Supervised Safety and Feasibility Evaluation of the Zone-MPC Control Algorithm Integrated Into the iAPS in Pregnant Patients With Type 1 Diabetes With Extension Into Outpatient at Home
Phase: NA
Conditions: Type 1 Diabetes, Pregnancy
Sponsor: Sansum Diabetes Research Institute

 
 
 
APPENDIX C 
 
Clinical Protocol 
 
IDE: G200099 
 
 
 

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Appendix C – Page 1   
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CLINICAL PROTOCOL 
 
Supervised Safety and Feasibility Evaluation of the Zone-
MPC Control Algorithm Integrated into the iAPS in 
Pregnant Patients with Type 1 Diabetes with Extension 
into Outpatient at Home 
 
 
Site Principal Investigators 
 
 
Harvard University/Sansum Diabetes Research Institute 
Eyal Dassau, PhD 
 
Sansum Diabetes Research Institute 
Kristin Castorino, DO 
 
Mayo Clinic Rochester 
Yogish C. Kudva, MD 
 
Mt Sinai Hospital, New York City 
Carol Levy, MD  
 
VERSION 2.1 
Date: November 30, 2021 
 
 

G200099                                                      Confidential 
 
Appendix C – Page 2   
   Contains trade secrets and/or confidential information exempt from disclosure from 21 CFR 20.61 
 
 
Name 
Function/  
Title 
Signature 
Date 
Prepared 
by 
Dr. Jordan 
Pinsker, MD 
Senior Research Physician,  
Sansum Diabetes Research 
Institute 
 
03/15/2021 
Approved 
by 
Dr. Eyal 
Dassau, PhD 
Senior Investigator & 
Diabetes Team Research 
Manager, John A. 
Paulson School of 
Engineering and Applied 
Sciences, Harvard 
University 
 
      
 
03/15/2021 
 
 
SPONSOR 
 Sansum Diabetes Research Institute  
Principal Investigator: Kristin Castorino, DO, BC-ADM.  
Senior Research Physician  
2219 Bath Street  
Santa Barbara, CA 93105  
Phone: 805-682-7640 
Fax: 805-682-3332 
 
 

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Table of Contents 
1 
EXECUTIVE SUMMARY ........................................................................................................................... 5 
2 
Background Information ........................................................................................................................ 5 
2.1 
Introduction ........................................................................................................................................ 6 
2.2 
Pregnancy and Automated Insulin Delivery ....................................................................................... 9 
2.3 
Results of G200099 48-Hour AP in Pregnancy Study Showing Safety and Efficacy ......................... 12 
3 
DESCRIPTION OF DEVICES .................................................................................................................... 13 
3.1 
Overview and hardware ................................................................................................................... 13 
A. 
Dexcom G6 (Study CGM) .................................................................................................................. 15 
B. 
Tandem t:AP Pump........................................................................................................................... 15 
C. 
Study Glucometer and Ketone Meter .............................................................................................. 16 
D. 
Phone Device .................................................................................................................................... 16 
3.2 
Control Algorithm with HMS ............................................................................................................ 16 
4 
STUDY OVERVIEW ................................................................................................................................ 17 
4.1 
Study Overview ................................................................................................................................ 17 
4.2 
Primary Objective ............................................................................................................................. 17 
4.3 
Secondary Endpoints ........................................................................................................................ 17 
5 
BACKGROUND INFORMATION ............................................................................................................. 18 
5.1 
General Background ......................................................................................................................... 18 
5.2 
Description of Population Studied ................................................................................................... 18 
6 
TRIAL DESIGN ....................................................................................................................................... 18 
6.1 
Overview .......................................................................................................................................... 18 
6.1.1 
Limitations on the Number of Subjects that can be Enrolled ..................................................... 18 
6.2 
Eligibility and Exclusion Criteria ....................................................................................................... 19 
6.2.1 
Inclusion Criteria .......................................................................................................................... 19 
6.2.2 
Exclusion Criteria.......................................................................................................................... 19 
6.3 
Schedule of Events ........................................................................................................................... 20 
6.4 
Screening Visit .................................................................................................................................. 24 
6.5 
Open Loop Data Collection .............................................................................................................. 24 
6.6 
Hybrid Closed-Loop Phase (~48-60 Hours) ...................................................................................... 25 
6.6.1 
Monitoring Frequency in the Closed-Loop Session ..................................................................... 27 
6.6.2 
Extension Phase ........................................................................................................................... 28 
6.6.3 
Pump Training .............................................................................................................................. 29 
6.6.4 
Study Phone Training ................................................................................................................... 29 
6.6.5 
General Usage Training and System Initiation............................................................................. 30 
6.7 
Remote Monitoring .......................................................................................................................... 31 
7 
ASSESSMENT OF SAFETY ...................................................................................................................... 32 
7.1 
Blood Volume Requirements ........................................................................................................... 32 
7.2 
Hypoglycemia and Hyperglycemia Prevention and Treatment ....................................................... 32 
7.3 
Potential Risks and Benefits of the Investigational Device .............................................................. 38 
7.3.1 
Known Potential Risks .................................................................................................................. 38 
8 
Adverse Events, Device Issues, and Stopping Rules ............................................................................ 41 
8.1 
Adverse Events ................................................................................................................................. 41 
8.1.1 
Definitions .................................................................................................................................... 41 
8.1.2 
Reportable Adverse Events .......................................................................................................... 42 

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8.1.3 
Relationship of Adverse Event to Study Device ........................................................................... 43 
8.1.4 
Intensity of Adverse Event ........................................................................................................... 43 
8.1.5 
Coding of Adverse Events ............................................................................................................ 44 
8.1.6 
Outcome of Adverse Event .......................................................................................................... 44 
8.2 
Reportable Device Issues ................................................................................................................. 45 
8.3 
Timing of Event Reporting ................................................................................................................ 45 
8.4 
Stopping Criteria ............................................................................................................................... 46 
8.4.1 
Participant Discontinuation of Study Device ............................................................................... 46 
8.4.2 
Criteria for Suspending or Stopping Overall Study ...................................................................... 46 
8.5 
Independent Safety Oversight ......................................................................................................... 47 
9 
Miscellaneous Considerations ............................................................................................................. 48 
9.1 
Drugs Used as Part of the Protocol .................................................................................................. 48 
9.2 
Prohibited Medications, Treatments, and Procedures .................................................................... 48 
9.3 
Participant Compensation ................................................................................................................ 48 
9.4 
Participant Withdrawal .................................................................................................................... 48 
9.5 
Confidentiality .................................................................................................................................. 48 
10 Data Collection and Monitoring .......................................................................................................... 48 
10.1 
Study Records Retention .................................................................................................................. 48 
10.2 
Quality Assurance and Monitoring .................................................................................................. 48 
10.3 
Protocol Deviations .......................................................................................................................... 49 
11 Ethics/Protection of Human Participants ............................................................................................ 49 
11.1 
Ethical Standard ............................................................................................................................... 49 
11.2 
Institutional Review Boards ............................................................................................................. 49 
11.3 
Informed Consent Process ............................................................................................................... 49 
11.3.1 
Consent Procedures and Documentation ............................................................................... 49 
11.3.2 
Participant and Data Confidentiality ....................................................................................... 50 
 
