% with HbA1c <7.0% 
445 
2.2.2 Transition Phase 
446 
All participants who complete BP use at the end of the RCT Period at 13 weeks (BP Group) will 
447 
be randomly assigned (1:1) to either transition back to their usual mode of therapy (MDI or 
448 
pump therapy) based on therapeutic guidance from the iLet BP system or transition back to their 
449 
usual mode of therapy based on what their own insulin regimens were prior to enrolling in the 
450 
RCT Period. For those randomized to using pre-study regimen, the dosing can be adjusted by the 
451 
investigator to mitigate safety issues but should follow pre-study regimen as closely as possible.  
452 
 
453 
2.3 Eligibility and Exclusion Criteria 
454 
2.3.1 Eligibility 
455 
To be eligible for the RCT, a participant must meet all of the following inclusion criteria and 
456 
none of the exclusion criteria at the time of screening (which may occur as part of a separate 
457 
screening protocol): 
458 
Inclusion 
459 
1. Clinical diagnosis of T1D for at least one year and using insulin for at least 1 year  
460 
2. Diabetes managed using the same regimen (either pump or MDI, with or without CGM) 
461 
for ≥ 3 months prior to collection of CGM data (either from personal Dexcom G6 device 
462 
or blinded G6 device) 
463 
3. Age ≥ 6 years old 
464 
4. Current use of a CGM, or if not a CGM user, at least 3 blood glucose meter tests daily on 
465 
average over the last 4 weeks (according to judgment of investigator if meter is not 
466 
available). 
467 
5. Willingness not to start any new non-insulin glucose-lowering agent during the course of 
468 
the trial. 
469 
6. For participants <18 years old, living with one or more parent/legal guardian 
470 
knowledgeable about emergency procedures for severe hypoglycemia. 
471 
7. For participants >18 years old who live alone, participant has a relative or acquaintance 
472 
who lives within 30 minutes of participant and is willing to be contacted to check on 
473 
participant if study staff feel that participant may be experiencing a medical emergency 
474 
and can’t be reached. 
475 
8. Investigator believes that the participant can safely use the iLet and will follow the 
476 
protocol 
477 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 35 OF 97 
The investigator will take into account the participant’s HbA1c level, compliance 
478 
with current diabetes management, and prior acute diabetic complications. For this 
479 
reason, there is no upper limit on HbA1c specified for eligibility. 
480 
9. If a GLP-1 agonist or pramlintide is being used, participant must be willing to 
481 
discontinue use while the iLet BP system is being used. 
482 
Exclusion 
483 
1. Unable to provide informed consent (e.g. impaired cognition or judgment). 
484 
2. Unable to safely comply with study procedures and reporting requirements (e.g. 
485 
impairment of vision or dexterity that prevents safe operation of the bionic pancreas, 
486 
impaired memory) 
487 
3. Unable to speak and read English. 
488 
• For pediatric participants, both caregivers and participants must be able to 
489 
speak and read English. 
490 
4. Plan to change usual diabetes regimen in the next 3 months 
491 
• This would include changing from MDI to pump, pump to MDI, change in 
492 
insulin automation delivery system, starting a CGM if not previously used, 
493 
changes in drug therapy specifically for glucose control except for changes in 
494 
one insulin analog to another.  
495 
o Changes in insulin dose, carb ratio, sensitivity factor and basal rate 
496 
profile are allowed. 
497 
5. Current use of non-FDA approved closed-loop or hybrid closed-loop insulin delivery 
498 
system. 
499 
6. Use of Apidra as the pre-study rapid-acting insulin analog and unwilling to switch to 
500 
lispro or aspart for the duration of the study. 
501 
7. Known hemoglobinopathy (sickle cell trait is not an exclusion). 
502 
8. Current participation in another diabetes-related clinical trial. 
503 
9. History of cystic fibrosis, pancreatitis, or other pancreatic disease, including 
504 
pancreatic tumor or insulinoma, or history of complete pancreatectomy. 
505 
10. Electrically powered implants (e.g. cochlear implants, neurostimulators) that might be 
506 
susceptible to RF interference. 
507 
11. Established history of allergy or severe reaction to adhesive or tape that must be used 
508 
in the study. 
509 
12. Current use of SGLT2 inhibitors or a sulfonylurea drug (use more than 3 months 
510 
prior to enrollment is acceptable). 
511 
• If using GLP1 agonist, pramlintide, or metformin drugs must be on a stable 
512 
dose for 3 months prior to enrollment (as per inclusion criterion #8,  must be 
513 
willing to discontinue use of GLP-1 agonist or pramlintide while using the 
514 
iLet BP system during the RCT).  
515 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 36 OF 97 
13. Pregnant (positive urine hCG), breast feeding, plan to become pregnant in the next 3 
516 
months, or sexually active without use of contraception.  
517 
If the visit is conducted virtually, a pregnancy test will be provided to the participant 
518 
and verbal report of the result will be acceptable.   
519 
14. For adults >18 years old, most recent (must be within the last 2 years) eGFR <30 
520 
ml/min OR currently in renal failure on dialysis  
521 
• If no eGFR is available for an adult participant during the last 2 years, one 
522 
must be obtained to confirm eligibility 
523 
15. Presence of a medical condition or use of a medication that, in the judgment of the 
524 
investigator, clinical protocol chair, or medical monitor, could compromise the results 
525 
of the study or the safety of the participant.  Conditions to be considered by the 
526 
investigator may include the following: 
527 
• Alcohol or drug abuse 
528 
• Use of prescription drugs that may dull the sensorium, reduce sensitivity to 
529 
symptoms of hypoglycemia, or hinder decision making during the period of 
530 
participation in the study 
531 
• Coronary artery disease that is not stable with medical management, including 
532 
unstable angina, angina that prevents moderate exercise (e.g. climbing a flight 
533 
of stairs) despite medical management, or within the last 12 months before 
534 
screening a history of myocardial infarction, percutaneous coronary 
535 
intervention, enzymatic lysis of a presumed coronary occlusion, or coronary 
536 
artery bypass grafting 
537 
• Congestive heart failure with New York Heart Association (NYHA) 
538 
Functional Classification III or IV 
539 
• History of TIA or stroke in the last 12 months 
540 
• Untreated or inadequately treated mental illness 
541 
• History of eating disorder within the last 2 years, such as anorexia, bulimia, or 
542 
diabulemia or omission of insulin to manipulate weight 
543 
• History of intentional, inappropriate administration of insulin leading to 
544 
severe hypoglycemia requiring treatment 
545 
16. Employed by, or having immediate family members employed by Beta Bionics, or 
546 
being directly involved in conducting the clinical trial, or having a direct supervisor at 
547 
place of employment who is also directly involved in conducting the clinical trial (as 
548 
a study investigator, coordinator, etc.); or having a first-degree relative who is 
549 
directly involved in conducting the clinical trial.  
550 
2.4 Eligibility Assessment and Baseline Data Collection 
551 
Potential participants will be evaluated for study eligibility through the elicitation of a medical 
552 
history and local laboratory testing as needed in the judgment of the investigator (as part of usual 
553 
care). 
554 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 37 OF 97 
In the event that in-person visits cannot be conducted due to institutional restrictions or the 
555 
participant’s unwillingness to attend an in-person clinic visit, visits may be conducted virtually 
556 
using video conference. Study staff will discuss the feasibility of conducting video visits with 
557 
each participant and provide support as needed to ensure adequate access.  
558 
2.5 Historical Information  
559 
A history will be elicited from the participant and/or parent/guardian where applicable and 
560 
extracted from available medical records with respect to the participant’s diabetes history, 
561 
current diabetes management, other past and current medical problems, past and current 
562 
medications, and drug allergies.   
563 
2.6 Screening Testing and Procedures 
564 
At the Screening Visit the following procedures will be performed: 
565 
Informed consent/assent process 
566 
Assessment of eligibility 
567 
HbA1c assessment via fingerstick or blood draw and measured at local laboratory or 
568 
using DCA2000 or equivalent NGSP-certified point-of-care method or (value within 28 
569 
days prior to enrollment acceptable) 
570 
o If the visit is conducted virtually, then verbal report of most recent HbA1c or most 
571 
recent HbA1c in medical record will be acceptable. 
572 
o If the participant was part of the separate screening protocol, the local HbA1c will 
573 
not be collected if the visit is conducted in clinic. 
574 
Measurement of height/weight  
575 
o If the visit is conducted virtually, a verbal report of the participant’s weight and 
576 
verbal report of height will be acceptable. A scale will be provided for participants 
577 
who do not already have a scale at home. 
578 
Urine pregnancy test for all post-menarche and premenopausal women who are not 
579 
surgically sterile 
580 
o If the visit is conducted virtually, a home pregnancy test will be provided and verbal 
581 
report of the result will be acceptable. 
582 
Completion of the Clarke Hypoglycemia Awareness Survey 
583 
Completion of baseline questionnaires (see chapter 8) 
584 
For participants who completed the separate screening protocol, eligibility will be reassessed at 
585 
the randomization visit.  Participants will not need to repeat the point of care/local HbA1c, 
586 
psychosocial questionnaires or baseline CGM data collection.   
587 
2.7  Baseline CGM Data Collection 
588 
Participants using a Dexcom G6 sensor with at least 85% of sensor values in the prior 14 days 
589 
can skip the baseline CGM data collection. 
590 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 38 OF 97 
For all other participants, a period of CGM usage must be completed prior to randomization.  
591 
Users of a personal Dexcom G6 can continue to use their personal sensor.  Users of a personal 
592 
Dexcom G5 will be provided with an unblinded Dexcom G6 for baseline data collection. All 
593 
others will use a blinded Dexcom G6 sensor that will be placed by the participant (or 
594 
parent/guardian) under the supervision of study staff.  Participants will be instructed on use and 
595 
care of the sensor and on placing a new sensor after 10 days (or sooner if necessary). The 
596 
supplies may be shipped to the participant and a virtual visit completed to monitor sensor 
597 
insertion and device startup along with training on use of the device. 
598 
2.8 Screen Failures 
599 
Individuals who do not initially meet study eligibility requirements may be rescreened at a later 
600 
date per investigator discretion. 
601 
 
602 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 39 OF 97 
Chapter 3: RCT Randomization Visit and Start Up 
603 
3.1 Timing of Visit 
604 
The RCT randomization visit will be scheduled to occur 14–21 days after the screening visit for 
605 
participants who must collect baseline CGM data and who did not participate in the separate 
606 
screening protocol .  Participants not in the separate screening protocol who meet criteria to skip 
607 
the baseline CGM data collection can complete the randomization visit on the same day of the 
608 
screening visit or any time within 21 days following the screening visit. 
609 
3.2 Testing and Procedures 
610 
The following will be done at the randomization visit: 
611 
Review CGM data to verify that there are a minimum of 14 days of CGM data and at 
612 
least 85% of CGM values during 14 days of CGM wear (unless CGM run-in was 
613 
skipped) 
614 
Review medical history since screening visit to verify that there have been no changes or 
615 
events that affect participant eligibility, and any adverse events that may have occurred 
616 
since their last study visit (if not on the same day as the screening visit) 
617 
Verify eligibility if randomization visit is not on the same day as the screening visit 
618 
Verify that participant understands the protocol and is willing to accept assignment to any 
619 
treatment group 
620 
Measure height and body weight (if not within 7 days of screening visit).  
621 
o If the visit is conducted virtually, a verbal report of the participant’s weight and 
622 
verbal report of height will be acceptable. A scale will be provided for participants 
623 
who do not already have a scale at home. 
624 
Perform urine pregnancy test for all post-menarche and premenopausal women who are 
625 
not surgically sterile (can be skipped if Randomization Visit occurs within 7 days of the 
626 
Screening Visit) 
627 
o If the visit is conducted virtually, a pregnancy test will be provided to the participant 
628 
and verbal report of the result will be acceptable. 
629 
Collect blood sample for central lab measurement of HbA1c  
630 
o If the visit is conducted virtually, a collection kit will be provided to the participant 
631 
and will be shipped to the central laboratory by the participant. 
632 
Collect blood sample for storage.   
633 
o Blood drawn may include serum and plasma; participants will have the option of 
634 
declining. 
635 
o If the participant consents to having blood samples stored, but the visit is conducted 
636 
virtually, the samples may be collected at a later in-clinic visit for the study. 
637 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 40 OF 97 
3.3 Randomization 
638 
Pediatric participants (6–<18 years old) for whom eligibility has been verified will be randomly 
639 
assigned in a 2:1 ratio to:  
640 
Insulin-only Bionic Pancreas (BP) Group with lispro or aspart  
641 
Control Group 
642 
Adult participants (≥18 years old) for whom eligibility has been verified will be randomly 
643 
assigned in a 2:2:1 ratio to  
644 
Insulin-only Bionic Pancreas (BP) Group with lispro or aspart  
645 
Insulin-only Bionic Pancreas (BP) Group with Fiasp 
646 
Control Group 
647 
The participant’s randomization group assignment is determined by entering the Randomization 
648 
Visit data on the study website.  The Coordinating Center will construct a Master Randomization 
649 
List using a block design separately for each center. 
650 
Note: randomization will not be stratified by age, HbA1c or other factors because of the small 
651 
number per site that is possible and considering the 2:2:1 randomization in adults and 2:1 
652 
randomization in pediatrics.  If an imbalance in age or baseline HbA1c exists among groups, 
653 
an adjustment will be made in the analytic model. 
654 
3.4 Study Procedures for the Control Group 
655 
Participants in the Control Group will be instructed to follow their usual diabetes management as 
656 
directed by their own diabetes care team (see section 4.2). For users of the Dexcom G6, they will 
657 
continue to use their own system but will be provided with transmitters and sensors. Those who 
658 
are not users of the Dexcom G6 will be trained on use of the Dexcom G6 system and will be 
659 
provided with the necessary supplies for the duration of the RCT phase. All participants in the 
660 
Control Group will be asked to use the Dexcom G6 daily throughout the RCT phase. 
661 
3.5 Study Procedures for the BP Group 
662 
Initiation of BP use for the BP Group will occur on the day of randomization. If the visit is 
663 
conducted virtually, initiation of the BP may be delayed until the device and supplies are 
664 
provided to the participant (via shipping or drop off/pickup) and training is provided. The 
665 
training may be done in person or via a Zoom, Skype, or similar video conference. 
666 
 
667 
The approach to training of the BP Group will depend on whether the participant is already a 
668 
pump and/or CGM user.  The training on use of the BP may occur completely at this visit or may 
669 
be spread out over a few days in multiple visits.  All participants in the BP Group will initiate 
670 
therapy on the iLet BP by being guided through the procedures outlined in the set of screens 
671 
under the Setup Screen onboard the iLet BP device. 
672 
Study staff will review the use of the study devices including the iLet BP, blood glucose 
673 
meter, and ketone meter, and the study CGM system. 
674 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 41 OF 97 
Participants will be trained to only use only fingersticks when measuring blood glucose 
675 
levels with the blood glucose meter. Alternate site testing will not be used. 
676 
Participants will be trained on the use and maintenance of the Dexcom G6 CGM. 
677 
o Participants will be trained on sensor insertion and optional calibration procedures.  
678 
They will insert their own sensor using an approved insertion site and study staff will 
679 
confirm they are doing it properly.  
680 
o All participants will be trained on possible CGM errors and how to respond promptly 
681 
to resume closed loop control by the BP. 
682 
The control algorithm will be initialized with the participant’s current weight. 
683 
The initial glucose target will be set.  This should be the default target in most cases, but 
684 
may be set to the “high” target in participants on MDI and using long-acting insulin at 
685 
baseline, in participants with very low insulin needs, or in participants who have a high 
686 
A1c and may experience hypoglycemic symptoms in the normal plasma glucose range. 
687 
The iLet BP will be configured to recognize the Dexcom G6 CGM signal and will be 
688 
paired with the participant’s transmitter. 
689 
Study staff will supervise the participant preparing the insulin cartridge, loading the 
690 
cartridge into the iLet and inserting the infusion set. 
691 
The participant will remove his/her own insulin infusion pump (if used) and the 
692 
participant will start the bionic pancreas. 
693 
The staff will confirm that the iLet BP is functioning properly prior to discharging the 
694 
participant. 
695 
Study staff will provide supplies for use with the study CGM, study glucose and ketone 
696 
meters and the iLet. 
697 
Due the adaptive nature of the BP, participants on multiple daily injections may simply be started 
698 
on the BP without a need for active management of the transition period by study staff, but the 
699 
new equilibrium will not be reached until all of the long-acting insulin glargine has completely 
700 
cleared their system, which may take 48 hours or more.  In participants using a long-acting 
701 
insulin pre-study, the glucose target may be set to the “high” setting for the 3 or more days 
702 
before moving down to the default target.  Participants will be trained that they may see 
703 
escalating dosing by the BP during this period. 
704 
 
705 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 42 OF 97 
Chapter 4: RCT Outpatient Study Procedures 
706 
4.1 Outpatient Procedures for Both Groups 
707 
Participants will be advised not to use alcohol or other drugs in sufficient quantity to reduce 
708 
sensitivity to symptoms of hypoglycemia or hinder appropriate decision-making. 
709 
Any medical advice needed by the participants during their participation that is not directly 
710 
related to the study protocol should be obtained in the usual manner with their own physician. 
711 
There are no restrictions of any kind on diet, exercise, or other activities. 
712 
Participants will be asked to complete a once-weekly survey including questions about 
713 
hypoglycemia and carbohydrate interventions that occurred in the prior 24 hours. 
714 
• With participant permission, text and/or email will be sent at the time when survey 
715 
completion is needed. 
716 
4.1.1 Resources for Participants 
717 
Questions relating to study protocol will be dealt with by a study staff member on call.  
718 
Participants will be referred to their own medical providers for issues not directly related to the 
719 
study and to local Emergency Medical Services for medical emergencies. 
720 
Participants will be instructed to contact the study staff for any issues that arise with the bionic 
721 
pancreas system.  The site staff will escalate the issue to Beta Bionics as needed. 
722 
4.1.2 Weekly At-Home Questionnaire 
723 
Participants in all RCT Groups will complete a questionnaire weekly. 
724 
Participants will be asked to report on hypoglycemia and treatment interventions during the prior 
725 
24 hours. 
726 
A link to the online survey will be sent via email or text message once a week. The day the 
727 
survey is sent may be rotated systematically so that all days of the week are sampled 
728 
approximately equally.  
729 
As part of the consent process, the participant will be asked to provide an email address or a 
730 
phone number for texting for this purpose.  A reminder will be sent on the scheduled day of the 
731 
weekly questionnaire.  For participants who do not have the ability to complete the 
732 
questionnaires electronically, paper questionnaires may be provided. Participants will be 
733 
reminded that their eligibility for the separate Extension Study (Control Group) is dependent on 
734 
missing no more than 3 of these questionnaires during the 13-week RCT, collection of at least 
735 
80% of the expected CGM data during the 13-week RCT, and on completion of all study visits. 
736 
4.2 Outpatient Procedures for Control Group 
737 
The Control Group will continue its pre-study diabetes management, including approach to 
738 
insulin delivery.  Diabetes management will be handled by the participant’s diabetes health care 
739 
provider. No adjustments to the diabetes care plan will be made by the study team. 
740 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 43 OF 97 
Participants using FDA-approved devices as part of their pre-study usual care, such as a CGM 
741 
system, insulin pump, or closed-loop system can continue use of their personal devices during 
742 
the study period.   Use of devices that are not FDA-approved are prohibited.  
743 
Participants who were using a G5 at the time of enrollment who were provided with a G6 
744 
transmitter and sensors will continue to use the unblinded G6 for the duration of the 13-week 
745 
RCT period. Sensors and transmitters will be provided to these participants as needed.  
746 
Participants not using a Dexcom G6 CGM also will be asked to use a Dexcom G6 CGM for the 
747 
duration of the 13-week RCT period. Training and supplies for the Dexcom G6 supplies will be 
748 
provided to these participants as needed.   
749 
• Participants will be trained on the insertion of the sensor at an approved sensor insertion 
750 
site and use of the Dexcom G6 CGM.  They will insert their own sensor and study staff 
751 
will confirm they are doing it properly.  Participants will be instructed to only use 
752 
approved insertion sites (abdomen for adults and abdomen or upper buttocks for 
753 
participants 6-<18), and to insert a new sensor every 10 days or sooner if the sensor 
754 
comes off prior to day 10 of CGM wear. 
755 
 
