Bihormonal Bionic Pancreas for the Treatment of Diabetes Post-Pancreatectomy in Children With Congenital Hyperinsulinism - A Pilot Study
Phase: NA
Conditions: Hyperinsulinism, Diabetes, Pancreatic Diseases, Pancreatectomy; Hyperglycemia
Sponsor: Children's Hospital of Philadelphia

 
 
Title: 
Bihormonal Bionic Pancreas for the Treatment of Diabetes 
Post-Pancreatectomy in Individuals with Congenital 
Hyperinsulinism – A Pilot Study 
Short Title 
Bionic Pancreas in HI - Pilot 
Device Name: 
Bionic-Pancreas Glycemic-Control System 
FDA IDE 
G150130 
NCT Number: 
NCT03303196 
Regulatory Sponsor: 
Ed Damiano, Ph.D. (IDE holder) 
eIRB Number: 
17-014144 
Protocol Date: 
August 24, 2017 
Amendment 1 Date: November 7, 2017 
Amendment 4 Date: July 9, 2018  
Amendment 2 Date: January 26, 2018 
Amendment 5 Date: December 22, 2018 
Amendment 3 Date: May 1, 2018 
 
 
Sponsor (IDE holder)/Funder 
Ed Damiano, PhD 
Department of Biomedical Engineering 
 Boston University 
44 Cummington Street 
Boston, MA 02215 
Funder 
Zealand Pharma A/S 
Smedeland 36 
2600 Glostrup (Copenhagen) 
Denmark 
 
CHOP Study Principal Investigator 
Diva D. De León, MD, MSCE 
Division of Endocrinology 
Children’s Hospital of Philadelphia 
3615 Civic Center Boulevard, Suite 802-A 
Philadelphia, PA 19104 
Phone: 215-590-3420 
E-mail: DeLeon@email.chop.edu 
 

 
 
 
 
 
 
 
 
 
 
ii
TABLE OF CONTENTS 
Table of Contents ................................................................................................................... ii 
Abbreviations and Definitions of Terms.............................................................................. v 
Abstract ................................................................................................................................. vi 
Protocol Synopsis ................................................................................................................. vii 
Table 1: Schedule of Study Procedures ............................................................................... x 
1 
BACKGROUND INFORMATION AND RATIONALE ....................................................................... 1 
 
INTRODUCTION ..................................................................................................................................... 1 
 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR INTERVENTION ..................................... 1 
 
FINDINGS FROM NON-CLINICAL AND CLINICAL STUDIES ..................................................................... 3 
 
Non-Clinical Studies ....................................................................................................................... 3 
 
Clinical Studies ............................................................................................................................... 3 
 
RELEVANT LITERATURE AND DATA ..................................................................................................... 5 
 
COMPLIANCE STATEMENT .................................................................................................................... 6 
2 
STUDY OBJECTIVES .............................................................................................................................. 6 
 
STUDY RATIONALE .............................................................................................................................. 6 
 
PRIMARY OBJECTIVE (OR AIM) ............................................................................................................ 7 
 
SECONDARY OBJECTIVES (OR AIM) ...................................................................................................... 7 
3 
INVESTIGATIONAL PLAN .................................................................................................................... 7 
 
GENERAL SCHEMA OF STUDY DESIGN ................................................................................................. 7 
 
Screening Phase .............................................................................................................................. 8 
 
Standard Care Admission ................................................................................................................ 8 
 
Bihormonal Bionic Pancreas Admission ......................................................................................... 8 
 
ALLOCATION TO TREATMENT GROUPS AND BLINDING ........................................................................ 9 
 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES ................................................................... 9 
 
Duration of Study Participation ...................................................................................................... 9 
 
Total Number of Subjects Projected ................................................................................................ 9 
 
Total Number of Sites ...................................................................................................................... 9 
 
STUDY POPULATION ............................................................................................................................. 9 
 
Inclusion Criteria ............................................................................................................................ 9 
 
Exclusion Criteria ......................................................................................................................... 10 
4 
STUDY PROCEDURES .......................................................................................................................... 11 
 
RECRUITMENT PROCEDURES .............................................................................................................. 11 
 
CONSENT PROCEDURES ...................................................................................................................... 11 
 
EXPERIMENTAL PROCEDURES AND DATA COLLECTION ..................................................................... 11 
 
Screening Visit .............................................................................................................................. 11 
 
STANDARD CARE ADMISSION ............................................................................................................ 12 
 
Run-in period (Day 0) ................................................................................................................... 12 
 
Days 1-3 ........................................................................................................................................ 13 
 
Discharge ...................................................................................................................................... 13 
 
BIHORMONAL BIONIC PANCREAS ADMISSION .................................................................................... 13 
 
Run-in Period (Day 0): ................................................................................................................. 13 
 
Days 1-3 ........................................................................................................................................ 14 
 
Discharge ...................................................................................................................................... 16 
 
STANDARDIZED MEALS ...................................................................................................................... 16 
 
PHYSICAL ACTIVITY ........................................................................................................................... 16 
 
PRIOR AND CONCOMITANT MEDICATION ........................................................................................... 16 
 
RESCUE MEDICATION ADMINISTRATION ............................................................................................ 17 

 
 
 
 
 
 
 
 
 
 
iii
 
Response to Hypoglycemia ............................................................................................................ 17 
 
Response to Hyperglycemia .......................................................................................................... 17 
 
Response to Nausea/Vomiting ....................................................................................................... 17 
 
MONITORING OF BIONIC PANCREAS PERFORMANCE .......................................................................... 17 
 
SUPERVISION BY STUDY STAFF .......................................................................................................... 18 
 
SUBJECT COMPLETION/WITHDRAWAL ............................................................................................... 18 
5 
STUDY EVALUATIONS AND MEASUREMENTS ............................................................................ 18 
 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ................................................ 18 
 
Medical Record Review ................................................................................................................. 18 
 
Physical Examination .................................................................................................................... 19 
 
Vital Signs ..................................................................................................................................... 19 
 
Laboratory Evaluations................................................................................................................. 19 
 
EFFICACY EVALUATIONS ................................................................................................................... 20 
 
SAFETY EVALUATION ......................................................................................................................... 20 
6 
STATISTICAL CONSIDERATIONS .................................................................................................... 20 
 
PRIMARY ENDPOINT ........................................................................................................................... 20 
 
SECONDARY ENDPOINTS .................................................................................................................... 20 
 
SAFETY ENDPOINTS ............................................................................................................................ 21 
 
EXPLORATORY OUTCOMES ................................................................................................................ 21 
 
CGMS ............................................................................................................................................ 21 
 
BG ................................................................................................................................................. 21 
 
Non-glycemic................................................................................................................................. 21 
 
STATISTICAL METHODS...................................................................................................................... 21 
 
Baseline Data ................................................................................................................................ 22 
 
Efficacy Analysis ........................................................................................................................... 22 
 
Safety Analysis .............................................................................................................................. 23 
 
SAMPLE SIZE AND POWER .................................................................................................................. 23 
 
Mean CGMS-measured glucose .................................................................................................... 23 
 
Proportion of time with a CGMS-measured glucose concentration below 60 mg/dL ................... 24 
 
INTERIM ANALYSIS ............................................................................................................................ 24 
7 
DRUGS/DEVICES ................................................................................................................................... 24 
 
DRUGS ................................................................................................................................................ 24 
 
DEVICES ............................................................................................................................................. 25 
 
Personal Insulin Pumps ................................................................................................................ 25 
 
Bionic Pancreas System ................................................................................................................ 25 
 
Continuous Glucose Monitoring System ....................................................................................... 26 
 
Bedside Glucometer ...................................................................................................................... 26 
 
Drug Accountability ...................................................................................................................... 26 
8 
SAFETY MANAGEMENT ..................................................................................................................... 27 
 
PREEXISTING CONDITION ................................................................................................................... 27 
 
GENERAL PHYSICAL EXAMINATION FINDINGS ................................................................................... 27 
 
CLINICAL ADVERSE EVENTS .............................................................................................................. 27 
 
DEFINITION OF AN ADVERSE EVENT .................................................................................................. 27 
 
ADVERSE EVENT REPORTING ............................................................................................................. 27 
 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ........................................................................... 28 
 
Relationship of SAE to Study Intervention .................................................................................... 28 
 
IRB/IEC NOTIFICATION OF SAES AND OTHER UNANTICIPATED PROBLEMS ...................................... 29 
 
Follow-up report ........................................................................................................................... 29 
 
INVESTIGATOR REPORTING OF A SERIOUS ADVERSE EVENT TO SPONSOR .......................................... 29 
 
MEDICAL EMERGENCIES .................................................................................................................... 29 

 
 
 
 
 
 
 
 
 
 
iv
9 
STUDY ADMINISTRATION ................................................................................................................. 29 
 
DATA COLLECTION AND MANAGEMENT ............................................................................................ 29 
 
Confidentiality of Data .................................................................................................................. 29 
 
Security .......................................................................................................................................... 30 
 
Anonymization, de-identification or destruction ........................................................................... 30 
 
CONFIDENTIALITY .............................................................................................................................. 30 
 
REGULATORY AND ETHICAL CONSIDERATIONS.................................................................................. 30 
 
Data and Safety Monitoring Plan ................................................................................................. 31 
 
Safety Monitoring .......................................................................................................................... 32 
 
Risk Assessment ............................................................................................................................. 32 
 
Potential Benefits of Trial Participation ....................................................................................... 33 
 
Risk-Benefit Assessment ................................................................................................................ 33 
 
RECRUITMENT STRATEGY .................................................................................................................. 34 
 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION ............................................................ 34 
 
PAYMENT TO SUBJECTS/FAMILIES ..................................................................................................... 34 
 
Reimbursement for travel, parking and meals .............................................................................. 34 
 
Payments to subject and parent for time and inconvenience (i.e. compensation) ......................... 35 
 
Gifts ............................................................................................................................................... 35 
10 
SPONSORSHIP AND FUNDING........................................................................................................... 35 
11 
PUBLICATION ........................................................................................................................................ 36 
12 
REFERENCES ......................................................................................................................................... 36 
 

 
 
 
 
 
 
 
 
 
 
v
ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
AE 
BG 
BP 
CBC 
CGMS 
CHI 
CHOP 
CMP 
CRF 
DKA 
FDA 
GUI 
HbA1c 
HI 
HIPAA 
ICF 
IM 
IRB 
LAR 
MGH 
PG 
PI 
SC 
T1D 
 
Adverse event 
Blood glucose 
Bihormonal bionic pancreas 
Complete blood count 
Continuous glucose monitoring system 
Congenital hyperinsulinism 
Children’s Hospital of Philadelphia 
Comprehensive metabolic panel 
Case report form 
Diabetic ketoacidosis 
(United States) Food and Drug Administration 
Graphical user interface 
Glycosylated hemoglobin 
Hyperinsulinism 
Health Insurance Portability and Accountability Act of 1996 
Informed consent form 
Intramuscular 
Institutional review board 
Legally-authorized representative 
Massachusetts General Hospital 
Plasma glucose 
Principle investigator 
Subcutaneous 
Type 1 diabetes 

 
 
 
 
 
 
 
 
 
 
vi
ABSTRACT 
Congenital hyperinsulinism (HI) is a disorder of ß-cell dysregulation in the pancreas that 
results in severe hypoglycemia. Frequently, pancreatectomy is necessary to control 
hypoglycemia. After near-total pancreatectomy, diabetes is common with 91% of the 
individuals requiring insulin before puberty. Current treatment involving insulin 
administration offers inadequate blood glucose (BG) control in these individuals. We 
propose a novel approach to better treat these individuals through use of a bihormonal 
“bionic pancreas” to replace both hormones, insulin and glucagon, through an automated 
glycemic management system.  
In collaboration with the Bionic Pancreas Project, we propose a pilot study to evaluate the 
efficacy and safety of the bionic pancreas in individuals with HI and post-pancreatectomy 
diabetes. Potential subjects will be recruited from The CHOP Congenital Hyperinsulinism 
Center. Eligibility entails six to 30 years in age, an HI diagnosis, and post-pancreatectomy 
diabetes managed by subcutaneous insulin pump. Subjects will be studied during two 
research inpatient admissions at the CHOP HI Center. During one admission - standard care 
- subjects will continue their home insulin regimen via their insulin pump; during the other 
admission – bihormonal bionic pancreas admission - subjects will receive insulin and 
glucagon via the bihormonal bionic pancreas.  Glycemic control will be evaluated through a 
continuous glucose monitoring system. Mean glucose and episodes of hypoglycemia will be 
compared during the two admissions. Data generated from this pilot study will be used to 
plan a larger study. 
 