 
 

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1 
EXECUTIVE SUMMARY 
This clinical trial is a safety and feasibility study to assess the performance of an artificial pancreas 
(AP) system using the Zone Model Predictive control (Zone-MPC) and Health Monitoring System 
(HMS) algorithms embedded into the iAPS platform (MAF-1625 1625, Amendment #10) for 
pregnant patients with type 1 diabetes (T1D). 
The system will be evaluated on up to 21 pregnant adult subjects with type 1 diabetes age 18-45 
years old at three clinical sites (Sansum Diabetes Research Institute, Mayo Clinic Rochester MN and 
Mt Sinai Hospital, New York City). We will recruit pregnant patients with T1D between 14-32 
weeks gestation. All racial/ethnic groups will be eligible for participation. Subjects will complete a 
48-60 hour closed-loop (CL) session in a supervised outpatient environment with medical staff 
present. During the session, subjects will bolus for all meals and snacks, and will perform their usual 
daily activities while being accompanied by study medical staff. The AP system to be used consists 
of an insulin pump, a Continuous Glucose Monitor (CGM), and a phone app as described in MAF-
1625, Amendment #10: Master File for Artificial Pancreas System (APS) Platform.  
For subjects who wish to continue use of the system, they will then be offered the option of 
continuing use of the system at home in an extension phase, for the rest of their pregnancy, with 
weekly remote review of safety and efficacy data.  
The primary endpoint is time within the target glucose range of 63-140 mg/dL overall as assessed 
by CGM, determining if the system can provide safe and effective glucose control, as recommended 
by the current international consensus on time in range for pregnant women with diabetes. 
Secondary safety and efficacy endpoints will include: sensor glucose time within the target range 
of 63-140 mg/dL overnight, sensor glucose time within the range of 63-140 mg/dL postprandial 
within 2 hours following meals; frequency of hypoglycemia below predefined thresholds of 63 
mg/dL and 54 mg/dL, and frequency of hyperglycemia above predefined thresholds of 140, 180 
mg/dL and 250 mg/dL. Additional secondary outcomes include markers of hypo- and 
hyperglycemia, as well as safety events, treatments for hypoglycemia, outside interventions needed, 
and a failure analysis of the devices/connectivity issues that may occur. 
The clinical study will also review any serious adverse events that occur: hypoglycemic events, 
hyperglycemic events, planned and unplanned outside intervention, other Adverse Events, Serious 
Adverse Events, Unanticipated Adverse Device Effects, and device complaints for the commercial 
devices used. A root cause analysis of each event will be performed to determine if it is related to the 
approved devices - the CGM or the Continuous Subcutaneous Insulin Infusion (CSII) pump - the 
insulin, the AP system, or the control algorithm. Safety of the patient and her fetus will remain the 
primary goal. The goal of the AP device is to operate without outside intervention apart from Health 
Monitoring System (HMS) alerts suggesting carbohydrate ingestion due to impending 
hypoglycemia. 
2 
BACKGROUND INFORMATION 

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2.1 
Introduction 
Prior Clinical Evaluations of the Proposed AP System  
Several clinical studies involving nonpregnant patients using the novel zone MPC control 
framework, which is the basis for the proposed research, have shown consistently that the AP system 
is able to improve glucose regulation in T1D. Dassau et al. (FDA IDE G090129) published in 2013 
results of a pilot clinical trial conducted at Sansum Diabetes Research Institute (SDRI), evaluating 
individualized, fully automated (no premeal bolus) AP using commercial devices (1). Two trials (n= 
22, n=17) were conducted using a multi parametric formulation of MPC and an insulin-on-board 
algorithm. CGM glucose was maintained in the near-normal range 70-180 mg/dL for an average of 
70% of the trial time. These results showed the ability of a control algorithm tailored to an 
individual's physiology to successfully regulate glycemia, even when faced with unannounced meals 
or initial hyperglycemia. We (FDA IDE G110093) studied the safety and efficacy of a fully 
automated AP using zone MPC with the health monitoring system (HMS) during unannounced 
meals and overnight and exercise periods. A fully automated closed-loop AP was evaluated in 12 
subjects with T1D and demonstrated 80 and 92% time in 
the 70–180 mg/dL range for the entire session and 
overnight, respectively. These results showed that the 
combination of the zone MPC controller and the HMS 
hypoglycemia prevention algorithm was able to safely 
regulate glucose in a tight range with no adverse events 
despite the challenges of unannounced meals and moderate 
exercise. The zone MPC algorithm was successfully used 
in 2015 (FDA IDE G130147), when Drs. Dassau and 
Doyle AP team, Mayo Clinic and SDRI, among other 
sites, showed in a randomized clinical trial of 32 subjects 
in a transitional environment (such as hotel) that 
algorithmic adjustment of individualized insulin dosing 
parameters was safe and effective for AP use (2). As part 
of the DP3DK094331 research project, the fruitful 
collaboration among Drs. Dassau and Doyle AP team, 
Mayo Clinic, SDRI and other collaborators yielded a large 
outpatient clinical trial of the zone MPC and HMS system 
(FDA IDE G150063), where 30 adult subjects each used 
AP at home for three months (3). This study resulted in a 
statistically significant decrease in HbA1c (−0.3, 95% CI 
−0.5 to −0.2, p<0.001) and time spent in hypoglycemia 
during the day from 5.0 to 1.9% (−3.1, 95% CI −4.1 to 
−2.1, p<0.001) over the three months of AP use (Figure 1).  
Figure 1. Change in HbA1c compared to percent 
time hypoglycemia in a three-month outpatient 
study comparing our zone MPC algorithm to SAP 
use in patients with T1D [3]. Mean HbA1c change 
and reduction in percent time CGM glucose <70 
mg/dL are shown by the black line and filled in 
black circles. Individual subjects are shown by the 
colored lines and colored circles. 