756 
4.3 Outpatient Procedures for BP Group 
757 
Participants using the iLet will not be allowed to travel outside the United States or its territories 
758 
for the entire time the system is in use.   
759 
Participants may perform calibrations of the Dexcom G6 CGM if it is inaccurate relative to a BG 
760 
measurement, per the device manufacturer’s instructions. 
761 
Study participants will be instructed to keep fast-acting carbohydrates and a glucagon emergency 
762 
kit easily accessible in case they are needed. 
763 
Following the initiation of use of the iLet, participants with hypoglycemia unawareness (Clarke 
764 
Hypoglycemia Awareness Survey score >=4) will be asked to perform an overnight fingerstick 
765 
blood glucose measurement (between 2-3AM) for 2-3 nights. They will be trained that if SMBG 
766 
is <70 mg/dL they should treat with carbohydrate, with less carbohydrate (e.g. 5 g) as the initial 
767 
treatment if the SMBG is >60 mg/dL or if the CGM trend is not sharply downward, and more 
768 
carbohydrate indicated if the SMBG is lower or if the CGM trend is sharply downward (up to 15 
769 
g), recheck in 15 minutes to confirm the hypoglycemia is adequately treated, and notify the 
770 
investigator or designee the next day for advice. Study staff will inquire about the fingersticks 
771 
and reinforce the importance of these fingersticks at the 1-2 day phone call. 
772 
The iLet BP will have CGM glucose alarm settings available to the participants. Study staff will 
773 
work with participants to configure the alarm settings in a way that will be most appropriate for 
774 
each individual.  
775 
Study staff will recommend a low CGM glucose alarm be set for 70 mg/dl or lower and a high 
776 
CGM glucose alarm be set for 250 mg/dl or higher. 
777 
If participants receive a high or low CGM glucose alarm, they will be trained to verify 
778 
the CGM glucose with a fingerstick glucose value using the Contour Next One 
779 
glucometer. 
780 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 44 OF 97 
If the glucometer confirms hypoglycemia, the participant will be trained to treat hypoglycemia 
781 
with rapid acting carbohydrates. This may be done according to their usual practice or with less 
782 
carbohydrate than their usual practice since the BP system will typically have suspended insulin 
783 
delivery prior to the occurrence of hypoglycemia. They will be trained to continue to monitor 
784 
their glucose levels until they return to normoglycemia. 
785 
If the glucometer confirms hyperglycemia, participants will be trained to assess their infusion set 
786 
and tubing for patency, the insulin reservoir for sufficient insulin supply, the iLet BP for 
787 
sufficient battery power, proper functioning, and insulin delivery. If hyperglycemia > 300 mg/dl 
788 
persists for more than 90 minutes they will be trained to check their blood ketone level using the 
789 
Precision Xtra blood ketone meter. 
790 
• If ketones are ≥0.6 mmol/l, they will be trained to replace their infusion set and to 
791 
inform study staff.  They will be trained to continue to monitor their glucose and 
792 
blood ketone levels until they return to normoglycemia and ketones are < 0.6 
793 
mmol/l. 
794 
• If ketones are <0.6 mmol/l, they will be advised to continue to monitor their glucose 
795 
until it returns to normoglycemia and to repeat the ketone measurement in 90 
796 
minutes if necessary 
797 
If the glucometer reading is not consistent with the CGM glucose reading, participants will be 
798 
trained to look for possible scenarios that could lead to an inaccurate CGM reading.  
799 
• They will be educated about the lag between interstitial and capillary glucose 
800 
readings, and to delay a calibration in times of rapid changes in glucose.  They will 
801 
also be trained about the standard difference between CGM and capillary glucose 
802 
readings, and to consider the CGM inaccurate if it is >20% different than their 
803 
capillary glucose reading. If their CGM glucose is not changing rapidly and is >20% 
804 
different from their capillary glucose reading, they will be instructed to calibrate 
805 
their CGM if possible. 
806 
• A compression artifact at the site of the sensor may cause false hypoglycemic 
807 
readings. This should resolve by removing the compression of the sensor.  
808 
If there is a technical fault with the iLet BP, the participant will be instructed to call the clinical 
809 
site immediately.   
810 
All contacts from a study participant will be documented on an Unscheduled Contact 
811 
form. The site will be responsible for all reporting of device issues and adverse events. 
812 
If necessary, a staff member will meet the participant to assist with troubleshooting.  
813 
This meeting may be delayed until morning if the problem occurs overnight —in this 
814 
case, the participant will use their own pump or use injectable insulin until a meeting is 
815 
possible.  A member of the study staff (within their scope of practice and under the 
816 
supervision of the site principal investigator) may advise them on how to manage their 
817 
diabetes in the interim.  If necessary, the BP device may be replaced. 
818 
• If there is a complete failure of the iLet BP operation and it is anticipated that 
819 
restarting it will take more than an hour, participants may revert to usual care using 
820 
their own insulin pump or with insulin injections until the iLet BP can be brought back 
821 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 45 OF 97 
online with the help of study staff. Every effort should be made to correct the problem 
822 
as soon as possible, which should almost always be within 12 hours. 
823 
• If the CGM sensor is not reading glucose levels, the system will provide basal insulin 
824 
based on past requirements and will allow announcement of meals and entry of 
825 
fingerstick BG measurements, which will be treated as CGM data and may result in 
826 
administration of insulin or temporary suspension of basal insulin. The system will 
827 
alarm and request a BG measurement every 2 hours when the CGM signal is not 
828 
available, but the system will remain in closed-loop mode even if CGM data are not 
829 
available. Participants will be trained in various ways to bring their study CGM sensor 
830 
back online. This may involve replacement of the Dexcom G6 CGM sensor. Normal 
831 
(online) BP control will resume automatically when the CGM sensor is reporting 
832 
glucose values again. 
833 
• Study staff will contact Beta Bionics for additional troubleshooting as necessary. 
834 
Participants will be encouraged to announce up to three major meals a day to the iLet BP. The 
835 
meal announcement will consist of choosing the size of the meal relative to typical meals for that 
836 
participant (more, usual for me, less, much less). Participants will be trained not to announce 
837 
snacks that occur between major meals.  
838 
Participants will be trained on the interface to change the glucose targets.  They will be asked to 
839 
consult with study staff before making any changes to the permanent target or to setting a 
840 
daily/night recurring target alteration schedule.  
841 
Participants will be asked to change their infusion set every 3 days or sooner if there is a 
842 
problem. 
843 
Participants will be instructed to change the insulin cartridges, cap connectors, and tubing 
844 
whenever one of two conditions are met: (1) when there is <20 units remaining in the cartridge, 
845 
or (2) the cartridge or tubing have been in place for the maximum number of days according to 
846 
the labeling for the insulin being used. 
847 
A new Dexcom CGM sensor will be placed in an approved sensor insertion site every 10 days 
848 
for Dexcom users if no replacement was required before this time.  The iLet BP will generate an 
849 
alarm when replacement is required. 
850 
Participants will be asked to charge their iLet BP routinely (preferably at least once daily, such 
851 
as when they are bathing) and whenever they notice the battery level is low.  The iLet BP will 
852 
alarm at low battery thresholds.  
853 
Participants will not tamper with or alter the iLet BP device in any way. 
854 
The iLet BP is water resistant but participants will be instructed to remove it for showering and 
855 
swimming and to keep it dry during exercise. 
856 
Participants will be trained to take appropriate precautions when they are disconnected from the 
857 
iLet BP, including frequent BG checks using the study Contour Next One glucometer if they are 
858 
not monitoring CGM glucose by another method (e.g. their phone) and to have carbohydrate 
859 
readily available.  They are urged to limit the amount of time they are disconnected from the iLet 
860 
BP to ensure optimal glucose control. 
861 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 46 OF 97 
If a participant develops an illness during the study, he/she can seek medical care as usual. If the 
862 
participant is unable to eat for a period exceeding one day, he/she must notify study staff so that 
863 
the medical staff can assess the safety of continuing to use the iLet BP.  iLet BP use may be 
864 
temporarily discontinued if study staff believe this is warranted. If a participant is hospitalized, 
865 
instructions will be provided to contact the study staff as soon as possible and discontinue iLet 
866 
BP System use. 
867 
If a participant discontinues use of the BP system either due to investigator judgment that it is 
868 
not safe for the participant to continue to use the iLet in closed loop mode or the participant’s 
869 
choice, the participant will  return to his/her prestudy insulin delivery and glucose monitoring 
870 
method. If the participant is not using a personal G6 sensor, he/she will be asked to wear a 
871 
blinded sensor for data collection at the scheduled time points as described in section 5.2.2. 
872 
 
873 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 47 OF 97 
Chapter 5: RCT Follow-up Study Visits 
874 
5.1 Timing of Visits 
875 
The schedule for follow-up visits and phone contacts is the same for all treatment groups. 
876 
Phone contacts will occur after 1-2 days and after 7 (± 2) days. 
877 
Clinic visits will occur after 2 weeks (± 4 days), and then at 6 weeks (± 4 days), and 10 weeks 
878 
(± 4 days) prior to the 13-week primary outcome visit (window 91-98 days from randomization). 
879 
In the event that in-person visits cannot be conducted due to institutional restrictions or the 
880 
participant’s unwillingness to attend an in-person clinic visit, visits may be conducted virtually 
881 
via a Zoom, Skype, or similar video conference mechanism.   
882 
5.2 Procedures at Phone Contacts and Follow-up Visits 
883 
5.2.1 Phone Contacts 
884 
Study staff will contact participants via phone twice in their first week of participation. Study 
885 
staff will query the participant for any adverse events and assess the participant’s ability to 
886 
follow protocol and use the device at this time. Participants will be asked about their glucose 
887 
control and study staff will educate as needed. The study staff may suggest a change to the 
888 
permanent glucose target if indicated. 
889 
5.2.2 Clinic Visits 
890 
The following procedures will be performed at each in-clinic visit, unless otherwise specified: 
891 
The date of the last menstrual period will be documented for female participants. 
892 
A urine pregnancy test will be performed for all women who are post-menarche, 
893 
premenopausal and have not been surgically sterilized through the 10-week visit. 
894 
o If the visit is conducted virtually, a pregnancy test will be provided to the 
895 
participant and verbal report of the result will be acceptable. 
896 
Study staff will measure the participant’s height and weight at 6 weeks and 13 weeks.  
897 
o If the visit is conducted virtually, a verbal report of the participant’s weight and 
898 
height will be acceptable. A scale will be provided for participants who do not 
899 
already have a scale at home. 
900 
o In the BP Group, if the weight has changed outside of ±15% of its current value, 
901 
then the weight will be updated on the iLet GUI with the new value.   
902 
Study staff will review any changes in the participant’s medical history or 
903 
medications to ensure continued eligibility, and any adverse events that may have 
904 
occurred since their last study visit. 
905 
For the BP Group, recent CGM data (e.g. on the iLet’s graph screen and/or in the 
906 
summary statistics provided on the mobile app used by the study staff to download 
907 
iLet data in the case of in-clinic study visits) will be reviewed and study staff may 
908 
suggest a change to the permanent glucose target if indicated. 
909 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 48 OF 97 
All study device data will be downloaded. In the BP Group, iLet data will be 
910 
downloaded to the Mobile App on the study tablet during each in-clinic visit.  For 
911 
participants where in-clinic visits are not possible, iLet data may be downloaded at 
912 
select mid-study visits (e.g. at the 6-week visit or more often as needed) by either (1) 
913 
a study staff member visiting the participant or (2) shipping a study tablet to the 
914 
participant and guiding the participant through the data download process remotely. 
915 
For the final 13-week visit, participants who come to clinic will give back their iLet 
916 
and participants who are unable to come to clinic will factory-reset their iLet (which 
917 
will end their 13-week iLet treatment session but will not delete the data for the 
918 
treatment session from the iLet) and ship the iLet back to the study site. In all cases, a 
919 
final full data download will be performed. 
920 
At all scheduled visits prior to the 13-week visit, a CGM sensor will be placed for 
921 
participants in the Control Group (unless the participant is already wearing one). A 
922 
CGM sensor will be placed for anyone in BP Group who has stopped using the iLet 
923 
BP system and discontinued CGM but is willing to wear a Dexcom G6 sensor.  
924 
Study staff will provide supplies as needed and will go over the study procedures 
925 
reminders. 
926 
Completion of the Clarke Hypoglycemia Awareness Survey at 13 weeks. 
927 
At 6 weeks and 13 weeks, blood will be collected for central HbA1c. 
928 
• At 13 weeks participants may have blood collected for storage.  Blood drawn may 
929 
include serum and plasma. Participants will have the option of declining. 
930 
At 6 weeks and 13 weeks, participants will complete questionnaires.  
931 
Parents/guardians where applicable also may complete questionnaires. 
932 
5.3 Evaluation of Control Group for Extension Study 
933 
For participants in the Control Group, an assessment will be made as to whether the participant 
934 
has completed all study visits, at least 10 out of 13 of the weekly questionnaires, and collected at 
935 
least 80% of the expected CGM data.  If yes, the participant will be offered participation in an 
936 
optional Extension Study in which the participant will use the iLet BP system for 13 weeks.  
937 
5.4 Transition Phase 
938 
All users of the iLet BP System who are using the BP system at the end of the RCT (BP Group) 
939 
will enter the Transition Phase and be randomly assigned (1:1) either to transition back to their 
940 
usual therapy based on therapeutic guidance from the iLet BP or to transition back to their usual 
941 
therapy based on their own insulin regimens prior to enrolling in the RCT.  See chapter 6 for 
942 
details about the Transition Phase procedures and visit schedule. 
943 
Note: randomization will be stratified by site but not by age, HbA1c or other factors because of 
944 
the small number per site.  If an imbalance in age or baseline HbA1c exists among groups, an 
945 
adjustment will be made in the analytic model used to analyze the Transition Study outcomes.  
946 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 49 OF 97 
Chapter 6: Transition Phase 
947 
6.1 Participants 
948 
All participants who are using BP in the RCT will enter the Transition Phase at the time that BP 
949 
use ends (assuming BP use does not stop prematurely before the intended end of use - in such 
950 
cases, therapeutic guidance will be provided by the investigator for the transition back to the 
951 
participant’s pre-study management). 
952 
6.2 Randomization 
953 
Participants in the Transition Phase will be randomly assigned (1:1) to either transition back to 
954 
their usual therapy based on therapeutic guidance from the iLet BP or transition back to their 
955 
usual therapy based on their own insulin regimens prior to enrolling in the RCT. For those 
956 
randomized to using their pre-study regimen, the dosing can be adjusted by the investigator to 
957 
mitigate safety issues but should follow the pre-study regimen as closely as possible.  
958 
6.3 iLet BP Guidance 
959 
For those participants who use CSII therapy for their usual care, the iLet BP will recommend the 
960 
basal insulin regimen, the average prandial insulin bolus for typical meals for the start, middle, 
961 
end, and sleeping periods of the day, and a correction factor and/or sliding scale of insulin for 
962 
hyperglycemia. 
963 
For those participants who use MDI therapy for their usual care, the iLet BP will recommend the 
964 
daily dose of long acting insulin, the average prandial insulin dose (e.g. insulin lispro or insulin 
965 
aspart) for typical meals for the start, middle, and end periods of the day, and a sliding-scale 
966 
correction dose of insulin (e.g. insulin lispro or insulin aspart) for hyperglycemia. 
967 
6.4 Visits 
968 
The Transition Phase will have one follow-up visit after 2-4 days. The visit may be conducted 
969 
virtually. A daily survey will be completed about hypoglycemia events, treatment and deviations 
970 
from recommended dosing. 
971 
 