 

 
 
 
 
 
 
 
 
 
 
vii
PROTOCOL SYNOPSIS 
Study Title 
Bihormonal Bionic Pancreas for the Treatment of Diabetes Post-
Pancreatectomy in Individuals with Congenital Hyperinsulinism – A 
Pilot Study 
Funder 
Zealand Pharma A/S 
Sponsor (IDE 
holder)/Funder 
Edward Damiano, PhD (Dept of Biomedical Engineering, Boston 
University) 
Clinical Phase 
Pilot Study  
Study Rationale 
The management of diabetes following pancreatectomy for HI 
generally consists of the same approaches that are used for 
individuals with type 1 diabetes (T1D). However, there are 
significant differences in individuals with HI and post-
pancreatectomy diabetes that increases the risk of hypoglycemia in 
these individuals and prevent achieving tight glycemic control. 
Individuals with HI have glucagon deficiency and unlike T1D, 
individuals with HI and post-pancreatectomy diabetes have residual 
dysregulated insulin secretion that results in marked hypo- and 
hyper-glycemia. Furthermore, pancreatic insufficiency can result in 
disturbances in nutrient absorption and fluctuations in glucose 
concentrations.  
Current treatment approaches with intermittent subcutaneous insulin 
administration or insulin pump therapy offer inadequate glycemic 
control in these individuals. We propose a novel approach to the 
management of these individuals with the bihormonal bionic 
pancreas to replace both hormones, insulin and glucagon, through 
an automated glycemic management system. 
Study Objective(s) 
Primary  
 
To determine if the bihormonal bionic pancreas improves 
glycemic control in individuals with HI who develop diabetes 
post-pancreatectomy. 
Secondary 
 
To evaluate the safety of the bihormonal bionic pancreas in 
individuals with HI who develop diabetes post-pancreatectomy.  
Test Article(s) 
 
The Bionic-Pancreas Glycemic-Control System has been shown to 
improve glycemic control and to reduce the frequency of 
hypoglycemia in children and adults with T1D. Insulin and 
glucagon are administered by a fully automated, bihormonal, bionic 
pancreas with the use of control algorithms that adapt to changes in 
insulin/glucagon requirements. The device consists of an iPhone®, 
which runs the control algorithm, and a Dexcom® continuous 
glucose monitor system (CGMS) connected by a custom software 

 
 
 
 
 
 
 
 
 
 
viii
interface. Insulin and glucagon are administered subcutaneously by 
a Tandem® t:slim™ infusion pump, which are controlled wirelessly 
by the iPhone®. In adults and children with T1D, the combination 
of insulin and glucagon has been shown to improve glycemic 
control and reduce the occurrence of hypoglycemia. 
Study Design 
 
This will be an open-label, pilot clinical trial to assess efficacy and 
safety of the bihormonal bionic pancreas in children and adults with 
HI who have developed post-pancreatectomy diabetes. Subjects will 
be studied during two research inpatient admissions at the CHOP HI 
Center. The order of the interventions will be randomized.   
Subject Population 
Abbreviated Inclusion Criteria 
1. Individuals 6 years to 30 years of age. 
2. Diagnosis of hyperinsulinism. 
3. Previous pancreatectomy. 
4. Diagnosis of diabetes. 
5. Treatment with subcutaneous insulin by pump at the time of 
recruitment. 
Abbreviated Exclusion Criteria 
1. Evidence of a medical condition that might alter results or 
compromise the interpretation of results, including active 
infection, kidney failure, severe liver dysfunction, severe 
respiratory or cardiac failure. 
2. Evidence of severe hematologic abnormality including 
severe anemia and/or thrombocytopenia. 
Number of Subjects 
12 subjects enrolled to produce 10 evaluable subjects 
Study Duration 
Each subject’s participation will last approximately 8 days 
(screening visit and two, 4-day inpatient admissions). The entire 
study is expected to last one year. 
Study Phases 
  
 Screening: medical records will be reviewed to determine 
eligibility. Medical history, physical examination, CBC, CMP, 
and HbA1c will be obtained during this visit after informed 
consent.  
 The order of admissions will be determined using a randomized, 
cross-over design and will occur at least 1 week apart. 
 Standard Care Admission: A 4-day inpatient admission in which 
subjects will continue their home insulin regimen. The first day 
will be a run-in period. The last 3 days involve collection of 
plasma glucose data for analysis (CGMS and fingerstick). 
 Bihormonal Bionic Pancreas Admission: A 4-day inpatient 
admission in which subjects will wear the bihormonal pancreas. 

 
 
 
 
 
 
 
 
 
 
ix
The bihormonal pancreas will be placed upon admission and 
there will be 1 day of run-in followed by 3 days of data collection 
for comparison with the data obtained from the standard of care 
during the control admission. Following this, the patient will 
transition back to their home regimen and discharged home. 
Efficacy Evaluations 
The co-primary efficacy evaluations are (1) mean glucose 
concentration as measured by the CGMS during the last 3 days of 
the Standard Care Admission and the last three days of the 
Bihormonal Bionic Pancreas Admission, and (2) the mean 
proportion of time that the CGMS-measured glucose concentration 
was less than 60 mg/dL during the same periods. 
Secondary efficacy evaluations include the proportion of time that 
CGMS-measured glucose concentrations are in clinically relevant 
ranges (< 70 mg/dL, 70-180 mg/dL, >180 mg/dL), the mean glucose 
concentration measured by fingerstick, the proportion of glucose 
concentrations measured by scheduled fingersticks that were below 
60 mg/dL, and the number of interventions required for 
hypoglycemia per day. 
Safety Evaluations 
Safety variables will be assessed by comparison of frequency of 
serious adverse events (SAEs) during the two study periods. 
Statistical and Analytic 
Plan 
This is a pilot study to generate data to assess feasibility of study 
design/procedures and for formal sample size estimation for a larger 
study of the efficacy of the bihormonal bionic pancreas in children 
and adults with hyperinsulinism and post-pancreatectomy diabetes. 
The sample size for this pilot study may be too small to detect 
statistical significance, however, we offer the following plan for 
analysis of the outcomes for this study.  
Descriptive statistics will be used to characterize demographic, 
baseline, and outcome measures in subjects. Mean CGMS-measured 
glucose concentration (calculated as the mean of all CGMS-
measured concentrations [measured every 5 min] over the study 
period) and the mean proportion of time when the CGMS-measured 
glucose concentration was < 60 mg/dL during the last 3 days on the 
bionic pancreas will be compared to the same outcomes during the 
standard care period by paired-sample Student’s t-test (or Wilcoxon 
signed rank test if data is not normally distributed) to determine if 
the intervention conferred an improvement in glycemic control. 
Secondary outcomes will be analyzed with univariate analysis.  
Data and Safety 
Monitoring Plan 
The Principle Investigator (PI) will be ultimately responsible for 
data quality management and ongoing assessment of safety. Safety 
variables will be assessed by comparison of frequency of serious 
adverse events (SAEs) during the two study periods. 

 
x  
 
 
 
 
 
 
 
Table 1: Schedule of Study Procedures  
Study Phase A 
Screening 
Standard Care Admission 
Bihormonal Bionic Pancreas 
Admission 
Visit ID 
S.1 
C.0 
C.1 
C.2 
C.3 
E.0 
E.1 
E.2 
E.3 
Informed consent/assent 
X 
 
 
 
 
 
 
 
 
Review inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
Demographic/medical history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
X 
 
 
 
X 
Vital Signs: Ht, Wt, Temp, BP, HR, RR 
X 
X 
X D 
X D 
X  
X 
X D 
X D 
X  
Pregnancy test B 
X 
 
 
 
 
 
 
 
 
Safety laboratory tests 
X 
 
 
 
 
 
 
 
 
Insulin administered per home regimen 
 
X 
 
Insulin/Glucagon administration via 
bionic pancreas 
 
 
X 
Standardized diabetic meals 
 
X 
BG check by fingerstick C 
 
X 
BG monitoring by CGMS 
 
X 
BG telemetric monitoring 
 
X 
Prior/Concomitant Medications  
X 
Adverse Event Assessment 
X 
 
A Order of admissions will be determined using a randomized, crossover design. 
B Pregnancy test will be completed for females 11 years of age or older. 
C BG will be checked by fingerstick before each meal, at bedtime, and at least once overnight; episodes of hypoglycaemia will be treated as 
per standard clinical practice with 15 grams of simple carbohydrates and/or glucagon, if necessary. 
D Vital signs will be measured twice daily on these days. Height will only be measured on Study ID Days S.1, C.0, and E.0. Weight will be 
measured on Study ID days S.1, C.0, E.0, and at discharge from each admission.

 
  
 
 
 
1
1 
BACKGROUND INFORMATION AND RATIONALE 
 
Introduction 
Congenital hyperinsulinism is a rare genetic disorder of pancreatic β-cell function 
characterized by dysregulated insulin secretion resulting in severe hypoglycemia that can 
cause brain damage or death if inadequately controlled. The estimated incidence of HI in the 
United States is 1 per 50,000 live births1. While HI can be managed with medication or a 
focal resection of affected pancreatic tissue in some patients, the most severe cases require a 
near-total pancreatectomy to control hypoglycemia.  
After near-total pancreatectomy, the frequency of diabetes increases over time with 91% of 
children diagnosed with diabetes before puberty2. There are significant differences between 
individuals with typical T1D and individuals with HI and post-pancreatectomy diabetes that 
require special emphasis. The slow evolution of diabetes post-pancreatectomy is 
characterized by marked hypo- and hyper-glycemia, resulting from dysregulated insulin 
secretion from the remaining pancreatic tissue and from glucagon deficiency. Furthermore, 
exocrine pancreatic dysfunction can affect absorption and result in unpredictable 
fluctuations in blood glucose concentrations. Current treatment approaches with intermittent 
subcutaneous insulin administration or insulin pump therapy offer inadequate glycemic 
control in these individuals. 
 
Name and Description of Investigational Product or Intervention 
Bihormonal Bionic Pancreas (BP) System: Our collaborators from Boston University and 
Massachusetts General Hospital have developed an autonomous, self-learning BP that 
requires only the subject's weight for initialization, and then autonomously adapts, modestly 
or dramatically, as needed, to cope with the wide range of insulin requirements of adults, 
adolescents, and pre-adolescents with diabetes.  The BP removes the need for the patient to 
know, or even appreciate, their insulin requirements, and does not require patients or 
caregivers to know carbohydrate-to-insulin ratios, basal rates, or insulin correction factors. 
The Bionic-Pancreas Glycemic-Control System, referred to as the bihormonal bionic 
pancreas, has been shown to improve glycemic control and to reduce the frequency of 
hypoglycemia in children and adults with T1D3–6. Insulin and glucagon are administered by 
a fully automated, bihormonal, bionic pancreas with the use of control algorithms that adapt 
to changes in insulin/glucagon requirements. The device consists of an iPhone®, which runs 
the control algorithm, and a Dexcom® continuous glucose monitor system (CGMS) 
connected by a custom software interface. Insulin and glucagon are administered 
subcutaneously by a Tandem® t:slim™ infusion pump, which are controlled wirelessly by 
the iPhone®.  
The core technology is the insulin controller, which orchestrates all subcutaneous (SC) 
insulin dosing. At its centerpiece is a model-predictive control algorithm, which bases 
insulin doses on the glucose data and insulin absorption kinetics. Our collaborators were the 
first to incorporate insulin pharmacokinetics (PK) into the algorithm, by augmenting it with 
a mathematical formulation for estimating the concentration of insulin in the blood and 
predicting its future concentration. It is essential to compensate for the slow absorption rate 

 
  
 
 
 
2
of SC insulin analogs (peak time in blood of 30-90 min, clearance in 4-8 hr), and to enable 
the algorithm to refrain from stacking and overdosing insulin.  Furthermore, the model 
predictive control algorithm automatically adjusts its insulin-dosing aggressiveness 
continuously and in real-time to different insulin needs between individuals and variable 
needs within the same individual.  Running in parallel with the model predictive control 
algorithm is an algorithm that automatically modulates basal insulin delivery over multiple 
time scales, and another algorithm that automatically adapts insulin doses in response to 
optional meal announcements.   
Unlike current insulin pumps, and all insulin-only control algorithms of which we are aware, 
the adaptive basal insulin algorithm does not require the user to set, or even know, his or her 
“basal-rate profile.”  Instead, it is capable of automatically adapting to, and compensating 
for, changes in an individual's basal insulin need, such as might occur over a period of hours, 
days, or weeks (e.g. circadian hormonal fluctuations, intercurrent illness, physical activity, 
or emotional state) or as might occur over a period of months or years due to developmental 
changes (e.g. hormonal changes that occur during puberty or menopause).  
Additionally, the adaptive meal dose controller does not require the user to set, or even 
know, his or her “carbohydrate-to-insulin ratios,” as it makes automatic adjustments based 
on dosing history for similar meal announcements made on previous days, and customizes 
the dose for each individual and for time of day. The BP also includes a proportional-
derivative algorithm governing SC micro-doses of glucagon to help prevent impending 
hypoglycemia. Glucagon dosing is based on the glucose level and rate of descent. It could 
occur preemptively even if glucose is above range and it includes a feedback term to account 
for the pending effects of recent glucagon doses.  
Taken together, these mathematical algorithms provide a universal framework for a 
glycemic control strategy that requires no quantitative input from, or participation by, the 
user (besides entering body weight to initialize the system), but which automatically adapts 
insulin and glucagon dosing to meet the individual needs of each user.  Another challenge 
the developers of the BP have met is enabling the technology to remain completely 
autonomous in managing insulin and glucagon delivery even when the Dexcom® CGMS is 
offline. Specifically, when the Dexcom® CGMS is offline, the BP invokes the high-
resolution “basal rate profile'' that it had recently learned and stored when the Dexcom® 
CGMS was online.  Based on what the system learned and stored about meal 
announcements when the Dexcom® CGMS was online, it can respond to meal 
announcements in the same manner when the Dexcom® CGMS is offline.   
Finally, it automatically responds to user-entered BG values when the Dexcom® CGMS is 
offline by issuing a correction dose of insulin or glucagon based on what it learned about the 
user's insulin and glucagon needs when the Dexcom® CGMS was online. Thus, the BP 
never relies on, or burdens the user with, the determination of subjective dosing decisions, 
which inevitably vary in quality and reliability among different users. The BP provides a 
turnkey solution for people with diabetes that comprehensively manages glycemia across a 
broad range of individual needs and a across a large spectrum of circumstances and 
challenges to glycemic control. 

