Clinical trial NCT03840278
Conditions: Type 1 Diabetes Mellitus
Keywords: bionic pancreas closed loop glucagon insulin
Sponsor: Massachusetts General Hospital
Start date: 2019-05-15; Completion date: 2019-07-03
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Our objective is to evaluate the function of the bihormonal configuration of the ILet bionic pancreas delivering dasiglucagon when compared to the insulin-only configuration of the ILet bionic pancreas in a home-use study in adults with type 1 diabetes.

Detailed description:
Our objective is to conduct a home-use study testing the Gen 3.2 iLet bionic pancreas system in the insulin-only configuration and the bihormonal configuration with dasiglucagion in 10 adult subjects (≥ 18 years old) with type 1 diabetes in a random-order crossover study under real-world conditions. The study will assess the safety and reliability of both iLet configurations. Our primary objective is to assess whether the iLet operates as designed comparing the insulin-only configuration of the Gen 3.2 iLet bionic pancreas system with the bihormonal configuration of the device using dasiglucagon at a concentration of 4 mg/ml. Our secondary objective is to assess the impact of both configurations of the Gen 3.2 iLet bionic pancreas system on glycemic control, quality of life, and treatment satisfaction among study participants, their caregivers, partners, and/or family members. The study follows a 2-treatment, 2-period crossover design, 2 and will consist of two 7-day study arms in random order: one bihormonal bionic pancreas arm using insulin lispro or insulin aspart and dasiglucagon, and one insulin-only bionic pancreas arm using insulin lispro or insulin aspart.

Arms: arm 1: Each sequence of the study will use the iLet Bionic Pancreas. The iLet is an autonomous infusion pump controlled by the bionic pancreas control algorithm that calculates and doses insulin and/or dasiglucagon based on glucose values received by the Dexcom G5 Continuous Glucose Monitor (CGM).

For this sequence, participants first used the bihormonal iLet bionic pancreas for 1 week. They then used the insulin-only iLet bionic pancreas for 1 week. arm 2: Each sequence of the study will use the iLet Bionic Pancreas. The iLet is an autonomous infusion pump controlled by the bionic pancreas control algorithm that calculates and doses insulin and/or dasiglucagon based on glucose values received by the Dexcom G5 Continuous Glucose Monitor (CGM).

For this sequence, participants first used the insulin-only iLet bionic pancreas for 1 week. They then used the bihormonal iLet bionic pancreas for 1 week.
Interventions: intervention 1: Bihormonal iLet Bionic Pancreas intervention 2: Insulin-only Bionic Pancreas intervention 3: Dasiglucagon
Intervention descriptions: intervention 1: Bihormonal iLet Bionic Pancreas using insulin and dasiglucagon intervention 2: Insulin-only iLet Bionic Pancreas using just insulin intervention 3: Experimental stable glucagon for use in the iLet Bionic Pancreas

Protocol documents:
Prot_SAP_000.pdf: 
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The Bihormonal iLet™ Bionic Pancreas Feasibility Study  
(Study 19-002) 
 
Principal Investigator: 
Steven J Russell, MD, PhD 
 
Co-Investigators: 
Courtney A Balliro, BS, RN, CDE 
Rabab Jafri, MD 
Jordan Sherwood, MD 
 
Sponsor: Beta Bionics 
 
 
Address correspondence to Steven J Russell, MD, PhD, MGH Diabetes Research Center, 50 Staniford Street 
Suite 301, Boston, MA, 02114, email: sjrussell@mgh.harvard.edu, phone: 617-726-1848, fax: 617-643-
0697, page: 617-726-2066 
 
 
 
 
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Table of Contents 
I. Background and Significance 
I. a. Background 
I. b. Bihormonal BP System 
I. c. Insulin-only BP System 
I. d. Glucagon-only BP System 
I. e. Preliminary Studies 
I. f. Fully Integrated Insulin-only, Glucagon-only, and Bihormonal Configurations of the iLet Bionic 
Pancreas System 
II. Objectives and Endpoints 
III. Study Design 
III.a Overall Design 
III.b Scientific Rationale for Study Design 
III.c End of Study Definition  
IV. Subject Selection 
IV. a. Inclusion Criteria 
IV. b. Exclusion Criteria 
IV. c. Sources of Subjects 
V. Subject Enrollment 
V. a. Number of Subjects 
V. b. Enrollment and Consent Procedures 
VI. Study Procedures 
VI. a. Screening Data 
VI. b. Drugs 
VI. c. Devices 
VI. d. Experimental Procedures and Data Collection 
VI. d. i. Screening Visit 
VI. d. ii. Randomization of Visit Order 
VI. d. iii. General Policies for Both Study Arms 
VI. d. iv. Remote Monitoring for Both Study Arms 
VI. d. v. Visit Procedures 
VI. d. vi. Response to Hypoglycemia 
VI. d. vii. Response to Hyperglycemia 
VI. d. viii. Response to Nausea and Vomiting 
VI. d. ix. Response to Other Medical Needs 
VI. d. x. Monitoring of Bionic Pancreas Performance 
VI. d. xi. Supervision by study staff 
VII. Statistical Considerations 
VII.a Statistical Hypotheses 
VII.b Sample Size Determination 
VII.c Populations for Analyses 
VII.d Statistical Analyses 
VII.d.i General Approach 
VII.d.ii Analysis of the Primary Efficacy Endpoint 
VII.d.iii Analysis of the Secondary Endpoints 
VII.d.iv Safety Analyses 
VII.d.v Baseline Descriptive Statistics 
VII.d.viii Tabulation of Individual participant Data 
VII.d.ix Exploratory Analyses  


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VI. e. Power Analysis 
VIII. Risks and Discomforts 
IX. Potential Benefits 
X. Data and Safety Monitoring 
IX. a. Monitoring of Source Data 
IX. b. Safety Monitoring 
IX. c. Adverse Event Reporting Guidelines 
XI. Subject Compensation 
XII. References 
 
 


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I. Background and significance 
I. a. Background 
Maintaining near-normal blood glucose (BG) levels (70–120 mg/dl) is a challenging and critically important 
task for people with type 1 diabetes (T1D). The Diabetes Control and Complications Trial (DCCT) Research 
Group definitively demonstrated that tight BG control can reduce long-term complications. The likelihood 
and severity of nephropathy, retinopathy, neuropathy, macrovascular disease, and skin disorders is 
reduced in proportion to reductions in glycated hemoglobin (HbA1c), which is closely correlated with 
long-term average BG levels. Risks for such complications are elevated by three- to five-fold with diabetes. 
On the other hand, tight BG control through conventional intensive insulin therapy increases the 
likelihood of episodic hypoglycemia, which carries acute risks, including convulsions, seizures, coma, and 
death. Conventional therapy also requires a relentless daily effort to count carbohydrates, frequently 
monitor BG throughout the day and night, and administer a daily insulin regimen. 
 
A more reliable method for achieving consistent BG control consists of an integrated artificial or bionic 
pancreas (BP) system, consisting of a continuous glucose monitor (CGM), an infusion pump, and a control 
algorithm that actuates the pump based on CGM glucose data. Such a system can automate and ease the 
burden of T1D management and vastly improve glycemic control relative to the current standard of care. 
 
Recent years have seen the development of several competing strategies for automated or semi-
automated management of glycaemia. One large difference between competing designs is whether they 
use insulin alone (insulin-only) and rely on the user treating with carbohydrates if the blood glucose falls 
too low, or insulin and glucagon (bihormonal) and use glucagon to automatically prevent and treat 
hypoglycemia, with carbohydrate treatment used only if glucagon treatment is not successful.  
 
Glucagon is an endogenous hormone that binds with high affinity to its cognate receptor. Glucagon is 
quantitatively the most important counter-regulatory hormone in normal glucose control physiology. In 
healthy individuals without T1D, glucagon levels rise during exercise, and in the late-postprandial period 
as glucose levels return to the normal range after a small hyperglycemic excursion. The production of 
glucagon is dysregulated early in the course of T1D and glucagon production in response to threatened 
hypoglycemia is lost. Therefore, people with T1D are functionally glucagon deficient.  
 
An important challenge for automated glucose control is that the physiologic need for insulin can change 
rapidly, but insulin is slowly absorbed when delivered subcutaneously. Even “rapid-acting” insulin analogs 
such as insulin lispro (Humalog) have a mean time-to-peak of ~70 minutes. This means that if the need for 
insulin decreases rapidly, such as in the case of exercise, there is already insulin-on-board that cannot be 
withdrawn. In contrast to insulin, glucagon is absorbed quickly, with a time-to-peak of ~15-20 minutes. 
Therefore, small doses of glucagon can be given to counter the effects of excess insulin that has already 
been delivered and cannot be withdrawn, and can prevent hypoglycemic events that could not be 
prevented by suspending insulin delivery alone.  
 
The use of glucagon provides the BP with a powerful tool to automatically prevent and treat 
hypoglycemia, but it does present two challenges. First, exogenous glucagon must be shown to be safe 
when administered in micro-doses intermittently on a chronic basis. A second challenge to the use of 
glucagon is that a form of glucagon that is stable near body temperature for at least several days in a 
pump must be available. When we first began developing our BP, there was no stable form of glucagon 
available; however, several companies are now developing stable analogs (Zealand, Eli Lilly) and stable 
formulations (Xeris, Adocia). The clinical programs for the Zealand analog are sufficiently advanced that 
we are now using it in the BP in clinical feasibility trials, and we expect it to be qualified for pivotal studies 
by the end of 2019. A third challenge is that, as with subcutaneously administered insulin, replacement of 


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glucagon by subcutaneous administration cannot perfectly mimic normal physiology, and peripheral levels 
must be higher than normal to generate adequate liver exposure for effectiveness. In our last inpatient 
study of the BP in adults and adolescents during over 2,300 patient-hours of exposure, frequent blood 
sampling showed that the aggregate mean glucagon levels were in the normal fasted range (<150 pg/ml 
by the Millipore radioimmunoassay) between 61% and 91% of the time. Based on these results, we expect 
that the doses of glucagon used by the bihormonal BP will be safe  
 
Given the potential different user preferences, we have developed a BP system that can be used in either 
a bihormonal, insulin-only, or glucagon-only mode.  
 
I. b. Bihormonal BP System 
We have developed an autonomous, self-learning BP that requires only the participant'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 T1D.  Our BP obviates the 
need for the patient to know, or even appreciate, their insulin requirements, and renders obsolete any 
need for patients or caregivers to know carbohydrate-to-insulin ratios, basal rates, or insulin correction 
factors. 
 
Our core technology is our 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. We were the first to incorporate insulin pharmacokinetics (PK) into our 
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 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, our MPC algorithm automatically 
adjusts its insulin-doing aggressiveness continuously and in real time to different insulin needs between 
individuals and variable needs within the same individual.  Running in parallel with our MPC 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 of the insulin-only control algorithms of which we are aware, our adaptive 
basal insulin algorithm obviates the need for 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). Our adaptive meal dose controller obviates the need for 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. Our 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 target range and it includes a feedback 
term to account for the pending effects of recent glucagon doses. The amount of glucagon dosed also 
feeds back on the insulin controller, so that large amounts of glucagon dosing decrease the 
aggressiveness of the insulin controller. 
 
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 we have met is enabling our technology to remain 


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completely autonomous in managing insulin and glucagon delivery even when the CGM is offline. 
Specifically, when the CGM is offline, our BP invokes the high-resolution “basal rate profile” that it had 
recently learned and stored when the CGM was online.  Based on what the system learned and stored 
about meal announcements when the CGM was online, it can respond to meal announcements in the 
same manner when the CGM is offline.  Finally, it automatically responds to user-entered BG values when 
the CGM 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 CGM was online. Thus, our BP never relies on, or burdens the 
user with, the determination of dosing decisions, which inevitably vary in quality and reliability among 
different users. The BP provides a turnkey solution for people with T1D that comprehensively manages 
glycaemia across a broad range of individual needs and a across a large spectrum of circumstances and 
challenges to glycemic control.  
 
I. c. Insulin-Only BP System 
The BP can also operate in an insulin-only mode. During operation in this mode, all the other features of 
the BP operate as usual except that glucagon is not given. In addition, the lowest glucose target that can 
be chosen by the user (towards which the insulin controller drives down the blood glucose levels) is 
increased from 100 mg/dl in the bihormonal system to 110 mg/dl in the insulin-only system. This works to 
reducing the aggressiveness of insulin dosing in the insulin-only system relative to its bihormonal 
counterpart, with the aim of keeping the amount of hypoglycemia low even at the potential cost of raising 
the mean glucose level achieved by the insulin-only system.  The intended use for such a system would be 
to provide glycemic control for people with type 2 diabetes who require insulin therapy, and early 
technology adopters with type 1 diabetes. 
 
I. d. Glucagon-Only BP System 
The BP can also operate in a glucagon-only mode. During operation in this mode, all the other features of 
the BP operate as usual except that insulin is not given. The intended use for such a system would be to 
treat glycemic disorders associated with chronic hypoglycemia (such as congenital hyperinsulinism, 
insulinoma syndrome, chronic hypoglycemia in post-bariatric surgery patients, etc.). 
 