972 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 50 OF 97 
Chapter 7: Study Drugs and Devices 
973 
7.1 Study Drugs 
974 
The study involves subcutaneous administration of insulin lispro (Humalog, Eli Lilly), insulin 
975 
aspart (Novolog, Novo Nordisk), or Fiasp (Novo Nordisk), the latter for adults only.  Lispro, 
976 
aspart and Fiasp are commercially available by prescription and are indicated for use in people 
977 
with diabetes who are on a pump or MDI regimen, but not on a BP.  
978 
Participants randomized to the Control Group will follow their standard diabetes regimen with 
979 
the insulin prescribed by their healthcare provider.  Pediatric subjects randomized to the BP 
980 
Group will fill the iLet ready-to-fill insulin cartridge with either lispro or aspart.  Adult subjects 
981 
randomized to the BP Aspart/lispro Group will fill the iLet ready-to-fill insulin cartridge with 
982 
either lispro or aspart. If a participant was using Fiasp, he/she will need to switch to either lispro 
983 
or aspart for the study.  Adult subjects randomized to the BP Fiasp Group will be provided with 
984 
Fiasp in PumpCart ® cartridges size 1.6 mL.  Fiasp will be called “Faster Aspart” on the cartridge 
985 
label. However, it will be clarified to the participants in the study informed consent form as well 
986 
as verbally and with a handout when Fiasp is dispensed, that this does not imply that Fiasp is 
987 
faster than insulin aspart in the iLet device. 
988 
The control system can administer bolus doses of insulin up to every five minutes.  A single 
989 
automated bolus of insulin will not exceed 3 units per 5-minute dose [30 µl] (or 6 units [60 µl] if 
990 
it is in response to isolated BG entries when the CGM is offline) and a single meal priming dose, 
991 
which is triggered by the user, will not exceed 24 units [240 µl].  The dual pump can administer 
992 
as little as 0.50 µl (0.05 units of U-100 insulin) in a single bolus dose.  Insulin exposure is 
993 
expected to be comparable to that of participants when not participating in the study. 
994 
7.2 Study Devices 
995 
7.2.1 iLet Infusion Sets 
996 
Participants in the BP Groups will be provided with iLet infusion sets for the system.  Study staff 
997 
will work with the participants to ensure they are properly inserting the infusion set and will help 
998 
them troubleshoot if problems related to the infusion set arise.  Participants will be instructed to 
999 
replace their infusion set as needed when it fails (or is suspected of failing) or falls out, or every 
1000 
2–3 days. 
1001 
7.2.2 iLet Ready-to-Fill Insulin Cartridges 
1002 
Participants in the BP Groups will be provided with iLet ready-to-fill insulin cartridges for the 
1003 
system (these are packaged with a drug-transfer hub and plunger rod, which are used in the 
1004 
process of transferring insulin from a vial to the ready-to-fill insulin cartridge).  Study staff will 
1005 
work with the participants to ensure they are comfortable with the fill process and are able to 
1006 
remove most of the air from the cartridge.  Participants will be instructed to replace their ready-
1007 
to-fill insulin cartridge as needed (when it is nearly empty), when it fails (or is suspected of 
1008 
failing), or every 3 days. 
1009 
7.2.3 Continuous Glucose Monitors 
1010 
Participants using the iLet BP in all phases will use a Dexcom G6 sensor. 
1011 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 51 OF 97 
7.2.3.1 Dexcom G6 CGM 
1012 
A transcutaneous glucose sensor for the Dexcom G6 CGM will be inserted in the subcutaneous 
1013 
tissue and will provide input to the controller.  Only approved insertion sites will be used 
1014 
(abdomen for adults and abdomen or upper buttocks for participants 6-<18). The sensor is 
1015 
powered by the battery within the transmitter that clips to the sensor and the whole assembly is 
1016 
held to the skin with an adhesive patch and communicates wirelessly with the bionic pancreas.  If 
1017 
the CGM sensor providing data to the iLet fails for any reason, it will be replaced promptly. 
1018 
The Dexcom G6 blinded CGM can record data for up to 10 days and will be used prior to 
1019 
randomization for participants who are not current users of a Dexcom G5 or G6 CGM. The 
1020 
unblinded Dexcom G6 CGM also can record data for up to 10 days and will be used post-
1021 
randomization for all participants randomized to the Control Group. 
1022 
7.2.4 iLet Bionic Pancreas  
1023 
The iLet BP has an integrated graphical user interface (GUI) and touchscreen display that 
1024 
displays the current CGM glucose from the Dexom G6 sensor, a graphical history of the CGM 
1025 
glucose, and doses of insulin delivered by the control algorithm.  The GUI can also be used to 
1026 
input optional meal announcements, designating qualitatively the meal carb content as “More”, 
1027 
“Usual for Me”, “Less”, or “Much Less”.  This will trigger a partial meal-priming bolus, the size 
1028 
of which will adapt during the course of the trial in accordance with the insulin needs for that 
1029 
size and mealtime (e.g. a portion of the mealtime insulin need). 
1030 
The target BG for the BP is 120 mg/dl by default (“Usual”), but the user may designate a lower 
1031 
default target (of 110 mg/dl, “Lower”) or a higher default target (of 130 mg/dl, “Higher”). 
1032 
A higher or lower default target can be set indefinitely, or for a limited time with automatic 
1033 
expiration, or for a recurring limited time with automatic renewal and expiration.  When a 
1034 
temporary target is set, upon expiration the target will revert to the previously chosen default 
1035 
target.  Although previous studies showed that the BP decreased hypoglycemia and the need for 
1036 
carbohydrate interventions relative to usual care, this will allow participants to raise the BG 
1037 
target for additional safety during periods when hypoglycemia would be particularly 
1038 
problematic, such as when driving or otherwise unable to check or attend to their BG for a period 
1039 
of time, or during periods when hypoglycemia is more likely, such as during exercise.  It may 
1040 
also be used to raise the mean BG if the average is unnecessarily low and the user prefers to 
1041 
further reduce the risk of hypoglycemia.  The use of this feature will be entirely optional—it will 
1042 
be presented to participants as an option that they may use or not, as they wish. 
1043 
The default glucose target setting will be the same in all study periods regardless of participant 
1044 
age or insulin they are using.  Participants transitioning to the BP from an MDI regimen or those 
1045 
who have a very low insulin TDD at baseline may be set to start the study period at the higher 
1046 
glucose target at the discretion of the site investigator.  Participants who have a high HbA1c at 
1047 
screening and who may have symptoms of hypoglycemia in the normoglycemic range may be set 
1048 
to start the study period at a higher target at the discretion of the site investigator.  Participants 
1049 
will be able to edit their glucose target in all BP Groups.  They will be instructed to contact study 
1050 
staff to discuss changing their default target. 
1051 
The GUI can also be used to manage meal boluses and correction boluses during periods when 
1052 
the CGM is offline, such as the period after a sensor is replaced and before the new sensor has 
1053 
been calibrated.  During these times the control algorithm will determine and direct the 
1054 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 52 OF 97 
administration of insulin basal rates either based on the participant's weight in the first 24 hours 
1055 
of the experiment, or on the average of adaptively determined basal rates for that time of day 
1056 
once sufficient experience has been accumulated (i.e. 24 hours or more) by the control algorithm. 
1057 
The controller also will administer insulin or decrease basal insulin as appropriate, in response to 
1058 
any entered BG values, just as if the BG values were CGM values. 
1059 
The device also displays visual alarms, sounds audible alarms, and generates vibration alarms for 
1060 
problems with the functioning of the iLet. 
1061 
The iLet can deliver insulin from pre-filled cartridges or sterile ready-to-fill cartridges. 
1062 
The iLet may be reused among participants. Before this occurs, the pump will be wiped with 
1063 
Cavicide, consistent with standardized disinfecting procedures.  
1064 
7.2.5 Contour Next Glucometer 
1065 
The Contour Next One glucometer is an FDA approved glucose meter that is commercially 
1066 
available. We have tested the accuracy of this meter and found it to be highly accurate and 
1067 
reliable BG measurements will be obtained via fingerstick with this meter in the BP Groups. 
1068 
7.2.6 Precision Xtra Blood Ketone Meter 
1069 
The Precision Xtra blood ketone meter is an FDA approved ketone meter that is commercially 
1070 
available.  Blood ketone measurements during episodes of hyperglycemia will be obtained via 
1071 
fingerstick with this meter in the BP Groups. 
1072 
7.3 Participant Access to Study Device at Study Closure 
1073 
Participants will be permitted to keep the blood glucometer and blood ketone meter at the end of 
1074 
the study, but will need to return all other devices. 
1075 
 
1076 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 53 OF 97 
Chapter 8: Laboratory Testing, Questionnaires and Focus Group 
1077 
8.1 Laboratory Testing 
1078 
HbA1c: 
1079 
Performed locally at the Screening visit. This may be skipped if the visit is conducted 
1080 
virtually. 
1081 
Collected for central lab analysis on a schedule as indicated in the visit grids for each 
1082 
phase. 
1083 
C-peptide and Glucose: 
1084 
• Collected for central lab analysis at the RCT randomization visit. 
1085 
o If the visit is conducted virtually, this will not be completed. 
1086 
 
1087 
Urine Pregnancy: 
1088 
Performed locally for females of child-bearing potential on a schedule as indicated in the 
1089 
visit grids for each phase.  This also can be done anytime pregnancy is suspected. For 
1090 
visits conducted virtually, a home pregnancy test will be provided and a verbal report of 
1091 
the result will be acceptable. 
1092 
8.2 Questionnaires 
1093 
8.2.1 Introduction 
1094 
Questionnaires are completed by all participants within 60 days of the screening visit.  During 
1095 
the RCT, questionnaires will be completed at the 6-week and 13-week visit (or within 1 week 
1096 
leading up to each timepoint).  In addition, there will be a customized questionnaire completed at 
1097 
the end of the Transition Phase that will query the participant about how they handled the 
1098 
transition and satisfaction with the iLet recommendations. 
1099 
Each questionnaire is described briefly below.  The procedures for administration will be 
1100 
described in the study procedures manual.  Age-appropriate versions of each questionnaire will 
1101 
be administered wherever possible.  Parents/guardians of pediatric participants may complete 
1102 
parent versions of these questionnaires where applicable. It is estimated that questionnaires will 
1103 
take less than 1 hour to complete for participants and parents of participants <18 years of age. 
1104 
8.2.2 Brief Description of Questionnaires 
1105 
 
1106 
Table 5. Psychosocial Questionnaires for the Person With Diabetes (PWD) 
1107 
Measure 
Construct Measured / Relevant 
Points 
Who 
Completes/Age 
Range 
Timing of 
Administration in 
RCT 
Diabetes-Specific 
Emotional Distress 
. DDS for Adults 
. PAID-C for 8-12 yrs 
. PAID-T for 13-<18 yrs 
Gold standard measures for 
understanding distress symptoms 
related to diabetes.  
.DDS = 28 items  
.PAID-C = 11 items  
• 
DDS: >18 
• 
PAID-C: 8-
12 
• 
PAID-T: 13-
<18
Baseline, 6 weeks and 
13 weeks 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 54 OF 97 
.PAID-T = 14 items 
Hypoglycemia 
Confidence 
Includes 8 different common 
situations where hypoglycemia occurs 
(e.g., physical activity, driving) and 
evaluates level of confidence in those 
situations (9 items)
>18 through 
adults 
Baseline, 6 weeks and 
13 weeks 
Diabetes Technology 
Attitudes 
Subjective questions about attitudes 
related to diabetes technologies and 
devices (5 items)
>18 through 
adults 
Baseline, 6 weeks and 
13 weeks 
INSPIRE Surveys 
• 
Adult Pre/Post  
• 
Youth Pre/Post 
 
Measures psychological expectations 
and response to closed loop treatment.  
Adult survey has 22 items 
Youth version 17 items.  
 
Adult: >18 
Youth: 8- <18 
All receive the Pre-
Inspire survey at 
baseline.  
 
ONLY those on the 
BP Group receive the 
POST-Inspire survey. 
Those post surveys 
will occur at 13 weeks
Fear of Hypoglycemia 
Scale 
 
• 
Adult Scale  
• 
Youth Scale 
The HFS measures several dimensions 
of fear of hypoglycemia among adults 
with type 1 diabetes.  
• 
Adults: Worry (18 items) and 
behavior (15 items)  
• 
Youth:  Worry (15 items) and 
behavior (10 items)  
Adult: >18 
Youth: 8- <18 
Baseline, 6 weeks and 
13 weeks 
Diabetes Treatment 
Satisfaction 
Questionnaire 
• 
. Baseline version 
(s) 
• 
.Change version (c)  
The DTSQ measures patient 
satisfaction with diabetes treatment 
and perceived frequency of 
hyperglycemia and hypoglycemia. 
Adult version (s and c) 8 items 
Teen version (s and c) 12 items 
Adult:  >18 
 
Youth (Teens): 
13-17 
 
 
Baseline (s) version at 
the baseline and at 13 
weeks for all 
 
Change (c )version at 
13 weeks for all  
EQ5D (5L and Y 
versions) 
NICE approved QOL measure that 
translates into economics  
5 items  
 
Y version: 
 
5L Version: >18 
Y Version: 8-
<18
Baseline, 6 weeks and 
13 weeks 
WHO-5 
5 items  
>8 through 
adults
Baseline, 6 weeks and 
13 weeks
Bionic Pancreas User 
Opinion Survey 
35 items  
>8 through 
adults 
ONLY administered at 
6 and 13 weeks, and 
ONLY to those who 
are using the BP. NOT 
to the Control Group
Past Experience with 
Artificial Pancreas 
Systems 
9 items 
>8 through 
adults 
ONLY administered at 
13 weeks, and ONLY 
to those who are using 
the BP. NOT to the 
Control Group
 
1108 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 55 OF 97 
Table 6. Psychosocial Questionnaires for Parents of Children Ages 6- <18 Years Old 
1109 
Measure 
Construct Measured / Relevant 
Points 
Age Range 
Timing of 
Administration in 
RCT 
Diabetes-Specific 
Emotional Distress 
. P-PAID-C for 8-12 
yrs 
. P-PAID-T for 13-<18 
yrs
Gold standard measures for 
understanding distress symptoms 
related to diabetes.  
.P-PAID-C = 16 items 
.P-PAID-T = 15 items 
P-PAID-C: 
Parents of those 
ages 6-12 
P-PAID-T: 
Parents of those 
ages 13-<18
Baseline, 6 weeks and 
13 weeks 
INSPIRE Surveys 
Parent Pre/Post  
 
Measures psychological expectations 
and response to closed loop treatment.  
Parent pre and post measures  
21 items 
 
Parents of youth 
ages 6-<18 
All Parents receive the 
Pre-Inspire survey at 
baseline.  
 
ONLY those on the 
BP Group receive the 
POST-Inspire survey 
at 13 weeks
Fear of Hypoglycemia 
Scale 
• 
Parent report 
scale 
 
The HFS measures several dimensions 
of fear of hypoglycemia among 
parents of youth with type 1 diabetes.  
. Parent: Worry (15 items) and 
behavior (11 items)  
Parents of youth 
ages 6-<18 
Baseline, 6 weeks and 
13 weeks 
Diabetes Treatment 
Satisfaction 
Questionnaire 
• 
Baseline 
version 
• 
Change 
version 
The DTSQ measures patient 
satisfaction with diabetes treatment 
and perceived frequency of 
hyperglycemia and hypoglycemia. 
Parent version (s and c) 14 items 
 
 
Parents of youth 
ages 6-<18 
Baseline (s) version at 
the baseline and at 13 
weeks for all 
 
Change (c )version at 
13 weeks for all 
Bionic Pancreas User 
Opinion Survey 
35 items  
Parents of youth 
ages 6-<18 
ONLY administered at 
6 and 13 weeks, and 
ONLY to those who 
are using the BP. NOT 
to the Control Group
Past Experience with 
Artificial Pancreas 
Systems 
9 items 
Parents of youth 
ages 6-<18 
ONLY administered at 
13 weeks, and ONLY 
to those who are using 
the BP. NOT to the 
Control Group
 
1110 
8.3 Focus Groups 
1111 
Focus Groups 
1112 
Focus groups will be completed for participants assigned to the BP Group who agree to 
1113 
participate. Focus groups (or individual interviews, depending on participants’ schedules) will 
1114 
occur within 1-3 weeks after they have completed the BP Group (this is 14-16 weeks post study 
1115 
start).  Virtual focus groups will be conducted using HIPAA-approved software supported by 
1116 
Northwestern University and run by researchers at Lurie Children’s Hospital, Department of 
1117 
Pediatrics of Northwestern University’s Feinberg School of Medicine. Focus groups will be run 
1118 
with 3-6 participants who are in the same developmental age group (e.g. children, adolescents, 
1119 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 56 OF 97 
young adults, adults, parents) and a script of open-ended questions will be used to gather 
1120 
feedback and reactions to the psychosocial impact of wearing the iLet BP system. There will also 
1121 
be time for discussion of content raised by participants. Use of a moderator with advanced 
1122 
training will help ensure consistency across groups. Trained study coordinators will observe the 
1123 
focus groups and take field notes. The study coordinator will keep time and manage group 
1124 
logistics. Sessions will be audio- and video-taped and transcribed by a professional transcription 
1125 
service. 
1126 
 