 
  
 
 
 
3
 
Findings from Non-Clinical and Clinical Studies  
 Non-Clinical Studies 
Our collaborators from Boston University and Massachusetts General Hospital (MGH) have 
developed the bihormonal artificial pancreas which was first tested in a swine model of 
T1D7.  Results from these preclinical studies supported further development efforts of the 
bihormonal pancreas to allow for better glycemic control. Our collaborators developed the 
device’s algorithm for insulin and glucagon infusion based on control studies that showed 
that the device was able to achieve near-normal mean BG, therefore demonstrating the 
feasibility of an in vitro bihormonal artificial endocrine pancreas8. 
 Clinical Studies 
1.3.2.1 Development and Summary of Clinical Studies 
The BP hardware platform has evolved over the years from a laptop-driven system, which 
was used in all the inpatient studies (between 2008--2012), to the first truly mobile wearable 
iPhone®-driven platform, which was used in all outpatient studies thus far (between 2013—
2015).  Using the iPhone®-driven BP system, our collaborators have conducted >110 
outpatient experiments of 5-11 days in duration in each subject (> 800 patient days or > 2 
patient years of data), and across subjects ranging in age between 6 and 76 years old and in 
body mass between 21 and 128 kg.  The robust adaptation capabilities of the BP is evident 
in the fact that the average total daily dose of insulin among these subjects varied by over 
13-fold (from 11 to 145 units/day).   
The preclinical studies at Boston University testing the BP in a diabetic swine model of 
T1D8,9 and all of the inpatient clinical trials in the Clinical Research Center at MGH testing 
the BP in adults and adolescents with T1D4,5,10 set the stage for the outpatient studies that 
followed.  In November 2012, our collaborators obtained FDA approval to conduct the first 
outpatient study testing the BP in adults 21 years or older with T1D. This study, which we 
referred to as the Beacon Hill Study, followed a random-order cross-over design in which 20 
adults with T1D participated in 5 days on our iPhone®-based BP and 5 days of usual care in 
which they wore a Dexcom® CGMS with blinded display and muted alarms.  In the BP arm, 
subjects kept to a three-square-mile geographic area centered around the Beacon Hill 
neighborhood in Boston.  They ate as they chose at local restaurants, and exercised at will 
with access to two gyms.  Analysis was pre-specified to focus on Days 2-5, since glycemic 
control is more representative of BP performance after most of the adaptation by the BP 
occurs on Day 111. Results are summarized in the plots and table of Figure 1 (unpublished 
data).  

 
  
 
 
 
4
 
 
Figure 1. Outpatient results summarizing the distribution of mean CGMS glucose levels and 
hypoglycemia in the BP and control arms. Mean CGMS glucose levels for each subject 
under usual care (shown as a red circle on the left) is connected with the subject's mean 
CGMS glucose level on the BP (shown as a black circle on the right). For each subject, the 
circle diameter is proportional to the percentage of CGMS glucose values < 60 mg/dL, and 
the size of the triangle is proportional to the percentage of CGMS glucose values > 180 
mg/dL.  The horizontal red dashed line refers to the glucose level corresponding to the ADA 
therapy goal for each age group tested, which corresponds to 154 mg/dL (HbA1c <7%) for 
adults and 169 mg/dL (HbA1c <7.5%) for children.  Results are summarized in the table 
below, where the co-primary outcomes (mean CGMS glucose level and percentage of 
CGMS glucose values < 60 mg/dL) for the BP are highlighted in red for each of the four 
studies6,11,12. 
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=29, 11-day experiments)
≥*21
142
0.6
78
165
1.6
61
<*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

 
  
 
 
 
5
In April 2013, our collaborators obtained FDA approval to conduct the first outpatient study 
testing the BP in adolescents 12--20 years old with T1D. This study, which we referred to as 
the 2013 Summer Camp Study, followed a random-order cross-over design in which 32 
adolescents with T1D participated in 5 days on the BP and 5 days of supervised camp care 
in which they wore a Dexcom® CGMS with blinded display and muted alarms.  Subjects 
were fully integrated into normal camp activities without restrictions on diet or exercise. The 
study used the same iPhone®-based BP that was used in the Beacon Hill Study.  The mean 
HbA1c of the entire all 32 subjects at baseline (pre-study) was 8.2%, which corresponds to a 
mean BG of 189 mg/dL.  Results are summarized in the plots and table of Figure 111.   
In April 2014, FDA approval was obtained to conduct the first outpatient study testing the 
BP in pre-adolescents 6--11 years old with T1D. This study, which we referred to as the 
2014 Summer Camp Study, was similar in design to the 2013 Summer Camp Study.  Results 
are summarized in the plots and table of Figure 1. In April 2014, FDA approval was 
obtained to conduct the first multi-center study, which was also the first home study, to test 
the BP in adults 18 years or older with T1D. This study, which we referred to as the Bionic 
Pancreas Multi-Center study, followed a random-order cross-over design in which 39 adults 
participated in 11 days on the BP and 11 days of usual care. Participants went to work as 
usual, and lived and slept at home, all without clinical supervision.  There were no 
restrictions placed on diet or exercise. The study included four medical centers (10 subjects 
per center), which included MGH, the University of Massachusetts Medical School, 
Stanford University, and the University of North Carolina at Chapel Hill.  
Preliminary results from an interim analysis of a subset of the data from the Bionic Pancreas 
Multi-Center study are summarized in the plots and table of Figure 1. 
1.3.2.2 Clinical Studies in Adolescents and Adults 
Twenty adults and 32 adolescents with T1D participated in a cross-over study comparing 
standard care (insulin pump) with a bihormonal bionic pancreas. Mean glucose was 
approximately 20 mg/dL lower in both adolescents and adults when using the bihormonal 
artificial pancreas. There was also a reduction in the percentage of time spent with 
hypoglycemia and the number of interventions required for hypoglycemia4 (Figure 1). 
1.3.2.3 Clinical Studies in Children 
The safety and efficacy of the bihormonal bionic pancreas was also demonstrated in children 
age 6-11 years old with T1D. This study was conducted in a summer camp setting and the 
design was similar to the adolescent and adult studies. The use of the bionic pancreas was 
associated with a lower mean CGMS-measured glucose compared to standard pump therapy 
(137±11mg/dL vs. 167±31mg/dL p=0.00037) and a lower proportion of time with a CGMS-
measured glucose concentration below 60 mg/dL (1.2±1.1% vs. 2.8±1.2% p<0.0001)6 
(Figure 1). 
 
Relevant Literature and Data 
Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in 
children, which can result in permanent brain damage11. For some infants with severe HI, 
medical treatment is not effective in controlling hypoglycemia, and pancreatectomy is 

 
  
 
 
 
6
necessary13. After near-total pancreatectomy diabetes is common with up to 91% of children 
requiring insulin before puberty2,11. Diabetes following pancreatectomy has unique features 
that make this condition difficult to manage. Unlike T1D, individuals with HI and post-
pancreatectomy diabetes have residual endogenous insulin secretion that is dysregulated in 
addition to glucagon deficiency14. Thus, the evolution of diabetes post-pancreatectomy is 
characterized by marked hypo- and hyper-glycemia. Furthermore, exocrine pancreatic 
insufficiency can affect absorption and result in unpredictable fluctuations in plasma glucose 
concentrations.  
Current treatment approaches with intermittent subcutaneous insulin administration or 
insulin pump therapy offer inadequate glycemic control in these individuals. We propose a 
novel approach to the management of post-pancreatectomy diabetes with the “bionic 
pancreas” to replace insulin and glucagon through an automated glycemic management 
system. The bihormonal artificial pancreas has been shown to reduce hypoglycemia and 
improve glycemic control in T1D3,4,6. This consists of a continuous glucose monitoring 
system (CGMS) paired with a pump that can administer glucagon and insulin in response to 
blood glucose concentrations11. In collaboration with the Bionic Pancreas project team, we 
propose to evaluate the efficacy and safety of the bihormonal bionic pancreas in individuals 
with HI and post-pancreatectomy diabetes. Our hypothesis is that the bihormonal bionic 
pancreas will result in improved glycemic control in these individuals.  
 
Compliance Statement 
This study will be conducted in full accordance all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws and 
regulations including 45 CFR 46; 21 CFR Parts 50, 54, 56, 312, 314 and 812; and the Good 
Clinical Practice: Consolidated Guideline approved by the International Conference on 
Harmonization (ICH). All episodes of noncompliance will be documented. 
The investigators will perform the study in accordance with ICH guidelines and this 
protocol, will obtain consent and assent, and will report unanticipated problems involving 
risks to subjects or others in accordance with The Children’s Hospital of Philadelphia IRB 
Policies and Procedures and all federal requirements. Collection, recording, and reporting of 
data will be accurate and will ensure the privacy, health, and welfare of research subjects 
during and after the study.  
2 
STUDY OBJECTIVES 
This is a pilot study to determine the efficacy and safety of a bihormonal bionic pancreas for 
the treatment of post-pancreatectomy diabetes in individuals with congenital 
hyperinsulinism. 
 
Study Rationale 
As discussed above, all experiments with the bihormonal bionic pancreas to date in human 
subjects with T1D have demonstrated the practicality of a wearable automated, bionic 
pancreas control system for robust glucose regulation using continuous glucose monitoring 
devices as input to the controller. These studies have shown that a bihormonal bionic 
endocrine pancreas is capable of achieving good glycemic control automatically with 

 
  
 
 
 
7
minimal hypoglycemia during the study in the face of unrestrained meals and exercise and 
with trivial patient input (optional announcement of meals). Additionally, the system spares 
the wearer the relentless tasks of carbohydrate counting, frequent blood glucose monitoring, 
estimating the effects of specific meals and exercise activity on blood glucose levels, and 
manual drug administration, which are inexact, demanding, aggravating, and require 
continuous diligence and vigilance. The degree of glycemic control achieved is predicted to 
dramatically reduce the deleterious and debilitating complications of diabetes. Moreover, a 
consistent finding in all of the bionic pancreas (BP) studies has been a reduction in 
hypoglycemia despite lower mean plasma glucose concentrations, relative to usual care. The 
potential of reducing episodes of hypoglycemia while achieving good glycemic control, 
during exercise and independent of meals is particularly important for individuals with 
hyperinsulinism and post-pancreatectomy diabetes.  
The current study is designed to determine the efficacy of the bihormonal bionic pancreas on 
achieving glycemic control and reducing hypoglycemia in individuals with hyperinsulinism 
and post-pancreatectomy diabetes.  
 
Primary Objective (or Aim) 
To determine if the bihormonal bionic pancreas improves glycemic control in individuals 
with HI and post-pancreatectomy diabetes. We hypothesize that, when compared with 
current standard diabetes care, the bihormonal bionic pancreas will reduce: (1) the mean 
glucose concentration, and (2) the fraction of time with glucose concentrations < 60 mg/dL.  
 