I.e. Preliminary Studies 
Our BP hardware platform has evolved over the years from a laptop-driven system, which we used in all 
of our inpatient studies (between 2008-2012), to the first truly mobile wearable iPhone-driven platform, 
which we have used in all of our outpatient studies thus far (between 2013–2016).  Using our iPhone-
driven BP system, we have conducted >110 outpatient experiments of 5–11 days in duration in each 
participant (> 800 patient days or > 2 patient years of data), and across participants ranging in age 
between 6 and 76 years old and in body mass between 21 and 133 kg.  The robust adaptation capabilities 
of our BP are evident in the fact that the average total daily dose of insulin among these participants 
varied by over 13-fold (from 11 to 145 units/day).   
 
All of our preclinical studies at BU testing our BP in a diabetic swine model of T1D (between 2005 and 
2009), and all of our inpatient clinical trials in the Clinical Research Center at MGH testing our BP in adults 
and adolescents with T1D (between 2008 and 2012) have set the stage for the outpatient studies that 
followed.  In November 2012 we obtained FDA approval to conduct our first outpatient study testing our 
bihormonal BP in adults 21 years or older with T1D. The Beacon Hill Study1 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 the usual care control arm the participants used conventional insulin pump therapy (and 
their own CGM if they had one), and they wore a CGM with blinded display and muted alarms.  In the BP 
arm, participants 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 


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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 1. Results are summarized in the 
plots and table of Figure 1.  
 
 
 
Figure 1. Outpatient results summarizing the distribution of mean CGM glucose levels and hypoglycemia 
in the bihormonal BP and control arms. Mean CGM glucose levels for each participant under usual care 
(shown as a red circle on the left) relates to the participant's mean CGM glucose level on the BP (shown as 
a black circle on the right). For each participant, the circle diameter is proportional to the percentage of 
CGM glucose values < 60 mg/dl, and the size of the triangle is proportional to the percentage of CGM 
glucose values > 180 mg/dl. The heavy circles and lines represent the group means. The horizontal red 
Mean CGMG (mg/dl)
90
120
154
180
210
240
1% <60 mg/dl
5% <60 mg/dl
10% >180 mg/dl
50% >180 mg/dl
Bionic
Pancreas
Control
Beacon Hill Study
Mean CGMG (mg/dl)
90
120
169
180
210
240
1% <60 mg/dl
5% <60 mg/dl
10% >180 mg/dl
50% >180 mg/dl
Bionic
Pancreas
Control
2013 Summer Camp Study
Mean CGMG (mg/dl)
90
120
150
169
180
210
240
1% <60 mg/dl
5% <60 mg/dl
10% >180 mg/dl
50% >180 mg/dl
Bionic
Pancreas
Control
2014 Summer Camp Study
Mean CGMG (mg/dl)
90
120
154
180
210
240
1% <60 mg/dl
5% <60 mg/dl
10% >180 mg/dl
50% >180 mg/dl
Bionic
Pancreas
Control
BP Multi-Center Study
Study
Age
Mean CGM
Mean CGM
Mean CGM
(years)
glucose level
<"60"mg/dl
70–180"mg/dl glucose level
<"60"mg/dl
70–180"mg/dl glucose level
<"60"mg/dl
70–180"mg/dl
(mg/dl)
(%)
(%)
(mg/dl)
(%)
(%)
Beacon Hill (n=20, 5-day experiments)
≥*21
133
1.5
80
159
3.7
59
<*0.001
0.020
<*0.001
2013 Summer Camp (n=32, 5-day experiments)
12–20
142
1.3
76
158
2.2
65
0.004
0.192
<*0.001
2014 Summer Camp (n=19, 5-day experiments)
6–11
137
1.2
81
168
2.8
58
0.004
0.001
<*0.001
BP Multi-Center (n=39, 11-day experiments)
≥*18
141
0.6
78
162
1.9
62
<*0.001
<*0.001
<*0.001
Bionic Pancreas (BP)
Control
p-value (BP versus Control) for:
% of CGM glucose levels
% of CGM goucose values
% of CGM glucose values


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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 the plots, where the co-primary outcomes (mean CGM glucose 
level and percentage of CGM glucose values < 60 mg/dl) for the BP are highlighted in red for each of the 
four studies. 
 
In April 2013, we obtained FDA approval to conduct our first outpatient study testing our bihormonal BP 
in adolescents 12–20 years old with T1D. The 2013 Summer Camp Study1 followed a random-order cross-
over design in which 32 adolescents with T1D participated in 5 days on our BP and 5 days of supervised 
camp care in the control arm. In the control arm the participants used conventional insulin pump therapy 
(and their own CGM if they had one), and they wore the BP without pumps and with blinded display and 
muted alarms for remote monitoring. Participants were monitored remotely according to identical criteria 
in all arms for proper device functioning and CGM glucose <70 mg/dl lasting more than 15 minutes, which 
would prompt study staff to call the participant and make sure they were treated.  Participants 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 our Beacon Hill Study.   The mean HbA1c of all 32 participants 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 1.   
 
In April 2014, we obtained FDA approval conduct our first outpatient study testing our bihormonal BP in 
pre-adolescents 6–11 years old with T1D. The 2014 Summer Camp Study2, was similar in design to our 
2013 Summer Camp Study.  Results are summarized in the plots and table of Figure 1.  
 
In April 2014, we obtained FDA approval to conduct our first multi-center study, which was also our first 
home study, to test our BP in adults 18 years or older with T1D. The Bionic Pancreas Multi-Center Study3 
followed a random-order cross-over design in which 39 adults participated in 11 days on our 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 participants per center), which included MGH, the University of Massachusetts Medical 
School, Stanford University, and the University of North Carolina at Chapel Hill.  Results are summarized in 
the plots and table of Figure 1. 
 
In July 2015, we obtained FDA approval to perform our first study testing the BP at different static glucose 
targets (“set-points”), including in both the bihormonal and insulin-only configurations. In the MGH Set-
point Study4 20 adults participated in 7 arms, each lasting 3 days. This study was the first to explore 
modifying the glucose target towards which the BP attempts to drive the glucose level. In all our previous 
studies, the target glucose was 100 mg/dl. Since this was the first study to test the BP in a configuration 
without glucagon, the insulin-only arms initially used significantly elevated glucose targets of 130 mg/dl 
and 145 mg/dl (not shown). We subsequently obtained approval to test glucose targets of 120 mg/dl and 
110 mg/dl in December 2015. Results for the insulin-only and control arms are summarized in Figure 2. 
The conclusion of this study was that the insulin-only system was safe, with minimal hypoglycemia, with 
the 120 mg/dl glucose target appearing to be a good compromise between mean glucose, amount of 
hypoglycemia, and insulin utilization. 
 


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Figure 2 Outpatient results summarizing the distribution of mean CGM glucose levels and hypoglycemia in 
the insulin-only BP (set-points 130, 120, and 110 mg/dl) and comparator arms. Mean CGM glucose levels 
for each participant in each arm (shown as a red circles) are connected by black lines. For each 
participant, the circle diameter is proportional to the percentage of CGM glucose values < 60 mg/dl.  The 
heavy circles and lines represent the group means. 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.   
 
In July 2015, we obtained FDA approval to perform our first study investigating a feature that allowed the 
target glucose to be determined automatically by the BP, an additional level of adaptation to the 
individual participant. In the Stanford Insulin-only Study5 16 adults participated in a week of usual care 
followed by another week on the insulin-only BP. Participants were monitored remotely according to 
identical criteria in both arms for proper device functioning and CGM glucose <50 mg/dl lasting more than 
15 minutes, which would prompt study staff to call the participant and make sure they were treated. The 
first week was a control arm in which participants managed their own conventional insulin pump therapy 
(using their own CGM if they had one) and wore the BP without pumps and with blinded display and 
muted alarms for remote monitoring. In the second week, the BP was initiated with target glucose of 130 
mg/dl, which could be lowered to 115 mg/dl if certain criteria were met. All but one participant was kept 
at a target of 130 mg/dl, and one was lowered to 115 mg/dl, for an overall average target of 129 mg/dl. 
During this week, the mean CGM glucose achieved was 159 mg/dl. There was only 0.8% time <60 mg/dl in 
the static set-point week. This was non-significantly lower than the 2.3% observed in the usual care arm. 
Results are summarized in Figure 3. This provided further reassurance that the insulin-only configuration 
of the BP is safe and effective.  
 


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Figure 3 Outpatient results summarizing the distribution of mean CGM glucose levels and hypoglycemia in 
the insulin-only BP and control arms. Mean CGM glucose levels for each participant under usual care 
(shown as a red circle on the left) relates to the participant's mean CGM glucose level on the BP (shown as 
a black circle on the right). For each participant, the circle diameter is proportional to the percentage of 
CGM glucose values < 60 mg/dl.  The heavy circles and lines represent the group means. 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.   
 
In April 2016, we obtained FDA approval to perform our first study removing remote telemetric 
monitoring for severe biochemical hypoglycemia from an outpatient study comparing the bihormonal 
bionic pancreas, the insulin-only bionic pancreas and the subject’s own usual care. In the Monitoring 
Study6 each arm was repeated with and without remote monitoring to allow for a direct comparison of 
glycemic control and hypoglycemia. Each BP hormonal configuration used the lowest glucose target 
previously tested: 100 mg/dl for the bihormonal BP and 110 mg/dl for the insulin-only BP. The results are 
summarized in figure 4. There was more hypoglycemia without monitoring vs. with monitoring in the two 
usual care arms (1.95 vs. 1.32%, p=0.02). However, there was no difference in hypoglycemia without 
monitoring vs. with monitoring in the two bihormonal BP arms (0.99 vs. 1.05%, p=0.82) and two insulin-
only BP (1.66 vs. 1.55%, p=0.74) arms. Without monitoring, hypoglycemia was reduced on the bihormonal 
BP vs. usual care (0.99 vs. 1.95%, p=0.02) and was comparable on the insulin-only BP vs. usual care (1.66 
vs. 1.95%, p=0.47). The mean CGMG was significantly lower in all BP vs. usual care arms. There were no 
mean CGMG differences between the two bihormonal, two insulin-only, and two usual care arms. We 
concluded that remote monitoring had no effect on hypoglycemia with the BP, and could be safely omitted 
from future studies even at the most aggressive set point. The default glucose set points of the iLet in all 
future studies will be higher in each configuration (110 mg/dl for bihormonal, and 120 mg/dl for insulin-
only), but users will be allowed to lower each set point if they desire without sacrificing their safety.  
Mean CGMG (mg/dl)
90
120
154
180
210
240
1% <60 mg/dl
5% <60 mg/dl
Control
Insulin Only
(n=16)
Mean: 151 +/- 26 mg/dl
1.9% <60,     26% >180
Mean: 160 +/-  9 mg/dl
0.9% <60,     30% >180
I: 0.57 U/kg


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Figure 4. Outpatient results summarizing the distribution of mean CGM glucose levels and hypoglycemia 
in usual care, on the insulin-only BP and the bihormonal BP, each with and without monitoring. Mean 
CGM glucose levels for each participant in each arm (shown as a red circles) are connected by black lines. 
For each participant, the circle diameter is proportional to the percentage of CGM glucose values < 60 
mg/dl.  The heavy circles and lines represent the group means. 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.   
 
In June 2016, we obtained FDA approval to perform a feasibility trial designed to compare an 
investigational glucagon analog, ZP4207 (Dasiglucagon, Zealand Pharma), with freshly reconstituted 
recombinant human glucagon (Eli Lilly) using the bihormonal BP. In the Dasiglucagon Feasibility Study7 20 
adults completed two 1-day study visits in random order (bihormonal BP using dasiglucagon and 
bihormonal BP using Lilly glucagon). The trial was designed to compare dasiglucagon and Lilly glucagon 
administered via the bihormonal BP under strenuous conditions by having each subject fast prior to each 
treatment visit, continuing the subject’s own insulin pump with up to double the basal insulin 
administration rate, and including an exercise session, which all together challenged the ability to 
maintain euglycemia. Under these conditions, the efficacy results demonstrated comparable automated 
glycemic control with dasiglucagon as compared to Lilly glucagon when used within the bihormonal BP 
system for up to 8 hours. Both dasiglucagon and Lilly glucagon were well tolerated and able to counteract 
decreasing and hypoglycemic plasma glucose levels. The mean CGM glucose and glucagon dosing for this 
trial are summarized in Figure 5. The results of this study allow us to use dasiglucagon in a bihormonal 
bionic pancreas in longer outpatient phase 2 and 3 trials in place of recombinant human glucagon.  
 
 
 


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Figure 5. The mean CGM glucose and mean glucagon dosing in the eight-hour study visit for the 
dasiglucagon arm (ZP-arm) and Lilly glucagon arm.  
 