 
1127 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 57 OF 97 
Chapter 9: Unanticipated Problems, Adverse Events, and 
1128 
Device Issue Reporting 
1129 
9.1 Unanticipated Problems 
1130 
Site investigators will promptly report to the Coordinating Center on an eCRF all unanticipated 
1131 
problems meeting the criteria below.  Problems meeting IRB reporting requirements will be 
1132 
reported to the IRB within 7 calendar days of the site becoming aware of the problem.   For this 
1133 
protocol, an unanticipated problem is an incident, experience, or outcome that meets all of the 
1134 
following criteria: 
1135 
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures 
1136 
that are described in the protocol related documents, such as the IRB-approved research 
1137 
protocol and informed consent document; and (b) the characteristics of the subject 
1138 
population being studied 
1139 
Related or possibly related to participation in the research (possibly related means there is 
1140 
a reasonable possibility that the incident, experience, or outcome may have been caused 
1141 
by the procedures involved in the research) 
1142 
Suggests that the research places participants or others at a greater risk of harm than was 
1143 
previously known or recognized (including physical, psychological, economic, or social 
1144 
harm) 
1145 
The Coordinating Center also will report to the IRB all unanticipated problems meeting reporting 
1146 
requirements, within 7 calendar days of becoming aware of the problem, that are not directly 
1147 
involving a specific site, such as unanticipated problems that occur at the Coordinating Center or 
1148 
at another participating entity such as the central laboratory. 
1149 
9.2 Adverse Events 
1150 
9.2.1 Definitions 
1151 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
1152 
relationship between the adverse event and the device(s) under investigation. 
1153 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
1154 
Results in death. 
1155 
Is life-threatening; (a non-life-threatening event which, had it been more severe, might 
1156 
have become life-threatening, is not necessarily considered a serious adverse event). 
1157 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
1158 
Results in persistent or significant disability/incapacity or substantial disruption of the 
1159 
ability to conduct normal life functions (sight threatening). 
1160 
Is a congenital anomaly or birth defect. 
1161 
Is considered a significant medical event by the investigator based on medical judgment 
1162 
(e.g., may jeopardize the participant or may require medical/surgical intervention to 
1163 
prevent one of the outcomes listed above). 
1164 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 58 OF 97 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
1165 
any life-threatening problem or death caused by, or associated with, a study device, if that effect, 
1166 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
1167 
investigational plan or application (including a supplementary plan or application), or any other 
1168 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
1169 
welfare of participants (21 CFR 812.3(s)). 
1170 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which a 
1171 
study device may have caused or to which the device may have contributed (note that an Adverse 
1172 
Event Form is to be completed in addition to a Device Deficiency or Issue Form, unless excluded 
1173 
from reporting as defined in section 9.2). An event that occurs solely due to participant (i.e., 
1174 
user) error in which the device functions properly generally will not be considered an ADE 
1175 
unless it is determined that the instructions on the screen of the device or user manual (or 
1176 
similar training materials) may have contributed to the event (note: the event may still meet 
1177 
criteria for reporting as an adverse event). 
1178 
Device Complaints and Malfunctions: A device complication or complaint is something that 
1179 
happens to a device or related to device performance, whereas an adverse event happens to a 
1180 
participant.  A device complaint may occur independently from an AE, or along with an AE.  
1181 
An AE may occur without a device complaint or there may be an AE related to a device 
1182 
complaint.  A device malfunction is any failure of a device to meet its performance specifications 
1183 
or otherwise perform as intended.  Performance specifications include all claims made in the 
1184 
labeling for the device.  The intended performance of a device refers to the intended use for 
1185 
which the device is labeled or marketed. (21 CFR 803.3).  Note: for reporting purposes, sites will 
1186 
not be asked to distinguish between device complaints and malfunctions. 
1187 
9.2.2 Reportable Adverse Events 
1188 
For this protocol, a reportable adverse event includes any untoward medical occurrence that 
1189 
meets one of the following criteria: 
1190 
• An SAE 
1191 
• An ADE as defined in section 9.2.1, unless excluded from reporting in section 9.3 
1192 
• An AE as defined in 9.2.1 occurring in association with a study procedure 
1193 
• An AE as defined in 9.2.1 not related to a device issue which leads to temporary or 
1194 
permanent discontinuation of  a study device 
1195 
• An AE as defined in 9.2.1 for which a visit is made to a hospital emergency department   
1196 
• Hypoglycemia meeting the definition of severe hypoglycemia as defined below 
1197 
• Diabetic ketoacidosis (DKA) as defined below or in the absence of DKA, hyperglycemia 
1198 
or ketosis event meeting the criteria defined below 
1199 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
1200 
events unless associated with an Adverse Device Effect.  Skin reactions from sensor placement 
1201 
are only reportable if severe and/or required treatment. 
1202 
All reportable AEs—whether volunteered by the participant, discovered by study personnel 
1203 
during questioning, or detected through physical examination, laboratory test, or other means—
1204 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 59 OF 97 
will be reported on an AE form online.  Each AE form is reviewed by the Medical Monitor to 
1205 
assess safety and to verify the coding and the reporting that is required. 
1206 
9.2.3 Hypoglycemic Events 
1207 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
1208 
event when the following definition for severe hypoglycemia is met: the event required 
1209 
assistance of another person due to altered consciousness, and required another person to actively 
1210 
administer carbohydrate, glucagon, or other resuscitative actions.  This means that the participant 
1211 
was impaired cognitively to the point that he/she was unable to treat himself/herself, was unable 
1212 
to verbalize his/ her needs, was incoherent, disoriented, and/or combative, or experienced seizure 
1213 
or loss of consciousness.  These episodes may be associated with sufficient neuroglycopenia to 
1214 
induce seizure or loss of consciousness.  If plasma glucose measurements are not available 
1215 
during such an event, neurological recovery attributable to the restoration of plasma glucose to 
1216 
normal is considered sufficient evidence that the event was induced by a low plasma glucose 
1217 
concentration. 
1218 
When a hypoglycemic event meets the above reporting requirements, a Hypoglycemia Form 
1219 
should be completed in addition to the Adverse Event Form. Severe hypoglycemia events are 
1220 
considered to be serious adverse events with respect to reporting requirements. 
1221 
9.2.4 Hyperglycemic/Ketotic Events 
1222 
Hyperglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
1223 
event when one of the following 4 criteria is met: 
1224 
The event involved DKA, as defined by the Diabetes Control and Complications Trial 
1225 
(DCCT) and described below 
1226 
Evaluation or treatment was obtained at a health care provider facility for an acute event 
1227 
involving hyperglycemia or ketosis, or the participant contacted the site and received 
1228 
guidance on how to manage the hyperglycemia/ketosis 
1229 
Blood ketone level ≥1.0 mmol/L, even if there was no communication with a health care 
1230 
provider (may not be identified until ketone meter data are uploaded) 
1231 
Hyperglycemic events are classified as DKA if the following are present: 
1232 
Symptoms such as polyuria, polydipsia, nausea, or vomiting; 
1233 
Serum ketones >1.5 mmol/L or large/moderate urine ketones; 
1234 
Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and 
1235 
Treatment provided in a health care facility. 
1236 
When a hyperglycemia/ketotic event meets the above reporting requirements, a 
1237 
Hyperglycemia/DKA Form should be completed in addition to the Adverse Event Form. Events 
1238 
meeting DKA criteria are considered to be serious adverse events with respect to reporting 
1239 
requirements. Hyperglycemia events not meeting criteria for DKA generally will not be 
1240 
considered as serious adverse events unless one of the SAE criteria in section 9.2.1 is met. 
1241 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 60 OF 97 
9.2.5 Relationship of Adverse Event to Study Device 
1242 
The study investigator will assess the relationship of any adverse event to be related or unrelated 
1243 
by determining if there is a reasonable possibility that the adverse event may have been caused 
1244 
by the study device. 
1245 
To ensure consistency of adverse event causality assessments, investigators should apply the 
1246 
following general guideline when determining whether an adverse event is related: 
1247 
Yes 
1248 
There is a plausible temporal relationship between the onset of the adverse event and the study 
1249 
intervention, and the adverse event cannot be readily explained by the participant’s clinical state, 
1250 
intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern 
1251 
of response to the study intervention; and/or the adverse event abates or resolves upon 
1252 
discontinuation of the study intervention or dose reduction and, if applicable, reappears upon 
1253 
re-challenge. 
1254 
No 
1255 
Evidence exists that the adverse event has an etiology other than the study intervention 
1256 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or concomitant 
1257 
medication); and/or the adverse event has no plausible temporal relationship to study 
1258 
intervention. 
1259 
9.2.6 Severity (Intensity) of Adverse Events 
1260 
The severity (intensity) of an adverse event will be rated on a three point scale: (1) mild, 
1261 
(2) moderate, or (3) severe.  A severity assessment is a clinical determination of the intensity of 
1262 
an event.  Thus, a severe adverse event is not necessarily serious.  For example, itching for 
1263 
several days may be rated as severe, but may not be clinically serious. 
1264 
MILD: Usually transient, requires no special treatment, and does not interfere with the 
1265 
participant’s daily activities. 
1266 
MODERATE: Usually causes a low level of inconvenience, discomfort or concern to the 
1267 
participant and may interfere with daily activities, but is usually ameliorated by simple 
1268 
therapeutic measures and participant is able to continue in study. 
1269 
SEVERE: Interrupts a participant’s usual daily activities, causes severe discomfort, may 
1270 
cause discontinuation of study device, and generally requires systemic drug therapy or other 
1271 
treatment. 
1272 
9.2.7 Expectedness 
1273 
For a serious adverse event that is considered possibly related to study device, the Medical 
1274 
Monitor will classify the event as unexpected if the nature, severity, or frequency of the event is 
1275 
not consistent with known risk information.  
1276 
9.2.8 Coding of Adverse Events 
1277 
Adverse events will be coded using the MedDRA dictionary. To facilitate coding, the clinical 
1278 
investigator will enter a preliminary MedDRA code which the Medical Monitor may accept or 
1279 
change (the Medical Monitor’s MedDRA coding will be used for all reporting). The Medical 
1280 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 61 OF 97 
Monitor will review the investigator’s assessment of causality and may agree or disagree.  Both 
1281 
the investigator’s and Medical Monitor’s assessments will be recorded.  The Medical Monitor 
1282 
will have the final say in determining the causality as well as whether an event is classified as a 
1283 
serious adverse event and/or an unanticipated adverse device effect. 
1284 
9.2.9 Outcome of Adverse Events 
1285 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
1286 
RECOVERED/RESOLVED: The participant recovered from the AE/SAE without sequelae.  
1287 
Record the AE/SAE stop date. 
1288 
RECOVERED/RESOLVED WITH SEQUELAE: The event persisted and had stabilized 
1289 
without change in the event anticipated.  Record the AE/SAE stop date. 
1290 
FATAL: A fatal outcome is defined as the SAE that resulted in death.  Only the event that 
1291 
was the cause of death should be reported as fatal.  AEs/SAEs that were ongoing at the time 
1292 
of death; however, were not the cause of death, will be recorded as “resolved” at the time of 
1293 
death. 
1294 
NOT RECOVERED/NOT RESOLVED (ONGOING): An ongoing AE/SAE is defined as the 
1295 
event was ongoing with an undetermined outcome. 
1296 
An ongoing outcome will require follow-up by the site in order to determine the final 
1297 
outcome of the AE/SAE. 
1298 
The outcome of an ongoing event at the time of death that was not the cause of death, will be 
1299 
updated and recorded as “resolved” with the date of death recorded as the stop date. 
1300 
UNKNOWN: An unknown outcome is defined as an inability to access the participant or the 
1301 
participant’s records to determine the outcome (for example, a participant that was lost to 
1302 
follow-up). 
1303 
If any reported adverse events are ongoing when a participant completes the study 
1304 
(or withdraws), adverse events classified UADEs will be followed until they are either 
1305 
resolved, or have no prospect of improvement or change, even after the participant has 
1306 
completed all applicable study visits/contacts.  For all other adverse events, data collection will 
1307 
end at the time the participant completes the study. Note: participants should continue to receive 
1308 
appropriate medical care for an adverse event after their participation in the study ends. 
1309 
9.3 Reportable Device Issues 
1310 
All UADEs and ADEs as defined in section 9.1.1 will be reported on both a device issue form 
1311 
and AE form, except for skin reactions from CGM sensor placement or pump infusion set 
1312 
placement that do not require pharmacologic treatment. As noted in section 9.1.1, events that 
1313 
occur due to participant (user) error generally will not require completion of a device issue form. 
1314 
Such ‘errors’ could include improper use of an insulin pump or using a pump infusion set or 
1315 
CGM sensor for a period of time longer than its labeling. 
1316 
Device complaints and device malfunctions will be reported except in the following 
1317 
circumstances. These occurrences are expected and will not be reported on a Device Issue 
1318 
Form assuming criteria for a UADE or ADE have not been met: 
1319 
CGM sensor lasting fewer days than expected per manufacturer 
1320 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 62 OF 97 
CGM tape adherence issues 
1321 
Battery lifespan deficiency due to inadequate charging or extensive wireless 
1322 
communication 
1323 
Intermittent device component disconnections/communication failures not requiring 
1324 
system replacement or workaround/resolution not specified in user guide/manual 
1325 
Device issues clearly addressed in the user guide manual that do not require additional 
1326 
troubleshooting 
1327 
9.4 Timing of Event Reporting 
1328 
SAEs possibly related to a study device or study participation and UADEs must be reported to 
1329 
the Coordinating Center within 24 hours of the site becoming aware of the event.  This can occur 
1330 
via phone or email, or by completion of the online serious adverse event form and device issue 
1331 
form if applicable.  If the form is not initially completed, it should be competed as soon as 
1332 
possible after there is sufficient information to evaluate the event. All other reportable ADEs and 
1333 
other reportable AEs should be submitted by completion on the on line form within 7 days of the 
1334 
site becoming aware of the event. 
1335 
The Coordinating Center will notify all participating investigators of any adverse event that is 
1336 
serious, related, and unexpected.  Notification will be made within 10 days after the 
1337 
Coordinating Center becomes aware of the event. 
1338 
Each principal investigator is responsible for reporting serious study-related adverse events and 
1339 
abiding by any other reporting requirements specific to his/her Institutional Review Board or 
1340 
Ethics Committee. 
1341 
Upon receipt of a UADE report, the Sponsor will investigate the UADE and if indicated, report 
1342 
the results of the investigation to the sites’ IRBs, and the FDA within 10 working days of the 
1343 
Sponsor becoming aware of the UADE per 21CFR 812.46(b) (2).  The Medical Monitor must 
1344 
determine if the UADE presents an unreasonable risk to participants.  If so, the Medical Monitor 
1345 
must ensure that all investigations, or parts of investigations presenting that risk, are terminated 
1346 
as soon as possible but no later than 5 working days after the Medical Monitor makes this 
1347 
determination and no later than 15 working days after first receipt notice of the UADE. 
1348 
Device malfunctions will be handled by the Sponsor or designee as described below.  In the case 
1349 
of a CGM transmitter or sensor device malfunction, information will be forwarded to Dexcom by 
1350 
the site personnel, to be handled by their complaint management system. 
1351 
9.5 Reporting to Novo Nordisk 
1352 
For NovoLog: Copies of reports submitted to the FDA.   
1353 
For Fiasp: 
1354 
• Copies of reports submitted to the FDA. 
1355 
• All non-serious adverse events  
1356 
• All Serious adverse events 
1357 
• All events of pregnancy 
1358 
• All technical issues with the product alone, all technical issues with the combined 
1359 
system (pump and Fiasp) and all issues with the packaging material and labelling 
1360 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 63 OF 97 
Prompt notification to Novo Nordisk of a SAE by the Coordinating Center will occur so that Novo 
1361 
Nordisk’s legal obligations and ethical responsibilities towards the safety of participants and the 
1362 
safety of a trial product under clinical investigation are met. Novo Nordisk has a legal 
1363 
responsibility to notify both the local regulatory authority and other regulatory agencies about the 
1364 
safety of a trial product under clinical investigation. Novo Nordisk will comply with country-
1365 
specific regulatory requirements relating to safety reporting to the regulatory authority, institution 
1366 
review board (IRB), independent ethics committee (IEC), and investigators. 
1367 
Drug related UADEs will also be reported to Novo Nordisk by the Coordinating Center within 15 
1368 
days of the Coordinating Center’s first knowledge of the event. At a minimum, the following 
1369 
should be reported: Study name, Patient identification (e.g. subject number, sex, age), Event 
1370 
(Preferably diagnosis), Trial drug, Reporter, Causality, and Outcome.  
1371 
9.6 Safety Oversight 
1372 
The study Medical Monitor will review all adverse events and adverse device events that are 
1373 
reported during the study.  SAEs typically will be reviewed within 24 hours of reporting.  
1374 
Other AEs typically will be reviewed on a weekly basis. Additionally, the Medical Monitor will 
1375 
review compiled safety data at periodic intervals (generally timed to the review of compiled 
1376 
safety data by the DSMB). 
1377 
The Clinical Study Director will be informed of all cases of severe hypoglycemia and DKA 
1378 
and the Medical Monitor’s assessment of relationship to the study device; and informed of all 
1379 
reported device issues. 
1380 
A Data and Safety Monitoring Board (DSMB) will provide safety oversight.  The DSMB will be 
1381 
informed of all cases of severe hypoglycemia and diabetic ketoacidosis irrespective of device 
1382 
relationship, all device-related SAEs, and all UADEs at the time that they occur during the study 
1383 
and will review compiled safety data at periodic intervals.  The DSMB also will be informed of 
1384 
any ADEs not meeting criteria for a UADE if the Medical Monitor requests the DSMB review.  
1385 
The DSMB can request modifications to the study protocol or suspension or outright stoppage of 
1386 
the study if deemed necessary based on the totality of safety data available.  Details regarding the 
1387 
DSMB’s role will be documented in a separate DSMB document. 
1388 
9.7 Stopping Criteria 
1389 
In the case of an unanticipated system malfunction resulting in a severe hypoglycemia or DKA 
1390 
event (or a malfunction that could have led to severe hypoglycemia or DKA), use of the BP 
1391 
system will be suspended while the problem is diagnosed. The UADE will be reported to the 
1392 
IRB, DSMB, and FDA. After assessment of the problem and any correction,  use of the system 
1393 
will not be restarted until approval is received from the IRB, DSMB, and FDA. 
1394 
In the absence of a device malfunction, use of the BP system by a participant will be 
1395 
discontinued if any of the following occur: 
1396 
The investigator believes it is unsafe for the participant to continue on the intervention.  
1397 
This could be due to the development of a new medical condition or worsening of an 
1398 
existing condition; or participant behavior contrary to the indications for use of the 
1399 
device that imposes on the participant’s safety 
1400 
The participant requests that the treatment be stopped 
1401 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 64 OF 97 
Participant pregnancy 
1402 
Two distinct episodes of DKA as defined in 9.2.4  
1403 
Two distinct severe hypoglycemia events as defined in section 9.2.3  
1404 
One episode of DKA as defined in 9.2.4 and one severe hypoglycemia event as defined in 
1405 
section 9.2.3 
1406 
Each DKA or severe hypoglycemia event will be reviewed by the Medical Monitor and by the 
1407 
DSMB with respect to determination of cause and whether the occurrence of the event can be 
1408 
attributed to use of the BP system.  
1409 
An additional requirement for continued system use following a single DKA or severe 
1410 
hypoglycemia event will be that (1) the site investigator believes that the event is explainable, 
1411 
unlikely to recur, and that it is safe for the participant to continue to use the system and (2) the 
1412 
Medical Monitor and DSMB concur. If either the Medical Monitor or DSMB determines that the 
1413 
occurrence of the event indicates that it is not safe for the participant to continue to use the BP 
1414 
system, use will be discontinued. 
1415 
9.7.1 Criteria for Suspending or Stopping Overall Study 
1416 
In addition to the suspension of device use due to a UADE as described in 9.7, study activities 
1417 
could be similarly suspended if the manufacturer of any constituent study device requires 
1418 
stoppage of device use for safety reasons (e.g. product recall).  The affected study activities may 
1419 
resume if the underlying problem can be corrected by a protocol or system modification that will 
1420 
not invalidate the results obtained prior to suspension. 
1421 
The Medical Monitor or the DSMB may request suspension of study activities or stoppage of the 
1422 
study if deemed necessary based on the totality of safety data available. 
1423 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 65 OF 97 
Chapter 10: Miscellaneous Considerations 
1424 
10.1 Collection of Medical Conditions and Medications 
1425 
Pre-Existing Conditions: Collection of pre-existing conditions will include any medical 
1426 
condition that is either present at screening, a chronic disease, or a prior condition that could 
1427 
impact the participant’s health during the course of the study (e.g., prior myocardial infarction or 
1428 
stroke). 
1429 
Medical Conditions during the study: The following medical conditions that do not qualify for 
1430 
reporting on an Adverse Event Form should be reported on the Medical Conditions Form: 
1431 
(1) new diagnosis of a chronic disease (i.e., not present at the time of enrollment) and (2) any 
1432 
medical condition that could affect the participant’s ability to carry out any aspect of the protocol 
1433 
or could affect an outcome assessment.  Transient conditions that do not affect the participant’s 
1434 
ability to carry out the protocol or study data related to any study outcome do not need to be 
1435 
reported. 
1436 
Medications: All medications that the participant is currently taking at screening and during the 
1437 
course of the study should be recorded.  Nutraceuticals and preventative treatment also should be 
1438 
recorded.  This will include the treatment of chronic pre-existing conditions, medical conditions 
1439 
that occur during the study (both reportable and not-reportable medical conditions), and/or 
1440 
adverse events. Medications only taken as needed either can be recorded when prescribed or only 
1441 
recorded if used during the study.  Glucagon for treatment of severe hypoglycemia will only be 
1442 
recorded if used during the study. 
1443 
10.2 Prohibited Medications, Devices, Treatments and Procedures 
1444 
Participants are not permitted to initiate use of a blood glucose lowering medication that was not 
1445 
in use and met eligibility criteria at the time of screening.  This includes but is not limited to 
1446 
SGLT2 inhibitor, sulfonylurea, GLP1, pramlintide, or metformin drugs. 
1447 
Participants are not permitted to use diabetes management devices that are not FDA approved 
1448 
(such as do-it-yourself closed-loop systems). 
1449 
10.3 Rescue Medications 
1450 
All participants will be required to have a commercially available glucagon (or glucagon analog) 
1451 
preparation for treatment as needed of severe hypoglycemia. 
1452 
10.4 Pregnancy Reporting 
1453 
If pregnancy occurs, the study intervention will be discontinued while continuing safety 
1454 
follow-up.  The occurrence of pregnancy will be reported to the Coordinating Center and to the 
1455 
JCHR IRB on the Unanticipated Problem form within 7 calendar days of becoming aware of the 
1456 
pregnancy. 
1457 
10.5 Participant Compensation 
1458 
Participant compensation will be described in the informed consent form. 
1459 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 66 OF 97 
10.6 Participant Withdrawal 
1460 
Participation in the study is voluntary, and a participant may withdraw at any time.  
1461 
For participants who withdraw, their data will be used up until the time of withdrawal. 
1462 
For participants using the BP who withdraw, a study provider will help them transition to their 
1463 
own CSII or MDI therapy safely. 
1464 
10.7 Confidentiality 
1465 
For security and confidentiality purposes, participants will be assigned identifiers that will be 
1466 
used instead of their names.  Protected health information gathered for this study will be shared 
1467 
with the Coordinating Center, the Jaeb Center for Health Research in Tampa, FL.  De-identified 
1468 
participant information may also be provided to research sites involved in the study. 
1469 
 