Secondary Objectives (or Aim) 
The secondary objective is to evaluate the safety of the bihormonal bionic pancreas in 
individuals with HI and post-pancreatectomy diabetes. We hypothesize that the bionic 
pancreas will be sufficiently well tolerated to permit continued clinical investigation in 
individuals with HI and post-pancreatectomy diabetes based on an assessment of clinical 
adverse events. 
3 
INVESTIGATIONAL PLAN 
 
General Schema of Study Design 
This will be an open-label, pilot clinical trial to assess efficacy and safety of the bihormonal 
bionic pancreas in individuals with HI and post-pancreatectomy diabetes. Subjects will be 
studied during two research inpatient admissions at the CHOP Congenital HI Center.  
 
 
 
 
 

 
  
 
 
 
8
Figure 2: General Schema of Study Design 
 
 Screening Phase 
Potential subjects will be screened using the protocol inclusion and exclusion criteria.  
Individuals with HI and post-pancreatectomy diabetes will be recruited from the CHOP 
Congenital Hyperinsulinism Center.  
Parental/guardian permission (informed consent) and, if applicable, child assent, will be 
obtained prior to any study related procedures being performed.   
Medical records will be reviewed to determine eligibility. Medical history, physical 
examination, CBC, CMP, and hemoglobin A1c will be obtained during this visit after 
informed consent. Blood samples will be drawn to confirm eligibility based on clinical 
laboratory parameters.  Females  11 years of age will have a urine pregnancy test. 
The order of admissions will be determined based upon a randomized, crossover design with 
at least one week between admissions. 
 Standard Care Admission 
Standard Care Admission: A 4-day inpatient admission in which subjects will continue their 
home insulin regimen. The first day will constitute a run-in period where no changes will be 
made to the participant’s home regimen.  Plasma glucose data from scheduled fingersticks 
and from CGMS will be collected throughout the admission. Data for analysis will be 
limited to data collected during the last 3 days. 
 Bihormonal Bionic Pancreas Admission 
Bihormonal Bionic Pancreas Admission: The BP will be placed on the subject upon 
admission and there will be 1-day run-in period to allow for transition to the bionic pancreas 
system. Plasma glucose data from scheduled fingersticks and from CGMS will be collected 
throughout the admission. Data for analysis will be limited to data collected during the last 3 
days. Following this, the patient will transition back to their home regimen and will be 
discharged home. 

 
  
 
 
 
9
 
Allocation to Treatment Groups and Blinding 
Because this is an open-label, pilot clinical trial, all subjects will receive study intervention 
(application of the bihormonal bionic pancreas).  No blinding will be pursued in this study. 
 
Study Duration, Enrollment and Number of Sites 
 Duration of Study Participation 
We anticipate most participants will complete the study in 8 days plus 1 hour for Screening. 
This consists of three phases: (1) 1 hour for Screening; (2) 4 days for Standard Care 
Admission; and (3) 4 days for Bihormonal Bionic Pancreas Admission. The Bihormonal 
Bionic Pancreas Admission may be slightly longer for subjects who require additional time 
to transition back to their home regimen but, as stated, we do not anticipate this to be the 
case in most subjects. 
 Total Number of Subjects Projected 
It is expected that approximately 12 subjects will be enrolled to produce 10 evaluable 
subjects.  
 Total Number of Sites 
The entirety of this research study will be conducted at one site, The Children’s Hospital of 
Philadelphia. 
 
Study Population 
Our study population will adhere to the following inclusion and exclusion criteria. 
 Inclusion Criteria 
1) Males or females age 6 to 30 years.   
2) Diagnosis of hyperinsulinism.  
3) Previous pancreatectomy. 
4) Diabetes confirmed by one or more of the following: 
a) Glycosylated A1c > 6.4%. 
b) Fasting glucose > 125 mg/dL. 
c) 2-hour post-prandial glucose > 200 mg/dL. 
d) Random glucose > 200 mg/dL with symptomatic hyperglycemia. 
5) On insulin therapy with a regimen of at least 11 units/day. 
6) Treatment with subcutaneous insulin by pump at the time of recruitment. 
7) Prescription medication regimen stable for > 1 month (except for medications that will 
not affect the safety of the study and are not expected to affect any outcome of the study, 

 
  
 
 
 
10
in the judgment of the site PI). 
 
8) Females  11 years of age must have a negative urine/serum pregnancy test and must use 
an acceptable method of contraception, including abstinence, a barrier method 
(diaphragm or condom), Depo-Provera, or an oral contraceptive, for the duration of the 
study. 
9) Parental/guardian permission (informed consent) and if appropriate, child assent. 
No subjects will be excluded based on gender or race. The requirement that subjects manage 
their diabetes using subcutaneous insulin infusion pump therapy is imposed because 
multiple daily injection therapy involves the use of medium-acting or long-acting basal 
insulin that would require an extended washout period.  
 Exclusion Criteria 
1) Unable to provide informed consent (e.g. impaired cognition or judgment). 
2) Evidence of a medical condition that might alter results or compromise the interpretation 
of results, including active infection, kidney failure, severe liver dysfunction, severe 
respiratory or cardiac failure. 
3) Evidence of severe hematologic abnormality including severe anemia and/or 
thrombocytopenia. 
4) Electrically powered implants (e.g. cochlear implants, neurostimulators) that might be 
susceptible to radio frequency interference. 
 
5) Unable to completely avoid acetaminophen for duration of study. 
6) History of adverse reaction to glucagon (including allergy) besides nausea and vomiting. 
 
7) Established history of allergy or severe reaction to adhesive or tape that must be used in 
the study. 
8) Use oral (e.g. thiazolidinediones, biguanides, sulfonylureas, glitinides, DPP-4 inhibitors, 
SGLT-2 inhibitors) anti-diabetic medications. 
9) Any investigational drug use within 30 days prior to enrollment.  
10) Pregnant or lactating females.  
11) History of more than one episode of DKA and/or severe hypoglycemia within the six 
months prior to study enrollment. 
12) Current history of sub-optimally treated nausea and/or vomiting. 
13) Parents/guardians or subjects who, in the opinion of the Investigator, may be non-
compliant with study schedules or procedures. 

 
  
 
 
 
11
14) Current and sustained use of insulin formulation (delivered via pump) not 
approved/advised to be used in the Tandem t:slim pump. 
Subjects that do not meet all the enrollment criteria may not be enrolled. Any violations of 
these criteria must be reported in accordance with IRB Policies and Procedures.  
4 
STUDY PROCEDURES 
Table 1: Schedule of Study Procedures (page x) provides a tabular view of the following 
information.  
 
Recruitment Procedures 
A study staff member will review the potential subject’s medical health record to determine 
eligibility for the study based upon inclusion/exclusion criteria.  When identified, the 
prospective participants and designated contacts will be briefed by a study staff member by 
phone, email, or during clinic visits regarding the study procedure and the inclusion and 
exclusion criteria. Subjects may also be informed about the study by internal and external 
recruitment methods (i.e., CHOP Congenital Hyperinsulinism Center newsletter, Congenital 
Hyperinsulinism International newsletter, Pediatric Endocrine Society newsletter). Potential 
subjects and contacts will be sent an informed consent document by mail, fax, or email, or 
will be given the consent form during their clinic visit.  
 
Consent Procedures 
Once potential subjects and/or parents/guardians have had time to review the consent 
document, they will speak with a study physician who can further explain the study and 
answer any questions the subject and/or parent/guardian may have. The subject will then 
complete the informed consent process with a study physician, should the subject desire to 
participate in the study. Study staff will answer any questions that the subjects may have 
during their participation. They will share any new information in a timely manner that may 
be relevant to the subject's willingness to continue participating in the trial. The subjects 
and/or parents/guardians may choose to discontinue their participation at any time without 
prejudice.  
 
Experimental Procedures and Data Collection 
 Screening Visit 
 After informed consent is obtained, all subjects will have a screening visit to confirm 
eligibility.  
 The subject will be interviewed and the case report form will be completed by study 
staff to establish whether the subject is eligible to continue with the screening 
according to inclusion/exclusion criteria, in the event the medical record review 
provided outdated data.   
 Demographic/medical history data to be recorded: 
o Age 
o Sex 
o Race and ethnicity 

 
  
 
 
 
12
o Date of HI diagnosis 
o Date of pancreatectomy and percentage removed 
o Date of diabetes diagnosis/insulin initiation 
o Medical, surgical, and social history, allergies, and review of systems relevant 
to inclusion and exclusion criteria 
o Medications (prescription and non-prescription)  
o Duration of insulin pump use 
o Type of insulin used in pump 
o Average total daily dose of insulin in the last 30 days (from pump history, as 
available – for comparison with insulin dosing during the standard care and 
bionic pancreas arms of the study) 
o Usage of CGMS, if any (type of CGMS, days per month worn, usage of data, 
whether insulin is dosed based on CGMS alone, alarm settings) 
o Physical examination 
o Vital Signs: height, weight, temperature, blood pressure, heart rate, respiratory 
rate 
o Pregnancy test (for female subjects 11 years and older) 
o Safety laboratory tests: CBC, CMP, hemoglobin A1c 
 Once all the laboratory results have been returned, a study physician will review the 
case report form to determine subject eligibility to continue in the study. If subjects 
are not eligible to continue in the study, the results of abnormal tests will be reported 
to the subjects.  
 Subjects who have been screened and are eligible can participate without having to 
be rescreened for a period of one year. The study staff should obtain verbal 
confirmation that there have been no health events that would make them ineligible 
if the interval between screening and participation is longer than 3 months.  
 Upon confirmation of eligibility and participant’s willingness to continue, subjects 
will be assigned to an order of admissions based upon a randomized, crossover 
design. There will be a minimum of 1 week time between admissions. 
 Pediatric subjects will be required to have a parent or guardian accompanying them 
during the inpatient admissions. 
 
 
Standard Care Admission 
A 4-day inpatient admission in which subjects will continue their home insulin regimen. 
Blood glucose data will be collected from finger-stick and from CGMS during the study.  
 Run-in period (Day 0) 
o Medical history 
o Prior/concomitant medications 
o Vital signs: height, weight, temperature, blood pressure, heart rate, 
respiratory rate 
o Standardized diabetic diet  
o Insulin administered via insulin pump per home regimen 
o Placement of Dexcom® CGMS for BG monitoring 

 
  
 
 
 
13
o Blood glucose check by finger-stick before breakfast, before lunch, before 
dinner, at bedtime, and at 03:00am.  PRN blood glucose checks may occur at 
the discretion of the study physician(s) 
o Initiation of telemetric monitoring of CGMS connectivity 
o Adverse event monitoring 
 Days 1-3 
o Vital signs: temperature, blood pressure, heart rate, respiratory rate every 12 
hours (appx.) 
o Standardized diabetic diet 
o Insulin administered via insulin pump per home regimen. Subjects will be 
asked to change their insulin infusion set and reservoir at least every two 
days, just as they will during the bionic pancreas arm 
o Study staff confirms CGMS is running 
o Dexcom® calibration twice daily (before breakfast and dinner). Calibration 
will be delayed if there is a steep rise or fall in the blood glucose or if there 
has been carbohydrate intake in the last 30 minutes. If a calibration is delayed 
for any of these reasons, it will be performed at the next opportunity. 
o Blood glucose check by finger-stick before breakfast, before lunch, before 
dinner, at bedtime, and at 03:00am.  PRN blood glucose checks may occur at 
the discretion of the study physician(s) 
o Telemetric monitoring of CGMS connectivity 
o Adverse event monitoring 
 Discharge 
Subjects will be discharged on the fourth day of the admission. 
 