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The zone MPC controller has also been used for outpatient studies in adolescents (FDA IDE 
G150122), with unannounced exercise and large meals multiple times per day. Mean CGM glucose 
was significantly lower during AP vs. sensor augmented pump (SAP) use (150±19 vs 173±32, P = 
0.042) (4). We also recently concluded a randomized-crossover study comparing glycemic control of 
the zone MPC AP system versus SAP therapy use at home in which insulin infusion set (IIS) and 
CGM failures were precipitated in 7 and 21 days of use, respectively, in which results were 
significantly better for zone MPC compared to SAP use (5). Our second generation target MPC AP 
system (enhanced MPC, or eMPC) (6) with the addition of a trust index that weights future insulin 
delivery based on past glucose predictions (7) was evaluated in 15 adult subjects studied for 48 hours 
in SDRI, and achieved 88% time in the target glucose range 70-180 mg/dL (8).  
Next Generation Artificial Pancreas: zone MPC and HMS on a Smartphone App 
The zone MPC algorithm has been implemented on iAPS (formerly referred to as “APS App”), a 
novel, user friendly smartphone application and the system was clinically evaluated in a feasibility 
study (FDA IDE G180011), where it achieved 83% time in glucose range 70-180 mg/dL and mean 
CGM at 136 mg/dL (9). 
iAPS is a smartphone-based artificial pancreas platform which 
provides seamless integration with Dexcom G5 and G6 CGM, and two 
different insulin pumps: Tandem t:slim and Insulet Omnipod. The app is 
designed to be cross-platform (Android and iOS), can be used 
concurrently with typical apps in a smartphone, and is designed to be 
interoperable and compatible with leading devices for diabetes 
management. As the app resides in a smartphone and connects wirelessly 
to the CGM and the insulin pump, the complete system is very portable 
and user friendly. 
 
In addition to the hardware integration, the iAPS app provides 
interface to the algorithms for AP glucose regulation namely the zone 
MPC and the HMS, which provides audio-visual advisory alarm for 
hypoglycemia. The app has an intuitive user interface (UI) allowing the 
user to request an insulin bolus for meal/correction and providing ability 
to log various activities such as exercise (Figure 2). It also provides alarms for system malfunction, 
e.g. loss of connectivity with devices, including text-messages to the subject’s care partners for 
alarm events such as impending hypoglycemia. A web-based remote monitoring facility 
complements the app running on the smartphone allowing the clinician to verify salient features of 
subject’s glycemic health.  
 
Our AP algorithms have been clinically evaluated in previous clinical studies (17 IDEs) with over 
76,000 hours of human use as shown in Table 1. iAPS is also now being evaluated in a 2-week 
outpatient trial comparing different stress assessments in the closed and open-loop setting (FDA IDE 
G180011/S002). 
Figure 2. iAPS Interface 

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Table 1. Summary of prior studies with the Artificial Pancreas System (APS) in different hardware configurations, as well as different variants of 
the Model Predictive Control (MPC) and Health Monitoring System (HMS) algorithms. 
Year 
IDE # 
Components 
Platform 
Hours of Human Use 
Location 
PubMed Link 
2020 
G200047 
t:slim-Dexcom  
(ZMPC and HMS) 
iAPS 
>75,000 Hours 
35 Subjects 
Outpatient at 
Home 
In Progress 
2019 
G180011/S002 
t:slim-Dexcom  
(ZMPC and HMS) 
iAPS 
>4,000 Hours 
12 Subjects 
Outpatient at 
Home 
32783473 
2019 
G180011/S001 
t:slim-Dexcom  
(ZMPC and HMS) 
iAPS 
>3,500 Hours 
10 Subjects 
Outpatient at 
Home 
32319791 
2018 
G160279/S002 
t:slim-Dexcom  
(ZMPC and HMS) 
iAPS 
800 Hours 
18 Subjects 
Supervised 
Outpatient 
In Progress 
2018 
G180011 
t:slim/OmniPod-Dexcom  
(ZMPC and HMS) 
iAPS 
300 Hours 
6 Subjects 
Supervised 
Outpatient 
30547670 
2017 
G150063 
Roche-Dexcom  
(ZMPC and HMS) 
DiAs 
>60,000 Hours 
30 Subjects 
Outpatient at 
Home 
29030383 
2017 
G150122/S003 
Roche-Dexcom  
(ZMPC and HMS) 
DiAs 
>6,000 Hours 
19 Subjects 
Outpatient at 
Home 
28584075 
2017 
G160281 
OmniPod-Dexcom  
(PBH algorithm) 
pAPS 
>50 Hours 
10 Subjects 
Supervised CRC 
29355439 
2017 
G160281 
OmniPod-Dexcom  
(Target eMPC and HMS) 
pAPS 
>700 Hours 
15 Subjects 
Supervised CRC 
29958023 
2016 
G150122 
Roche-Dexcom  
(ZMPC and HMS) 
DiAs 
>700 Hours 
10 Subjects 
Supervised Hotel 
28459617 
2016 
G160169 
OmniPod-Dexcom  
(Target eMPC and HMS) 
pAPS 
>1,950 Hours 
54 Subjects 
Supervised CRC 
29431513 
2015 
G130147 
Animas-Dexcom  
(ZMPC and HMS) 
pAPS 
>1,500 Hours 
32 Subjects 
Supervised CRC 
26204135 
2015 
G130236 
Animas-Dexcom  
(Target MPC/PID - HMS) 
pAPS 
>1,500 Hours 
30 Subjects 
Supervised CRC 
27289127 
2013 
G110093/S006 
Animas-Dexcom  
(ZMPC and HMS) 
APS 
36 Hours 
4 Subjects 
Supervised CRC 
24351171 
2013 
G110093/S003 
OmniPod-Dexcom  
(ZMPC/HMS, Inhaled Insulin) 
APS 
>200 Hours 
9 Subjects 
Supervised CRC 
25901023 
2012 
G110093 
Animas-Dexcom  
(Zone MPC and HMS) 
APS 
>275 Hours 
12 Subjects 
Supervised CRC 
24471561 
2012 
G110069 
Animas-Dexcom  
(ZMPC and HMS) 
APS 
>250 Hours 
13 Subjects 
Supervised CRC 
24876535 

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2.2 
Pregnancy and Automated Insulin Delivery 
 