1470 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 67 OF 97 
Chapter 11: Statistical Considerations 
1471 
11.1 Statistical and Analytical Plans 
1472 
The approach to sample size and statistical analyses are summarized below. A detailed statistical 
1473 
analysis plan will be written and finalized prior to the start of the study. 
1474 
11.2 Statistical Hypotheses 
1475 
The primary outcome is: 
1476 
• Superiority in HbA1c at 13 weeks 
1477 
 
1478 
A key secondary outcome is 
1479 
• Non-inferiority in CGM-measured time <54 mg/dL calculated over 13 weeks 
1480 
Only superiority in HbA1c at 13 weeks needs to be met to declare efficacy. Primary outcome 
1481 
analyses will combine pediatric and adult participants into a single analysis.  The study 
1482 
hypotheses can be stated as follows: 
1483 
HbA1c Outcome: 
1484 
• Null Hypothesis: There is no difference in the mean HbA1c at 13 weeks between BP 
1485 
aspart/lispro and Control Group  
1486 
• Alternative Hypothesis: There is a nonzero difference in the mean HbA1c at 13 weeks 
1487 
between BP aspart/lispro and Control Group  
1488 
Time <54 mg/dL Outcome: 
1489 
• Null Hypothesis: There is a mean difference of at least 1% in the percentage of time spent 
1490 
with a sensor glucose level below 54 mg/dL between the BP aspart/lispro and Control 
1491 
Group over the 13 weeks 
1492 
• Alternative Hypothesis: There is a mean difference of less than 1% in the percentage of 
1493 
time spent with a sensor glucose level below 54 mg/dL between the BP aspart/lispro and 
1494 
Control Group over the 13 weeks 
1495 
The primary analyses will include only the BP aspart/lispro Groups compared with the Control 
1496 
Group.  Separate analyses will be performed comparing BP Fiasp and Control Groups as 
1497 
described in Section 11.12, but no multiplicity adjustment will be applied as these can be 
1498 
considered two separate studies for purpose of analysis. 
1499 
11.3 Sample Size 
1500 
The sample size of 440 for the RCT was selected to provide sufficient exposure to the iLet BP 
1501 
system for regulatory purposes, with respect to different age groups and to use of both insulin 
1502 
aspart/lispro and Fiasp.  RCT completion is expected for 200 participants randomized to BP 
1503 
aspart/lispro Group, 100 to the BP Fiasp Group, and 100 to the Control Group. 
1504 
The primary analysis for BP aspart/lispro vs. Control Group will include both the pediatric and 
1505 
adult participants in a single analysis. Superiority for HbA1c at 13 weeks and non-inferiority for 
1506 
time <54 mg/dL measured with CGM at intervals over the 13 weeks are considered primary 
1507 
endpoints.  Statistical power for each endpoint was computed assuming the following: 
1508 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 68 OF 97 
HbA1c: Statistical power is >99%, assuming true mean HbA1c difference of 0.4% between BP 
1509 
aspart/lispro and Control Group, standard deviation of 13-week HbA1c of 0.8%, correlation 
1510 
between baseline and 13-week HbA1c of 0.40, two-sided type 1 error of 5% 
1511 
Time <54 mg/dL: Statistical power is 99%, assuming no true difference in mean time <54 mg/dL 
1512 
between BP aspart/lispro and Control Group, a non-inferiority margin of 1%, standard deviation 
1513 
of percent time <54 mg/dL of 2.0%, correlation between baseline and follow-up of 0.40, and 
1514 
one-sided type 1 error of 0.025% 
1515 
Power calculations comparing BP Fiasp and Control Group are described in Section 11.12. 
1516 
11.4 Efficacy Outcome Measures 
1517 
11.4.1 Primary and Key Secondary Efficacy Endpoints 
1518 
HbA1c at 13 weeks (superiority) 
1519 
CGM time < 54 mg/dL (non-inferiority) 
1520 
To preserve the overall type 1 error, a hierarchical gatekeeping testing procedure will be used 
1521 
with HbA1c at 13 weeks tested first.  If the HbA1c analysis results in a statistically significant 
1522 
result (p < 0.05), then testing will proceed to the CGM time <54 mg/dL analysis. 
1523 
11.4.2 Additional Secondary Efficacy Endpoints 
1524 
11.4.2.1 Secondary Efficacy Endpoints Included in Hierarchical Analysis 
1525 
Assuming the primary and key secondary endpoints meet statistical significance as described 
1526 
above, the following CGM-measured secondary endpoints will be tested for superiority in a 
1527 
hierarchical fashion as described in Section 11.6.4. 
1528 
Mean glucose 
1529 
Time 70-180 mg/dL 
1530 
Time >180 mg/dL 
1531 
Time >250 mg/dL 
1532 
Standard deviation 
1533 
Time <70 mg/dL 
1534 
Time <54 mg/dL 
1535 
Coefficient of variation 
1536 
11.4.2.2 Other Secondary Efficacy Endpoints 
1537 
The following endpoints are considered exploratory. Type 1 error for these endpoints will be 
1538 
controlled using the false discovery rate (FDR).  The Fiasp and aspart/lispro groups will be 
1539 
pooled for analyses of the secondary efficacy endpoints listed in this section if there are not 
1540 
statistically significant differences comparing the Fiasp and aspart/lispro groups for the primary 
1541 
and key secondary outcomes, as described in section 11.14.  
1542 
HbA1c: 
1543 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 69 OF 97 
HbA1c <7.0% at 13 weeks 
1544 
HbA1c <7.0% at 13 weeks in participants with baseline HbA1c >7.5% 
1545 
HbA1c <7.5% at 13 weeks 
1546 
HbA1c <8.0% at 13 weeks 
1547 
HbA1c >9.0% at 13 weeks 
1548 
HbA1c improvement from baseline to 13 weeks >0.5% 
1549 
HbA1c improvement from baseline to 13 weeks >1.0% 
1550 
HbA1c relative improvement from baseline to 13 weeks >10% 
1551 
HbA1c improvement from baseline to 13 weeks >1.0% or HbA1c <7.0% at 13 weeks 
1552 
CGM-Measured: 
1553 
Time in range 70-140 mg/dL 
1554 
Time in range 70-120 mg/dL 
1555 
Time <60 mg/dL 
1556 
Area over the curve (70 mg/dL) 
1557 
Low blood glucose index 
1558 
CGM-measured hypoglycemic events (≥15 minutes with glucose concentration <54 
1559 
mg/dL) 
1560 
CGM-measured hyperglycemic events (≥15 minutes with glucose concentration >300 
1561 
mg/dL) 
1562 
Time >300 mg/dL  
1563 
Area under the curve (180 mg/L) 
1564 
High blood glucose index 
1565 
Time in range 70-180 mg/dL >70% 
1566 
Time in range 70-180 mg/dL improvement from baseline to 13 weeks ≥5% 
1567 
Time in range 70-180 mg/dL improvement from baseline to 13 weeks ≥10% 
1568 
Mean of daily difference (MODD) 
1569 
Time <70 mg/dL <4% 
1570 
Time <54 mg/dL <1% 
1571 
Combined Secondary Outcomes: 
1572 
Improvement in HbA1c > 0.5% without an increase in time < 54 mg/dl by > 0.5% OR 
1573 
improvement in time < 54 mg/dl by > 0.5% without an increase in HbA1c by > 0.5% 
1574 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 70 OF 97 
Improvement in time 70–180 mg/dl by >10% without an increase in time < 54 mg/dl by > 
1575 
0.5%  OR improvement in time < 54 mg/dl by > 0.5% without a decrease in time 70–180 
1576 
mg/dl by > 10% 
1577 
BGRI = LBGI + HBGI 
1578 
Mean glucose <154 mg/dL and time <54 mg/dL <1%  
1579 
Time in range 70-180 mg/dL >70% and time <54 mg/dL <1% 
1580 
Other Secondary Outcomes: 
1581 
Questionnaires scores on each questionnaire that is administered (see chapter 8) 
1582 
Insulin 
1583 
o Total daily insulin (units/kg) 
1584 
o Percentage change in the TDD of insulin over the first two-week period relative to 
1585 
the TDD of insulin in last two-week period (iLet Group only) 
1586 
Weight and Body Mass Index (BMI)  
1587 
From the weekly questionnaires, number of hypoglycemic events requiring carbohydrate 
1588 
treatment per 24 hours 
1589 
From the weekly questionnaires, grams of carbohydrate taken specifically to treat 
1590 
hypoglycemic events per 24 hours 
1591 
11.5 CGM Metrics Calculations 
1592 
Baseline values for each CGM metric will be computed from either the participant’s personal 
1593 
Dexcom G6 data or from the G6 wear prior to randomization. The most recent two weeks of 
1594 
CGM data prior to randomization will be included in the calculation of baseline CGM metrics. 
1595 
During the RCT,  CGM metrics will be calculated from the CGM data collected from the Control 
1596 
Group for comparison with the CGM data from the BP Group.  Percentage of CGM values that 
1597 
fall within a specified range will be calculated by dividing the number of CGM values that fall 
1598 
within the range by the total number of CGM readings. 
1599 
11.6 Analysis of the Primary and Secondary Efficacy Endpoints 
1600 
The primary analysis will include both the pediatric and adult participants in a single analysis.  
1601 
All analyses comparing the BP aspart/lispro with the Control Group will follow the intention-to-
1602 
treat (ITT) principle with the data from each participant analyzed according to the treatment 
1603 
assigned by randomization.   
1604 
A per-protocol analysis that includes participants adhering to the protocol will be performed and 
1605 
detailed in the SAP.  Sensitivity analyses on the primary and key secondary outcomes also will 
1606 
be described in the SAP. 
1607 
11.6.1 HbA1c Analyses (Superiority) 
1608 
HbA1c at 13 weeks will be compared between the BP aspart/lispro and Control Groups using a 
1609 
linear mixed effects regression model adjusting for baseline HbA1c, age, and clinical center 
1610 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 71 OF 97 
(random factor).  HbA1c is expected to be normally distributed, but regression diagnostics will 
1611 
be performed to check the residuals and an appropriate alternative transformation or a 
1612 
nonparametric analysis based on ranks will be performed if the residuals have a skewed 
1613 
distribution.  In the event that some HbA1c values are not available at 13 weeks, then the linear 
1614 
mixed effect regression model will use the method of direct likelihood to incorporate information 
1615 
from baseline measurements to calculate the maximum likelihood at 13 weeks. Only central lab 
1616 
HbA1c measurements will be used in the analyses. 
1617 
Other secondary HbA1c outcomes will be tested and described in the SAP. 
1618 
11.6.2 Time <54 mg/dL (Noninferiority) 
1619 
Time below 54 mg/dL will be calculated over 13 weeks for each subject as described in 
1620 
Section11.5.  A two-sided 95% confidence interval on the mean difference in % time <54 mg/dL 
1621 
between BP aspart/lispro and Control Group will be performed based on a linear mixed effects 
1622 
regression model adjusting for baseline % time <54 mg/dL, age, and clinical center (random 
1623 
factor).  Noninferiority will be assessed by comparing the upper bound of this confidence 
1624 
interval to a noninferiority limit of 1%.  Missing data will be handled by the method of direct 
1625 
likelihood.  Residuals values will be examined for an approximate normal distribution.  If the 
1626 
values are highly skewed, then a transformation or nonparametric method will be used instead.  
1627 
A two-sided p-value will be reported, and a 5% significance level will be used to declare 
1628 
significance. 
1629 
Since noninferiority is typically framed in terms of a one-sided test, it is worth noting that the left 
1630 
half of a two-sided test at alpha = 0.05 gives the same rejection region as a one-sided test at alpha 
1631 
= 0.025.  Therefore, reporting a two-sided 95% confidence interval will provide flexibility to test 
1632 
for inferiority if noninferiority cannot be declared while maintaining the overall type 1 error rate 
1633 
of 5%. 
1634 
11.6.3 Secondary CGM Metrics (Superiority) 
1635 
Summary statistics (mean ± SD or median (quartiles)) will be reported for the CGM-measured 
1636 
metrics at baseline and during follow up as well as for differences from baseline by treatment 
1637 
group. 
1638 
Secondary CGM metrics will be calculated as described in Section 11.5.  CGM metric 
1639 
differences between BP and Control Groups will be compared using a linear mixed effects 
1640 
regression model adjusting for the baseline value of the metric, age, and clinical center (random 
1641 
effect).  Residual values will be examined for an approximate normal distribution.  If residuals 
1642 
are highly skewed, then a transformation or robust statistical method (e.g., non-parametric or 
1643 
MM estimation) will be used instead. Missing data will be handled using direct likelihood. 
1644 
11.6.4 Hierarchical Analyses 
1645 
To preserve the overall type 1 error for the primary endpoint and key secondary endpoint as 
1646 
defined in section 11.4.1 and selected secondary endpoints listed in section 11.4.2.1, a 
1647 
hierarchical testing procedure will be used.  If the primary analysis for HbA1c results in a 
1648 
statistically significant result (p < 0.05), then testing at the 0.05 level will proceed to the next 
1649 
outcome metric.  This process continues iteratively moving to the next variable down on the list 
1650 
until a non-significant result is observed, or all 10 variables have been tested.  If a non-
1651 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 72 OF 97 
significant result is encountered, then formal statistical hypothesis testing is terminated and any 
1652 
variables lower on the list will not be formally tested. 
1653 
Regardless of the results of the hierarchical testing, summary statistics appropriate to the 
1654 
distribution will be tabulated by treatment group for each hierarchical outcome.  A 95% 
1655 
confidence interval for the treatment group difference also will be calculated for all hierarchical 
1656 
outcomes listed above.  However, a confidence interval that excludes zero will not be considered 
1657 
a statistically significant result if an outcome variable higher on the hierarchical list failed to 
1658 
reach statistical significance. 
1659 
11.6.5 Questionnaires and Other Outcomes Analyses 
1660 
For questionnaires administered to both randomization groups, comparisons will be made using 
1661 
similar linear models as described above for the primary and key secondary outcomes. If 
1662 
questionnaires include a total score, separate models will be run for the total score and any 
1663 
subscales listed in section 8.2.2. 
1664 
Similarly, for insulin, weight and BMI metrics comparisons will be made using similar linear 
1665 
models as described above for the primary HbA1c analysis. 
1666 
Details of the questionnaire scoring and other outcome assessment will be detailed in the SAP. 
1667 
11.7 Safety Analyses 
1668 
All randomized participants will be included in the safety analyses and all of their post-
1669 
randomization safety events will be reported.  Separately, any adverse events occurring between 
1670 
screening and randomization will be reported. 
1671 
All reportable adverse events will be tabulated by treatment group (aspart/lispro and Fiasp 
1672 
groups will be reported separately).  Details will be provided in a listing of each event, including 
1673 
Medical Dictionary for Regulatory Activities (MedDRA) term and MedDRA System Organ 
1674 
Class.  Safety analyses for the RCT will include events occurring on or after randomization until 
1675 
and including the 13-week visit or Day 98 from randomization, whichever occurs first.  
1676 
Formal statistical testing only will be performed for selected safety endpoints. For the following 
1677 
outcomes, mean ± SD or summary statistics appropriate to the distribution will be tabulated by 
1678 
treatment group and formal statistical comparisons will be performed if there are enough events 
1679 
(at least 5 events combined between the BP aspart/lispro and Control Group): 
1680 
Number of SH events and SH event rate per 100 person-years 
1681 
Number of DKA events and DKA event rate per 100 person-years 
1682 
Other serious adverse events 
1683 
Worsening of HbA1c from baseline to 13 weeks by >0.5% 
1684 
If enough events occur for the severe hypoglycemia and DKA outcomes and other serious 
1685 
adverse events, the numbers of events will be compared between the two treatment groups 
1686 
during the RCT using a robust Poisson regression as detailed in the SAP.   
1687 
Since the Control Group is not provided with a study blood glucose meter or blood ketone meter, 
1688 
no treatment group comparisons of meter data will be performed.  Additionally, no formal 
1689 
statistical comparison will be made of all reported adverse events combined since there are 
1690 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 73 OF 97 
specific requirements in the protocol for reporting certain events in real-time for the BP Group 
1691 
but not the Control Group, and adverse device effects are only reported for the BP Group. 
1692 
11.7.1 Safety Tabulations Specific to the BP Group 
1693 
For the BP Group, all of the following will be tabulated separately for the BP aspart/lispro Group 
1694 
and the Fiasp Group: 
1695 
Adverse device effects (ADE) 
1696 
Serious adverse device events (SADE) 
1697 
Unanticipated adverse device effects (UADE) 
1698 
11.8 Additional Tabulations and Analyses 
1699 
The following tabulations will be performed according to treatment group: 
1700 
Baseline demographics and clinical characteristics 
1701 
A flow chart accounting for all participants for all visits 
1702 
Visit completion rates for each follow-up visit 
1703 
Protocol deviations 
1704 
Modifications in diabetes management class in the Control Group (e.g. change between 
1705 
MDI/CSII) during the study  
1706 
Number and reasons for unscheduled visits and phone calls 
1707 
11.8.1 Tabulations Specific to the BP Group 
1708 
Number of participants who stopped BP use and reasons 
1709 
% time in closed loop 
1710 
Occlusion events that occur while using the iLet BP system 
1711 
Device malfunctions requiring study team contact and other reported device issues 
1712 
11.9 Planned Interim Analyses 
1713 
No formal interim efficacy analyses are planned as study recruitment is expected to be rapid and 
1714 
the duration of follow up short.  The DSMB will review safety data at intervals, with no formal 
1715 
stopping rules other than the guidelines provided in the participant-level and study-level stopping 
1716 
criteria (as defined in Section 9.6 of the protocol). 
1717 
 