Bihormonal Bionic Pancreas Admission 
Study staff at CHOP will undergo thorough in-person training on all functions of the Bionic 
Pancreas System by the device’s developers from Massachusetts General Hospital. Briefly, 
this training will constitute application and removal of the BP to a human subject, operating 
and overseeing the BP system daily functioning, filling and priming the pumps, 
understanding the information and settings on the BP’s display screen, using the meal bolus 
feature, and troubleshooting of expected and unexpected issues. Our colleagues at 
Massachusetts General Hospital will be available throughout the study to respond to 
questions, concerns, and comments.   
The bihormonal pancreas will be placed upon admission and there will be 1 day run-in 
period. This will be followed by 3 days of data collection for comparison with the data 
obtained from the standard of care during the Control Admission. Following this, the patient 
will transition back to their home regimen and will be discharged home.  
 Run-in Period (Day 0): 
o Medical history 
o Prior/concomitant medications 
o Vital signs: height, weight, temperature, blood pressure, heart rate, 
respiratory rate 

 
  
 
 
 
14
o Standardized diabetic diet 
o Insulin administered via insulin pump per home regimen until transition to 
the BP 
o Placement of Dexcom® CGMS for BG monitoring 
o Blood glucose check by finger-stick before breakfast, before lunch, before 
dinner, at bedtime, and at 03:00am.  PRN blood glucose checks may occur at 
the discretion of the study physician(s). 
o Initiation of telemetric monitoring of CGMS connectivity 
o The study staff will place the two infusion sets, fill and prime one Tandem® 
t:slim™ pump with insulin and one Tandem® t:slim™ pump with glucagon 
and label all pieces appropriately 
o The control algorithm will be initialized only with the subject weight 
o Diagnostics will be performed to ensure that the CGMS device is 
appropriately calibrated and that all of the components of the bionic pancreas 
(Dexcom® G5® Platinum AP, iPhone® running the control algorithm, 
Tandem® t:slim™ infusion pumps) are in good communication with each 
other 
o The subject's own insulin infusion pump will be stopped and disconnected, 
and its infusion set will be removed 
o The staff will start the bionic pancreas as close as possible to a minute 
divisible by 5 minutes (i.e. on a 5-minute mark) and before 4:00 PM.   
o We will initiate bionic pancreas control with a glucose target of 110 mg/dL to 
130 mg/dL, according to the Investigator’s discretion. Study physician(s) 
reserve the right to adjust the subjects’ glucose targets to a value between 110 
mg/dL and 140 mg/dL (inclusive), according to Investigator’s discretion.  
 
 Days 1-3 
o Vital signs: temperature, blood pressure, heart rate, respiratory rate twice 
daily 
o Standardized diabetic diet 
o Study staff confirms CGMS is running 
o Blood glucose check by finger-stick before breakfast, before lunch, before 
dinner, at bedtime, and at 03:00am.  PRN blood glucose checks may occur at 
the discretion of the study physician(s). 
o CGMS calibration twice daily (before breakfast and dinner). Calibration will 
be delayed if there is a steep rise or fall in the blood glucose (>2 mg/dL/min), 
there has been carbohydrate intake in the last 30 minutes, or there has been a 
glucagon dose in the last 15 minutes. In the immediate aftermath of 
carbohydrate intake or glucagon dosing it is possible for BG to be rising 
without a change in interstitial fluid glucose. If a calibration is delayed for 
any of these reasons, it will be performed at the next opportunity. Additional 
calibrations may be performed if the CGMS is inaccurate relative to a BG 
measurement as long as it is not calibrated within 30 minutes of food intake 
or 15 minutes of glucagon dosing. Extra calibrating will not be performed if 
the CGMS is within 15 mg/dL when the BG is ≤ 75 mg/dL and within 20% if 
the BG is >75 mg/dL at times when the rate of change is low.  

 
  
 
 
 
15
o Telemetric monitoring of CGMS connectivity. Alarms will sound if the 
CGMS glucose is less than 50 mg/dL. The first step for all glucose-related 
alarms will be to perform a fingerstick BG measurement. If the BG 
measurement is not consistent with the fact that a threshold alarm has 
occurred:  
 The staff will assess the possibility of a compression artifact. If a 
compression artifact is suspected, steps to relieve the pressure on the 
transmitter will be taken. If no compression is suspected, the CGMS 
will be calibrated as long as there has been no carbohydrate intake in 
the last 30 minutes, no glucagon dosing in the last 15 minutes, and 
there is no steep rise or fall in glucose (>2 mg/dL/min). If a 
calibration is delayed for this reason, it will be performed at the next 
opportunity.  
 If the BG measurement is consistent with a low threshold alarm, the 
hypoglycemia will be treated with carbohydrate ingestion according 
to the usual practice. The staff will investigate the glucagon infusion 
set and consider replacing it.  
 The first step in responding to hyperglycemia according to the CGMS 
will be to perform a fingerstick BG measurement. If the BG 
measurement is not consistent with the CGMS, the CGMS will be 
calibrated as long as there has been no carbohydrate intake in the last 
30 minutes and there is no steep rise or fall in glucose (>2 
mg/dL/min). If a calibration is delayed for this reason, it will be 
performed at the next opportunity. If the BG measurement is 
consistent with the CGMS, the insulin infusion site will be 
investigated and replacement will be considered.  
o If there is a complete failure of bionic pancreas operation and it is anticipated 
that restarting it will take more than an hour, subjects may take over their 
own BG control using their own insulin pump or with insulin injections until 
the bionic pancreas can be brought back online with the help of study staff. 
During the day, this should be rare. If the failure occurs at night, every effort 
should be made to correct the problem as soon as possible, which should 
almost always be possible within 12 hours. 
o If a CGMS sensor fails during the course of an experiment, the system will 
provide basal insulin based on past requirements and will allow 
announcement of meals and entry of fingerstick BG measurements, which 
will be treated as CGMS data and may result in administration of insulin 
and/or glucagon. The CGMS sensor will be replaced as soon as possible and 
normal bionic pancreas control will resume when the new sensors is 
calibrated. 
o Subjects will be asked to announce the three major meals of the day, but not 
snacks, to the bionic pancreas. The meal announcement will consist of 
choosing the type of meal (breakfast, lunch, dinner) and the size of the meal 
relative to typical meals for that subject (snack, smaller than typical, typical, 
larger than typical). 
o The insulin infusion set and reservoir will be changed at least every two days. 

 
  
 
 
 
16
o The glucagon reservoir will be replaced every day. Each reservoir will be 
filled with two vials of freshly reconstituted Lilly glucagon. The glucagon 
infusion set will be changed daily with the reservoir change. 
o On days when both the insulin and glucagon reservoirs will be changed, they 
will be changed at different times in the day, separated by at least one hour. 
The infusion sets and tubing will be labeled to avoid confusion or cross 
connection.  
o All episodes of hypoglycemia, carbohydrate interventions, any nausea and/or 
vomiting, any other adverse events, time spent exercising, and any 
unscheduled infusion set changes, alcohol use, etc. will be recorded. 
o Adverse event monitoring. 
o At the end of the 4-day period, subjects will return the bionic pancreas. 
 Discharge 
o Bionic pancreas will be disconnected and the subject will be asked to connect 
and initiate home insulin pump. 
o Meters and the bionic pancreas will be downloaded. 
o The body weight of the subject will be documented. 
o Physical exam prior to hospital discharge. 
o Subjects will be discharged on the fourth day or afterward if the subject 
requires additional time to transition back to his/her home regimen. Prior to 
discharge, subjects must have a recent history and glucose trajectory that is 
sufficiently stable for safe discharge in the judgment of a study provider.  
 
 
Standardized Meals 
Standardized meals will be provided on all inpatient admission study days. A bio-nutritionist 
will speak with each participant to develop a meal plan during the inpatient admissions. All 
efforts will be made to have daily meals identical across admissions; in that, the same 4-day 
meal plan will be used for both admissions.  All subjects will receive standard diabetic diets 
with meals containing the range of carbohydrates that constitute the subjects typical amount 
of carbohydrates for each meal type and size (e.g., 50-60 g of carbohydrates for breakfast, 
etc.). Subjects will be asked to try to consume their meal as much as possible.   
 
Physical Activity 
This study will take place in the inpatient setting; therefore subjects will not be engaging in 
any significant physical activity (aerobic or anaerobic) but will be allowed to ambulate 
within the hospital boundaries. 
 
Prior and Concomitant Medication 
All prior and concomitant medications used within 1 week prior to the screening visit and 
through the end of the study will be recorded. The dates of administration, dosage, and 
reason for use will be included.  

 
  
 
 
 
17
 
Rescue Medication Administration 
 Response to Hypoglycemia 
 BG will be checked for any symptoms of hypoglycemia.  
 Hypoglycemia will be treated according to standard of practice according to the “rule 
of 15s”: take 15 grams of rapid acting carbohydrate and recheck in 15 minutes, then 
repeat as needed. For severe episodes of hypoglycemia that are not responsive to 
carbohydrate ingestion or if the subject cannot drink/eat, 1 mg of glucagon 
subcutaneously or intramuscularly will be administrated as necessary. 
 During the bionic pancreas admission the glucagon infusion site and the bionic 
pancreas will be checked for normal operation any time hypoglycemia occurs. If 
there is any suspicion of glucagon infusion set malfunction, the site will be replaced. 
 If a subject experiences a seizure or unconsciousness associated with hypoglycemia, 
his or her participation in the study will be discontinued. 
 
 Response to Hyperglycemia 
 Beta hydroxybutyrate will be collected and recorded when BG is > 240 mg/dL. 
 The insulin infusion site and the pump or bionic pancreas will be checked for normal 
operation any time BG is greater than 300 mg/dL. If there is any suspicion of insulin 
infusion set malfunction, the site will be replaced.  
 If no correctable fault is found, but there is doubt regarding the correct function of 
the bionic pancreas system, an entirely new backup bionic pancreas system will be 
used. 
 If a subject experiences diabetic ketoacidosis, his or her participation in the study 
will be discontinued. 
 
 Response to Nausea/Vomiting  
If significant nausea or vomiting occurs during the bionic pancreas study the study staff will 
troubleshoot, such as checking the calibration of the CGMS (excessive glucagon dosing may 
occur if the CGMS is reading lower than the true blood glucose).  If a subject experiences 
persistent nausea and vomiting thought to be related to glucagon dosing, his or her 
participation in the study will be discontinued. 
 Monitoring of Bionic Pancreas Performance 
The Bionic Pancreas team will be readily available by phone for consultation at all times 
during the course of each experiment. They will have the capability of viewing diagnostic 
information regarding the connection of the CGMS with the bionic pancreas, the functioning 
of the bionic pancreas, and the connection of the bionic pancreas with the insulin and 
glucagon pumps remotely during the experiment, in order to monitor and assist in any 
needed troubleshooting. The connection will be secure and password protected, and will be 
set up so that only viewing of the screen is possible - no input or changes to the controller 
can be made remotely.  

 
  
 
 
 
18
 Supervision by Study Staff 
A study physician (MD or NP) will be on call at all times during the course of each 
experiment. All trained staff will have the capability of remotely viewing diagnostic 
information on an iPhone® or iPad® to facilitate phone troubleshooting and decide about 
whether additional assistance is needed. 
 Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They 
may also be discontinued from the study at the discretion of the Investigator for lack of 
adherence to study treatment or visit schedules, AEs, or SAEs.  The Investigator may also 
withdraw subjects who violate the study plan, or to protect the subject for reasons of safety 
or for administrative reasons.  It will be documented whether or not each subject completes 
the clinical study. If the Investigator becomes aware of any serious, related adverse events 
after the subject completes or withdraws from the study, they will be recorded in the source 
documents and on the CRF. When a subject discontinues/withdraws prior to study 
completion, the study staff reserves the right to analyze data from studies completed prior to 
withdrawal. 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
Adverse events and concomitant medication use will be monitored continuously throughout 
subject confinement. Procedures should be performed as close to the scheduled time as 
possible, and in all cases the actual time of the procedure will be accurately recorded. 
 
Screening and Monitoring Evaluations and Measurements 
 Medical Record Review  
Medical history will be recorded at Screening and will include full HI and diabetes history 
and history of all other significant conditions for the previous 10 years. Data that will be 
collected includes: 
 Date of birth 
 Sex 
 Race and ethnicity 
 Data of last menstrual period for female volunteers 
 Date of HI diagnosis 
 Date of pancreatectomy 
 Date of diabetes diagnosis/insulin initiation 
 Medical, surgical, and social history, allergies, and review of systems relevant to 
confirmation of inclusion and exclusion criteria (i.e., date of pancreatectomy) 
 Medications (prescription and non-prescription) and date of last change in 
medication regimen 
 Duration of insulin pump use 
 Insulin regimen (basal rate, sensitivity factor, and carbohydrate ratio) 
 Average total daily dose of insulin in the last 30, 60, and 90 days as available (from 
pump history) 

 
  
 
 
 
19
 Usage of CGMS, if any (type of CGMS, days per month worn, usage of data, 
whether insulin is dosed based on CGMS alone, alarm settings) 
 History of insulin types used (beef insulin, pork insulin, regular human insulin, NPH 
insulin, ultralente insulin, insulin aspart, insulin lispro, insulin glulisine, insulin 
detemir, insulin glargine) 
 Average number of BG tests daily in the last 30, 60, and 90 days as available (from 
meter download – if more than on meter is used all will be downloaded) 
 Dietary patterns (estimation of daily carbohydrate and calorie intake) 
 Results from any previous imaging studies of relevance 
 Results from previous HI tests 
 Previous hemoglobin A1c results 
 
 Physical Examination 
All physical examinations include, at a minimum, assessment of the following systems: skin, 
head, ears, eyes, nose and throat, respiratory system, cardiovascular system, gastrointestinal 
system, neurological condition, blood and lymphatic systems, and the musculoskeletal 
system. 
A licensed physician or nurse practitioner (or equivalent) will examine each subject. 
Physical examination may be performed at various unscheduled time points if deemed 
necessary by the Investigator. 
 Vital Signs 
Body height will be measured in centimeters (cm) via standiometer.  Body weight will be 
measured in kilograms (kg) with a step-on scale. Vital signs include body temperature 
(measured in ˚C with an automated device), respiratory rate (measured manually while 
subject is seated and relaxed), blood pressure (measured with an automated device on the 
subject’s upper arm while subject is seated and relaxed), and heart rate (measured manually 
by qualified personnel or by an automated machine). 
Vital signs may be measured at unscheduled time points, if deemed necessary by the 
Investigator. 
 Laboratory Evaluations 
Blood sampling will be performed for the following laboratory evaluations 
 Hematology 
 Chemistry profile 
 Hemoglobin A1c 
5.1.4.1 Table: Clinical Laboratory Tests 
Category 
Tests 
Hematology 
RBC, hemoglobin, hematocrit, platelet count, WBC  
Liver function tests 
SGOT/AST, SGPT/ALT, total Bilirubin 

 
  
 
 
 
20
Renal function tests 
Other 
BUN, creatinine 
Hemoglobin A1c 
5.1.4.2 Pregnancy Testing 
A urine pregnancy test will be performed for female subjects  11 years of age and girls <11 
years who are physically capable of becoming pregnant. 
 