Pregnancy in patients with T1D is associated with significant maternal and fetal morbidity 
linked to suboptimal glycemic control. Maternal pregnancy complications in patients with T1D 
include preeclampsia, medically indicated preterm delivery, labor abnormalities, need for cesarean 
delivery and maternal birth trauma, all linked to hyperglycemia throughout gestation(10-13), as well 
as severe hypoglycemia. Fetal and neonatal morbidity includes increased risk of congenital 
malformations, growth and fluid abnormalities (either fetal growth restriction, small [SGA] or large 
for gestational age [LGA] fetus or neonate) (14; 15), fluid abnormalities (oligo- and poly-
hydramnios), stillbirth, birth trauma, neonatal hypoglycemia, hyperbilirubinemia, hypocalcemia, and 
polycythemia, neonatal intensive care admission, as well as possible seizures. Table 2 shows data 
from cohort studies in Europe with no similar recent cohort studies from the US. When compared to 
control pregnancies, mothers with T1D in Sweden had an odds ratio of 4.47 for preeclampsia, 4.86 
for preterm birth, 3.08 for very preterm birth, 5.31 for cesarean delivery, 2.5 for fetal congenital 
malformation, 3.34 for stillbirth, 3.29 for perinatal mortality, and 11.45 for LGA baby. 
Pregestational and gestational elevated hemoglobin A1c (HbA1c), time in target range, time in 
hyperglycemia, and perhaps incidence of severe hypoglycemia have been associated with poorer 
outcomes (16-19). Recent studies on the use of closed-loop systems (artificial pancreas or AP) with 
T1D patients have shown significant reduction in HbA1c as well as percent time <70 mg/dL and 
percent time in hyperglycemia; however, research in the pregnant population has been limited (3; 20; 
21). This underserved population should benefit from the best in class glucose control provided by 
an automated insulin delivery using zone MPC and remote safety supervision system via the iAPS. 
Table 2. Morbidity during Pregnancy in T1D 
Study  
Geographic 
region 
(number of 
patient) 
Pre- 
eclam
psia 
Preterm 
birth 
C-section 
Congenital 
malformation 
Still 
birth 
Perinatal 
mortality 
LGA 
Persson et al 
2009 (14) 
Sweden 
(5089) 
14% 
21% 
46% 
4.7% 
1.5% 
0.02% 
31% 
Mackintosh et 
al 2006 (22) 
UK 
(1707) 
NR 
NR 
NR 
4.8% 
2.6% 
3.17% 
NR 
Evers et al 
2004(15) 
Netherlands 
(323) 
12.7% 
32.2% 
44.3% 
8.8% 
1.86
% 
2.8% 
45.1% 
Murphy et al 
2017 (23) 
England/Wales 
(1563) 
NR 
39.7% 
NR 
4.62% 
 
1.07
% 
0.81% 
46.4% 
Jensen et al 
2004 (24) 
Denmark 
(1218) 
18.1% 
41.7% 
55.% 
5% 
2.1% 
3.1% 
62.5% 
 
(NR=not recorded) 
Type 1 diabetes management in pregnancy: Despite the evidence supporting the relationship 
between glycemic control and pregnancy outcomes, optimal glycemic goals in T1D during 
pregnancy are still debated. Because there are very few prospective studies available from the US 
that attempted to control T1D tightly throughout pregnancy, the Endocrine Society Clinical 

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Guidelines group concluded that the evidence to support tight glucose control is of low quality (25) 
in contrast to stricter targets recommended by the ADA. The NIH-funded interdisciplinary Diabetes 
in Pregnancy Program Project Grant (1978-1993) project concluded that programs emphasizing 
preconception diabetes care and strict glycemic control would significantly decrease the rate of 
perinatal mortality and congenital malformations in patients with T1D (26). Despite revolutionary 
changes in diabetes treatment technologies, there are very few studies testing their impact on 
patients who are pregnant with T1D or planning pregnancy, the subset of patients who, with 
their offspring, specifically might benefit the most. 
Data from Sweden, and the Continuous Glucose Monitoring in Women With Type 1 Diabetes in 
Pregnancy Trial (CONCEPTT) control group (27), report 50% time-in-range (TIR) in the first 
trimester, improving to 60% time-in-range (TIR) in the third trimester, reflecting contemporary 
antenatal care. Of note, these data confirm that the time below range < 63 mg/dL recommendation of 
4% is safely achievable, especially after the first trimester. Furthermore, 33% of women achieved 
the recommendation of 70% TIR 63–140 mg/dL in the final (>34) weeks of pregnancy. Preliminary 
data suggest that closed-loop systems may allow pregnant women to safely achieve 70% TIR at an 
earlier (>24 weeks) stage of gestation. Law et al. analyzed data from two early CGM trials 
describing the associations between CGM measures and risk of large-for-gestational-age (LGA) 
infants. Taken together, the Swedish and CONCEPTT data confirm that a 5–7% higher TIR during 
the second and third trimesters is associated with decreased risk of LGA and other adverse neonatal 
outcomes including macrosomia, shoulder dystocia, neonatal hypoglycemia, and neonatal intensive 
care admissions.  
Glucose variability in pregnancy: More stringent glucose targets for pregnant T1D patients, makes it 
more difficult to achieve glucose goals. The quest to reduce hyperglycemia results in a significantly 
higher risk of hypoglycemia compared to non-pregnant T1D patients (28). The greatest risk for both 
hyperglycemia and hypoglycemia often occurs overnight when patients are least able to make insulin 
dose adjustments. Hypoglycemia in pregnancy leads to greater risk of hypoglycemia unawareness 
and dangerously low glucose levels. The CONCEPTT study revealed benefits of continuous glucose 
monitoring (CGM) use in pregnant women with T1D, demonstrating that in the setting of 
comparable overall good glucose control as reflected in HbA1c level (mean HbA1c 6.35% in CGM 
group vs 6.53% in non-CGM group; p=0.0207), pregnant CGM users spent more time in target 
(68% vs 61%; p=0.0034) and less time hyperglycemic (27% vs 32%; p=0.0279) than did pregnant 
control participants, with comparable severe hypoglycemia episodes (18 CGM and 21 control) and 
time spent hypoglycemic (3% vs 4%; p=0.10) (27). Fewer fetal adverse outcomes were reported for 
subjects wearing CGM. CGM wear in this study was reported at 70% using the Medtronic Guardian 
sensor which requires calibration 4 times a day and has to be replaced every 6 days. This study 
suggests that other metrics of glucose variability such as TIR and reduced post-prandial 
hyperglycemia, as opposed to HbA1c, may be stronger predictors of adverse maternal and fetal 
outcomes. 
Artificial pancreas during pregnancy in T1D has been understudied and has significant therapeutic 
potential: There have been 3 AP studies published from European investigators showing safety and 
efficacy in pregnant women with T1D. The first study by Murphy et al in 2011 conducted AP studies 
for 24 hours in an inpatient clinical research center in 10 pregnant women with T1D at 14.8 and 28 