In May 2018, we obtained FDA approval to perform our first pilot study testing the insulin-only 
configuration of the iLet in the home-use setting in adults and children. The aims of the Insulin-only 
Bridging Study were to assess the efficacy, safety, and reliability of the insulin-only configuration of the 
bionic pancreas in regulating glycaemia in a short-term, outpatient study under real-world conditions. In a 
preliminary test run we enrolled 7 adult subjects ≥ 18 years old with T1D.  The test run was completed in 
June 2018 and consisted of an uncontrolled, 7-day experimental period that tested the insulin-only 
configuration of the iLet along with the iLet pigtail adapter, the iLet ready-to-fill insulin cartridge, the 
Contact Detach infusion set (Unomedical), the Dexcom G5 CGM, and the insulin analog that each subject 
normally used for their usual care (either Humalog or Novolog).  Participants were followed with round-
the-clock, remote, telemetric monitoring for hyperglycemia (> 300 mg/dl for ≥ 90 minutes) and 
hypoglycemia (< 50 mg/dl for ≥ 15 minutes).  The primary glucose target was set to 120 mg/dl by default 
for all subjects.  All 7 adult participants had a designated contact, who served as an emergency contact 
person and were available in the event study staff were unable to reach the participant. The mean CGM 
glucose over the last five days of the study (days 3–7) for the entire cohort was 145 ± 10 mg/dl and the 
time < 60 and 54 mg/dl was 1.7 ± 0.6 and 0.8 ± 0.6%, respectively.  
 
The test run was followed by the random-order, cross-over, outpatient Insulin-only Bridging Study8 
comparing the insulin-only mode of the iLet to usual care (UC) for 7 days each. The study enrolled adults 
with T1D who used either MDI (n=12) or CSII (n=22) for their UC. Participants enrolled at Massachusetts 
General Hospital (n=17) used the Eversense while those at Stanford (n=17) used the G5 as the input CGM 
signal for the iLet. There was no statistically significant difference between the iLet and UC in % time <54 
mg/dl (0.6 [0.2,1.1] vs. 0.6 [0.1,1.2], p=0.87) or mean CGM glucose (155±12 vs. 162±26 mg/dl, p=0.097). 
The iLet significantly increased % time within 70-180 mg/dl vs UC (70.1% vs 61.5%, p=0.006). The mean 
insulin TDD was not significantly different between iLet and UC (44±20 vs. 42±20 u/day). No serious 
adverse events occurred during either arm. These results suggest that the iLet, using either the Eversense 
or G5 CGMs, may provide safe and effectively glucose control to users with MDI or CSII as their UC. 
 


Version 2, February 21st, 2019  
 
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Figure 6. Outpatient results summarizing the distribution of mean CGM glucose levels and hypoglycemia 
in usual care and on the insulin-only iLet. Mean CGM glucose levels for each participant in each arm 
(shown as a red or blue circles for participants on MDI or CSII during ususal care, respectively) are 
connected by lines. For each participant, the circle diameter is proportional to the percentage of CGM 
glucose values < 54 mg/dl.  The heavy circles and lines represent the group means. The horizontal red 
dashed line refers to the glucose level corresponding to the ADA therapy goal for adults, which 
corresponds to 154 mg/dl (HbA1c <7%).   
 
I. f. Fully Integrated Insulin-Only, Glucagon-Only, and Bihormonal Configurations of the iLet Bionic 
Pancreas System 
We have designed, built, and tested our first-generation working prototype BP system, which we refer to 
as the iLet bionic pancreas system, and which consists of a dual-chamber autonomous infusion pump. The 
iLet has been built according to Class III medical device standards, adheres to a comprehensive and robust 
quality system, and is fully compliant with ISO 13485 standards and document control practices.  The 
bihormonal configuration of the iLet includes a dual motor and drivetrain assembly, which independently 
actuates the delivery of insulin and/or glucagon from glass cartridges that are separately loaded into the 
iLet housing.  Each drivetrain utilizes a lead screw, which is driven by a precision micromotor, a gear case 
assembly, and a motor controller unit, in a manner that is commonly found in many insulin infusion 
pumps on the market today. Our mathematical control algorithms, the integrated CGM (Dexcom G5 or 
Senseonics Eversense), and the native user interface (UI) software, are all interconnected through a host 
controller software module and reside as embedded systems on printed circuit board assemblies 
contained within the device housing. Our touchscreen-enabled, menu-driven UI and onboard 
microprocessor provide a comprehensive and standalone platform, which allows the iLet to operate 
independently of smartphones or other devices and without the need for internet support during routine 
operation. The iLet has dosing accuracy that is comparable to the most accurate FDA-approved insulin 
pumps currently on the market.  
 
The iLet is set to either an insulin-only, bihormonal, or glucagon-only configuration by manually selecting 
the configuration in the user interface.  When in the bihormonal configuration, the control algorithm 
would occasionally and automatically invoke the same insulin-only dosing mode as in the insulin-only 
configuration during periods when the glucagon cartridge has not been loaded, is empty, or becomes 
 
USUAL CARE 
BIONIC PANCREAS 


Version 2, February 21st, 2019  
 
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empty during use, or if there is a pump occlusion detected along the glucagon fluid path.  Whenever 
the control algorithm is in the insulin-only configuration, the minimum glucose target is 110 mg/dl.  The 
minimum glucose target in the bihormonal or glucagon-only configurations, when the glucagon cartridge 
is available for dosing and the glucagon fluid path is patent, is 100 mg/dl. 
 
In addition to the iLet device itself, the entire iLet bionic pancreas system includes a glass insulin cartridge, 
a glass glucagon cartridge, pigtail adapters that connect the drug cartridges to infusion sets, and a self-
monitored blood-glucose (SMBG) meter.  The SMBG meter that we will use is the Contour Next One 
(Ascensia).  This meter is the successor to the Contour Next SMBG meter (Bayer), which was found to be 
the most accurate meter assessed in all three blood-glucose ranges tested (< 70, from 70 to 179, and ≥ 
180 mg/dl) in a comparative accuracy study involving 19 point-of-care glucometers [REF]. 
 
II. Objectives and Endpoints  
Our objective is to conduct a home-use study testing the Gen 3.2 iLet bionic pancreas system in the 
insulin-only configuration and the bihormonal configuration with dasiglucagion in 10 adult subjects (≥ 18 
years old) with type 1 diabetes in a random-order crossover study under real-world conditions. The study 
will assess the safety and reliability of both iLet configurations.  
 
Primary objective: To assess whether the iLet operates as designed comparing the insulin-only 
configuration of the Gen 3.2 iLet bionic pancreas system with the bihormonal configuration of the device 
using dasiglucagon at a concentration of 4 mg/ml. 
 
Secondary objective: To assess the impact of both configurations of the Gen 3.2 iLet bionic pancreas 
system on glycemic control, quality of life, and treatment satisfaction among study participants, their 
caregivers, partners, and/or family members. 
 
Primary endpoint 
The primary endpoint will capture the operational characteristics of the Gen 3.2 iLet bionic pancreas 
system for each of the patient’s two treatment periods.  A 7-day treatment period will be considered to 
have successfully met its primary endpoint if each of the following is true during the time that the iLet is 
powered on over the entire treatment period: 
 
1. The percentage of time that valid CGM glucose readings are captured by the iLet is ≥80%.  
2. The percentage of the time that each drug channel (insulin, and if applicable, glucagon) is 
available is ≥95%.  
3. The ratio of cumulative drug doses delivered to cumulative drug doses attempted is between 0.95 
and 1.05, inclusive, for insulin and, if applicable, for glucagon.  
 
Key secondary endpoint 
 
Proportion of time with CGM glucose < 54 mg/dl across days 2-7 
 
Secondary endpoints 
 
Mean grams of carbohydrate per day ingested to treat hypoglycemic events (reported daily by 
subjects) 
 
Mean CGM glucose across days 2-7 
 
Proportion of time across days 2-7 within the CGM glucose range of 70-180 mg/dl 
 
Quality of life among study participants, their caregivers, partners and/or family members 
 
Treatment satisfaction among study participants, their caregivers, partners and/or family 
members 


Version 2, February 21st, 2019  
 
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Safety endpoints 
 
Frequency of adverse events  
 
Frequency of severe hypoglycemia 
 
Frequency of diabetic ketoacidosis 
 
Other endpoints 
 
Proportion of time across days 2-7 within each of the following CGM glucose ranges: 
o < 50 mg/dl 
o < 60 mg/dl 
o < 70 mg/dl 
o 70-120 mg/dl>180 mg/dl 
o >250 mg/dl 
 
Number of episodes of symptomatic hypoglycemia (reported daily by subjects) 
 
Percentage of subjects with mean Dexcom CGMG < 154 mg/dl (estimated average glucose 
corresponding to an A1c of 7%) 
 
MARD for the Dexcom G5 with the Contour Next One glucose meter as the reference 
 
Total daily dose of insulin 
 
Mean daily basal insulin dose 
 
Mean daily bolus insulin dose 
 
Total daily dose of glucagon 
 
Number of user-intiated glucagon doses 
 
Number of meal announcements 
 
Glucose variability measured with coefficient of variation (CV) and with mean of daily difference 
(MODD) 
 
Mean nausea severity from VAS 
 
Number of unscheduled insulin and glucagon cartridge/infusion set changes 
 
Mean glucose target  
 
III. Study Design 
 
III.a Overall Design 
The study follows a 2-treatment, 2-period crossover design, 2 and will consist of two 7-day study arms in 
random order: one bihormonal bionic pancreas arm using insulin lispro or insulin aspart and dasiglucagon, 
and one insulin-only bionic pancreas arm using insulin lispro or insulin aspart, as seen in Figure 1. 
 


Version 2, February 21st, 2019  
 
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Figure 7. Study design 
 
 
Questionnaires will be administered to participants and their partners (designated contacts) at the 
beginning of the study and the end of each arm to gather data on attitudes towards bionic pancreas BG 
control, confidence, device burden and treatment satisfaction. This information will be used to make the 
best choices about how the final version of the bionic pancreas should be configured and used.  
 
III.b Scientific Rationale for Study Design 
A crossover study design was chosen to reduce the impact of inter-subject variability and to increase the 
statistical power to detect differences in secondary outcomes despite the relatively small number of 
subjects. 
 
III.c End of Study Definition 
The study will end for subjects when they have completed the second follow-up visit scheduled 25 (± 4) 
days after the final day 7 visit, or at the time they chose to withdraw from the study or are removed from 
the study by decision of the principle investigator.  
 
VI. Subject Selection 
VI.a. Inclusion Criteria 
Subjects 
1. Age ≥ 18 years and have had clinical type 1 diabetes for at least one year  
2. Diabetes managed using an insulin pump for ≥ 3 months 
3. Prescription medication regimen stable for > 1 month (except for medications that will not affect 
the safety of the participant and are not expected to affect any outcome of the study, in the 
judgement of the principal investigator) 
4. Willing to wear one Dexcom CGM sensor, and up to two steel cannula infusion sets (6 mm 
Contact Detach) and change infusion sets frequently (if the subject is known not to tolerate steel 
infusion sets then a plastic set may be used)  
5. Have used a CGM for at least one cumulative month over the last 24 months 
6. Willing to stay within a 250-mile radius of the designated base throughout the study. Air travel is 
not permitted. 
7. Informed consent obtained before any trial-related activities 
8. Have a designated contact (an adult ≥ 18 years of age) willing to serve as an emergency contact 
for them throughout the study. 
Days from treatment initiation
Randomization
Treatment period 1
Optional wash-out period
of up to 7 days
Treatment period 2
Screening
0
7
14
10 subjects
with T1DM
insulin and dasiglucagon
insulin alone
insulin alone
insulin and dasiglucagon
Insulin lispro or insulin aspart with dasiglucagon
Insulin lispro or insulin aspart alone
Study visit


Version 2, February 21st, 2019  
 
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Designated Contacts 
1. Age ≥ 18 years 
2. Have an established relationship with the study participant 
3. Willing to answer questionnaires about their experience with the participant’s diabetes and the 
bionic pancreas 
4. Willing to answer calls and check on the participant’s wellbeing as needed 
5. Able to provide informed consent (e.g. no condition that impairs cognition or judement) 
 