Efficacy Evaluations 
See section 6.5.2 Efficacy Analysis.  
 
Safety Evaluation 
Subject safety will be monitored by adverse events, vital signs, physical examinations, and 
laboratory data.  Additionally, see sections 4.8 Prior and Concomitant Medications through 
4.12 Subject Completion/Withdrawal.  
6 
STATISTICAL CONSIDERATIONS 
All analytical data will be collected and stored on a 21 CFR Part 11 compliant LIMS system. 
The analyses of the data obtained from this study will be conducted by the investigators.  
 
Primary Endpoint 
The co-primary outcomes are (1) mean glucose concentration as measured by the CGMS 
during the final 3 days of each admission, and (2) the mean proportion of time that the 
CGMS-measured glucose concentration was less than 60 mg/dL during the same periods. 
Both metrics will be generated from the Dexcom® CGMS data during the Standard Care 
Admission and the Bihormonal Bionic Pancreas Admission.   
 
Secondary Endpoints 
All following metrics will be generated from the Dexcom® CGMS data during the Control 
and Experimental Admissions. Each of these measures will be calculated for the entire 
period and separately for the daytime and nighttime (based on self-reported sleep time and 
wake times self-reported on daily questionnaire). 
 Mean CGMS  
 Fraction of time spent within each of the following glucose ranges: 
o < 50 mg/dL 
o < 60 mg/dL 
o < 70 mg/dL  
o 70-120 mg/dL 
o 70-180 mg/dL  
o >180 mg/dL 
o >250 mg/dL 
 Percentage of subjects with mean CGMS < 154 mg/dL (estimated average glucose 
corresponding to an A1c of 7%). 
 Percentage of schedule fingerstick checks < 70 mg/dL, < 60 mg/dL, <50 mg/dL. 

 
  
 
 
 
21
 
 
Safety Endpoints 
All of following metrics will be generated during both phases of the study. Each of these 
measures will be calculated for the entire period and, as appropriate, separately for the 
daytime and nighttime. 
 Number of episodes of symptomatic hypoglycemia. 
 Number of carbohydrate interventions for hypoglycemia. 
 Total grams of carbohydrate taken for hypoglycemia. 
 Insulin total daily dose (TDD). 
 Glucagon total daily dose during the bionic pancreas use (TDD). 
 Fraction of time bionic pancreas off-line or not functioning properly (e.g. due to 
system crash, communication problem between CGMS and bionic pancreas, 
communication problem between bionic pancreas and pumps, pump malfunction). 
 Mean daily nausea score (0-10 cm VAS). 
 
 
Exploratory Outcomes 
 CGMS 
 Reliability index, calculated as percent of possible values actually recorded by 
CGMS. 
 CGMS mean absolute relative difference versus time-stamped BG values from meter 
downloads (any other BG values will not be considered). 
 BG 
 Mean number of daily BG measurements downloaded from the subject’s meter. 
 Non-glycemic 
All following metrics will be generated during the bionic pancreas and standard care 
admissions. Each of these measures will be calculated for the entire period and, as 
appropriate, separately for the daytime and nighttime (based on self-reported sleep time and 
wake times self-reported on daily questionnaire). 
 Number of glucagon doses. 
 Mean daily basal insulin dose. 
 Mean daily bolus insulin dose. 
 Number of unscheduled infusion set replacements. 
 Number of unscheduled CGMS sensor changes. 
 List of technical faults associated with the bionic pancreas including cause and 
resolution. 
 
 
Statistical Methods 
Only data from subjects that complete both study periods will be included in the analysis. In 
patients that complete the study, the primary analysis of the designated endpoints will be 
calculated on an intention-to-treat basis, including data from periods when the bionic 
pancreas was not in use, if available (CGMS data may not be available in some failure 

 
  
 
 
 
22
modes). We may also perform secondary, exploratory analyses excluding bionic pancreas 
down-time, since this may better represent the performance possible with a fully integrated 
system. We will calculate percentages, means, standard deviations, and ranges in 
descriptive analyses. We will use paired t-test for comparison of means. In a secondary 
analysis, we will look for any period effect and any interaction between treatment and 
period, although no such interaction is predicted and there is probably insufficient power to 
identify a small interaction. We may, in exploratory analyses, also stratify subjects for 
secondary analyses of the pre-specified endpoints by the following characteristics: sex, age, 
usual care insulin total daily dose, body mass index, A1c, and use of CGMS in usual care.  
The following populations are defined for the analysis and reporting of data.  
 All Subjects as Treated (AST): All subjects who had the bihormonal artificial 
pancreas placed for any period of time. This population will be used for assessment 
of safety and tolerability. 
 Per-Protocol (PP): The set of data generated by subjects who received protocol 
procedures sufficiently to ensure that these data will be likely to exhibit the effects of 
treatment, according to the underlying scientific model. 
 
 Baseline Data  
Descriptive statistics will be used to characterize baseline measures in subjects. 
 Efficacy Analysis 
As a general strategy, continuous endpoints will be summarized using the five-number 
summary (mean, standard deviation, median, minimum, and maximum). Categorical 
endpoints will be summarized using frequency distributions.  
Subgroup analyses may also be performed to further delineate study data. These analyses 
may include t-tests, Wilcoxon rank-sum tests, and Pearson correlation/Spearman correlation 
for continuous measures; for categorical variables, chi-square and Fisher’s exact tests may 
also be performed, as appropriate. 
This is a pilot study to generate data to assess feasibility of study design/procedures and for 
formal sample size estimation for a larger study of the efficacy of the bihormonal bionic 
pancreas in children and adults with hyperinsulinism and post-pancreatectomy diabetes. The 
sample size for this pilot study may be too small to detect statistical significance, however, 
we offer the following plan for analysis of the outcomes for this study.  
Mean CGMS-measured glucose concentration (calculated as the mean of all CGMS-
measured concentrations [measured every 5 min] over the study period) and the mean 
proportion of time when the CGMS-measured glucose concentration was < 60 mg/dL during 
the last 3 days on the bionic pancreas will be compared to the same outcomes during the 
control period by paired-sample Student’s t-test (or Wilcoxon signed rank test if data is not 
normally distributed) to determine if the intervention conferred an improvement in glycemic 
control. Secondary outcomes will be analyzed with univariate analysis.   

 
  
 
 
 
23
 Safety Analysis 
Safety will be assessed through an examination of the incidence, severity, and type of 
treatment-emergent adverse events and changes in vital signs, physical examination results, 
glucose monitoring, and use of concomitant medications and concomitant treatment from 
baseline to specified time points throughout the trial. All subjects entered study at either 
admission will be included in the safety analysis. The frequencies of AEs by type, body 
system, severity and relationship to study device will be summarized. SAEs (if any) will be 
described in detail. Safety variables will be assessed by comparison of frequency of adverse 
events (AEs) and serious adverse events (SAEs) during the two study periods.    
 
Sample Size and Power 
The proposed sample size of 10 subjects for this pilot study is a sample of convenience based 
on the number of subjects that we can feasibly study during one year and with the funds 
available. The study may not be powered to achieve statistically significant differences 
between the bihormonal bionic pancreas study period and the standard care period, but the 
data from this pilot study will be used for formal sample size estimation for a larger study. 
However, we offer the following sample size considerations based on previous studies in 
children and adolescents with type 1 DM.  
The two co-primary outcomes are (1) mean glucose concentration as measured by the CGMS 
during the final 3 days of each admission, and (2) the mean proportion of time that the CGMS-
measured glucose concentration was less than 60 mg/dL during the same periods. In children 
and adolescents with type 1 DM, the use of the bionic pancreas was associated with a lower 
mean CGMS-measured glucose compared to standard pump therapy (137±11mg/dL vs. 
167±31mg/dL, p=0.00037) and a lower proportion of time with a CGMS-measured glucose 
concentration below 60 mg/dL (1.2±1.1% vs. 2.8±1.2%, p<0.0001)6. The standard deviation 
of the difference will depend on the within-subject correlation r in this crossover study design. 
If we assume that the standard deviation of both groups would be the same as above the 
following table shows the sample size needed to detect a similar difference (an effect size of 
1.2 and 2, respectively) with an alpha of 0.05 and a power of 0.8 for different values of r.  
 Mean CGMS-measured glucose 
r 
Sample size  
(1-β=0.8) 
0.001 
12 
0.01 
12 
0.05 
12 
0.1 
11 
0.2 
11 
0.3 
10 
0.4 
10 
0.5 
9 

 
  
 
 
 
24
 Proportion of time with a CGMS-measured glucose concentration below 60 
mg/dL 
r 
Sample size  
(1-β=0.8) 
0.001 
11 
0.01 
11 
0.05 
10 
0.1 
10 
0.2 
9 
0.3 
8 
0.4 
8 
0.5 
7 
 
Interim Analysis 
This is an open label study. Safety data will be examined on an ongoing basis to ensure 
safety of the study subjects. 
 
7 
DRUGS/DEVICES 
 
Drugs 
The study involves subcutaneous administration of insulin lispro (Humalog®, Lilly) or 
insulin aspart (Novolog®, Novo Nordisk); and rDNA-origin glucagon for injection 
(Glucagon™, Lilly). All are commercially available by prescription and are indicated for 
patients with diabetes, but not for use in a bionic pancreas. Subjects will use their usual 
rapid-acting insulin analog during the usual care arm of the study and during the bionic 
pancreas arm. The study also involves subcutaneous administration of glucagon for 
injection, which is indicated for the treatment of severe hypoglycemia, but not for use in a 
bionic pancreas.    
The control system can administer bolus doses of each drug up to every five minutes. A 
single automated bolus of insulin will not exceed 3 units per 5-minute dose [30 µl] and a 
single meal-priming dose, which is triggered by the user, will not exceed 12 units [120 µl]. 
A single bolus of glucagon will not exceed 80 µg [80 µl]. The insulin pumps can administer 
as little as 0.5 µl (0.05 units of U-100 insulin or 0.5 µg of 1 mg/ml glucagon) in single 
programmable bolus doses.  
It is expected that the total daily dose of glucagon will be < 1.5 mg daily as in previous 
studies. The mean daily glucagon dose in the previous outpatient study was 0.72 mg/day 
(range 0.22-1.34 mg/day). The recommended dose of glucagon for patients suffering from 
severe hypoglycemia is 1 mg as a single injection. Mean glucagon levels in the previous 
inpatient studies have been above the normal fasting range for glucagon only 1% of the 
time. Therefore, the glucagon exposure of subjects is expected to be modest. 