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weeks of pregnancy (29). The system required data entry by an RN every 15 minutes into a laptop 
computer that stored the algorithm. Overnight time in range was 84% and 100% (63-140 mg/dL) in 
the early and late gestation groups, respectively, with no hypoglycemia. Two follow up studies (30; 
31) utilized a Sooil insulin pump and freestyle Navigator II CGM. Neither of these off the shelf 
devices is available in the United States. Subjects (16 in each study) were studied in a randomized 
crossover fashion and served as their own controls. Subjects wore the system for 4 weeks overnight 
in Stewart et al., 2016 and wore the system day and night in Stewart et al., 2018. In both studies, 
subjects used SAP for 4 weeks as the control arm and had an option for study extension. Results 
(summarized in Table 3) revealed the safety of the system in the home setting with fewer episodes of 
hypoglycemia and increased overnight time in the target glucose range of 63-140 mg/dL. In the 
overnight study, time in range (74.7 vs. 59.5% [95% CI 6.1 to 24.2]; P = 0.002) was significantly 
longer and mean glucose (119 vs. 133 mg/dL, P = 0.009)  was significantly lower while using the 
closed loop system. Time above goal was significantly reduced (>140 mg/dL: 24% vs 38.6%, P= 
0.005; >180 mg/dL 7.4% vs 15.7%, P=0.004). In the day and night study, there were significantly 
fewer hypoglycemic episodes (median [range] 8 [1–17] vs. 12.5 [1–53] over 28 days; P =0.04) and 
percent time spent below goal was less (<63 mg/dL: 1.6 vs. 2.7%; P = 0.02; <50-mg/dL: 0.24 vs. 
0.47%; P = 0.03). The time in range overall for the latter study was comparable between groups, but 
there was a trend toward higher overnight time in target (67.7 vs. 60.6%; P = 0.06). Maternal 
glycemia was variable, however. Five (31%) of the study participants spent less time in target range 
and had higher mean glucose levels during AP therapy. Maternal and fetal outcomes for both studies 
are shown in Table 4.  
Table 3. Reported Glycemic Outcomes in AP Studies 
 
Stewart et al, 
2016 
(overnight) 
Stewart et al, 
2018 
(day and night) 
 
CL 
SAP 
CL 
SAP 
Time in range 
74.7%* 
59.5% 
62.3% 
60.1% 
Mean glucose (mg/dL) 
119* 
133 
131.4 
131.4 
Standard deviation (mg/dL) 
25 
27 
36 
37.8 
Time >140mg/dL 
24%* 
38.6% 
36.1% 
36.6% 
Time >180mg/dL 
7.4%* 
15.7% 
14.6% 
14.8% 
Time <63mg/dL 
1.3% 
1.9% 
1.6%* 
2.7% 
Time <50mg/dL 
0.3% 
0.6% 
0.2%* 
0.5% 
Median # of hypo events 
3 
2.5 
8* 
12.5 
(*indicates P value<0.05) 
 
 
Table 4. Reported Maternal and Fetal Outcomes in AP Studies 
 
Stewart et al, 
2016 
Stewart et al, 
2018 
Baseline HbA1c 
6.8±0.6% 
8.0±1.1% 
Pre-eclampsia 
31% 
12.5% 
Preterm 
44% 
NR 
C-section 
94% 
81% 
NICU admission 
75% 
69% 
LGA 
81% 
44% 
Congenital 
malformations 
Not recorded 
12.5% 

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Our consortium also is following a prospective cohort of 30 women who are participating in the 
Longitudinal Observation of Insulin Requirements and Sensor Use in Pregnancy (LOIS-P) study 
designed to track glycemic control and insulin pump setting changes throughout pregnancy. All 
subjects are enrolled before 17 weeks gestation, are using insulin pumps, are provided Dexcom G6 
CGM, and are followed prospectively throughout their pregnancy and for 6 weeks post-partum. All 
subjects are contacted every 2 weeks. Data collected include CGM, insulin delivery, self-monitoring 
of blood glucose (SMBG), and maternal and fetal outcomes of pregnancy. Activity and diet logs are 
also being collected during 1 week in the 2nd and 3rd trimesters. This is a unique dataset that will 
pave the way for better understanding of the dynamic insulin requirements during pregnancy. 
As of Jan 15, 2021, we have analyzed results from 25 subjects enrolled in the LOIS-P study referred 
to above. Only six participants achieved >70% recommended TIR for pregnancy. Between 18-24 
and 26-30 weeks, mean daily percentage of CGM TIR was significantly lower, and time above range 
was significantly higher compared to the reference biweek. Time below target was unchanged. All 
primary outcomes were statistically significant (p<0.003). Daily basal insulin per kilogram was 
higher during weeks 6-10 and 28-40. Daily bolus and total insulin per kilogram were higher during 
weeks 22-40. Carbohydrate intake stayed stable. All insulin parameters were significantly increased 
from 22 weeks onwards. We conclude that insulin dosing changes significantly with advancing 
gestation and most participants did not achieve >70% TIR. This further illustrates the urgent unmet 
need for automated insulin delivery systems customized to this population’s targets. 
These data support the importance of studying AP systems further in pregnant women with T1D. 
The potential of a system with FDA approved devices (including the Dexcom G6 CGM with high 
accuracy, mean absolute relative difference (MARD) <10, and no acetaminophen impact (32)) with 
a smartphone-based operator has not been studied. We believe a system that has adjustable glucose 
targets and adapts to changes in insulin sensitivity as pregnancy progresses will provide an increased 
time in glucose target range of 63-140 mg/dL as well as benefit to mother and fetus. 
2.3 
Results of G200099 48-Hour AP in Pregnancy Study Showing Safety and Efficacy 
As of Jan 15, 2021, eight pregnant women with T1D from three US sites have participated in the 48-
hour clinical trial from this IDE G200099 (NCT04492566). Per protocol, women were enrolled after 
completing the first trimester period. CL sessions used the iAPS running a Zone-Model Predictive 
Control algorithm designed for stricter glycemic targets of pregnancy. Glycemic target zones were 
80-110 mg/dL during the day and 80-100 mg/dL overnight, with assertive insulin delivery in the 
postprandial period. All subjects completed the trial. Participants were 29.3±3.5 years, gestational 
age of 22.2±3.6 weeks, BMI of 28.2±5.1, and had an HbA1c of 5.7±0.5%. Mean CGM TIR was 
79.3±12.8% during closed-loop, compared to 60.8±18.8% for the week prior in open loop at home 
(p=0.03, Table 5). All subjects completed the study safely, with almost all showing increased time-
in-range compared to their prior care (Figure 3). Unrestricted carbohydrate intake at meals ranged 
from 7 to 78 grams during the CL sessions. No severe hypoglycemia or adverse events occurred. 
 