VI.b. Exclusion Criteria 
1. Unable to provide informed consent (e.g. impaired cognition or judgment) 
2. Unable to safely comply with study procedures and reporting requirements (e.g. impairment of 
vision or dexterity that prevents safe operation of the iLet, impaired memory, unable to speak 
and read English) 
3. Current participation in another clinical trial with administration of investigational drug.  
4. Current participation in another diabetes-related clinical trial that, in the judgment of the 
principal investigator, will compromise the results of this study or the safety of the participant 
5. Previous exposure to dasiglucagon (otherwise known as ZP4207) 
6. Pregnant (positive urine HCG), breast feeding, plan to become pregnant in the next 12 months, or 
sexually active without use of contraception 
a. Subjects must use acceptable contraception for the two weeks prior to the study, 
throughout the study and for the two weeks following the study. 
b. Acceptable contraception methods include: 
 Oral contraceptive pills (OCP) 
 Intrauterine Device (IUD, hormonal or copper) 
 Male condoms 
 Female condoms 
 Diaphragm or cervical cap with spermicide 
 Contraceptive patch (such as OrthoEvra) 
 Contraceptive implant (such as Implanon, Nexplanon) 
 Vaginal ring (such as Nuvaring) 
 Progestin shot (such as Depo-Provera) 
 Male partner with a vasectomy proven to be effective by semen analysis 
7. Current alcohol abuse (intake averaging >4 drinks daily in last 30 days) or other substance abuse 
(use within the last 3 months of controlled substances other than marijuana without a 
prescription)  
8. Unwilling or unable or to avoid use of drugs that may dull the sensorium, reduce sensitivity to 
symptoms of hypoglycemia, or hinder decision making during the period of participation in the 
study (use of benzodiazepines or narcotics, even if by prescription, may be excluded according to 
the judgment of the principal investigator) 
9. Renal failure on dialysis 
10. History of cystic fibrosis, pancreatitis, or other pancreatic disease, including pancreatic tumor or 
insulinoma, or history of complete pancreatectomy 
11. Coronary artery disease that is not stable with medical management, including unstable angina, 
angina that prevents moderate exercise (e.g. exercise of intensity up to 6 METS) despite medical 
management, or within the last 12 months before screening a history of myocardial infarction, 
percutaneous coronary intervention, enzymatic lysis of a presumed coronary occlusion, or 
coronary artery bypass grafting  
12. Abnormal EKG consistent with increased risk of malignant arrhythmia including, but not limited 


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to, evidence of active ischemia, proximal LAD critical stenosis (Wellen’s sign), or prolonged QT 
interval (QTc > 500 ms). Other EKG findings, including stable Q waves, are not grounds for 
exclusion as long as the participant is not excluded according to other criteria. A reassuring 
evaluation by a cardiologist after an abnormal EKG finding may allow participation.  
13. Unwilling or unable to avoid drugs known to cause torasdes de pointe or bradycardia throughout 
the entire dosing period. Subjects will also be given a list of drug classes to avoid without checking 
with study staff and will be told to call study staff before any new drug, including over the counter 
drugs but excluding topicals, so that it may be checked against a comprehensive list of drugs 
associated with torsades de pointes. Any medications in these classes taken by subjects at 
baseline will be checked against a comprehensive list of medications associated with torsades de 
pointes and subjects taking such medications will be excluded. The list of drug classes is 
intentionally over-inclusive (i.e. the drug classes listed contain many drugs that are NOT 
associated with torsades de pointes) to facilitate recognition of drugs to be checked against a 
definitive list.  
a. Antibiotics  
b. Antifungals  
c. Antivirals 
d. Antipsychotics 
e. Antiderpressants 
f. Mood stabilizers 
g. Anticonvulsants 
h. Antiemetics  
i. 
Diuretics 
j. 
Antihypertensives 
k. Antihistamines 
l. 
Anesthetics 
m. Opiods 
n. Cocaine 
14. Congestive heart failure with New York Heart Association (NYHA) Functional Classification III or IV  
15. History of TIA or stroke in the last 12 months 
16. History of liver disease that is expected to interfere with the anti-hypoglycemic action of glucagon 
(e.g. liver failure or cirrhosis). Other liver disease (e.g. active hepatitis, steatosis, active biliary 
disease, any tumor of the liver, hemochromatosis, glycogen storage disease) may exclude the 
subject if it causes significant compromise to liver function or may do so in an unpredictable 
fashion.  
17. Personal history of pheochromocytoma, MEN 2A, MEN 2B, neurofibromatosis, or von Hippel-
Lindau disease 
a. Fractionated metanephrines will be tested to rule out pheochromocytoma in patients 
with symptoms that could be related to a catecholamine secreting tumor, including those 
with: 
 Episodic or treatment refractory (requiring 4 or more medications to achieve 
normotension) hypertension 
 Paroxyms of tachycardia, pallor or headache 
18. History of adrenal disease or tumor that has not undergone characterization for endocrine 
function 
19. Hypertension with systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg 
despite treatment 
20. Recent history of diabetic ketoacidosis (DKA) or severe hypoglycemia in the last 6 months. Severe 
hypoglycemia is defined as an event that required assistance of another person due to altered 


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consciousness, and required another person to actively administer carbohydrate, glucagon, or 
other resuscitative actions.  This means that the participant was impaired cognitively to the point 
that he/she was unable to treat himself/herself, was unable to verbalize his/ her needs, was 
incoherent, disoriented, and/or combative, or experienced seizure or coma.   
21. History of more than 1 episode of DKA requiring hospitalization in the last 2 years  
22. History of more than 1 episode of severe hypoglycemia in the last year. 
23. Untreated or inadequately treated mental illness (indicators would include symptoms such as 
psychosis, hallucinations, mania, and any psychiatric hospitalization in the last year), or treatment 
with anti-psychotic medications that are known to affect glucose regulation. 
24. Electrically powered implants (e.g. cochlear implants, neurostimulators) that might be susceptible 
to RF interference 
25. Unable or unwilling to completely avoid acetaminophen for duration of study 
26. Established history of allergy or severe reaction to adhesive or tape that must be used in the 
study 
27. History of adverse reaction to glucagon (including allergy) besides nausea or vomiting 
28. History of severe hypersensitivity to milk proteins or lactose 
29. History of eating disorder within the last 2 years, such as anorexia, bulimia, or diabulemia or 
omission of insulin to manipulate weight 
30. Current or planned use of SGLT2 inhibitors (prior use more than 3 months prior to enrollment is 
acceptable; SGLT2 inhibitors should not be initiated during the trial) 
31. If using GLP1, pramlintide, or metformin must be on a stable dose for 3 months prior to 
enrollment (these agents should not be initiated during the trial) 
32. Required use of 2 or more steroid bursts in the 6 months prior to the trial 
33. History of intentional, inappropriate administration of insulin leading to severe hypoglycemia 
requiring treatment 
34. Any factors that, in the opinion of the site principal investigator or clinical protocol chair, would 
interfere with the safe completion of the study, including medical conditions that may require 
hospitalization during the trial  
 
VI. c. Sources of Subjects 
Volunteers who fit the selection criteria will be considered as candidates for this study. We will contact 
individuals who have previously inquired about participation in our studies and have asked us to have 
their contact information kept on file. In addition, advertisements for the study may be posted at the 
MGH Diabetes Center and other places, and may be distributed in the weekly broadcast email of research 
studies seeking volunteers. A letter may be sent to adult endocrinologists in the Boston metropolitan area 
as well as selected nearby endocrinologists informing them of the study and asking them to refer to any 
eligible patients who might be interested. We will post information about the trial along with contact 
information on our website www.bionicpancreas.org and on www.clinicaltrials.gov. 
 
No individuals will be excluded based on gender or race.  An equal gender distribution between males and 
females is anticipated.   
 
V. Subject Enrollment 
V. a. Number of Subjects 
It is expected that we will have 10 subjects complete the study with a consistent protocol. We expect that 
the experiments and the analysis can be accomplished over a period of 6-12 months. Up to 20 subjects 
will be enrolled. The upper bound is based on the expectation that some volunteers will be excluded after 
the screening visit and the possibility that some experiments may have to be discontinued before 
completion (due to, for instance, intercurrent illness or subject withdrawal). Each subject will have up to 


Version 2, February 21st, 2019  
 
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two designated contacts enrolled who will serve as an emergency contact for the participant, and 
complete questionnaires based on their experience with the bionic pancreas. Therefore, total enrollment 
for the study including these partners will be 60. 
 
V. b. Enrollment and Consent Procedures 
Prospective participants will be briefed by a study staff member by phone or by e-mail regarding the study 
procedure and the inclusion and exclusion criteria. Potential subjects will be sent an informed consent 
document by mail, fax or e-mail.  
 
Once potential subjects have had time to review the consent document, they will meet with a study 
provider (MD or NP) that will explain the study, answer any questions, and administer informed consent 
prior to any data collection or study-specific procedures. If a volunteer is a patient of one of the study 
MDs or NPs, another staff MD or NP will answer questions and administer consent. A licensed physician 
investigator will be available to speak with the subjects during the consent process in the event of an NP 
administering consent. The principal investigator will be responsible for assuring that the informed 
consent process is properly followed and that each study participant is well informed about the study and 
the participant’s responsibilities. 
 
Once identified by enrolled subjects, designated contacts will be sent a consent form to review. They will 
then meet with a member of the study team (RN, NP or MD) in person or over the phone that will explain 
their role, answer any questions and administer informed consent prior to any data collection. A licensed 
physician investigator will be available to speak with the subjects during the consent process in the event 
of an RN or NP administering consent. The principal investigator will be responsible for assuring that the 
informed consent process is properly followed and that each partner is well informed about the study and 
their responsibilities. 
 
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 may choose to discontinue participation at any time.  
 
VI. Study Procedures 
VI. a. Screening Data 
Subjects 
 
Age 
 
Sex 
 
Race and ethnicity 
 
Date of last menstrual period in female pre-menopausal females 
 
Date of diabetes diagnosis 
 
Medical, surgical, and social history, allergies and review of systems relevant to inclusion and 
exclusion criteria 
 
Medication (prescription and non-prescription) and date of last change in medication regimen 
 
Duration of insulin pump use 
 
Type of insulin used in pump 
 
Average total daily dose of insulin in the last 30 days 
 
Usage of CGM (type of CGM, days per month worn, usage of data, whether insulin dosing is based 
on CGM alone, alarm settings) 
 
Assessment of impaired awareness of hypoglycemia 
 
Height and weight 


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 
Blood pressure 
 
Heart rate 
 
EKG  
 
Urine HCG (if applicable) 
 
Hemoglobin A1c 
 
Fractionated metanephrines (if applicable) 
 
Designated Contacts: 
 
Age 
 
Sex 
 
Race and ethnicity 
 
Contact information (i.e. e-mail address, mailing address) 
 
VI. b. Drugs 
The study involves subcutaneous administration of insulin lispro (Humalog, Eli Lilly) or insulin aspart 
(Novolog, Novo Nordisk). Humalog and Novolog are commercially available by prescription and are 
indicated for patients with type 1 diabetes, but not for use in a bionic pancreas.  
 
The study also involves subcutaneous administration of the glucagon analog, dasiglucagon. Dasiglucagon 
will be made available by Zealand Pharma A/S, Denmark as liquid formulation of 4 mg/mL in 1 mL prefilled 
cartridges. Dasiglucagon is a peptide analog of human glucagon that is being developed to treat 
hypoglycemia in patients with insulin-treated diabetes mellitus. Dasiglucagon exhibits improved physical 
and chemical stability in aqueous media and is suitable for liquid formulation. Dasiglucagon is comprised 
of 29 amino acids and has 7 amino acid substitutions when compared to native glucagon. 
 
The iLet bionic pancreas system can administer bolus doses of each drug up to every five minutes. A single 
autonomous bolus of insulin will not exceed 3 units per 5-minute dose [30 µl] (except when it is in 
response to an isolated BG entry, where the dose will not exceed 12 units [120 µl]) and a single meal-
priming dose, which is triggered by the user but automatically determined by the control system, will not 
exceed 18 units [180 µl]. A single bolus of glucagon will not exceed 80 µg [20 µl]. The iLet can administer 
as little as 0.10 µl (0.01 units of U-100 insulin) in single bolus doses. Insulin exposure is expected to be 
comparable to that of participants when not participating in the study. It is expected that the total daily 
dose of glucagon will be < 1.0 mg daily as in previous studies. The recommended dose of glucagon for 
adult patients suffering from severe hypoglycemia is 1 mg as a single injection. Mean glucagon levels in 
our previous inpatient studies have been above the normal fasting range for glucagon only 1% of the 
time.  The mean daily glucagon dose in a previous 7-day outpatient study using the bihormonal BP at a set 
point of 100 mg/dl was 0.58 mg/day (range 0.20-0.90 mg/day). Our previous data using the bihormonal 
BP at a set point of 110 mg/dl, which will be used in this study, resulted in a mean daily glucagon dose of 
0.41 mg/day (range 0.15-0.78 mg/day).  The total dasiglucagon dose delivered over the 8-hour period of 
our in-clinic study was 0.59 mg (range 0.28-1.33 mg) compared with 0.73 mg (range 0.35-1.33 mg) Lilly 
Glucagon. Therefore, the glucagon exposure of subjects is expected to be modest.  
 
Subjects will also be provided with an emergency glucagon kit, for treatment of severe hypoglycemia as 
needed.  
 
VI. c. Devices 
Infusion Sets: Participants will be provided with leur lock compatible infusion sets for both study arms. 
Participants will be instructed to replace both their glucagon infusion and their insulin infusion set every 


Version 2, February 21st, 2019  
 
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other day throughout the study. If the infusion set fails for any reason during the experiment it will be 
replaced promptly.. 
 