1718 
Upon completion of the RCT, the efficacy and safety analyses will be performed in preparation 
1719 
for PMA submission. 
1720 
11.10 Subgroup Analyses 
1721 
In exploratory analyses, the primary and key secondary outcomes plus time in range 70-180 
1722 
mg/dL and mean glucose will be assessed separately for interaction with certain baseline 
1723 
variables, including baseline HbA1c, prior pump/CGM use, and other baseline characteristics as 
1724 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 74 OF 97 
described in the SAP.  The Fiasp and aspart/lispro Groups will be pooled if there are not 
1725 
statistically significant differences comparing the Fiasp and aspart/lispro Groups for the primary 
1726 
endpoints as described in section 11.14, with the exception of subgroup analyses by age, in 
1727 
which only the BP aspart/lispro group will be compared with the Control Group. All primary and 
1728 
key secondary variables will be evaluated in the predefined age groups (>18 years old and <18 
1729 
years old, and further subdivided as 6-<13, 13-<18, 18-<26, 26-<50, >50 years 
1730 
old).Interpretation of the subgroup analyses will be made with caution, particularly if the primary 
1731 
analysis is not significant.  
1732 
11.11 Multiple Comparison/Multiplicity 
1733 
Hierarchical Analyses 
1734 
The hierarchical testing procedure described above in Section 11.6.1 will be used to control the 
1735 
overall type 1 error for the primary endpoint and key secondary endpoints plus eight additional 
1736 
secondary outcomes identified above. 
1737 
All Other Secondary Analyses 
1738 
For the other secondary analyses, the false discovery rate will be controlled using the adaptive 
1739 
Benjamini-Hochberg procedure. 
1740 
11.12 Additional Exploratory Analyses 
1741 
Additional analyses comparing treatment groups will include: 
1742 
Comparison of aspart/lispro BP Group versus Control Group in adults >18 years old for 
1743 
the efficacy and safety outcomes described for the main RCT analyses 
1744 
Separate CGM analyses for daytime and nighttime 
1745 
Total daily dose of insulin at 13 weeks and at 2 weeks according to baseline HbA1c 
1746 
Intersubject variability of HbA1c  
1747 
11.13 BP Fiasp Versus Control Group 
1748 
All of the above analyses with the exception of subgroup analyses by age group will be 
1749 
replicated comparing the BP Fiasp and Control Groups.  This analysis will be treated as a 
1750 
separate study, so the multiple hypothesis testing in the BP aspart/lispro vs Control comparison 
1751 
will not be adjusted for the BP Fiasp vs. Control Group comparison.  However, the same 
1752 
hierarchical testing procedure will be performed for the BP Fiasp versus Control comparison for 
1753 
primary and secondary endpoints and the false discovery rate will be controlled for the other 
1754 
secondary endpoints as described in Section 11.11. 
1755 
This analysis will include approximately 100 participants in BP Fiasp and 50 participants in 
1756 
Control Group. Statistical power for each primary endpoint was computed assuming the 
1757 
following: 
1758 
HbA1c: Statistical power is 91%, assuming true mean HbA1c difference of 0.4% between BP 
1759 
Fiasp and Control Group, standard deviation of 13-week HbA1c of 0.8%, correlation between 
1760 
baseline and 13-week HbA1c of 0.40, two-sided type 1 error of 5% 
1761 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 75 OF 97 
Time <54 mg/dL: Statistical power is 86%, assuming no true difference in mean time <54 mg/dL 
1762 
between BP Fiasp and Control Group, a non-inferiority margin of 1%, standard deviation of 
1763 
percent time <54 mg/dL of 2.0%, correlation between baseline and follow-up of 0.40, and one-
1764 
sided type 1 error of 0.025% 
1765 
11.14 Comparison of Aspart/Lispro Group and Fiasp Group 
1766 
For the primary and key secondary endpoints, the BP aspart/lispro Group and the BP Fiasp 
1767 
Group will be compared.  If neither analysis has a p value >0.05 for superiority, then these 
1768 
groups will be pooled for the exploratory secondary and subgroup analyses that are not part of 
1769 
the hierarchy analyses.  
1770 
11.15 Transition Phase 
1771 
In the 2-4-day Transition Phase, participants are randomly assigned to transition back to their 
1772 
usual therapy based on therapeutic guidance from the bionic pancreas or transition back to their 
1773 
usual therapy based on their own insulin regimens prior to enrolling in the RCT. 
1774 
Analyses will be considered exploratory.  The primary analyses will be for safety, tabulating 
1775 
events.  Exploratory analyses will include mean CGM glucose level and time of CGM measured 
1776 
time < 54 mg/dL. 
1777 
 
1778 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 76 OF 97 
Chapter 12: Data Collection and Monitoring 
1779 
12.1 Case Report Forms and Other Data Collection 
1780 
The main study data are collected on electronic case report forms (eCRFs).  When data are 
1781 
directly collected in electronic case report forms, this will be considered the source data.  For any 
1782 
data points for which the eCRF is not considered source (e.g. lab results that are transcribed from 
1783 
a printed report into the eCRF), the original source documentation will be maintained in the 
1784 
participant’s study chart or medical record.  This source must be readily verifiable against the 
1785 
values entered into eCRF.  Even where all study data are directly entered into the eCRFs at office 
1786 
visits, evidence of interaction with a live subject must be recorded (e.g., office note, visit record, 
1787 
etc.). 
1788 
Electronic device data files are obtained from the study software and individual hardware 
1789 
components.  These electronic device files are considered the primary source documentation. 
1790 
HbA1c measurements will be made by the central laboratory and the data will be transmitted to 
1791 
the Coordinating Center. 
1792 
12.2 Study Records Retention 
1793 
Each participating site will maintain appropriate medical and research records for this trial, in 
1794 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
1795 
confidentiality of participants. 
1796 
Study documents should be retained for a minimum of 3 years after the final NIH grant 
1797 
reporting.  These documents should be retained for a longer period, however, if required by local 
1798 
regulations.  No records will be destroyed without the written consent of the sponsor, if 
1799 
applicable.  It is the responsibility of the sponsor to inform the investigator when these 
1800 
documents no longer need to be retained. 
1801 
12.3 Quality Assurance and Monitoring 
1802 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
1803 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
1804 
conducted and data are generated, documented and reported in compliance with the protocol, 
1805 
Good Clinical Practice (GCP) and the applicable regulatory requirements, as well as to ensure 
1806 
that the rights and wellbeing of trial participants are protected and that the reported trial data are 
1807 
accurate, complete, and verifiable.  Adverse events will be prioritized for monitoring. 
1808 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
1809 
of the study, consistent with the FDA “Guidance for Industry Oversight of Clinical 
1810 
Investigations—A Risk-Based Approach to Monitoring” (August 2013).  Study conduct and 
1811 
monitoring will conform with 21 Code of Federal Regulations (CFR) 812.  This plan describes in 
1812 
detail who will conduct the monitoring, at what frequency monitoring will be done, at what level 
1813 
of detail monitoring will be performed, and the distribution of monitoring reports. 
1814 
The data of most importance for monitoring at the site are participant eligibility and adverse 
1815 
events.  Therefore, the RBM plan will focus on these areas.  As much as possible, remote 
1816 
monitoring will be performed in real-time with on-site monitoring performed to evaluate the 
1817 
verity and completeness of the key site data.  Elements of the RBM may include: 
1818 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 77 OF 97 
Qualification assessment, training, and certification for sites and site personnel 
1819 
Oversight of Institutional Review Board (IRB) coverage and informed consent 
1820 
procedures 
1821 
Central (remote) data monitoring: validation of data entry, data edits/audit trail, protocol 
1822 
review of entered data and edits, statistical monitoring, study closeout 
1823 
On-site monitoring (site visits): source data verification, site visit report 
1824 
Agent/Device accountability 
1825 
Communications with site staff 
1826 
Patient retention and visit completion 
1827 
Quality control reports 
1828 
Management of noncompliance 
1829 
Documenting monitoring activities 
1830 
Adverse event reporting and monitoring 
1831 
Coordinating Center representatives or their designees may visit the study facilities at any time 
1832 
in order to maintain current and personal knowledge of the study through review of the records, 
1833 
comparison with source documents, observation and discussion of the conduct and progress of 
1834 
the study.  The investigational site will provide direct access to all trial related sites, source 
1835 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
1836 
inspection by local and regulatory authorities. 
1837 
12.4 Protocol Deviations 
1838 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
1839 
requirements.  As a result of deviations, corrective actions are to be developed by the site and 
1840 
implemented promptly. 
1841 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements.  
1842 
Further details about the handling of protocol deviations will be included in the monitoring plan. 
1843 
 
1844 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 78 OF 97 
Chapter 13: Ethics/Protection of Human Participants 
1845 
13.1 Ethical Standard 
1846 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
1847 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
1848 
21 CFR Part 56, and/or the ICH E6. 
1849 
13.2 Institutional Review Boards 
1850 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
1851 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
1852 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
1853 
require review and approval by the IRB before the changes are implemented to the study.  All 
1854 
changes to the consent form will be IRB approved; a determination will be made regarding 
1855 
whether previously consented participants need to be re-consented. 
1856 
13.3 Informed Consent Process 
1857 
13.3.1 Consent Procedures and Documentation 
1858 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
1859 
the study and continues throughout the individual’s study participation.  Extensive discussion of 
1860 
risks and possible benefits of participation will be provided to the participants and their families.  
1861 
Consent forms will be IRB-approved, and the participant and if applicable, parent/guardian will 
1862 
be asked to read and review the document.  The investigator will explain the research study to 
1863 
the participant and answer any questions that may arise.  All participants will receive a verbal 
1864 
explanation in terms suited to their comprehension of the purposes, procedures, and potential 
1865 
risks of the study and of their rights as research participants.  Participants will have the 
1866 
opportunity to carefully review the written consent/assent form and ask questions prior to 
1867 
signing. 
1868 
The participants should have the opportunity to discuss the study with their surrogates or think 
1869 
about it prior to agreeing to participate.  The participant’s electronic consent signature will be 
1870 
obtained prior to any procedures being done specifically for the study.  The participants may 
1871 
withdraw consent at any time throughout the course of the trial.  A copy of the informed consent 
1872 
document will be given to the participants for their records.  The rights and welfare of the 
1873 
participants will be protected by emphasizing to them that the quality of their medical care will 
1874 
not be adversely affected if they decline to participate in this study. 
1875 
13.3.2 Participant and Data Confidentiality 
1876 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, 
1877 
and the sponsor(s) and their agents.  This confidentiality is extended to cover testing of 
1878 
biological samples and genetic tests in addition to the clinical information relating to 
1879 
participants.  Therefore, the study protocol, documentation, data, and all other information 
1880 
generated will be held in strict confidence.  No information concerning the study or the data will 
1881 
be released to any unauthorized third party without prior written approval of the sponsor. 
1882 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 79 OF 97 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, 
1883 
regulatory agencies or company supplying study product may inspect all documents and records 
1884 
required to be maintained by the investigator, including but not limited to, medical records 
1885 
(office, clinic, or hospital) and pharmacy records for the participants in this study.  The clinical 
1886 
study site will permit access to such records. 
1887 
The study participant’s contact information will be securely stored at each clinical site for 
1888 
internal use during the study.  At the end of the study, all records will continue to be kept in a 
1889 
secure location for as long a period as dictated by the reviewing IRB, institutional policies, or 
1890 
sponsor requirements. 
1891 
Study participant research data, which is for purposes of statistical analysis and scientific 
1892 
reporting, will be transmitted to and stored at the Coordinating Center.  This will not include the 
1893 
participant’s contact or identifying information, unless otherwise specified in the informed 
1894 
consent form.  Rather, individual participants and their research data will be identified by a 
1895 
unique study identification number.  The study data entry and study management systems used 
1896 
by clinical sites and by the Coordinating Center research staff will be secured and password 
1897 
protected.  At the end of the study, all study databases will be de-identified and archived at the 
1898 
Coordinating Center. 
1899 
To further protect the privacy of study participants, a Certificate of Confidentiality will be 
1900 
obtained from the NIH.  This certificate protects identifiable research information from forced 
1901 
disclosure.  It allows the investigator and others who have access to research records to refuse to 
1902 
disclose identifying information on research participation in any civil, criminal, administrative, 
1903 
legislative, or other proceeding, whether at the federal, state, or local level.  By protecting 
1904 
researchers and institutions from being compelled to disclose information that would identify 
1905 
research participants, Certificates of Confidentiality help achieve the research objectives and 
1906 
promote participation in studies by helping assure confidentiality and privacy to participants. 
1907 
13.3.3 Future Use of Data 
1908 
Data collected for this study will be analyzed and stored at the Coordinating Center.  After the 
1909 
study is completed, the de-identified, archived data will be archived at the Jaeb Center.  A 
1910 
publicly-accessible, de-identified dataset will be made available on the Jaeb Center website 
1911 
and/or the NIDDK data repository. 
1912 
13.3.4 Future Use of Biologic Samples 
1913 
With the participant’s approval and as approved by local IRBs, de-identified biological samples 
1914 
will be shipped to the central laboratory for temporary storage and later batch shipped for long-
1915 
term storage at Massachusetts General Hospital. These samples could be used for diabetes-
1916 
related research, including its treatment (including insulin assays), its causes, its complications 
1917 
and other conditions for which individuals with diabetes are at increased risk, and to improve 
1918 
treatment.  The Massachusetts General Hospital will also be provided with a code-link that will 
1919 
allow linking the biological specimens with the phenotypic data from each participant, 
1920 
maintaining the masking of the identity of the participant. 
1921 
During the conduct of the study, an individual participant can choose to withdraw consent to 
1922 
have biological specimens stored for future research.  However, withdrawal of consent with 
1923 
regard to biosample storage will not be possible after the study is completed. 
1924 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 80 OF 97 
Chapter 14: Ancillary Study to Test the iLet with Inputted Blood 
1925 
Glucose Measurements 
1926 
14.1 Objective 
1927 
This Ancillary Study will assess the safety of utilizing blood glucose measurements instead of 
1928 
CGM measurements as input into the iLet for ~48-60 hours.  The Study is intended to mirror a 
1929 
real-world situation where CGM may not be available for an extended period of time (eg, user 
1930 
runs out of sensors and is awaiting new shipment).  
1931 
14.2 Sample Size 
1932 
Participation in the Ancillary Study will be offered to participants who are using the iLet at the 
1933 
time of the 13-week randomized trial visit. The goal for sample size is to have234 complete the 
1934 
Ancillary Study, with a goal of 71 pediatric participants and 163 adults (with a goal to have 
1935 
approximately half of the adults using Fiasp and half using lispro/aspart).   The maximum 
1936 
number in the Ancillary Study will be 260 and the final number will be dependent on the number 
1937 
who are willing to participate. 
1938 
14.3 Eligibility Criteria 
1939 
Participants must be currently using the iLet and be completing the 13-week visit of RCT on the 
1940 
day of enrollment into the Ancillary Study.   
1941 
Inclusion in the Ancillary Study requires investigator judgment that it is safe for the individual to 
1942 
participate.  
1943 
Participants < 18 years old must be living with one or more parent/legal guardian knowledgeable 
1944 
about emergency procedures for severe hypoglycemia. Participants >18 years old who live alone 
1945 
must have a companion with them during the 2 overnights of the study.   
1946 
 
1947 
14.4 Study Protocol 
1948 
On the day of the 13-week RCT visit, informed consent (and assent where indicated) will be 
1949 
obtained from interested participants, and eligibility will be verified.  The iLet used in the 
1950 
preceding RCT will be continued, using the same insulin as used in the RCT. The first day of the 
1951 
Study will be referred to as Day 1 and the final day as Day 3.   
1952 
At the clinic visit on Day 1 (13-week visit of the RCT), participants will be trained on the study 
1953 
protocol. Outpatient procedures described in Chapter 4 will be continued, with the exception of 
1954 
references to CGM.  A new instruction sheet will be provided to participants with respect to the 
1955 
identification and management of hypoglycemia and hyperglycemia.  The real-time CGM sensor 
1956 
will be removed and a blinded G6 Pro sensor will be placed.   
1957 
For the next ~48-60 hours, the participant will use the study blood glucose meter to enter glucose 
1958 
measurements into the iLet at least every 2 hours during waking hours and at least once during 
1959 
each overnight. Participants will be instructed to measure and input blood glucose before and 2 
1960 
hours after every meal plus prior to bedtime.  The iLet will alarm to request the blood glucose 
1961 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 81 OF 97 
entry every 2 hours; however, during the overnight period, only one blood glucose measurement 
1962 
will be required. 
1963 
Phone/video contact will be made on Day 2 for a safety check.  
1964 
On Day 3, phone/video contact will be made and the participant will be instructed to stop the 
1965 
iLet session and to remove the iLet and to insert an unblinded G6 sensor.  The participant will 
1966 
then continue to the Transition Phase as described in chapter 6.  The iLet, blood glucose meter, 
1967 
ketone meter, and blinded CGM transmitter will be returned to the site at the end of the 
1968 
Transition Phase.  A clinic visit can be substituted for the Day 3 contact. 
1969 
14.5 Outcomes and Analysis Plan 
1970 
A separate statistical analysis plan will be written for the Ancillary Study. 
1971 
Outcomes will include the following: 
1972 
Key Safety Outcomes: 
1973 
• Severe hypoglycemia 
1974 
• Diabetic ketoacidosis 
1975 
• Other serious adverse events 
1976 
• Time <54 mg/dL 
1977 
• Time >300 mg/dL 
1978 
• CGM-measured hypoglycemic events 
1979 
• CGM-measured hyperglycemic events 
1980 
Other Outcomes 
1981 
• Mean glucose 
1982 
• Time 70-180 mg/dL 
1983 
• Time >180 mg/dL 
1984 
• Time >250 mg/dL 
1985 
• Standard deviation 
1986 
• Time <70 mg/dL 
1987 
• Coefficient of variation 
1988 
For each participant, the number of inputted blood glucose meter measurements each day will be 
1989 
tabulated and summarized across participants.   Adverse events will be listed.   CGM metrics will 
1990 
be computed overall and separately for daytime and nighttime. 
1991 
14.6 Safety Monitoring 
1992 
Safety oversight will be the same as for the RCT, as described in section 9.6.  Additionally, an 
1993 
initial analysis of the safety outcomes listed in section 14.5 will be performed after data are 
1994 
available from 20 participants.    
 