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Table 5. Mean±SD continuous glucose monitoring (CGM) metrics for the closed-loop control (CLC) sessions, 
compared to the week prior for 8 pregnant women with type 1 diabetes.  
Sensor Glucose 
Metric (mg/dL) 
48 Hour 
CLC Session 
Week Prior CGM Use 
at Home 
p-value 
Percent time 63-140 
79.3±12.8 
60.8±18.8 
0.03* 
Percent time 70-180  
89.3±5.8 
78.1±11.8 
0.02* 
Mean CGM Glucose 
112.5±11.9 
131.9±26.4 
0.05 
Percent time <54 
0.4±0.5 
1.2±1.4 
0.11 
Percent time <63 
1.6±2.2 
3.5±4.5 
0.2 
Percent time >140 
19.1±12.5 
35.7±21.0 
0.06 
Percent time >180 
6.1±4.4 
15.6±13.7 
0.07 
Percent time >250 
0.4±1.0 
3.7±4.9 
0.09 
SD CGM Glucose 
33.1±9.2 
43.6±12.7 
0.07 
CV CGM Glucose (%) 
29.1±7.1 
32.8±5.8 
0.21 
* Statistically significant with p<0.05 (paired t-test) 
 
Figure 3. Change in the percentage of time spent in target range (TIR, 63-140 mg/dL) and below range per 
participant during the open-loop management at home vs. 48-hour closed loop study. Median change in the 
TIR and percent time CGM < 63 mg/dL are shown by the black line and filled in black circles. 
 
3 
DESCRIPTION OF DEVICES 
3.1 
Overview and hardware 
The interoperable Artificial Pancreas System (iAPS) is an artificial pancreas system (as described in 
MAF-1625, Amendment #10), comprised primarily of an insulin pump, a continuous glucose 
monitor (CGM), and a cellular phone device to connect the components. The portable AP device is 
intended to adjust insulin doses when glucose concentration is, or is predicted to be, outside the 

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specified target range of 80-100 mg/dL. It includes a redundant safety control that will send 
warnings of impending hypoglycemia and recommend ingesting carbohydrates immediately to 
prevent hypoglycemia (Health Monitoring System). 
The interoperable Artificial Pancreas System (iAPS) used in this study is described in MAF-1625, 
Amendment #10, and includes: 
• A cellular phone device to connect to the insulin pump and CGM transmitter (Google Pixel 1, 2 
or 3/3a) 
• Dexcom G6 Sensor & Transmitter (G160069) 
• Tandem t:AP insulin pump (San Diego, CA) (MAF-2032-A003) 
• The same control algorithm successfully used with iAPS in G180011/002 and G200047 (Zone 
MPC with HMS), with modifications to the tighter target glucose range as recommended for 
pregnant women with diabetes to achieve increased time in range 63-140 mg/dL, and reduce 
postprandial hyperglycemia.  
• The same Health Monitoring System (HMS) algorithm used in G180011/002 and G200047, 
which issues safety notifications to the subject and support personnel to prevent impending 
hypoglycemia, with minor modifications to the algorithm as noted above. 
 
A schematic of the iAPS system being used in the study is shown in Figure 4. 
 
 
 

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Figure 4: Schematic of the representative principal system hardware components. The 
iAPS works with both Dexcom G5/G6 and with OmniPod and Tandem t:AP pumps. In this 
study we will only be using Dexcom G6 and Tandem pumps. 
 
 
Letters of authorization for all devices used as part of iAPS system are included in MAF-1625, 
Amendment #10. 
A. Dexcom G6 (Study CGM) 
The AP System will be integrated with the Dexcom G6 (study CGM). The G6 transmitter sends data 
points directly to iAPS.  
B. Tandem t:AP Pump 
The Tandem t:AP insulin pump is a modified version of the Tandem t-slim insulin pump that is 
modified to work with an AP controller. It otherwise functions identically to the commercially 
available product. No other pumps will be used in this study. 

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C. Study Glucometer and Ketone Meter 
Subjects will use the Contour NEXT blood glucose monitoring system (K150942 - Ascensia 
Diabetes Care US, Inc., 5 Wood Hollow Rd, Parsippany, NJ 07054 USA) to measure capillary blood 
glucose for CGM calibration and confirmation of CGM readings.   
Subjects will use the Precision Xtra® ketone meter (K040814 - Abbott Diabetes Care Inc., 1360 
South Loop Road, Alameda, CA 94502 USA) to test blood ketones as needed during the study. 
D. Phone Device 
The phone device that will run the iAPS in this study is a stock Google Pixel 1, 2 or 3/3a Phone, 
with the iAPS as described in MAF-1625, Amendment #10. The version of Android used in the 
phone for this study is version 7.1.2, 8.1, 9, 10 or 11. The phone is set to not allow automatic 
upgrades of the OS. However, if a phone OS upgrade does occur, study staff will not allow subject 
use of the device and will not release the interlock on the study RM website if the OS version 
upgrades past the last version that has been tested and verified to support full AID functionality. In 
that case, the subject’s study phone will be replaced. 
3.2 
Control Algorithm with HMS 
A detailed description of the Zone-MPC and HMS control algorithms, meal bolus strategy, and 
insulin-on-board calculations are provided in Appendix B of the IDE. 
 
The meal bolus strategy used in this study uses full meal boluses for each meal as long as sensor 
glucose is above 70 mg/dL, as this is necessary for achieving tight glycemic control in pregnancy. 
The user may adjust the bolus dose up or down at the time of the bolus and needs to approve and 
confirm the bolus before it is given. This is similar to how boluses are performed in all current 
insulin pumps, with the dose adjusted, reviewed and confirmed by the user. 
 