Continuous Glucose Monitors: One transcutaneous glucose sensor for the Dexcom G5 will be inserted in 
the subcutaneous tissue 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 iLet. If the Dexcom G5 CGM sensor fails for any reason 
during the experiment it will be replaced promptly. The G5 sensor will be replaced at least every 7 days. 
 
iPhone: The Dexcom G5 app is installed and will run on a stock iPhone. The Dexcom G5 app captures CGM 
glucose values via Bluetooth Low Energy from the transmitter worn on the body. The Dexcom G5 CGM 
app on the iPhone allows for calibration and maintenance of the sensor session.  
 
iLet Bionic Pancreas Control Unit: The Gen 3.2 iLet bionic pancreas system receives the same CGM 
glucose values from the Dexcom transmitter worn on the body. The iLet has an integrated graphical user 
interface (GUI) and touchscreen display that displays the current CGM glucose, a graphical history of the 
CGM glucose, and doses of insulin delivered by the control algorithm. The GUI can also be used to input 
optional meal announcements, designating the size of the meal as “Large for Me” “Typical for Me”, “Small 
for Me”, or “Tiny for Me”, and the mealtime as the “Start”, “Middle”, “End”, or “Sleeping” periods of the 
day. This will trigger a partial meal-priming bolus, the size of which will adapt throughout the course of 
the trial to meet a target of 75% of the insulin needs for that size and mealtime. Participants will be 
instructed to announce meals in the same way when using the insulin-only and bihormonal configurations 
of the iLet.  
 
 
The factory-set “usual” glucose target level for the bionic pancreas in the bihormonal mode is 110 mg/dl, 
and in the insulin-only mode is 120 mg/dl. A higher (+10 mg/dl) or lower glucose target (-10 mg/dl) can be 
set indefinitely as the “usual” target, or as “temporary” for a limited time with automatic expiration, or as 
“recurring” with automatic renewal and expiration times. When a temporary target is set, or when a 
recurring target period is on, upon expiration the target will revert to the currently chosen usual glucose 
target.  Although our previous studies showed that the bionic pancreas decreased hypoglycemia and the 
need for carbohydrate interventions relative to usual care, this will allow participants to raise the glucose 
target for additional safety, particularly temporarily during periods when hypoglycemia may become 
problematic, such as when driving or otherwise unable to check or attend to their BG for a period of time, 
or during periods when hypoglycemia is more likely, such as during exercise. It may also be used to raise 
the mean BG if the mean is unnecessarily low and the user prefers to further reduce the risk of 
hypoglycemia.  
 
For the purposes of this trial, the default target will be set at 110 mg/dl for both arms so that any 
difference in outcomes associated with the use of the bihormonal system vs. the insulin-only system will 
not be obscured by a difference in the target. Subjects must not change the permanent target without 
consulting with the study team. A change in the permanent target will be made only if, in the judgement 
of the principle investigator, this is important for subject safety. For example, the permanent target may 
be raised in an individual subject if there is excessive hypoglycemia, glucagon utllization, or need for 
carbohydrate treatment for hypoglycemia at the 110 mg/dl target. This is consistent with the intended 
clinical use of the iLet, in which a health care provider will consult with the user on the appropriate target. 
Subject may use the temporary target feature, but will be encouraged to use it only for short periods and 
for specific situations, such as exercise.  
 
The user will have the option during the bihormonal bionic pancreas arm to trigger the administration of a 


Version 2, February 21st, 2019  
 
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glucagon dose, intended to be used prior to device disconnection (e.g. for taking a shower or for 
swimming). The size of the glucagon dose will be automatically determined by the bionic pancreas based 
on the subject’s body mass and will be between 40 and 80 micrograms. This option will provide a means 
for subjects to raise their BG if they anticipate they will be at risk for hypoglycemia during a period of 
disconnection, based on their glucose level and glucose trend at the time. 
 
During periods when the CGM is offline, such as after a sensor is replaced and before the new sensor has 
been calibrated, the control algorithm will determine and direct the administration of insulin basal rates 
either based on the participant's weight in the first 24 hours of 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 user will also be able to enter meal announcements 
in the GUI, in order to trigger automatically calculated meal boluses, in the same way as when the CGM 
was online. Finally, the user can trigger an automated correction bolus during such periods by entering a 
BG value in the GUI. The controller will administer insulin or decrease basal insulin as appropriate, in 
response to entered BG values during such CGM-offline periods, to a large extent as if the BG values were 
CGM values. 
 
The device also displays visual alarms, sounds audible alarms, and generates vibration alarms for 
problems with the functioning of the bionic pancreas.   
 
Ascensia Diabetes Care Contour Next One Glucose Meter:  The Contour Next One glucometer is FDA 
approved and commercially available. Blood glucose measurements for Dexcom CGM calibrations and 
other required BG measurements will be obtained via finger stick with the Contour Next One in all study 
arms. 
 
Abbott Precision Xtra Ketone Meter: The Precision Xtra ketone meter is FDA approved and commercially 
available. Blood ketone measurements will be obtained via fingerstick using the Precision Xtra ketone 
meter in all study arms. 
 
 
VI. d. Experimental Procedures and Data Collection 
VI. d. i. Screening Visit 
 
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.   
 
A urine pregnancy test will be performed in pre-menopausal female volunteers. If the test is 
positive the volunteer will be informed of the result and the visit will be ended. 
 
Height, weight, heart rate and blood pressure will be measured. An EKG will be performed. 
 
If the volunteer is not excluded based on historical criteria, blood pressure, EKG or urine 
pregnancy test, blood will be drawn for hemoglobin A1c, and fractionated metanephrines if 
applicable. A study MD or NP will review the case report form to determine subject eligibility. If 
subjects are not eligible to continue in the study the results of abnormal tests will be reported to 
the subjects and to a health care provider of their choosing.  
 
A questionnaire will be administered to assess impaired awareness of hypoglycemia. 
 
Subjects who have been screened and are eligible can participate without having to be re-screened 
for a period of 3 months. The study staff should verbally confirm that there have been no health 
events that would make them ineligible at every study visit, and rescreen subjects for eligibility if it 
has been greater than three months.  
 
Once enrolled, subjects will identify up to 2 designated contacts (caregivers/family 


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members/friends) who are willing to serve as an emergency contact for the participant, requiring 
them to answer phone calls and check on the participants wellbeing as needed. If possible, they 
would also be an appropriate person to answer questionnaires about their experiences and 
attitudes towards the subject’s diabetes and the impact of the bionic pancreas.  
o Study staff will confirm the designated contacts are able to provide informed consent and 
are willing and able to serve as an emergency contact, and can recognize and treat 
hypoglycemia. If possible, they will confirm the contacts also have an appropriate 
relationship with the study participants to answer these questionnaires. Informed consent 
will be obtained from these contacts, and study staff will collect basic demographic 
information (age, sex, race/ethnicity) as well as contact information.  
o All designated contacts will be trained in the symptoms of hypoglycemia and response to 
severe hypoglycemia, including the administration of glucagon. They will also be trained to 
recognize the symptoms of hyperglycemia, and when to contact study staff and local EMS. 
o Designated contacts will complete two validated questionnaires, the Diabetes Distress 
Scale and the INSPIRE AID, which are both designed to be completed by partners. These 
questionnaires will be completed at baseline, and at the end of each study arm. 
 
They will have the option to complete these forms in person at a study visit, or 
online using RedCap.  
 
VI. d. ii. Randomization of Visit Order 
Once the subject has been enrolled and eligibility has been established, subjects will be randomized to 
one of two possible visit schedules. 
 
VI. d. iii. General Policies and Protocols for Days 1-7 of Both Study Arms 
 
Subjects will remain within a geographic boundary established based on 250 miles from the 
designated base for study personnel at all times and will avoid any air travel.  
 
Subjects will keep a charged mobile phone on their person (or at their bedside) at all times and will 
answer calls from the study staff.   
 
Study subjects will keep a Contour Next One glucometer easily accessible at all times in case a 
calibration is needed, and they will do all calibrations with this meter. They will keep a glucometer, 
fast-acting carbohydrates, and a glucagon emergency kit easily accessible at home for 
hypoglycemia as needed.  
 
Subjects should use the study provided Contour Next One glucometer for all BG checks throughout 
the study. They are encouraged to check their BG at least four times a day, before meals and before 
bedtime. They will also be encouraged to check before exercise and at intervals during exercise, 
and for any symptoms of hypoglycemia. There are no restrictions on additional checks and subjects 
should check as often as they wish to confirm the accuracy of the Dexcom CGM and for safety.  
 
Subjects will wear the study provided 6 mm steel cannula (Contact Detach) infusion sets throughout 
the study. If the subject is known not to tolerate steel infusion sets or are found not to do well with 
them during the study, then an alternative infusion set may be used. 
 
Subjects will not use any recreational drugs or drugs of abuse, other than alcohol. The need to take 
prescription drugs that dull the sensorium, reduce sensitivity to symptoms of hypoglycemia, or 
hinder appropriate decision-making may be grounds for exclusion from the trial or discontinuation 
of participation, a decision that will be made by the principal investigator. 
 
Subjects may not take acetaminophen throughout the study due to potential interference with 
CGM sensing. Acetaminophen is known to interfere with the accuracy of the Dexcom CGM.   
 
Subjects will contact study staff before taking any new drugs. Subjects may not take any drugs 
known to cause torsades de pointe or bradycardia throughout the study.  


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 
Subjects will not tamper with the bionic pancreas device in any way, including changing any 
settings.  
 
Subjects will keep their iPhone charged, which will require charging at least once per day. In 
addition, subjects will change the iLet batteries every two days and use only Lithium AAA batteries. 
Alkaline batteries should be avoided unless they are needed temporarily until lithium batteries can 
be placed. Subjects may change their batteries more frequently as needed.  
 
The bionic pancreas is not water resistant and therefore must be removed for showering. Subjects 
are urged to take appropriate precautions when they are disconnected from the bionic pancreas, 
including frequent BG checks and having carbohydrates readily available.  
o The Dexcom CGM transmitter is water resistant and can be left on for bathing and 
swimming.  
o Subjects may not remove the bionic pancreas for more than 1 hour at a time (e.g. for 
bathing) and may not remove it for more than 2 hours total in any 24-hour period.   
 
Any medical advice needed by the subjects during their participation, which is not directly related 
to BG control during the experiment, should be obtained by them in the usual manner with their 
primary care physician or endocrinologist.  
o If a subject develops an illness during the experiment, they can seek medical care as usual. 
As long as the subject is not hospitalized, the study can be continued. If the subject is unable 
to eat for a period exceeding one day, they must notify study staff so that the medical staff 
can assess the safety of continuing in the study. 
 
Subjects may participate in any activities that they wish, as long as they abide by the policies above.  
 
There are no restrictions of any kind on diet or exercise, although subjects should attempt to 
maintain similar dietary habits and exercise habits during each arm of the study. The bionic 
pancreas must be kept dry during exercise.  
 
Participants in both study periods will complete a web-based questionnaire daily.  Participants will 
be asked to report certain events occurring during the prior day such as hypoglycemia, other 
medical conditions, alcohol use, exercise, and use of a personal CGM as a part of usual care. In 
addition, events during the prior 24 hours including nausea and/or vomiting will be solicited. 
 
Participants will be encouraged to announce the three major meals of the day to the iLet in both 
arms. The meal announcement will consist of choosing the timing of the meal relative to one’s 
regular sleep period (first of the day, middle of the day, end of the day, or during what would be 
regular sleep hours if one occasionally happens to be up) and the size of the meal relative to 
typical meals for that participant (snack, smaller than typical, typical, larger than typical). 
Participants will be trained not to announce snacks that occur between major meals.  
 
The subjects will calibrate the Dexcom CGM twice daily, preferably before breakfast and supper 
using the Contour Next One. 
o Subjects will be advised to delay calibration if there is a steep rise or fall in the blood 
glucose (>2 mg/dl/min), if they got a dasiglucagon dose in the last 15 minutes, or if there 
has been carbohydrate intake in the last 30 minutes. In the immediate aftermath of 
glucagon dosing or carbohydrate intake, it is possible for the 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. 
o Subjects may perform additional calibrations if the Dexcom CGM is inaccurate relative to 
a BG measurement as long as they do not calibrate within 30 minutes of food intake. 
Subjects will be discouraged from performing extra calibrations if the Dexcom CGM 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. They will also be trained to understand that the apparent 
error can be higher than this when the BG is changing rapidly, and that it is typical for the 


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Dexcom CGM to underestimate BG when the trend is upward and to overestimate BG 
when the trend is downward as a result of physiologic lag. Errors in these directions 
should typically not prompt extra calibrations unless they are very large (≥ 50%). 
 
Subjects may choose to withdraw from the study at any time. If they withdraw from the study, they 
should contact a provider immediately who will help them transition to their own insulin regimen 
safely. 
 