1995 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 82 OF 97 
 
1996 
Appendix A: Prior Studies Conducted Using the 
1997 
Bionic Pancreas System 
1998 
A.1 Studies Conducted with the iPhone-Based BP System 
1999 
A.1.1 The Beacon Hill Study, the 2013 and 2014 Summer Camp Studies, and the 
2000 
Bionic Pancreas Multi-Center Study 
2001 
All of our preclinical studies at BU testing our BP in a diabetic swine model of T1D (between 
2002 
2005 and 2009), and all of our inpatient clinical trials in the Clinical Research Center at MGH 
2003 
testing our BP in adults and adolescents with T1D (between 2008 and 2012) set the stage for the 
2004 
outpatient and home-use studies that followed.  In November 2012 we obtained FDA approval to 
2005 
conduct our first outpatient study testing our bihormonal BP in adults 21 years or older with 
2006 
T1D.  This study, which we referred to as the Beacon Hill Study, followed a random-order 
2007 
cross over design in which 20 adults with T1D participated in 5 days on our iPhone-Based BP 
2008 
and 5 days of usual care. In the usual-care control arm the participants used conventional insulin 
2009 
pump therapy (and their own CGM if they had one), and they wore a CGM with blinded display 
2010 
and muted alarms.  In the BP arm, participants kept to a three-square-mile geographic area 
2011 
centered around the Beacon Hill neighborhood in Boston.  They ate as they chose at local 
2012 
restaurants, and exercised at will with access to two gyms.  Analysis was pre-specified to focus 
2013 
on Days 2–5, since glycemic control is more representative of BP performance after most of the 
2014 
adaptation by the BP occurs on Day 1. Results are summarized in the plots and table of Figure 2. 
2015 
 
2016 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 83 OF 97 
 
2017 
 
2018 
Figure 2. Outpatient results summarizing the distribution of mean CGM glucose levels and 
2019 
hypoglycemia in the bihormonal BP and control arms from the Beacon Hill Study, 2013 and 
2020 
2014 Summer Camp Studies, and the Bionic Pancreas Multi-Center Study.  Mean CGM glucose 
2021 
levels for each participant under usual care (shown as a red circle on the left) is connected with 
2022 
the participant's mean CGM glucose level on the BP (shown as a black circle on the right). 
2023 
For each participant, the circle diameter is proportional to the percentage of CGM glucose values 
2024 
< 60 mg/dl, and the size of the triangle is proportional to the percentage of CGM glucose values 
2025 
> 180 mg/dl.  The heavy circles and lines represent the group means.  The horizontal red dashed 
2026 
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
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

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 84 OF 97 
line refers to the glucose level corresponding to the ADA therapy goal for each age group tested, 
2027 
which corresponds to 154 mg/dl (HbA1c < 7%) for adults with T1D ≥ 18 years old and 169 
2028 
mg/dl (HbA1c < 7.5%) for children with T1D < 18 years old.  Results are summarized in the 
2029 
table below the plots, where the co-primary outcomes (mean CGM glucose level and percentage 
2030 
of CGM glucose values < 60 mg/dl) for the BP are highlighted in red for each of the four studies. 
2031 
In April 2013, we obtained FDA approval to conduct our first outpatient study testing our 
2032 
bihormonal BP in adolescents 12–20 years old with T1D.  This study, which we referred to 
2033 
as the 2013 Summer Camp Study, followed a random-order cross-over design in which 
2034 
32 adolescents with T1D participated in 5 days on our BP and 5 days of supervised camp care in 
2035 
the control arm.  In the control arm the participants used conventional insulin pump therapy (and 
2036 
their own CGM if they had one), and they wore the BP without pumps and with blinded display 
2037 
and muted alarms for remote monitoring.  Participants were monitored remotely according to 
2038 
identical criteria in all study arms for proper device functioning and CGM glucose < 70 mg/dl 
2039 
lasting more than 15 minutes, which would prompt study staff to call the participant and make 
2040 
sure they were treated.  Participants were fully integrated into normal camp activities without 
2041 
restrictions on diet or exercise.  The mean HbA1c of all 32 participants at baseline (pre-study) 
2042 
was 8.2%, which corresponds to a mean BG of 189 mg/dl.  Results are summarized in the plots 
2043 
and table of Figure 2. 
2044 
In April 2014 we obtained FDA approval conduct our first outpatient study testing our 
2045 
bihormonal BP in pre-adolescents 6–11 years old with T1D.  This study, which we referred to as 
2046 
the 2014 Summer Camp Study, was similar in design to our 2013 Summer Camp Study.  
2047 
Results are summarized in the plots and table of Figure 2. 
2048 
In April 2014, we obtained FDA approval to conduct our first multi-center study, which was also 
2049 
our first home-use study, to test our BP in adults 18 years or older with T1D.  This study, which 
2050 
we referred to as the BPMC Study, followed a random-order cross-over design in which 39 
2051 
adults participated in 11 days on our BP and 11 days of usual care.  Participants went to work as 
2052 
usual, and lived and slept at home, all without clinical supervision.  There were no restrictions 
2053 
placed on diet or exercise.  The study included four medical centers (10 participants per center), 
2054 
which included MGH, the University of Massachusetts Medical School, Stanford University, and 
2055 
the University of North Carolina at Chapel Hill.  Results are summarized in the plots and table of 
2056 
Figure 2. 
2057 
A.1.2 The Bionic Pancreas Set Point Study 
2058 
In July 2015 we obtained FDA approval to perform our first study testing the BP at different 
2059 
static glucose targets (“set-points”) in both the bihormonal and insulin-only configurations.  
2060 
In this study, which we referred to as the MGH Set-point Study, 20 adults participated in 7 study 
2061 
arms, each lasting 3 days.  In all of our previous studies, the target glucose for the bihormonal 
2062 
BP was set to 100 mg/dl.  Since this was the first study to test the BP in a configuration without 
2063 
glucagon, the insulin-only study arms initially used significantly elevated glucose targets of 
2064 
130 mg/dl and 145 mg/dl (not shown).  We subsequently obtained approval from the FDA to test 
2065 
glucose targets of 120 mg/dl and 110 mg/dl in December 2015.  Results from the insulin-only BP 
2066 
arms and the usual-care arm are summarized in Figure 3.   Results from the bihormonal BP arms 
2067 
and the usual-care arm are summarized in Figure 4. 
2068 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 85 OF 97 
Based on results from this study, we determined that, in terms of striking an optimal balance 
2069 
between minimizing mean glucose and hypoglycemia and maximizing patient satisfaction, the 
2070 
insulin-only configuration of the BP performed best with a glucose target of 120 mg/dl and the 
2071 
bihormonal configuration of the BP performed best with a glucose target of 110 mg/dl. 
2072 
 
2073 
Figure 3. Outpatient results summarizing the distribution of mean CGM glucose levels and 
2074 
hypoglycemia in the insulin-only BP arms (with set-points 130, 120, and 110 mg/dl) and 
2075 
usual-care arm (control) from the Bionic Pancreas Set-Point Study.  Mean CGM glucose levels 
2076 
for each participant in each study arm (shown as a red circles) are connected by black lines.  
2077 
For each participant, the circle diameter is proportional to the percentage of CGM glucose values 
2078 
< 60 mg/dl.  The heavy circles and lines represent the group means.  The horizontal red dashed 
2079 
line refers to the glucose level corresponding to the ADA therapy goal for each age group tested, 
2080 
which corresponds to 154 mg/dl (HbA1c <7%) for adults with T1D ≥ 18 years old. 
2081 
Mean CGMG (mg/dl)
90
120
154
180
210
240
1% <60 mg/dl
5% <60 mg/dl
Control
Mean: 158 +/- 31 mg/dl
1.4% <60,     34% >180
Insulin Only
(130 mg/dl)
Mean: 161 +/- 17 mg/dl
0.8% <60,     30% >180
I: 0.57 U/kg
Insulin Only
(120 mg/dl)
Mean: 156 +/- 15 mg/dl
1.1% <60,     28% >180
I: 0.57 U/kg
Insulin Only
(110 mg/dl)
Mean: 153 +/- 15 mg/dl
1.3% <60,     26% >180
I: 0.70 U/kg
(n=20)

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 86 OF 97 
 
2082 
Figure 4. Outpatient results summarizing the distribution of mean CGM glucose levels and 
2083 
hypoglycemia in the bihormonal BP arms (with set-points of 130, 110, and 100 mg/dl) and 
2084 
usual-care arm (control) from the Bionic Pancreas Set-Point Study. Mean CGM glucose levels 
2085 
for each participant in each study arm (shown as a red circles) are connected by black lines.  
2086 
For each participant, the circle diameter is proportional to the percentage of CGM glucose values 
2087 
< 60 mg/dl.  The heavy circles and lines represent the group means.  The horizontal red dashed 
2088 
line refers to the glucose level corresponding to the ADA therapy goal for each age group tested, 
2089 
which corresponds to 154 mg/dl (HbA1c <7%) for adults with T1D ≥ 18 years old. 
2090 
A.1.3 The Stanford Insulin-Only Study 
2091 
In July 2015 we obtained FDA approval to perform our first study investigating a feature that 
2092 
allowed the target glucose to be determined automatically by the BP, an additional level of 
2093 
adaptation to the individual participant.  In this study, which we called the Stanford Insulin-Only 
2094 
Study, 16 adults participated in a week of usual care followed by another week on the 
2095 
insulinonly BP.  Participants were monitored remotely according to identical criteria in both 
2096 
study arms for proper device functioning and CGM glucose <50 mg/dl lasting more than 
2097 
15 minutes, which would prompt study staff to call the participant and make sure they were 
2098 
treated.  The first week was a control arm in which participants managed their own conventional 
2099 
insulin pump therapy (using their own CGM if they had one) and wore the BP without pumps 
2100 
and with blinded display and muted alarms for remote monitoring.  In the second week, the BP 
2101 
was initiated with target glucose of 130 mg/dl, which could be lowered to 115 mg/dl if certain 
2102 
criteria were met.  Results of the study are summarized in Figure 5.  All but one participant was 
2103 
kept at a target of 130 mg/dl, and one was lowered to 115 mg/dl, for an overall average target of 
2104 
129 mg/dl.  During this week the mean CGM glucose obtained during the insulin-only BP arm 
2105 
was 159 ± 8 mg/dl (which was similar to the mean CGM glucose of 161 ± 17 mg/dl obtained 
2106 
during the insulin-only BP arm of the Bionic Pancreas Set-Point Study when the glucose target 
2107 
Mean CGMG (mg/dl)
90
120
154
180
210
240
1% <60 mg/dl
5% <60 mg/dl
Control
Mean: 158 +/- 31 mg/dl
1.4% <60,     34% >180
Bihormonal
(130 mg/dl)
Mean: 156 +/- 12 mg/dl
0.5% <60,     28% >180
I: 0.53 U/kg,  G: 2.2 mcg/kg
Bihormonal
(110 mg/dl)
Mean: 148 +/- 17 mg/dl
0.4% <60,     22% >180
I: 0.67 U/kg,  G: 5.1 mcg/kg
Bihormonal
(100 mg/dl)
Mean: 136 +/- 14 mg/dl
0.8% <60,     17% >180
I: 0.58 U/kg,  G: 8.3 mcg/kg
(n=20)

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 87 OF 97 
was set to 130 mg/dl).  Although the mean glucose was statistically significantly higher 
2108 
(p=0.001) during the insulin-only BP arm than during the usual-care arm (145 ± 20 mg/dl) in the 
2109 
very well controlled cohort of the Stanford Insulin-Only Study, there was a significant decrease 
2110 
in the time spent <60 mg/dL during the insulin-only BP arm relative to the usual-care arm 
2111 
(mean of 0.84 ± 0.91 versus mean 2.3 ± 2.1%, p = 0.04). 
2112 
 
2113 
Figure 5. Outpatient results summarizing the distribution of mean CGM glucose levels and 
2114 
hypoglycemia in the insulin-only BP and control arms from the Stanford Insulin-Only Study.  
2115 
Mean CGM glucose levels for each participant under usual care (shown as a red circle on the 
2116 
left) is connected with the participant's mean CGM glucose level on the BP (shown as a black 
2117 
circle on the right).  For each participant, the circle diameter is proportional to the percentage of 
2118 
CGM glucose values < 60 mg/dl.  The heavy circles and lines represent the group means.  
2119 
The horizontal red dashed line refers to the glucose level corresponding to the ADA therapy goal 
2120 
for each age group tested, which corresponds to 154 mg/dl (HbA1c <7%) for adults with T1D ≥ 
2121 
18 years old. 
2122 
A.1.4 The Bionic Pancreas Monitoring Study 
2123 
In April 2016, we obtained FDA approval to perform our first study removing remote telemetric 
2124 
monitoring for severe biochemical hypoglycemia from an outpatient study comparing the 
2125 
bihormonal bionic pancreas, the insulin-only bionic pancreas and the subject’s own usual care. 
2126 
In the Monitoring Study6 each arm was repeated with and without remote monitoring to allow 
2127 
for a direct comparison of glycemic control and hypoglycemia.  Each BP hormonal configuration 
2128 
used the lowest glucose target previously tested: 100 mg/dl for the bihormonal BP and 110 mg/dl 
2129 
for the insulin-only BP.  The results are summarized in Figure 6.  There was more hypoglycemia 
2130 
without monitoring relative to with monitoring in the two usual-care arms (1.95 versus 1.32%, 
2131 
p=0.02).  However, there was no difference in hypoglycemia without monitoring relative to with 
2132 
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_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 88 OF 97 
monitoring in the two bihormonal BP arms (0.99 versus 1.05%, p=0.82) and two insulin-only BP 
2133 
arms (1.66 versus 1.55%, p=0.74) arms.  Without monitoring, hypoglycemia was reduced in the 
2134 
bihormonal BP arm relative to the usual-care arm (0.99 versus 1.95%, p=0.02) and was 
2135 
comparable on the insulin-only BP relative to usual care (1.66 versus 1.95%, p=0.47).  The mean 
2136 
CGMG was significantly lower in all BP arms relative to the usual-care arms.  There were no 
2137 
mean CGMG differences between the two bihormonal, two insulin-only, and two usual-care 
2138 
arms.  We concluded that remote telemetric monitoring had no effect on hypoglycemia with the 
2139 
BP and could be safely omitted from future studies even at the most aggressive glucose set 
2140 
points.  As a result of this study and the Bionic Pancreas Set-Point Study, we concluded that the 
2141 
default glucose set points should be set in future studies to 110 mg/dl for the bihormonal 
2142 
configuration and 120 mg/dl for insulin-only configuration.  We further concluded that users 
2143 
could be allowed to lower each set point (to a minimum of 100 mg/dl for the bihormonal 
2144 
configuration and 110 mg/dl for insulin-only configuration) should they so desire without 
2145 
sacrificing their safety. 
2146 
 
2147 
Figure 6. Outpatient results summarizing the distribution of mean CGM glucose levels and 
2148 
hypoglycemia in the insulin-only BP and control arms from the Bionic Pancreas Monitoring 
2149 
Study.  Mean CGM glucose levels for each participant under usual care (shown as a red circle on 
2150 
the left) is connected with the participant's mean CGM glucose level on the BP (shown as a black 
2151 
circle on the right).  For each participant, the circle diameter is proportional to the percentage of 
2152 
CGM glucose values < 60 mg/dl.  The heavy circles and lines represent the group means.  
2153 
The horizontal red dashed line refers to the glucose level corresponding to the ADA therapy goal 
2154 
for each age group tested, which corresponds to 154 mg/dl (HbA1c <7%) for adults with T1D ≥ 
2155 
18 years old. 
2156 
Mean CGMG (mg/dl)
90
120
154
180
210
240
1% <60 mg/dl
5% <60 mg/dl
Control, N
Mean: 165 +/- 29 mg/dl
2.0% <60,     36% >180
Control, Y
Mean: 164 +/- 29 mg/dl
1.3% <60,     36% >180
Insulin Only
110 mg/dl, N
Mean: 148 +/- 11 mg/dl
1.7% <60,     24% >180
I: 0.59 U/kg
Insulin Only
110 mg/dl, Y
Mean: 151 +/- 13 mg/dl
1.6% <60,     26% >180
I: 0.61 U/kg
Bihormonal
100 mg/dl, N
Mean: 139 +/- 11 mg/dl
1.0% <60,     19% >180
I: 0.64 U/kg,  G: 7.4 mcg/kg
Bihormonal
100 mg/dl, Y
Mean: 139 +/- 13 mg/dl
1.0% <60,     18% >180
I: 0.62 U/kg,  G: 7.1 mcg/kg
(n=23)

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 89 OF 97 
A.2 Studies Conducted with the Gen 3 iLet Bionic Pancreas System 
2157 
All of the studies described below used the Gen 3 iLet BP System, rather than the commercial 
2158 
Gen 4 iLet system, and all used either the G5 Dexcom CGM or Senseonics Eversense CGM, 
2159 
rather than the G6 Dexcom CGM.  The Insulin-Only Bionic Pancreas Pivotal Trial will use the 
2160 
Gen 4 iLet BP System with the G6 Dexcom CGM. 
2161 
A.2.1 The iLet Insulin-Only Bionic Pancreas Bridging Study 
2162 
The Insulin-Only Bionic Pancreas Bridging Study was conducted between July and October 
2163 
2018 at MGH and Stanford University in adult subjects ≥ 18 years old with type 1 diabetes.  
2164 
The study was designed as a random-order, cross-over, home-use trial that compared the 
2165 
insulin-only configuration of the iLet using lispro or aspart to the insulin-only configuration of 
2166 
the iLet using Fiasp to each subject’s own usual care (UC) for 7 days each.  The study enrolled 
2167 
12 subjects who used multiple daily injection therapy and 22 subjects who used insulin-pump 
2168 
therapy for their UC. Participants enrolled at MGH (n = 17) used the Senseonics Eversense CGM 
2169 
while those at Stanford (n = 17) used the G5 Dexcom CGM as the input CGM signal for the iLet.  
2170 
Results from the Insulin-Only Bionic Pancreas Bridging Study are summarized in Figure 7. 
2171 
 