 
  
 
 
 
25
 
Devices 
 Personal Insulin Pumps 
Subjects will retain and wear their personal insulin pumps for the Control Admission.  There 
will be no intervention to the subjects’ insulin pumps as part of this study, except for them 
being removed during the Bihormonal Bionic Pancreas Admission of this study. 
 Bionic Pancreas System 
Infusion sets: Subjects will wear two FDA approved commercially available infusion sets, 
one for insulin infusion and one for glucagon infusion, when applicable. Infusion sets that 
are compatible with the Tandem® t:slim™ insulin pump (leur lock connection) will be used 
during the bionic pancreas phase that are similar to the infusion sets they use during the 
control phase. If an infusion set falls off or is clinically suspected of failing, it will be 
replaced with a new one. The insulin infusion set will be changed at least every 48 hours; 
the glucagon infusion set will be changed every 24 hours.  
Bionic Pancreas Control Unit: The Beta Bionics mobile application that runs the control 
algorithm and the Dexcom® G5® app are both installed on a stock iPhone® 6s running iOS 
10. The Betabionics app receives the CGM glucose values that are captured by the 
Dexcom® G5® app.  
The control algorithm app has a graphical user interface (GUI) that displays the current 
Dexcom® CGM glucose, a graphical history of the Dexcom® CGM glucose, and doses of 
insulin and glucagon delivered by the control algorithm. The GUI can also be used to input 
meal announcements, designating the size of the meal as larger than typical, typical in size, 
smaller than typical, or just a bite, and the type of meal as breakfast, lunch, or dinner. This 
will trigger a partial meal-priming bolus the size of which will adapt during the trial to meet 
a target of 75% of the insulin needs for that size and type of meal.  
The target glucose level in the bionic pancreas will be programmed by the study staff prior 
to the start of each admission. This will be locked and the subject will be unable to 
accidentally change or tamper with this setting. Subjects will be aware of what their glucose 
target is. 
The GUI can also be used to manage meal boluses as usual, and will administer correction 
boluses in response to entered BG values, during periods when the Dexcom® CGM is 
offline, such as the period after a sensor is replaced and before the new sensor has been 
calibrated. During these times the control algorithm will determine and direct the 
administration of insulin basal rates either based on the subject's weight early in the 
experiment, or on the average of adaptively determined basal rates for that time of day once 
sufficient experience has been accumulated (i.e. 24 hours or more) by the control algorithm. 
The controller will also administer insulin and/or glucagon as appropriate in response to any 
entered BG values, just as if they were Dexcom® CGM values. 
The GUI also displays local audio and visual alarms if communication is dropped between 
the Dexcom® CGM transmitter and the bionic pancreas control unit or between the control 
unit and the two insulin pumps. The Dexcom® CGM also has its own hard-coded alarm 

 
  
 
 
 
26
distinct from the bionic pancreas when the CGM glucose crosses below 55 mg/dl. These 
alarms may be configured so that they require the entry of a code to dismiss.   
The iPhone® communicates wirelessly via the Bluetooth Low Energy (BTLE) protocol with 
up to two Tandem® t:slim™ insulin pumps to deliver insulin and glucagon. 
In all configurations, if communication failures between the Dexcom® CGM and the bionic 
pancreas or the bionic pancreas and the cloud are not resolved within 15 minutes they trigger 
alerts to study staff who will then contact the wearer according to study protocol. If 
communication failure between the bionic pancreas and pumps is not resolved within 15 
minutes this triggers and alert to study staff who will contact the wearer. Also in both 
configurations, if the Dexcom® CGM glucose drops below 50 mg/dl and the user does not 
enter a BG into the bionic pancreas GUI within 15 minutes, this will trigger an alert to study 
staff, who will then contact the wearer according to the study protocol. Monitoring will be 
the same in all study arms.  
Tandem® t:slim™ Pumps: These pumps are FDA approved insulin pumps with reservoirs 
capable of holding 300 units (3 ml) of insulin or 3 ml of a glucagon solution. The pumps 
have a mechanical dosing resolution of 1/120 (0.00833) unit and can deliver liquids at a 
maximal rate of ~ 33 µl per minute (2 ml per hour). They are slave to the bionic pancreas 
control unit and are controlled wirelessly via the Bluetooth Low Energy protocol by the 
iPhone® 6S. 
 Continuous Glucose Monitoring System 
During each admission, a Dexcom® G5® continuous glucose monitor system (CGMS) will 
be placed to measure glucose concentration continuously. The CGMS will be calibrated 
twice daily before breakfast and dinner and as requested by the CGMS. During Control 
Admission, the CGMS will be connected to an iPhone® to allow remote monitoring. During 
Experimental Admission, the CGMS will be part of the bionic pancreas system and will 
provide input to the controller. The sensor is powered by the battery within the transmitter 
that clips to the sensor and the whole assembly is held to the skin with an adhesive patch and 
communicates wirelessly with the CGMS receiver. If the CGMS sensor fails for any reason 
during the experiment it will be replaced promptly. 
Prior to any reuse of the CGM transmitter between patient admissions, study staff will 
thoroughly clean and disinfect the transmitter according to the manufacturer’s best practices 
(detailed instructions included in the Dexcom® User Guide). 
 Bedside Glucometer 
Capillary glucose will be monitored before each meal, at bedtime, at least once overnight 
and PRN (Nova StatStrip® point-of-care glucose monitor, Nova Biomedical Corporation, 
Waltham, MA).  
 Drug Accountability 
For this study, patients will be administered rDNA-origin glucagon for injection 
(Glucagon™, Lilly) via the Bionic Pancreas.  Dosage is 1 mg/mL; route of administration is 
subcutaneous. The glucagon drug supply for this study will be purchased from 

 
  
 
 
 
27
Investigational Drug Service at The Children's Hospital of Philadelphia. Drug will be 
dispensed by Investigational Drug Service following prescription by the Investigator or her 
medically-licensed designee and may not be used for any purpose other than that described 
in this protocol. At study completion, all drug supplies, including partially used and empty 
containers, will be disposed of according to manufacturer recommendations.  
Adequate records of study drug purchase and dispensation will be maintained by the CHOP 
Investigational Drug Service. Records of investigational drug orders, dispensing records, 
and disposition forms may be examined during the course of the study.  
8 
SAFETY MANAGEMENT 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting 
condition will be recorded as an adverse event if the frequency, intensity, or the character of 
the condition worsens during the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality will be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event will also be recorded and documented as an adverse 
event. 
 
Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
 
Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a subject who has received an 
intervention (drug, biologic, or other intervention).  The occurrence does not necessarily 
have to have a causal relationship with the treatment.  An AE can therefore be any 
unfavorable or unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. 
All AEs (including serious AEs) will be noted in the study records and on the case report 
form with a full description including the nature, date and time of onset, determination of 
non-serious versus serious, intensity (mild, moderate, severe), duration, causality, and 
outcome of the event. 
 
Adverse Event Reporting 
Unanticipated problems related to the research involving risks to subjects or others that 
occur during this study (including SAEs) will be reported to the IRB in accordance with 
CHOP IRB SOP 408: Unanticipated Problems Involving Risks to Subjects. AEs that are not 
serious but that are notable and could involve risks to subjects will be summarized in 
narrative or other format and submitted to the IRB at the time of continuing review.  

 
  
 
 
 
28
 Reporting Hypoglycemia and Hyperglycemia Adverse Events 
To maintain consistency across protocols under the Bionic Pancreas IDE, we have consulted 
with the team who holds the IND at Boston University and our clinical trial collaborators at 
Massachusetts General Hospital to determine appropriate and consistent methods for 
reporting the expected adverse events of hypoglycemia and hyperglycemia.  Study team will 
report hypoglycemia and hyperglycemia if they meet the threshold of a severe adverse 
event. Hypoglycemia and hyperglycemia will be reported in line with CHOP and FDA 
requirements (and GCP guidelines) requirements for reporting serious adverse events.   
Specifically, hypoglycemia will be reported if a patient experiences hypoglycemia that 
results in a compromised neurologic status to the extent that the patient requires assistance 
to treat, including seizure or loss of consciousness.   Hyperglycemia will be reported as an 
AE if it is prolonged and associated with replacing the infusion set, or removing the BP and 
giving correction insulin. Additionally, hyperglycemia will be recorded as an AE if the 
subject mounts ketones > 0.6 mmol/L.  Hyperglycemia will be recorded as a serious adverse 
event if the subject becomes diabetic-ketoacidodic.   
 
Definition of a Serious Adverse Event (SAE) 
An SAE is any adverse drug experience occurring at any dose that results in any of the 
following outcomes:  
 death, 
 a life-threatening event (at risk of death at the time of the event),  
 requires inpatient hospitalization or prolongation of existing hospitalization, 
 a persistent or significant disability/incapacity, or 
 a congenital anomaly/birth defect in the offspring of a subject.   
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug event when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
A distinction should be drawn between serious and severe AEs.  A severe AE is a major 
event of its type.  A severe AE does not necessarily need to be considered serious.  For 
example, nausea which persists for several hours may be considered severe nausea, but 
would not be an SAE.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke, but would be an SAE.  
 Relationship of SAE to Study Intervention 
The relationship of each SAE to the study intervention will be characterized using one of the 
following terms in accordance with CHOP IRB Guidelines: definitely, probably, possibly, 
unlikely, or unrelated.  

 
  
 
 
 
29
 
IRB/IEC Notification of SAEs and Other Unanticipated Problems 
The Investigator will promptly notify the IRB of all on-site unanticipated, serious Adverse 
Events that are related to the research activity. Other unanticipated problems related to the 
research involving risk to subjects or others will also be reported promptly. Written reports 
will be filed using the eIRB system and in accordance with the timeline below. External 
SAEs that are both unexpected and related to the study intervention will be reported 
promptly after the investigator receives the report.  
Type of Unanticipated Problem 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Internal (on-site) SAEs 
Death or Life Threatening  
24 hours 
Within 2 calendar days 
Internal (on-site) SAEs 
All other SAEs 
7 days 
Within 7 business days 
Unanticipated Problems Related 
to Research 
7 days  
Within 7 business days 
All other AEs 
N/A 
Brief summary of important AEs 
may be reported at time of 
continuing review 
 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all relevant 
new or reassessed information (e.g., concomitant medication, medical history) will be 
submitted to the IRB. The investigator is responsible for ensuring that all SAE are followed 
until either resolved or stable.  
 
Investigator Reporting of a Serious Adverse Event to Sponsor 
Reporting will be consistent with regulatory requirements. 
 
Medical Emergencies 
As this study involves inpatient hospital admissions, any medical emergencies will be 
handled per standard operating procedure.  
 
9 
STUDY ADMINISTRATION 
As this is an open-label, pilot clinical trial, there will be no control or experimental cohort 
assignments and no blinding. 
 
Data Collection and Management 
 Confidentiality of Data 
All information that is collected for this research protocol will be kept confidential. All 
subjects will be assigned a unique study identification number (study ID). This study ID will 
be used on all case report forms (CRFs). The investigators will maintain a master list 

 
  
 
 
 
30
separate from data forms that have only a study number.  Only password-protected files will 
be used to store the data. 
 Security 
A copy of the password-protected file will be kept in the investigator’s office computer, with 
the original in one of the Hospital’s secure servers. 
 Anonymization, de-identification or destruction 
All data will be maintained the longer of either (A) 6 years after completion of the study or 
(B) 2 years after the last marketing approval or if no application is filed or approved, 2 years 
after the FDA is notified of discontinued application. The investigator maintains a file 
drawer specifically for such archives, each folder labeled “Destroy by….,” with the earliest 
dates at the front. The CHOP PI will monitor and review the study progress and the accuracy 
and security of the emerging data. 
 
Confidentiality 
All data and records generated during this study will be kept confidential in accordance with 
Institutional policies and HIPAA on subject privacy.  The Investigators and other site 
personnel will not use such data and records for any purpose other than conducting the 
study. Safeguards are described under Data Collection and Management.  
No identifiable data will be used for future study without first obtaining IRB approval. The 
investigator will obtain a data use agreement between the provider (the PI) of the data and 
any recipient researchers (including others at CHOP) before sharing a limited dataset (PHI 
limited to dates and zip codes).  
 
Regulatory and Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures.  
Investigators will follow ICH guidelines as they pertain to this study. 
This protocol and any amendments will be submitted to a properly constituted Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study conduct.  The decision of the IRB concerning the conduct of the study will be made in 
writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study. This consent form will be submitted with the protocol for review 
and approval by the IRB for the study.  The formal consent of a subject, using the EC/IRB-
approved consent form, will be obtained before that subject is submitted to any study 
procedure.  This consent form will be signed by the subject or legally acceptable surrogate, 
and the investigator-designated research professional obtaining the consent. 