Subjects will be asked to change their insulin infusion set and reservoir at least every other day 
throughout the study.  
 
Subjects will be asked to change their glucagon infusion set at least every other day throughout 
the study. Dasiglucagon is stable in the reservoir for more than seven days, so it may not need to 
be replaced during the study. Subjects will be provided with an extra reservoir to use as needed.  
 
Subject will be instructed to change the iLet batteries every two days, or sooner as needed.  
 
A new Dexcom G5 CGM sensor will be placed every 7 days if no replacement was required before 
this time. The Dexcom G5 app will generate an alarm when replacement is required. 
o If the CGM sensor fails during the experiment, the system will provide automated basal 
insulin based on past requirements, and will allow announcement of meals (with 75% of 
predicted insulin delivered based on past requirements), and entry of fingerstick BG 
measurements (which will be treated as CGM data and may result in administration of 
insulin or temporary suspension of basal insulin). The system will alarm and request a BG 
measurement every two hours when the CGM signal is not available, but the system will 
remain in closed-loop mode even if CGM data are not available. The CGM sensor will be 
replaced as soon as possible and normal (online) iLet control will resume when the new 
sensor is calibrated.  
 
If there is a technical fault with the iLet, the participant will call the technical support line 
immediately. If necessary, a staff member will meet the participant to assist with troubleshooting. 
This meeting may be delayed until morning if the problem occurs overnight - in this case, the 
participant will use their own pump or use injectable insulin until a meeting is possible. A member 
of the study staff (within their scope of practice and under the supervision of the site principal 
investigator) may advise them on how to manage their diabetes in the interim. If necessary, the 
iLet device may be replaced.  This should occur in most cases within 12 hours. Staff will not go 
into subjects’ houses or other non-public places; nor will they go to any place to meet the subject 
that is not public or where they do not feel safe. 
o If there is a complete failure of iLet operation and it is anticipated that restarting it will 
take more than an hour, participants may revert to usual care using their own insulin 
pump or with insulin injections until the iLet can be brought back online with the help of 
study staff. Every effort should be made to correct the problem as soon as possible, which 
should almost always be possible within 12 hours. 
 
Participants will not change the default glucose target of the bionic pancreas without consulting 
with the study staff.  
 
Participants may use the temporary target feature of the bionic pancreas but should use for for 
limited periods and for a specific purpose, such as exercise.   
 
Local Alarms 
 
All alarm settings will be the same in both study arms.  
 
Alarms will sound and a visual alert will appear on the screen of the G5 mobile app when the CGM 
glucose is ≤ 70 mg/dl and the iLet will alarm when the CGM glucose is ≤ 50 mg/dl.  
o Participants will be trained to test their BG with the study glucometer in response to such 
an alarm and take any necessary measures to treat hypoglycemia. 


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o Participants will be trained on troubleshooting for various scenarios that could lead to low 
threshold alarms. For instance, a threshold alarm could be due to true hypoglycemia, 
inaccurate CGM readings, or a compression artifact at the site of the sensor.  
 
The first step for all glucose-related alarms will be to perform a fingerstick BG 
measurement with the study provided glucometer (provided).  
 
If the BG measurement is not consistent with the fact that a threshold alarm has 
occurred, then the participant will assess the accuracy of the CGM, and the 
possibility of a compression artifact (they will be trained in the causes and 
recognition of these events). If a compression artifact is suspected, they will take 
steps to relieve the pressure on the transmitter. If no compression is suspected, 
the participant will calibrate the CGM. 
 
If the BG measurement is consistent with a low threshold alarm, the participant 
will treat hypoglycemia with carbohydrate ingestion according to their usual 
practice. Study staff will recommend the standard of care, 15 grams of rapid 
acting carbohydrates and re-testing BG in 15 minutes. Study staff will recommend 
the participant continue to monitor their BG until it returns to normoglycemia, 
and to contact study staff with any questions or concerns. 
 
Participants will be asked to investigate their dasiglucagon infusion set and 
consider replacing it, check for any occlusions along the fluid path, and check to 
make sure that the cartridge is not empty.  
 
Alarms will sound and a visual alert will appear on the Dexcom CGM app if CGM glucose is > 250 
mg/dl.  
o Participants will be trained to test their BG with the study glucometer and the ketone level 
with the study ketone meter (provided) in response to such an alarm and take necessary 
measures to treat the hyperglycemia.  
o Participants will be trained on troubleshooting for various scenarios that could lead to 
persistent or severe hyperglycemia. For instance, hyperglycemia could be due to true 
hyperglycemia (caused by a missed insulin dose or a failed infusion set for example) or 
inaccurate CGM readings.  
o The first step in responding to severe or persistent hyperglycemia according to the CGM 
will be to perform a fingerstick BG and, if necessary, ketone measurement.  
 
If the BG measurement is not consistent with the CGM readings, the participant 
will calibrate the CGM.  
 
If the BG measurement is consistent with the CGM readings: 
 
Participants will be asked to investigate their insulin infusion set and 
consider replacing it, check for any occlusions along the fluid path, and 
check to make sure that the cartridge is not empty.  
 
Study staff will recommend the participant continue to monitor their BG 
until it returns to normoglycemia, and to contact study staff with any 
questions or concerns.  
o If ketones >0.6 mmol/L are present: 
 
Participants will be advised to change their pump infusion set and will be reminded 
that the BP should dose insulin accordingly. 
 
Study staff will recommend the participant continue to monitor their ketone levels 
and BG every 60 minutes until ketones return to < 0.6 mmol/L and BG is < 180 
mg/dl, and to contact study staff with any questions.  
o If participants experience persistent hyperglycemia lasting more than 2 hours, they will be 
instructed to contact study staff for consideration of infusion set replacement and/or 
correction insulin according to the above protocol.  


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Remote Monitoring Protocol 
 
All remote monitoring will be the same in both study arms.  
 
Real-time remote telemetric monitoring for biochemically severe hypoglycemia or persistent 
hyperglycemia will be performed by the study staff 24 hours a day. There will be at least one 
provider (MD, NP, or PA) on call at all times. Additional study staff members may assist with on call 
duties. A staff member will make contact with participants as necessary and help them 
troubleshoot any issues that may arise.  
 
When an alert comes in, a study staff member will call the participant. Depending on the 
circumstances, they may call locations the participant is known to frequent (e.g. usual work 
location) or they may be dispatched to make contact with the participant (if the location is nearby 
and reaching the location would be no risk to the safety of staff member or violate employment 
rules).  
 
If study staff are not able to get in contact with the participant, they may contact the designated 
contact. These designated contacts should have access to where the participant may be sleeping if 
necessary. 
 
Remote monitoring is only possible when the participant has Verizon network coverage and data 
can be transmitted to the cloud service.  There may be times when a participant enters an area 
where Verizon coverage is not available.  We may also encourage participants to connect to public 
but secure wireless networks if they are having trouble connecting to cellular service. 
 
An alert will be generated if remote monitoring indicates that a participant is offline.   
o If there are no indications of device malfunction as the cause for lost connectivity, the 
glucose level is in safe range, and a participant chooses to remain in an area with poor 
network coverage, we will instruct the participant to check the iLet display or CGM at least 
every 20 minutes for alert icons and to be aware that we are unable to monitor for severe 
lows or highs at this time.  
o We will call the participant every 2 hours to check on safety and device function until 
remote monitoring is restored.   
o The same rules will be used for checking in when the participant in both study periods. 
 
The remote monitoring system will generate an alarm if the CGM glucose is < 50 mg/dl for 15 
minutes.  
o Study staff will verify the participants are aware of the hypoglycemia and taking action to 
treat it. Participants will be reminded of the protocol for hypoglycemia, and the study 
provider will ensure they understand and will follow study procedures. Participants will be 
encouraged to follow up with any questions or concerns. All contact with the participants 
in response to hypoglycemia alarms will be documented.  
o In the case of a low threshold alarm with no response from the participant and no success 
in locating them or their designated contact, the site principal investigator will be 
immediately informed. If remote monitoring shows ongoing hypoglycemia, a decision may 
be made to dispatch emergency medical services to the locations the participant is known 
to frequent. 
o Remote monitoring for hypoglycemia will be the same in both study periods. 
 
The remote monitoring system will generate an alarm if the CGM glucose is > 300 mg/dl for 90 
minutes.  
o Participants will be reminded of the protocol for prolonged hyperglycemia, and the study 
provider will ensure they understand and will follow study procedures. Participants will be 
encouraged to follow up with any questions or concerns. All contact with the participants 
in response to hyperglycemia alarms will be documented. 


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o Remote monitoring for hyperglycemia will be the same in both study periods. 
 
VI. d. iv. Visit Procedures 
Day 1 Visit: 
Participants may be trained on the operation of the all study devices in a group setting or may be trained 
one-on-one. Both the participant and the study staff must be satisfied that the participant is comfortable 
with the operation of all study devices before he/she begins the study. Additional training sessions may 
be arranged as needed.  
 
 
Participants will complete their baseline psychosocial questionnaires 
 
Their body weight, heart rate and blood pressure will be documented 
 
Blood will be drawn for a chemistry panel and complete blood count, and a baseline assessment 
of anti-drug antibodies.  
 
Study staff will review any changes in the participant’s medical history or medications to ensure 
continued eligibility, and any adverse events that may have occurred since their screening visit. 
Study staff will specifically ask subjects if they had any infusion site reactions or other skin 
irritation in the past 7 days, and will document any reactions.  
 
Participants will be trained on the insertion and use of the Dexcom G5 CGM. Participants will 
insert their own CGM sensor and study staff will confirm they are doing it correctly.  
 
Study staff will review all study procedures and policies (including the use of the Dexcom G5, the 
Contour Next One, the Precision Xtra ketone meter, and the iLet device) and the upcoming visit 
schedule.  
 
The Dexcom G5 will be calibrated by the participant using the Ascensia Contour Next One SMBG 
glucometer, and study staff will confirm they are doing it properly. 
 
Participants will be trained on the use of the iLet. 
 
The control algorithm will be initialized with the participant’s current weight 
 
The participant will remove his/her own insulin infusion pump and the participant will set up and 
start the iLet under the supervision of study staff. Participants will be instructed to not take any 
further insulin outside of the iLet throughout the study.  
 
The staff will confirm that the iLet is functioning properly prior to discharging the participant.   
 
All participants will be given Dexcom G5 CGM sensors, an Ascensia Contour Next One SMBG 
meter with test strips, ketone meter with strips, insulin, dasiglucagon for the bihormonal study 
arm, a glucagon emergency kit, an iLet, iLet pigtail adapters and Contact Detach infusion sets (an 
alternate infusion set may be supplied if the subject is known not to do well with the Contact 
Detach).  
 
Day 7/Day 1 Visit: 
 
There may be no washout between the two study arms or the washout period may be up to 7 
days.  
 
At the end of the first 7-day arm, subjects will return to the clinic and answer the post 
questionnaires for the study arm.  
 
The body weight, heart rate and blood pressure of the subject will be documented 
 
Blood will be drawn for a chemistry panel and complete blood count.  
 
Study staff will review any changes in the participant’s medical history or medications to ensure 
continued eligibility, and any adverse events that may have occurred since their last study visit. 
Study staff will specifically ask subjects if they had any infusion site reactions or other skin 
irritation in the past 7 days, and will document any reactions. 
 
The iLet and the study glucometer will be downloaded. The memory of the iLet will be wiped and 


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it will be re-initialized for the next study period.  
 
Participants will replace their CGM sensor and calibrate when prompted if they haven’t already.  
 
Study staff will review all study procedures and policies (including the use of the Dexcom G5, the 
Contour Next One, and the iLet) and the upcoming visit schedule.  
 
The control algorithm will be initialized with the participant’s current weight. The participant will 
set up and start the iLet under the supervision of study staff. Participants will be instructed to not 
take any further insulin outside of the iLet throughout the study.  
 
The staff will confirm that the iLet is functioning properly prior to discharging the participant.   
 
All participants will be given additional supplies as needed.   
 
Final Day 7 Visit: 
 
At the end of the second 7-day arm, subjects will return to the clinic and answer the post 
questionnaires for the study arm.  
 
The body weight, heart rate and blood pressure of the subject will be documented. 
 
Blood will be drawn for a chemistry panel and complete blood count.  
 
An EKG will be performed. This EKG will be assessed relative to the baseline EKG to identify any 
potential changes.  
 
Any changes to medications or medical history and any adverse events that may have occurred 
since their last study visit will be documented. Study staff will specifically ask subjects if they had 
any infusion site reactions or other skin irritation in the past 7 days, and will document any 
reactions. 
 
The iLet and the study meters will be downloaded.  
 
All equipment will be collected and cleaned. The Dexcom G5 transmitter will be cleaned using the 
validated cleaning and disinfecting procedures. 
 
A study provider will review the last few hours of glucose trend data and insulin and dasiglucagon 
on board from the iLet, and assist the participants in resuming their usual diabetes management.  
 