2172 
Figure 7. Distribution of mean glucose and hypoglycemia in the Insulin-Only Bionic Pancreas 
2173 
Bridging Study.  Mean CGM glucose level for each subject is shown over Days 3–7 under 
2174 
usual care, (left panel), on the iLet in the insulin-only configuration using lispro or aspart 
2175 
(middle panel), and on the iLet in the insulin-only configuration using Fiasp (right panel).  
2176 
The diameter of each circle is proportional to the percentage time spent < 60 mg/dl for each 
2177 
subject under each study arm over Days 3–7.  The mean CGM glucose was 155 ± 13 mg/dl with 
2178 
the iLet in the insulin-only configuration using lispro or aspart, 155 ± 11 mg/dl with the iLet in 
2179 
the insulin-only configuration using Fiasp, and 163 ± 26 mg/dl under usual care.  The time < 60 
2180 
mg/dl was 1.2% using lispro or aspart, 1.2% with the iLet using Fiasp, and 1.3% under usual 
2181 
Mean CGMG (mg/dl)
90
120
154
180
210
240
1% <60 mg/dl
5% <60 mg/dl
(n=35)
Control (33% ADA)
Mean: 163 +/- 26 mg/dl
1.30% <60,     35% >180
Insulin Only (42% ADA)
Mean: 155 +/- 13 mg/dl
1.19% <60,     27% >180
I: 0.65 U/kg
Insulin Only (44% ADA)
(Fiasp)
Mean: 155 +/- 11 mg/dl
1.19% <60,     27% >180
I: 0.64 U/kg

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 90 OF 97 
care.  Red lines and circles correspond to data from subjects who used multiple daily injection 
2182 
therapy for their usual care and blue lines and circles correspond to data from subjects who used 
2183 
insulin-pump therapy for their usual care. 
2184 
The Insulin-Only Bionic Pancreas Bridging Study was unprecedented in several ways.  It is the 
2185 
only study of an automated insulin delivery system to test (1) two different CGM devices, (2) an 
2186 
ultra-rapid insulin analog, and (3) a cohort that was comprised subjects coming from multiple 
2187 
daily injection (MDI) therapy and insulin pump therapy.  Since only the patient’s body weight is 
2188 
required to initialize the iLet, and no other information is required about either insulin therapy 
2189 
regimen (either MDI or insulin pump therapy), the iLet is the only device that can be tested in 
2190 
this way.  All other automated insulin delivery systems first require transition to pump therapy 
2191 
and weeks-long run-in periods or device training periods to determine a baseline pump therapy 
2192 
regimen before automated insulin delivery can be initiated.  The iLet, on the other hand, requires 
2193 
no run-in periods or device training periods; it is ideally suited, therefore, for use in underserved 
2194 
populations, in insulin-pump-naïve populations, and in populations where endocrinologists and 
2195 
diabetologists are not available or in short supply.  The Insulin-Only Bionic Pancreas Bridging 
2196 
Study demonstrated that the iLet performed equally well on subjects coming from MDI therapy 
2197 
as it did on subjects coming from insulin pump therapy (see Figure 7). 
2198 
A.2.2 The iLet Day-Camp Transitional Study in Pediatrics 
2199 
The Pediatric Transitional Study was conducted in July and August 2018 at Nemours Children’s 
2200 
Health System, the Barbara Davis Center at the University of Colorado, and Stanford University 
2201 
in pediatric subjects 6–17 years old with type 1 diabetes.  The study was designed as a 
2202 
random-order, cross-over, outpatient trial that compared the insulin-only configuration of the 
2203 
iLet (using lispro or aspart) to each subject’s own usual care (UC) for 5 days each.  The study 
2204 
enrolled 20 subjects who used insulin-pump therapy for their UC (n = 6 at Nemours, n = 6 at 
2205 
Colorado, and n = 8 at Stanford).  Results from the Pediatric Transitional Study are summarized 
2206 
in Figure 8. 
2207 
 
2208 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 91 OF 97 
 
2209 
Figure 8. Distribution of mean glucose and hypoglycemia in the Pediatric Day-Camp 
2210 
Transitional Study.  Mean CGM glucose level for each subject is shown over Days 2–5 in the 
2211 
control arm, as a red circle on the left side, connected with the corresponding mean CGM 
2212 
glucose level on the iLet, as a black circle on the right.  The diameter of each circle is 
2213 
proportional to the percentage time spent < 60 mg/dl for each subject under each study arm over 
2214 
Days 2–5.  The mean CGM glucose with the iLet in the insulin-only configuration was 162 ± 16 
2215 
mg/dl and the CGM glucose was < 60 mg/dl 0.8% of the time, whereas the mean CGM glucose 
2216 
under usual care was 161± 28 mg/dl and the CGM glucose was < 60 mg/dl 1.0% of the time. 
2217 
 
2218 
A.2.3 The iLet Bihormonal Cross-Over Study 
2219 
The Bihormonal Cross-Over Study was conducted in May and June 2019 at MGH in adult 
2220 
subjects ≥ 18 years old with type 1 diabetes.  The study was designed as a random-order, cross-
2221 
over, home-use trial that compared the insulin-only configuration of the iLet using lispro or 
2222 
aspart to the bihormonal configuration of the iLet using lispro or aspart and dasiglucagon (4 
2223 
mg/ml) for 7 days each.  The study enrolled 10 subjects who used insulin-pump therapy for their 
2224 
usual care.  Results from the Bihormonal Cross-Over Study are summarized in Figure 9. 
2225 
 
2226 
Mean CGMG (mg/dl)
90
120
169
180
210
240
1% <%60 mg/dl
5% <%60 mg/dl
Control (55% ADA)
Mean: 161 +/- 28 mg/dl
1.0% <%60,     33% >180
Insulin Only (75% ADA)
Mean: 162 +/- 16 mg/dl
0.8% <%60,     32% >180
I: 0.94 U/kg
(n=20)

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 92 OF 97 
 
2227 
Figure 9. Distribution of mean glucose and hypoglycemia in the Bihormonal Cross-Over Study.  
2228 
Mean CGM glucose level for each subject is shown over Days 2–7 in the insulin-only iLet arm, 
2229 
as a black circle on the left side, connected with the corresponding mean CGM glucose level on 
2230 
the bihormonal iLet with dasiglucagon, as a black circle on the right.  The diameter of each circle 
2231 
is proportional to the percentage time spent < 54 mg/dl for each subject under each study arm 
2232 
over Days 2–7.  The mean CGM glucose with the iLet in the insulin-only configuration was 149 
2233 
± 13 mg/dl and the CGM glucose was < 54 mg/dl 0.6% of the time, whereas the mean CGM 
2234 
glucose with the iLet in the bihormonal configuration with dasiglucagon was 139 ± 11 mg/dl and 
2235 
the CGM glucose was < 54 mg/dl 0.3% of the time. 
2236 
iPhone bionic pancreas (BP) and iLet BP Studies – Insulin-only exposure only 
2237 
 
2238 
 
Year Name of 
Study 
Setting,  
Population,  
Device 
exposure1 
BP 
Configuratio
n,  
Set Points 
tested, 
Medications 
used
Protocol 
Description 
Results:  
Mean CGM 
glucose, % < 60 
Conclusion
s 
1
201
5-
201
6 
BP Set 
Point 
Study 
 
IDE: 
G150130 
Outpatient, 
unsupervised 
at home 
 
20 adults aged 
18 and older 
 
4 arms, 4 days 
each
Insulin-only 
iPhone BP 
with one 
Tandem 
t:slim pump 
and Dexcom 
G4 AP CGM 
 
Glucose 
RCT with 4 
insulin-only 
glucose targets 
compared with 
usual care and 
bihormonal 
configurations
. This was the 
first testing of 
110 mg/dl: 
153±15 mg/dl, 
1.3% 
 
120 mg/dl:  
156±15 mg/dl, 
1.1% 
 
130 mg/dl:
The results 
of this 
study 
helped 
identify the 
glucose 
target 
settings 
that will be 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 93 OF 97 
 
7,680 hours 
targets:  
110 mg/dl 
120 mg/dl 
130 mg/dl  
145 mg/dl 
 
Insulin lispro 
(Eli Lilly) & 
Insulin aspart 
(Novo 
Nordisk) 
the insulin-
only 
algorithm.  
 
 
Remote 
telemetric 
monitoring 
 
 
161±17 mg/dl, 
0.8% 
 
145 mg/dl:  
174±23 mg/dl, 
1.0% 
 
UC:  
158±31 mg/dl, 
1.4% 
used in 
future 
studies. 
These were 
set to range 
from 110 
mg/dl to 
130 mg/dl, 
with a 
default of 
120 mg/dl. 
2
201
5 
Stanford 
Insulin-
only 
Study 
 
IDE: 
G150142 
Outpatient, 
unsupervised 
at home 
 
16 adults aged 
18 and older 
 
2 arms, 7 days 
each 
 
5,376 hours 
Insulin-only 
iPhone BP 
with one 
Tandem 
t:slim pump 
and Dexcom 
G4 AP CGM 
 
Glucose 
targets:  
115 to 130 
mg/dl 
 
Insulin lispro 
(Eli Lilly) & 
Insulin aspart 
(Novo 
Nordisk)
RCT 
comparing 
insulin-only 
BP with usual 
care 
 
Remote 
telemetric 
monitoring 
 
 
BP:  
160±9 mg/dl, 
0.9%  
 
UC:  
151±26 mg/dl, 
1.9% 
The results 
of this 
study 
helped 
identify the 
glucose 
target 
settings 
that will be 
used in 
future 
studies. 
3
201
7 
Monitori
ng Study 
 
IDE: 
G150130 
Outpatient, 
unsupervised 
at home 
 
23 adults aged 
18 and older 
 
2 arms, 7 days 
each 
 
7,728 hours 
Insulin-only 
iPhone BP 
with one 
Tandem 
t:slim pump 
and Dexcom 
G5 CGM 
 
Glucose 
target:  
110 mg/dl 
 
Insulin lispro 
(Eli Lilly) & 
Insulin aspart 
(Novo 
Nordisk) 
 
RCT with the 
insulin-only 
BP set at the 
lowest 
allowed 
glucose target 
for the insulin-
only system, 
repeated with 
and without 
monitoring for 
hypoglycemia, 
and compared 
with usual 
care and the 
bihormonal 
BP. 
 
Remote 
telemetric 
monitoring in 
With monitoring: 
Insulin-only: 
151±13 mg/dl, 
1.6% 
 
UC:  
164±29 mg/dl, 
1.3% 
 
Without 
monitoring: 
Insulin-only: 
148±11 mg/dl, 
1.7% 
 
UC: 
165±29 mg/dl, 
2.0% 
The results 
of this 
study 
confirmed 
that the 
insulin-
only BP set 
at the 
lowest 
possible 
glucose 
target (110 
mg/dl) was 
safe to be 
used in the 
outpatient 
setting 
without 
any remote 
monitoring 
for 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 94 OF 97 
half of the 
study arms.  
hypoglyce
mia.  
4
2018 Adult 
Bridging 
study 
 
IDE: 
G180083 
Outpatient, 
unsupervised 
at home, 2 
centers 
 
34 adults aged 
18 and older 
 
2 arms, 7 days 
each 
 
11,424 hours 
Insulin-only 
Gen 3 iLet 
BP using 
Senseonics 
Eversense 
CGM (MGH) 
or Dexcom 
G5 CGM 
(Stanford) 
 
Glucose 
target:  
120 mg/dl 
 
Insulin lispro 
(Eli Lilly),  
Insulin aspart 
(Novo 
Nordisk) & 
Fiasp 
PumpCart 
(Novo 
Nordisk) 
RCT 
comparing the 
insulin-only 
BP in 2 arms 
with usual 
care.  
 
One BP arm 
used insulin 
lispro or 
aspart, the 
other BP arm 
used Fiasp. 
The BP was 
set at the 
default 
glucose target 
of 120 and 
tmax setting 
of 65 minutes 
for both arms.  
 
Remote 
telemetric 
monitoring 
BP: 
155±13 mg/dl, 
1.19% 
 
BP with Fiasp:  
155±11 mg/dl, 
1.19% 
 
UC: 
163±26 mg/dl, 
1.30% 
The results 
of this 
study 
demonstrat
ed that the 
insulin-
only iLet 
BP was 
safe and 
effective 
using both 
Fiasp or 
aspart/lispr
o at the 
default PK 
settings 
consistent 
with the 
results of 
the iPhone 
BP studies, 
preparing 
the path for 
a larger and 
longer 
study using 
the same 
device 
settings 
and 
insulins. 
5
2018 Day-
camp 
Transitio
nal Study 
 
IDE: 
G180083 
Supervised 
day camp 
setting 
followed by 
unsupervised 
at home 
nightly, 2 
centers 
 
20 children 
aged 6-17 
 
5 days 
 
2,400 hours 
Insulin-only 
Gen 3 iLet 
BP using 
Dexcom G5 
CGM 
 
Glucose 
target:  
120 mg/dl 
 
Insulin lispro 
(Eli Lilly) & 
Insulin aspart 
(Novo 
Nordisk) 
RCT 
comparing the 
insulin-only 
BP with usual 
care.  
 
Remote 
telemetric 
monitoring 
BP: 
162±16 mg/dl, 
0.8% 
 
UC: 
161±28 mg/dl, 
1.0% 
The results 
of this 
study 
demonstrat
ed that 
under 
stressful 
conditions, 
the insulin-
only iLet 
BP was 
safe and 
effective to 
use in 
adolescent 
and pre-
adolescent 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 95 OF 97 
children, 
preparing 
the path for 
a larger and 
longer 
study using 
the same 
device 
settings in 
this age 
group. 
6
2019 Fiasp 
Explorat
ory Study 
 
IDE: 
G180150 
48 hour 
supervised 
hotel stay, 
followed by 5 
days 
unsupervised 
at home 
 
24 adults aged 
18 and older 
 
2 arms, 7 days 
each 
 
8,064 hours 
Insulin-only 
Gen 3 iLet 
BP using 
Dexcom G5 
CGM 
 
Glucose 
target:  
120 mg/dl 
 
Fiasp 
PumpCart 
(Novo 
Nordisk) 
RCT to 
compare 
default insulin 
PK settings 
(tmax = 65 
minutes) with 
faster PK 
settings (tmax 
= 50, 40 and 
30 minutes). 
Faster PK 
setting was 
escalated over 
three cohorts 
of 8 subjects 
 
Remote 
telemetric 
monitoring
Pending analysis.  
7
2019 Bihormo
nal 
Crossove
r Study 
 
IDE: 
G190028 
Outpatient, 
unsupervised 
at home 
 
10 adults aged 
18 and older 
 
7 days 
 
1,680 hours 
Insulin-only 
Gen 3 iLet 
BP using 
Dexcom G5 
CGM 
 
Glucose 
target:  
120 mg/dl 
 
Insulin lispro 
(Eli Lilly) & 
Insulin aspart 
(Novo 
Nordisk) 
RCT to 
compare 
insulin-only 
with 
bihormonal 
using 
dasiglucagon, 
testing 
bihormonal 
iLet for the 
first time 
 
Remote 
telemetric 
monitoring 
Insulin-only: 
149±13 mg/dl, 
1.25% 
The results 
of this 
study 
confirm the 
insulin-
only iLet 
BP at the 
lowest 
target 
glucose set 
point is 
safe and 
effective in 
the 
outpatient 
setting, 
consistent 
with results 
achieved in 
the iphone 
BP studies. 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 96 OF 97 
8
2019 MultiPK 
BP Study 
 
IDE: 
G180254 
Outpatient, 
unsupervised 
at home 
 
6 adults aged 
18 and older 
completed to 
date 
 
3 arms, 7 days 
each 
 
3,024 hours 
Insulin-only 
Gen 3 iLet 
BP using 
Dexcom G5 
CGM 
 
Glucose 
target:  
120 mg/dl 
 
Insulin lispro 
(Eli Lilly),  
Insulin aspart 
(Novo 
Nordisk) & 
BioChaperon
e lispro 
(Adocia)
RCT with one 
week each on 
insulin lispro, 
insulin aspart 
and 
BioChaperone 
lispro using 
the default 
tmax setting 
(65 minutes) 
for all three 
insulins 
 
Remote 
telemetric 
monitoring 
Pending analysis, experiments 
ongoing 
1 – Total device exposure is calculated based on cohort size used in the study analysis and includes 
2239 
insulin-only arms only 
2240 
 
 
2241 

 
IOBP_PIVOTAL_PROTOCOL_V10.0_25APR2021_CLEAN 
PAGE 97 OF 97 
Pediatric iPhone bionic pancreas (BP) and iLet BP studies – insulin-only and bihormonal (ages 6 to < 18 
2242 
years) 
2243 
 
Yea
r 
Name 
of 
Study 
Setting,  
Population,  
Device 
exposure1 
BP 
Configura-
tion,  
Set Points 
tested, 
Medication
s used
Protocol 
Description 
Results:  
Mean CGM 
glucose, % < 
60 
Conclusio
ns 
1
201
3 
2013 
Summer 
Camp 
Study 
 
IDE: 
G13006
5 
Supervised 
summer 
camp setting 
 
32 
adolescents 
aged 12 to 
20 
 
5 days 
 
3,840 hours 
Bihormonal 
iPhone BP 
with two 
Tandem 
t:slim 
pumps and 
Dexcom G4 
AP CGM 
 
Glucose 
target:  
100 mg/dl 
 
Insulin 
lispro (Eli 
Lilly) & 
Glucagon 
(Eli Lilly)
RCT 
comparing 
bihormonal 
iPhone BP 
with usual 
care at camp 
 
Remote 
telemetric 
monitoring 
BP:  
142±12 mg/dl, 
1.3%  
 
UC: 
158±27 mg/dl, 
2.2% 
The 
results of 
this study 
demonstr
ated that 
under 
stressful 
condition
s, the 
bihormon
al BP was 
safe and 
effective 
to use in 
adolescen
t 
children. 
2
201
4 
2014 
Summer 
Camp 
Study 
 
IDE: 
G13006
5 
Supervised 
summer 
camp setting 
 
19 pre-
adolescents 
aged 6 to 11 
 
5 days 
 
2,280 hours 
Bihormonal 
iPhone BP 
with two 
Tandem 
t:slim 
pumps and 
Dexcom G4 
AP CGM 
 
Glucose 
target:  
100 mg/dl 
 
Insulin 
lispro (Eli 
Lilly) & 
Glucagon 
(Eli Lilly)
RCT 
comparing 
bihormonal 
iPhone BP 
with usual 
care at camp 
 
Remote 
telemetric 
monitoring 
BP: 
137±11 mg/dl, 
1.2% 
 
UC: 
168±30 mg/dl, 
2.8% 
The 
results of 
this study 
demonstr
ated that 
under 
stressful 
condition
s, the 
bihormon
al BP was 
safe and 
effective 
to use in 
pre-
adolescen
t children 
 
2244