 
  
 
 
 
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 Data and Safety Monitoring Plan 
The principal investigator will monitor study progress, ensure subject safety, and the 
accuracy and security of the data at CHOP, and will report any adverse events in accordance 
with the FDA regulations and IRB policies.  
Prior to trial initiation, pre-trial visit will be completed by the Office of Research 
Compliance (ORC) to confirm trial readiness.  After the first subject enrolls and completes 
the first investigational admission, the PI will contact ORC to arrange a monitoring visit. 
Thereafter, ORC will monitor the study annually. Monitoring activities will be guided by 
ICH E6 section 5.18. Interim monitoring activities will include a review of regulatory files 
as well as a percentage of enrolled subject records, source documents, applicable informed 
consent forms, and case report forms. The percentage of subject data review may be 
amended throughout the course of the study based on an ongoing risk assessment. A tapered 
approach to monitoring may be employed if conduct and documentation of the study reaches 
a level of reliability that would permit valid conclusions based upon a sampling of data. 
During the experiment, CGMS data will be collected in various ways. CGMS data, 
calibration data, insulin dosing data, and glucagon dosing data will be automatically stored 
in the bionic pancreas device (from which it will be downloaded) and wirelessly streamed to 
the cloud where it will be stored to provide redundancy in data storage and mitigate the risk 
of data loss. During the control phase, CGMS data will be downloaded at intervals. All data 
will be combined in a single database that will be compared against the primary data files 
for integrity. The computer database will be backed up at least monthly and the backup 
media stored in a secure location.  
The PI and the Bionic Pancreas team will be involved in education of the staff prior to the 
start of the protocol and will communicate with staff as required during the performance of 
the trial. Study staff will be encouraged to raise any concerns they may have or problems 
they have identified at any time. The PI will decide a course of corrective action, and 
resolution or progress will be assessed no later than the next meeting.  
A numeric code will be substituted for the subjects personal identifying information in the 
study database, which will be password protected. The key linking the medical record 
number of the subject with the numeric code, along with case report forms, and all 
information that is personally identifiable, will be kept in a locked filing cabinet in an 
investigator’s locked office. All electronic records will be kept in a password protected 
computer database.  All printed computer data will be disposed of confidentially when no 
longer needed. Only the study staff will have access to the study database. Subjects may not 
withdraw from the de-identified database, but they may elect to have the key linking their 
medical record to the de-identified database destroyed. 
Data/CRFs will be stored in OnCore Clinical Trials Management System, a CHOP Research 
IS secured electronic data capture system. OnCore Clinical Trials Management System is a 
secure electronic data capture system with access controls and a data backup plan. The 
system is password protected. Only study team members will have access to subject data and 
case report forms stored in OnCore. Access to the system is monitored and logged for 
review if needed. 

 
  
 
 
 
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The study data will be shared with collaborators from the Bionic Pancreas team, but only in 
a form in which all personally identifiable information has been removed (e.g. combined 
database including blood glucose values, record of insulin and glucagon delivered by the 
device, and blood insulin and glucagon levels). Shared data will be in the form of a database 
in which only a number identifies subjects.  
Subjects may not withdraw their data, as it will be stored in non-personally identifiable 
form.  
 Safety Monitoring 
An Independent Safety Officer with expertise in Diabetes and Clinical Trials will oversee 
the conduct of the study and review its results after 3 subjects have completed the study and 
again when all subjects complete the study. Additionally, the Safety Officer will be 
informed in the event of any severe or unexpected adverse events. The Safety Officer will be 
informed if there are any changes to the study protocol that could significantly impact the 
safety or scientific validity of the study. Safety and efficacy data will also be reported to the 
FDA in compliance with applicable regulations. 
The study will stop and discussion with the Safety Officer will be required to restart it if 
more than one subject experiences the same adverse event due to malfunction of the bionic 
pancreas system:  
 Diabetic ketoacidosis requiring hospitalization 
 Seizure or unconsciousness associated with hypoglycemia 
 Persistent nausea and vomiting thought to be related to glucagon dosing. 
If more than 3 subjects must be withdrawn from the study for these reasons, the study will 
stop and discussion with the Safety Officer will be required to restart it. All serious and 
unexpected events will be reported to the Safety Officer within 72 hours.  
Note that subjects may discontinue participation at any time and subjects may be removed 
from the trial for other reasons, for instance failure to comply with study procedures or inter-
current illness that is unrelated to the bionic pancreas but that precludes safe participation. 
Discontinuation of participation for these reasons will not contribute to a decision to 
discontinue the trial. 
 Risk Assessment 
This study involves greater than minimal risk and limited prospect of direct benefit to the 
subject, but likely to yield generalizable knowledge about the condition. The interventions 
and procedures included in the study are commensurate with those experienced by 
individuals with this condition. 
Subjects may experience mild discomfort associated with the insertion of the infusion sets 
and sensor into the subcutaneous tissues. In the bionic pancreas phase, the risk discomfort 
due to insertion of infusion sets and sensors is expected to be greater than in their lives 

 
  
 
 
 
33
outside the trial because more infusion sets and sensors will be inserted. In the control phase, 
these risks are expected to be of the same nature and magnitude as during the subjects’ lives 
outside of the trial. 
There is a potential risk of hypoglycemia, since exogenous insulin will be administered. Due 
to remote monitoring of severe biochemical hypoglycemia, the risk is expected to be 
reduced relative to during the subjects’ lives outside the trial. In the bionic pancreas phase, 
this risk is expected to be further reduced relative to the risk during the subjects’ lives 
outside of the trial based on data from earlier trials.  
This study will take place in the inpatient setting; therefore subjects will not be engaging in 
any significant physical activity (aerobic or anaerobic) but will be allowed to ambulate 
within the hospital boundaries. Thus, the risk of exercise-induced hypoglycemia is minimal. 
There is a risk of headache, nausea, or vomiting in subjects due to the administration of 
exogenous glucagon. There is a possible risk of skin rash due to administration of exogenous 
glucagon. The magnitude of other possible risks due to daily administration of small 
amounts of glucagon are unknown, but are not expected to be high because mean glucagon 
levels have been in the normal fasted range in previous trials and there have be no other 
adverse events in previous bionic pancreas trials lasting up to five days. Of note, the risk of 
nausea or vomiting has been extremely low in prior studies.  
 Potential Benefits of Trial Participation 
Based on evidence from previous trials of the bionic pancreas and the design of this trial, 
subjects enrolled in the study my benefit from a reduction in risk of hypoglycemia and 
hyperglycemia and a better mean glucose during the bionic pancreas admission. They may 
also benefit from a reduction in risk of severe hypoglycemia during the standard care 
admission due to monitoring for severe events. However, because of the short duration of 
this study, these potential benefits are minimal. 
The data derived from this study will allow us to evaluate the robustness and effectiveness 
of the bionic pancreas control system. The data obtained may be used to further improve the 
bionic pancreas.  
This study is a necessary step in the process of making the bionic pancreas available to 
people with hyperinsulinism and post-pancreatectomy diabetes. Wide availability of the 
bionic pancreas could improve the care of children and adults with hyperinsulinism and 
post-pancreatectomy diabetes. 
 Risk-Benefit Assessment 
Overall, this study involves greater than minimal risk and limited prospect of direct benefit 
to the subject, but it is likely to yield generalizable knowledge that would benefit individuals 
with hyperinsulinism and post-pancreatectomy diabetes. This study is a necessary step in the 
process of making the bionic pancreas available to people with hyperinsulinism and post-
pancreatectomy diabetes. Because of the difficulties in the management of diabetes in 
individuals with hyperinsulinism and post-pancreatectomy diabetes, the prospect of having 
access to a treatment paradigm that will improve glycemic control and reduce the risk of 
hypoglycemia, makes the risk-benefit favorable and justifies this trial.  

 
  
 
 
 
34
 
Recruitment Strategy 
Subjects will be recruited from the Congenital Hyperinsulinism Center at The Children’s 
Hospital of Philadelphia, the largest center in this country caring for children with disorders 
of insulin regulation. Every year our center treats approximately 30 children with medically 
unresponsive hyperinsulinism that require pancreatectomy. Currently we have 
approximately 1200 in-patient days a year. Additionally, we follow many of our patients in 
the outpatient setting which entails managing the patients’ post-pancreatectomy diabetes.  
This put us in a unique position to conduct research directed to develop new therapies for 
this disorder.   
 
Informed Consent/Assent and HIPAA Authorization 
A written Institutional Review Board (IRB)-approved informed consent and Health 
Insurance Portability and Accountability Act of 1996 (HIPAA) authorization must be 
obtained from each subject, and legally authorized representative (LAR) if applicable, 
before any study related activities are conducted. The Investigator must retain all original 
signed and dated ICFs (together with any subsequent IRB-approved amended versions) in 
the subject’s file. A copy of the signed and dated ICF (and any amendments) must be given 
to the subject and LAR. 
The ICF documents the study-specific information the Investigator provides to the subject 
and subjects LAR and the subject’s and subjects LAR’s agreement to participate. Among 
other things, the Investigator or his/her designee will fully explain in layman’s terms the 
nature of the study, along with the aims, methods, anticipated benefits, potential risks, and 
any discomfort participation may entail. Potential participants will be allowed time to review 
the study procedures prior to consenting.  Any questions the potential participants and/or 
LARs have regarding the study will be answered by the Investigator or a designated study 
staff member.   
Subjects and LAR will be informed of findings from earlier or concurrent bihormonal bionic 
pancreas clinical studies (including AEs and SAEs), if it is considered that such information 
could potentially affect subject’s willingness to participate or continue in the study. 
Depending on the nature, severity, and seriousness of these AEs and/or SAEs, the ICF may 
be amended as deemed appropriate. The original and any amended signed and dated ICF(s) 
and subject information sheet(s) must be retained in the subject’s file at the study site; and a 
copy must be given to the subject and subject’s LAR. 
If applicable, separate pediatric assent documents required by the IRB will be implemented 
per the same process detailed above. 
The informed consent form and subject information sheet will be appropriately signed and 
dated before the subject enters the study. 
 
Payment to Subjects/Families 
 Reimbursement for travel, parking and meals 
Many of the subjects that will be recruited for this study live outside the tri-state area.  
Therefore, these subjects will be offered reimbursement for travel expenses depending on 

 
  
 
 
 
35
distance up to a maximum of $2,000 for the whole study. Whenever possible the air/train 
travel for participants will be booked and pre-paid by study staff. If a subject books his/her 
own travel, they will receive reimbursement for travel at the end of their participation. If for 
some reason, the subject cannot complete the study at the time of study visit, they will still 
receive the travel reimbursement.  This reimbursement will be in the form of a check.  If a 
subject is under the age of 18, the compensation will be paid to the parent or legal guardian 
of the subject.   
 
 Payments to subject and parent for time and inconvenience (i.e. compensation) 
This study requires that subjects and their family must take time out of their schedules in 
order to participate.  For Subjects under 18 years of age, a time and inconvenience 
compensation of $25/scheduled day of admission (maximum $200) will be given to the 
subject and a compensation of $50/scheduled day of admission (maximum $400) will be 
given to the parent or legal guardian.  If subjects under 18 years and their parents remain 
admitted to the hospital after the study procedures are complete as a means for the PI to 
monitor the subject on his/her home regime, subjects and their parent will receive $25 and 
$75, respectively, for each additional day up to 3 days (maximum $300 total).  
Subjects 18 years of age or older will receive a time and inconvenience compensation of 
$75/scheduled day of admission (maximum $600).  If these adult subjects remain admitted 
to the hospital after the study procedures are complete as a means for the PI to monitor the 
subject on his/her home regime, subjects will receive $100 for each additional day up to 3 
days (maximum $300 total). 
Subjects/parents or legal guardians will receive this compensation only once (even if they 
must return to CHOP for further testing) at the completion of the study. If for some reason, 
the subject cannot complete the study at the time of study visit, they will still receive the 
time and inconvenience compensation.  This compensation will be in the form of a pre-paid 
bank card.  
 Gifts 
Gifts will not be distributed to research subjects nor their parents/legal guardians. 
10 SPONSORSHIP AND FUNDING 
The BP system will be provided by Edward Damiano, Ph.D. and, per the requirements of 
The Children’s Hospital of Philadelphia’s IRB, Dr. Damiano is listed as a Funder for this 
study.   As Dr. Damiano’s group also holds the FDA’s Investigational Device Exemption, he 
is also listed as the Sponsor of the study.  Dr. Damiano nor his group will be providing 
financial support for this study beyond that of providing the BP devices and requisite 
training to the CHOP study staff.   
Zealand Pharma A/S will be providing financial support for this study.   

 
  
 
 
 
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11 PUBLICATION 
The investigators intend to present the results at national conferences and to publish the 
results in peer-reviewed medical journals. 
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De León, D. D. & Stanley, C. A. Mechanisms of Disease: advances in diagnosis and 
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Lord, K., Dzata, E., Snider, K. E., Gallagher, P. R. & De León, D. D. Clinical 
Presentation and Management of Children with Diffuse and Focal Hyperinsulinism: A 
Review of 223 Cases. J. Clin. Endocrinol. Metab. 98, E1786–E1789 (2013). 
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Hussain, K., Bryan, J., Christesen, H. T., Brusgaard, K. & Aguilar-Bryan, L. Serum 
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Diabetes. N. Engl. J. Med. 371, 313–325 (2014). 

 
  
 
 
 
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