The HMS algorithm is also incorporated into the system to provide alerts to the user and clinician of 
impending hypoglycemia that may require treatment such as fast-acting carbohydrate consumption. 
Although the HMS algorithm uses the same CGM data as the MPC algorithm, it utilizes a separate 
algorithm for predicting glucose values. This HMS algorithm was also developed by engineers at 
Harvard University in collaboration with Sansum Diabetes Research Institute, and the same 
algorithm was successfully used in G150063, G150122, G160281, G130236, G130147, G180011, 
G180011/S001, G180011/S002, and G160279/S002. In this study, the HMS will produce an alert on 
the phone screen when it predicts a glucose value below 65 mg/dL within the next 15 minutes. 
Treatment will be given at the discretion of the investigator and subject when confirmatory 
fingerstick glucose is ≥ 63 mg/dL to prevent hypoglycemia as per the subject’s usual routine and 
investigator direction. Treatment with carbohydrates is mandated for hypoglycemia, which is 
defined as fingerstick glucose < 63 mg/dL and/or symptomatic. 

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4 
STUDY OVERVIEW 
4.1 
Study Overview 
In this study, subjects will use the iAPS for ~48-60 hour period in a supervised outpatient 
environment. All meals will be bolused for as per usual care. In addition, subjects will perform their 
usual daily activities (excluding intense exercise) while being accompanied by study medical staff. 
This includes following a lower carbohydrate diet that women are normally prescribed in pregnancy. 
Extension Phase 
For subjects who wish to continue use of the system beyond the 48-hour session, they will be trained 
on use of the study pump and the iAPS during the 48-hour study, and staff will complete the study 
training checklists. Subjects will then be able to continue with home use of the system all the way 
through to delivery if they desire, with a 24-hour, 48-hour and 72-hour follow up call, and then at 
least weekly follow up during the course of the study. The outpatient studies will be closely 
supervised with easy access for subjects to clinical study teams at each site. High risk obstetrics 
physician will be available at each site for the clinical research study team. 
4.2 
Primary Objective 
The primary endpoint is time within the target glucose range of 63-140 mg/dL overall as assessed 
by CGM. 
4.3 
Secondary Endpoints 
Secondary safety and efficacy endpoints will include: time within the target range of 63-140 
mg/dL overnight, within the range of 63-140 mg/dL postprandial within 2 hours following meals; 
frequency of hypoglycemia below predefined thresholds of 63 mg/dL and 54 mg/dL, and frequency 
of hyperglycemia above predefined thresholds of 140, 180 mg/dL and 250 mg/dL. Additional 
secondary outcomes include markers of hypo- and hyperglycemia, as well as safety events, 
treatments for hypoglycemia, outside interventions needed, and a failure analysis of the 
devices/connectivity issues that may occur. 
The clinical study will also review any serious adverse events that occur: hypoglycemic events, 
hyperglycemic events, planned and unplanned outside intervention, other Adverse Events, Serious 
Adverse Events, Unanticipated Adverse Device Effects, and device complaints for the commercial 
devices used. A root cause analysis of the event will be performed to determine if it is related to the 
approved devices - the Continuous Glucose Monitor (CGM) or the Continuous Subcutaneous Insulin 
Infusion (CSII) pump - the insulin, the AP system, or the control algorithm. Safety of the patient and 
the fetus will remain the primary goal. The goal of the AP device is to operate without outside 
intervention apart from HMS alerts suggesting carbohydrate ingestion due to impending 
hypoglycemia. 

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5 
BACKGROUND INFORMATION 
5.1 
General Background 
This study is being conducted in compliance with the policies described in the study policies 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with the 
protocol described herein, and with the standards of Good Clinical Practice. 
Informed consent will be obtained before the study procedures are conducted. 
Data for this study will be collected on a combination of paper and electronic case report forms, 
which will be considered the source data. If possible, data will be directly entered into the eCRF as 
applicable. 
A risk-based monitoring approach will be followed, consistent with the FDA “Guidance for Industry 
Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 2013). 
5.2 
Description of Population Studied 
The system will be evaluated on up to 21 pregnant adult subjects with type 1 diabetes age 18-45 
years old at three clinical sites (Sansum Diabetes Research Institute, Mayo Clinic Rochester MN and 
Mt Sinai Hospital, New York City). We will recruit pregnant patients between 14-32 weeks 
gestation. All racial/ethnic groups will be eligible for participation. Subjects will complete a ~48-60 
hours closed-loop (CL) session in a supervised outpatient environment with medical staff present, 
and then have the option to use the CL system at home throughout the remainder of their pregnancy 
if desired.  
6 
TRIAL DESIGN 
6.1 
Overview 
This study is a 3-site early feasibility study of pregnancy-specific AP in which we will recruit a total 
of 21 pregnant women with T1D for a complete 48-60 hours of AP control in a supervised outpatient 
environment. After completing the 48-hour session, we will offer continued use of the system at home, 
through as far as delivery if desired, to each subject. Subject data will be reviewed for safety at 24 
hours, 48 hours and at 72 hours of home use, and then weekly before being extended a week at a time 
for the rest of the pregnancy. 
 
6.1.1 Limitations on the Number of Subjects that can be Enrolled 
 
Enrollment will be limited to a maximum of 4 active subjects across all clinical sites at any given 
time. This will allow for subjects to finish the study before the next is enrolled, and assure available 
resources for the maximum of 4 possible subjects who may run concurrently. 
 
Enrollment is also limited to only 3 active subjects at a given clinic site at any one time, and each 
site may only enroll 2 subjects per week maximum.  

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These limits will remain in place throughout the study. 
 
6.2 
Eligibility and Exclusion Criteria 
6.2.1 Inclusion Criteria 
To be eligible to enroll in this study, subjects must meet all of the following including criteria: 
1) 
Age ≥ 18 and ≤ 45 years at the time of screening. 
2) 
Clinical diagnosis of type 1 diabetes  
3) 
Currently using an insulin pump at the time of screening. 
4) 
HbA1c ≤ 9%, as performed by point of care or central laboratory testing. A1c will be 
assessed at the screening visit. 
5) 
Pregnant  140/7  to 326/7 weeks gestation. 
6) 
Singleton pregnancy without any other significant known complications, such as 
preeclampsia, premature rupture of membranes, 2nd/3rd trimester bleeding, fetal growth or 
fluid abnormalities. 
7) 
No proven or suspected fetal malformations diagnosed in the current pregnancy. 
8) 
Bolus for all meals and snacks that contain ≥ 5 grams of carbohydrate. 
9) 
Willing to switch to Novolog or Humalog, or continue Novolog or Humalog for the duration 
of closed-loop use. 
10) 
Willingness not to start any new non-insulin glucose-lowering agent during the course of the 
trial. 
11) 
Willing to abide by the study protocol and use study-provided devices. 
12) 
Have a care partner with the following responsibilities: knowing subject whereabouts and 
being promptly available for contact by study staff during the day and night, residing in the 
same dwelling as subject during the night, being agreeable to all device training during the 
supervised HCL session and additional training on hyper- and hypoglycemia treatment, and 
assisting with emergency care if needed, such as transportation to the hospital or emergency 
department. 
6.2.2 Exclusion Criteria 
Subjects would not be eligible to enroll in this study if they meet any of the following exclusion 
criteria: 
1) Known unstable cardiac disease or untreated cardiac disease, as revealed by history or physical 
examination. 
2) Concurrent use of Afrezza or any non-insulin glucose-lowering agent other than metformin 
(including GLP-1 agonists, Pramlintide, DPP-4 inhibitors, SGLT-2 inhibitors, sulfonylureas). 
3) Hemophilia or any other bleeding disorder 
4) Prior history of Preterm Premature Rupture of Membranes (PPROM) 