Follow Up Visits 
 
Subjects will return for a follow up visit 10 days (± 3 days) after the final day 7. 
o Any changes to medications or medical history and any adverse events that may have 
occurred since their last study visit will be documented. Study staff will specifically ask 
subjects if they had any infusion site reactions or other skin irritation since their last study 
visit, and will document any reactions. 
o Blood will be drawn for anti-drug antibodies.  
o If the EKG on the final Day 7 visit showed any changes relative to the baseline EKG, an 
additional EKG will be performed at this follow up visit.  
 
Subjects will return for a second follow up visit 25 days (± 4 days) after the final day 7. 
o Any changes to medications or medical history and any adverse events that may have 
occurred since their last study visit will be documented. Study staff will specifically ask 
subjects if they had any infusion site reactions or other skin irritation since their last study 
visit, and will document any reactions. 
o Blood will be drawn for a chemistry panel, complete blood count, and anti-drug 
antibodies.  
 
VI. d. v. Response to Hypoglycemia 
 
The response to hypoglycemia will be the same in both arms. Subjects will be reminded that the 
iLet decreases insulin dosing in response to decreasing CGMG in both the insulin-only and 
bihormonal configurations. 


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 
The Dexcom G5 app will generate a local low glucose threshold alarm if the subject’s CGM value is 
≤70 mg/dl and the iLet will generate an alarm for a CGMG < 50 mg/dl. 
 
In all study arms subjects are encouraged to check their BG for any symptoms of hypoglycemia.  
 
Subjects are encouraged to treat hypoglycemia according their usual practice or according to the 
“rule of 15s”: take 15 grams of rapid acting carbohydrate and recheck in 15 minutes, then repeat 
as needed. Subjects will be reminded to check their glucagon infusion site and their bionic pancreas 
for normal operation anytime they experience hypoglycemia during the bihormonal arm. If there is 
any suspicion of glucagon infusion set malfunction, the site should be replaced.  
 
Subjects may contact a study provider (RN, MD or NP) for advice at any time, and may contact the 
troubleshooting support team, as they wish. Subjects will be assisted in checking the bionic 
pancreas for any malfunction and correcting any problems that are found.  
o 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 may be brought 
to the subject’s location by study staff. 
 
If a subject experiences severe hypoglycemia in the study, his or her participation in the study will 
be discontinued.  
 
VI. d. vi. Response to Hyperglycemia 
 
The response to hyperglycemia will be the same in both arms.  
 
The Dexcom G5 app will generate a local high glucose threshold alarm if the subject’s CGM value 
is > 250 mg/dl. Subjects will be instructed to check their insulin infusion site and their bionic 
pancreas for normal operation any time they get this alarm, or BG is greater than 250 mg/dl. If 
there is any suspicion of insulin infusion set malfunction, the site should be replaced. 
 
Subjects may contact a study provider (RN, MD or NP) for advice at any time, and may contact the 
troubleshooting support team, as they wish. Subjects will be assisted in checking the bionic 
pancreas for any malfunction and correcting any problems that are found.  
 
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 may be brought to the subject’s 
location by study staff. 
 
If a subject experiences diabetic ketoacidosis requiring hospitalization during the study, his or her 
participation in the study will be discontinued.  
 
VI. d. vii. Response to Nausea and Vomiting 
 
If significant nausea, nausea that prevents the subject from eating normally, or any vomiting 
occurs during either arm of the study, subjects will be encouraged to contact a study provider 
(MD or NP). They will document the report of nausea or vomiting.  
 
If this occurs during the bihormonal bionic pancreas arm, they may assist the subject in 
troubleshooting, such as checking the BG and the calibration of the Dexcom CGM (excessive 
glucagon dosing may occur if the Dexcom CGM is reading lower than the true BG). 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.  
 
VI. d. viii. Response to Other Medical Needs 
If the subject experiences any non-emergent medical concerns outside the scope of diabetes care, he or 
she will see their personal physician. If the subject experiences urgent or emergent medical concerns 
outside the scope of diabetes care and their primary care physicians, they should visit a walk-in clinic or 
emergency room, or if necessary call 911. 
 


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VI. d. ix. Monitoring of Bionic Pancreas Performance 
A Beta Bionics engineer will be readily available by phone for consultation at all times during the course of 
each experiment to assist with any needed troubleshooting.  
 
VI. d. x. Supervision by study staff 
A study provider (MD or NP) will be on call at all times during the course of all study arms. All trained staff 
will have the capability of remotely viewing diagnostic information to facilitate phone troubleshooting 
with subjects and decide whether additional assistance is needed. 
 
VII. Statistical Considerations 
VII.a Statistical Hypotheses 
The primary endpoint evaluates if the iLet system performs as designed, receiving CGM signals and 
delivering drug doses (insulin and, when applicable, glucagon) calculated by the control algorithm with an 
acceptable degree of reliability and accuracy. No formal test of the primary endpoint is planned. 
 
The null hypothesis tested for the key secondary endpoint is: 
 
The amount of hypoglycemia using the bihormonal configuration of the iLet is equal to the 
amount of hypoglycemia using the insulin-only configuration of the iLet. 
 
The proportion of time with CGM glucose < 54 mg/dl across days 2-7 estimates the amount of 
hypoglycemia. 
 
VII.b Sample Size Determination 
No formal statistical comparisons have been done for this study. This study is primarily intended to verify 
that the iLet is operating as expected (based on its design and on bench testing) in each configuration in 
the outpatient setting.  A sample size of 10 subjects in a crossover design is considered adequate for this 
purpose.  
 
VII.c Populations for Analyses 
Adult subjects (≥ 18 years old) with type 1 diabetes. 
 
VII.d Statistical Analyses 
VII.d.i General Approach 
An intention-to-treat analysis will be performed. Descriptive statistics will be used to summarize patient 
characteristics and assessments. No formal testing will be conducted to establish superiority. In general, 
all data will be summarized with descriptive statistics for each treatment group. Unless otherwise 
specified, continuous data will be summarized by presenting the number of non-missing observations, 
mean, standard deviation (SD), median, minimum, and maximum. Categorical data will be summarized by 
presenting the number of patients and percentage for each category. P-values can be displayed to aid 
interpretation, not for inference. Tables, figures and listings of all primary, secondary and safety 
endpoints will be created. 
 
Baseline and demographic data will be summarized using descriptive statistics.All comparisons will be 
between treatments within patients. Listings of individual patient data will be presented. 
 
Data from periods when the bionic pancreas was not in use will be included, if available (Dexcom CGM 
data may not be available in some failure modes). In cases where an arm was not completed we will use 
the available data from that arm in the data analysis. 


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VII.d.ii Analysis of the Primary Efficacy Endpoint 
The primary endpoint is whether the iLet operates as designed during the study arms.  An arm will be 
considered to have successfully met its primary endpoint if each of the following is true during the time 
that the iLet is powered on over the entire treatment period (days 1–7): 
 
1. The percentage of time that valid CGM glucose readings are captured by the iLet is ≥80%. Sensor 
warm-up periods, occasions of failed communication between the iLet and sensor–transmitter 
unit, or other sensor failure conditions are all counted as times when valid CGM glucose reading 
are not captured.  
2. The percentage of the time that each drug channel (insulin, and if applicable, glucagon) is 
available is ≥95%. A channel is considered to be available if a cartridge is successfully loaded, 
there is no pending occlusion alarm or other system failure to prevent attempting a delivery on 
that channel, and the cartridge is not yet considered empty.  
3. The ratio of cumulative drug doses delivered to cumulative drug doses attempted is between 0.95 
and 1.05, inclusive, for insulin and, if applicable, for glucagon. Attempted doses refer to calculated 
doses that are issued for delivery when the channel is available. Doses delivered refers to the 
dose amounts reported back by the motor controller after the delivery attempts are completed. 
 
If all three evaluations hold true for a patient’s treatment period, the patient-period is operationally 
successful. The proportion of patients that are operationally successful will be presented by pump type. 
 
VII.d.iii Analysis of the Secondary Endpoints 
The proportion of time spent with CGMG <54 mg/dl and the mean CGMG are analyzed using methods for 
paired data. The treatment means and mean difference between treatments will be estimated  together 
with the corresponding 95% confidence interval and compared using a paired t-test for normally 
distributed data or Wilcoxon signed-rank test for non-normally distributed data. Time <54 mg/dl and 
mean glucose will be computed from all available CGM data during days 2-7 for both study arms. 
 
All questionnaire data for patients who have completed a minimum of 4 days with a device will be 
included. Patients who do not complete a questionnaire will be excluded from the patient analyses. 
Results will be compared by Wilcoxon signed-rank test. 
 
VII.d.iv Safety Analyses 
No inferential tests of safety data will be performed. Descriptive summaries of safety data will be 
presented. Adverse events (treatment-emergent unless otherwise specified) will be presented by system 
organ class (SOC) and preferred term (PT) for each treatment group. Treatment-emergent AEs are defined 
as AEs with onset date on or after the first day of exposure to randomized treatment. 
 
VII.d.v Baseline Descriptive Statistics 
The number and percentage of patients who were screened, randomized, discontinued (with reason for 
discontinuation), and completed the trial will be summarized descriptively for all screened patients. 
 
VII.d.viii Tabulation of Individual participant Data 
Listings of individual patient data will be presented. 
 
VII.d.ix Exploratory Analyses  
The performance of the iLet in each period can be compared with historical data from previous bionic 
pancreas trials using previous generations of hardware. If the performance of the iLet in this study is 


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comparable to our previous data from trials using the iPhone-based bionic pancreas that will support the 
hypothesis that both configurations of the iLet are effective and safe implementations of the bionic 
pancreas. All participants with at least 24 hours of CGM data during days 2-7 of any treatments periods 
will be included in these analyses.  
 
We may, in exploratory analyses, also stratify subjects for secondary analyses of the pre-specified 
endpoints by subject characteristics including: sex, age, baseline A1c, usual care insulin total daily dose, 
body mass index, phase of menstrual cycle (follicular vs. luteal).  
 
VII. e Data Collected 
VII. e. i. Prior to the start of the experiment: 
 
Age 
 
Sex 
 
Race and ethnicity 
 
Date of last menstrual period in female subjects  
 
Date of diabetes diagnosis 
 
Medical, surgical, and social history, allergies, and review of systems relevant to inclusion and 
exclusion criteria 
 
Medications (prescription and non-prescription) and date of last change in medication regimen  
 
Duration of insulin pump use  
 
Type of insulin used in pump  
 
Average total daily dose of insulin in the last 30 days as available  
 
Usage of CGM (type of CGM, days per month worn, usage of data, whether insulin is dosed based 
on CGM alone, alarm settings) 
 
Height and weight  
 
Blood pressure 
 
Heart rate 
 
EKG 
 
Hemoglobin A1c 
 
Fractionated metanephrines, if applicable 
 
Urine HCG (pre-menopausal females) 
 
VII. e. ii. During study arms 
 
CGMG (CGM glucose) every five minutes from the Dexcom CGM  
 
All fingerstick BG measurements taken by the subject (meter download)  
 
Average glucose target used 
 
Insulin total daily dose from bionic pancreas download 
 
Glucagon total daily dose from bionic pancreas download 
 
Timing of meal announcements and size of meals announced from bionic pancreas download 
 
Time subjects were not under bionic pancreas control  
 
List of technical faults associated with the bionic pancreas including cause and resolution 
 
Body weight after each study arm 
 
Blood pressure after each arm 
 
Heart rate after each arm 
 
Skin reactions, if any, after each arm 
 
EKG after completion of the second arm, and at the first follow up visit if applicable 
 
Information collected from the daily email survey:  


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o Number of reported hypoglycemic events requiring carbohydrate intervention  
o Total grams of carbohydrates taken to treat hypoglycemia  
o Number of severe hypoglycemic events (defined as subject required assistance to treat)  
o Mean nausea severity from VAS  
o Number of unscheduled insulin cartridge/infusion set changes  
o Number of unscheduled glucagon cartridge/infusion set changes  
o Alcohol use (mean drinks per day)  
o Exercise duration and exposure (duration X intensity) 
 
Data from questionnaires about attitudes and expectations regarding the bionic pancreas at 
baseline and on day 7 of each arm. 
 
 
VIII. Risks and Discomforts 
Subjects may experience mild discomfort associated with the insertion of infusion sets and the Dexcom 
CGM sensor into the SC tissues. The risk of discomfort due to insertion of infusion sets and sensors may 
be greater than in their lives outside the trial because more infusion sets and sensors are required than 
are used in usual care.  
 
There is a risk of hypoglycemia. This risk is expected to be less than the risk during the subjects’ lives 
outside of the trial based on data from earlier trials. All of our previous studies have shown that 
hypoglycemia is significantly reduced in all configurations of the bionic pancreas when compared with 
usual care.  
 
There is a risk of hyperglycemia. This risk is expected to be less than the risk during the subjects’ lives 
outside of the trial based on data from earlier trials. All of our previous studies have shown that 
hyperglycemia is significantly reduced in all configurations of the bionic pancreas when compared with 
usual care.  
 
There is a risk of headache, nausea or vomiting due to the administration of exogenous glucagon. There is 
a possible risk of skin rash due to administration of exogenous glucagon. There may be risks of daily, low-
level glucagon administration that have not become apparent during trials lasting up to 11 days. Possible 
risks include changes in body weight, blood pressure or blood chemistries or blood counts, or 
development of anti-drug antibodies. The magnitude of the 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 fasted range in previous trials. Of note, the risk of nausea and vomiting 
has been low in prior studies. There may be other unknown risks associated with dasiglucagon.  
 
IX. Potential Benefits 
It is expected that this protocol will yield increased knowledge about using an automated closed-loop to 
control the glucose level.  This research is one step on the path towards development of a fully closed-
loop system, and is particularly important for establishing the safety and efficacy of a bihormonal system 
for larger and longer future studies.  The individual participant may not benefit from study participation. 
 
Based on evidence from previous trials of the bionic pancreas and the design of this trial, subjects enrolled 
in the study may benefit from a reduction in risk of hypoglycemia and hyperglycemia and a better mean 
glucose than they typically achieve.  
 
Subjects will be financially compensated for participating in the study.  
 
X. Data and Safety Monitoring 


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X. a. Monitoring of Source Data 
During the experiment, CGM data, insulin dosing data, and glucagon dosing data will be automatically 
stored in the bionic pancreas device (from which it will be downloaded at intervals). All of the 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.  
 
Study staff will be encouraged to raise any concerns they may have or problems they have identified at any 
time. The PI, in consultation with the co-investigators, will decide a course of corrective action, and 
resolution or progress will be assessed no later than the next meeting.  
 
An audit of procedures, regulatory documentation, and a sample of subject files will be performed by a 
member of the Diabetes Research Center at least biannually. The audit will be conducted by a staff member 
who is not directly involved in the conduct of the study. This audit will include a review of regulatory 
documentation, such as IRB and FDA correspondence, and a review of subject files, including a review of 
consents, case report forms, and other data from study visits.  
 
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. 
 
The study data will be shared with collaborators at Beta Bionics, Inc. and Zealand Pharma, but only in a form 
in which all personally identifiable information has been removed (e.g. combined database including BG 
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.  
 
X. b. Safety Monitoring 
This study is considered moderate risk. An external Data and Safety Monitoring Board (DSMB) will oversee 
the conduct of the study and review its results on a regular basis. Additionally, they will be informed of all 
serious adverse events and any unanticipated adverse device events that occur during the study and will 
review compiled safety data at periodic intervals.  The DSMB will be informed if there are any changes to 
the study protocol that could significantly impact the safety or scientific validity of the study. A final DSMB 
meeting will convene after the completion of the study. Safety and efficacy data will also be reported to 
the IRB and FDA in compliance with applicable regulations. 
 
The participation of individual subjects in the study will be discontinued if: 
 
Subjects experience one episode of diabetic ketoacidosis (DKA) requiring hospitalization 
o Hyperglycemic events will be classified as DKA if the following are present: 
 
Symptoms including but not limited to polyuria, polydipsia, nausea or vomiting 
 
Serum ketones > 1.5 mmol/L or large/moderate urine ketones 
 
Either arterial blood pH <7.30 or venous pH < 7.24, or serum bicarbonate < 15 
 
Treatment provided in a healthcare facility 
 
Subjects experience one episode of severe hypoglycemia, defined as requiring the assistance of 


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another person due to altered consciousness, and required another person to actively administer 
carbohydrate, glucagon or other resuscitative actions. This means the participant was impaired 
cognitively to the point that he/she was unable to treat himself/herself, was unable to verbalize 
his/her needs, was incoherent, disoriented, and/or combative, or experienced seizure or coma. If 
plasma glucose measurements are not available during such an event, neurological recovery 
attributable to the restoration of plasma glucose to normal is sufficient evidence that the event 
was induced by a low plasma glucose concentration.  
 
Subjects experience persistent nausea and vomiting thought to be related to glucagon dosing in 
the bi-hormonal bionic pancreas arm 
 
The investigator believes it is unsafe for the participant to continue in the study 
 
A participant becomes pregnant 
 
The participant requests that the study be stopped 
 
If more than 1 subject must be withdrawn from the study for severe hypoglycemia or DKA, the study will 
stop and a vote of the DSMB will be required to restart it. All serious and unexpected events will be 
reported to the DSMB within 72 hours.  
 
Study participation is voluntary, and participants may withdraw at any time. The investigator may 
withdraw a participant who is not complying with the protocol. For participants who withdraw, their data 
will be used up until the time of withdrawal. For participants using the iLet who withdraw, a study 
provider will help them transition to their own therapy safely. 
 
In case of a recurring system malfunction or participant safety issue observed with multiple participants, 
the overall study will be suspended while the problem is diagnosed.  The study may resume if the 
underlying problem can be corrected by a protocol or system modification that will not invalidate the 
results obtained prior to suspension. 
 
X. c. Adverse Event Reporting Guidelines 
Definitions 
An adverse event is defined as any untoward or unfavorable medical occurrence in a human subject 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or 
disease, temporally associated with the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research (modified from the definition of adverse events in the 
1996 International Conference on Harmonization E-6 Guidelines for Good Clinical Practice). 
 
Hypoglycemic events are recorded as Adverse Events (severe hypoglycemic event) if the event required 
assistance of another person due to altered consciousness, and required another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions. This means that the participant was 
impaired cognitively to the point that he/she was unable to treat himself/herself, was unable to verbalize 
his/ her needs, was incoherent, disoriented, and/or combative, or experienced seizure or coma. These 
episodes may be associated with sufficient neuroglycopenia to induce seizure or coma.  If plasma glucose 
measurements are not available during such an event, neurological recovery attributable to the 
restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by a 
low plasma glucose concentration. 
 
Hyperglycemic events are recorded as Adverse Events (severe hyperglycemic event) if the event involved 
DKA, as defined by the Diabetes Control and Complications Trial (DCCT) and described below, or in the 
absence of DKA if evaluation or treatment was obtained at a health care provider facility for an acute 
event involving hyperglycemia or ketosis.  


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Hyperglycemic events are classified as DKA if the following are present:  
 
Symptoms such as polyuria, polydipsia, nausea, or vomiting;  
 
Serum ketones >1.5 mmol/L or large/moderate urine ketones;  
 
Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15; and 
 
Treatment provided in a health care facility     
 
The PI and co-investigators will review any adverse events after each experiment to determine severity 
(serious or non-serious), expectedness (expected or unexpected) and relatedness (related, possibly 
related or unrelated).  The study investigator will assess the relationship of any adverse event to be 
related or unrelated by determining if there is a reasonable possibility that the adverse event may have 
been caused by the study intervention.  
 
To ensure consistency of adverse event causality assessments, investigators should apply the following 
general guideline when determining whether an adverse event is related: 
 
Related: There is a plausible temporal relationship between the onset of the adverse event and the study 
intervention, and the adverse event cannot be readily explained by the participant’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the adverse event follows a known pattern of 
response to the study intervention; and/or the adverse event abates or resolves upon discontinuation of 
the study intervention or dose reduction and, if applicable, reappears upon re-challenge. 
 
Possibly Related: Possibly related to the research means there is a reasonable possibility that the adverse 
event, incident, experience or outcome may have been caused by the procedures involved in the research 
(modified from the definition of associated with use of the drug in FDA regulations at 21 CFR 312.32(a)). 
Reasonable possibility means that the event is more likely than not related to participation in the research 
or, in other words, there is a >50% likelihood that the event is related to the research procedures 
 
Not Related: Evidence exists that the adverse event has an etiology other than the study intervention 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, or concomitant medication); 
and/or the adverse event has no plausible temporal relationship to study intervention.    
 
Serious adverse event means any event temporally associated with the subject’s participation in research 
that meets any of the following criteria:  
 
results in death 
 
is life threatening (places the subject at immediate risk of death from the event as it occurred) 
 
requires inpatient hospitalization or prolongation of existing hospitalization;  
 
results in a persistent or significant disability/incapacity 
 
results in a congenital anomaly/birth defect 
 
any other adverse event that, based upon appropriate medical judgment, may jeopardize the 
subject’s health and may require medical or surgical intervention to prevent one of the outcomes 
listed above (examples of such events include allergic bronchospasm requiring intensive 
treatment in the emergency room or at home, blood dyscrasias or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug abuse). 
 
Reporting Guidelines 
Any serious adverse events or unexpected but related or possibly related adverse events will be 
communicated to the PI as soon as possible and within 48 hours of the time they are detected.  Adverse 


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events will be reported promptly to the Partner’s IRB and to the BU IRB, the DSMB, Beta Bionics and 
Zealand Pharma. Collaborator Ed Damiano is the sponsor of the Investigational Device Exception (IDE) for 
the bionic pancreas to be used in this trial. Zealand Pharma is the sponsor for the Investigational New 
Drug (IND) application for dasiglucagon to be used in this trial. Reports of adverse events will be made to 
the FDA in compliance with the terms of IDE and IND.  
 
XI. Subject Compensation 
Financial compensation will be provided to all subjects who complete the screening visit. Subjects will be 
paid $25 for completing the screening visit whether or not they are eligible to participate in the study.  
 
Study participants will be compensated $50 for completing each study visit. Thus, the total compensation 
for a subject who completed screening and all five study visits would be $275.  
 
Parking expenses will be paid for up to $30 per subject for each visit. Subjects who are unable to complete 
the study or chose to stop participation will receive prorated compensation for the portion of the study 
visits that they complete. 
 
Designated contacts will be compensated $25 for completing the screening visit, $25 for completing the 
study, and $25 for completing their questionnaires. The total compensation available for designated 
contacts is $75.  
 
 
XII. References 
1. Russell SJ, El-Khatib FH, Sinha M, Magyar KL, McKeon K, Goergen LG, Balliro C, Hillard MA, Nathan 
DM, Damiano ER. Outpatient glycemic control with a bionic pancreas in type 1 diabetes. The New 
England journal of medicine. 2014;371(4):313-25.   
2. Russell SJ, Hillard MA, Balliro C, Magyar KL, Selagamsetty R, Sinha M, Grennan K, Mondesir D, 
Ehklaspour L, Zheng H, Damiano ER, El-Khatib FH. Day and night glycaemic control with a bionic 
pancreas versus conventional insulin pump therapy in preadolescent children with type 1 
diabetes: a randomised crossover trial. Lancet Diabetes Endocrinol. 2016;4(3):233-43.   
3. El-Khatib FH, Balliro C, Hillard MA, Magyar KL, Ekhlaspour L, Sinha M, Mondesir D, Esmaeili A, 
Hartigan C, Thompson MJ, Malkani S, Lock JP, Harlan DM, Clinton P, Frank E, Wilson DM, DeSalvo 
D, Norlander L, Ly T, Buckingham BA, Diner J, Dezube M, Young LA, Goley A, Kirkman MS, Buse JB, 
Zheng H, Selagamsetty RR, Damiano ER, Russell SJ. Home use of a bihormonal bionic pancreas 
versus insulin pump therapy in adults with type 1 diabetes: a multicentre randomised crossover 
trial. Lancet. 2017;389(10067):369-80.   
4. Balliro C, Ehklaspour L, Esmaeili A, El-Khatib FH, Mondesir D, Selagamsetty R, Hillard MA, Maheno 
M, Jafri RZ, Damiano ER, Russell SJ. Effects of Glucose Target on the Performance of a Bihormonal 
Bionic Pancreas. Diabetes. 2016; 65:A259-A259. 
5. Ehklaspour L, Esmaeili A, El-Khatib FH, Selagamsetty R, Damiano ER, Buckingham, BA. Unpublished 
results 2017. 
6. Balliro CA, Jafri1 RZ, Maheno M, Hillard MA, O’Donovan A, Selagamsetty R, El-Khatib FH, Damiano 
ER, Russell SJ. Withdrawal of Remote Real-time Telemetric Monitoring Increases Hypoglycemia 
During Usual Care But Not During Automated Glucose Management with an Insulin-only or 
Bihormonal Bionic Pancreas. Diabetes Technology and Therapeutics. 2018;20:A60. 
7. Jafri RZ, Maheno M, Balliro CA, El-Khatib FH, Væver Bysted B, Mouritzen U, Damiano ER, Russell 
SJ. The Stable Glucagon Analog Dasiglucagon is Well-tolerated and as Effective as Recombinant 
Human Glucagon When Delivered by the Bionic Pancreas in Response to Insulin Excess. Diabetes 
Technology and Therapeutics. 2018;20:A13. 


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8. Jafri RZ, Balliro CA, Sherwood JS, Hillard MA, Ekhlaspour L, Hsu L, Selagamsetty R, Costik J, Sloane 
JL,  Riddlesworth T, Buckingham BA, El-Khatib FH, Damiano ER, Russell SJ. Unpublished results 
2019.