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5) Significant hyperemesis interfering with carbohydrate intake 
6) Laboratory results: 
a. A1C > 9%  
b. Abnormal liver or renal function (Transaminase >2 times the upper limit of 
normal, creatinine > 1.5 mg/dL) 
c. Liver and renal function testing drawn at screening visit or within three months 
prior to screening (for other purposes) will suffice for enrollment purposes 
7) Dermatological conditions that would preclude wearing a CGM sensor or infusion site. 
8) Any condition that could interfere with participating in the trial, based on investigator judgment. 
9) Participation in another pharmaceutical or device trial at the time of enrollment or during the 
study. 
10) Having a direct supervisor at place of employment who is also directly involved in conducting 
the clinical trial (as a study investigator, coordinator, etc.); or having a first-degree relative who 
is directly involved in conducting the clinical trial 
11) History of severe hypoglycemia in the past 6 months  
12) History of DKA requiring hospitalization in the past 6 months  
13) Significant chronic kidney disease (eGFR < 60) or hemodialysis  
14) Significant liver disease  
15) History of adrenal insufficiency  
16) History of abnormal TSH consistent with hypothyroidism or hyperthyroidism that is not 
appropriately treated  
17) History of high dose steroid use in the past 8 weeks   
 
6.3 
Schedule of Events 
The trial consists of: 
1) A screening visit to assess eligibility 
2) One to two week open-loop data collection while wearing Dexcom G6 CGM 
3) A 48-60 hour closed-loop session in a supervised outpatient environment with at least one 
licensed medical provider present at all times 
4) A follow up phone call 2 hours after discharge from the closed-loop session to assure subject 
safety and safe transition back to the subject’s home insulin pump if they are not continuing in the 
extension phase. 
5) Continued use of the system at home, optionally though the end of pregnancy, for subjects who 
wish to continue use of the system. To achieve this, 
a. Subjects must consent to training for the extension phase at the time of signing their 
informed consent form. 

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b. Subjects will be trained on use of the study pump and phone while attending the 48-hour 
study session. Study staff will complete the study pump and phone training checklists, and 
the site investigator will sign off attestation that the subject is ready to use the study devices 
at home. 
c. Subjects will have a documented 24-hour, 48-hour and 72-hour check in after taking the 
system home, requiring the study team to review the remote monitoring system data, and 
then at least weekly documented contact with each subject. Providers may adjust insulin 
delivery settings as clinically indicated. 
d. During the first two weeks of home use of the study device, subjects will continue to perform 
scheduled fingersticks (SMBG) prior to meals, 2 hours after meals, and at bedtime, in 
addition to fingersticks mandated by the hyperglycemia and hypoglycemia study safety plan. 
After two weeks, the study glucometer will be downloaded, and if ≥90% of CGM values are 
within 20%/20 mg/dL of SMBG readings, this will be documented in a study contact CRF 
and the scheduled SMBG requirement for the remainder of that particular participant’s time 
in the study may be removed. However, the participant will still be instructed to perform the 
confirmatory fingerstick requirements for safety criteria. If a subject’s particular data set does 
not support removing this requirement, that subject will continue to perform scheduled 
fingersticks per protocol in addition to following the confirmatory fingerstick requirements 
for safety criteria. This analysis will be repeated for each subject in the study. 
e. Subject’s glycemic data will be reviewed and a documented contact will be completed at 
least weekly after the 72-hour check. If there is a significant deterioration of glycemic control 
as determined at any time or during the scheduled weekly contacts, leading to a significant 
worsening time in range compared to baseline (10% or more worsening of time in target 
range) and time in range consistently below 50%, the site clinical investigator will end the 
subject’s participation in the study (Stopping criteria, section 8.4) 
f. After ~4 weeks, the study Data Safety and Monitoring Board (DSMB) will review a 
summary of the subject’s glycemic data, to include any adverse events, to approve continued 
use of the system through the remainder of pregnancy if the subject desires. Success criteria 
based on CGM glycemic metrics, to be presented to the DSMB, before approval can be 
granted to move beyond three subjects, are the following: 
a. CGM % Time ≤ 54 mg/dL = 2% or less 
b. CGM % Time 63-140 mg/dL = greater than or equal to 50% 
c. No Unanticipated Adverse Device Effects (UADE’s) 
g. Follow up visit after delivery: Subjects will be called or seen in person before hospital 
discharge to ensure they have transitioned safely to their home devices. Maternal and 
neonatal outcomes will be recorded.   
Subjects will be considered enrolled when, after completing the screening visit, the investigator has 
reviewed all enrollment criteria and signed off on the subject’s enrollment. Up to 21 subjects may be 
enrolled. 

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In case of illness or cancellation, the visits may be rescheduled at the discretion of the investigator. 
Study schedule and interventions are summarized in the table below: 

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Table . Schedule of Assessments Including Extension 
 
 
Screening 
Open Loop Data 
Collection 
Hybrid 
Closed-Loop 
Phase  
End of Study 
Phone Call 
(Last study visit) 
Extension Phase 
Informed Consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Diabetes History 
X 
 
 
 
 
Medication Use 
X 
 
 
 
 
Vital Signs1 
X 
 
X 
 
 
Skin inspection (Sensor/Infusion Set Sites) 
X 
 
 
 
 
Fetal Doptones 
 
 
X 
 
 
Laboratory  
X 
 
 
 
 
 
Point-of-care HbA1c 
X 
 
 
 
X4 
Insulin pump/CGM/glucometer data download 
X 
 
X 
 
 
CGM Training 
 
X 
X 
 
 
CGM Placement 
 
X 
X 
 
 
iAPS & Study Pump Closed-Loop Use 
 
 
X 
X 
X 
Fingersticks BG as required per protocol2 
 
X 
X 
X 
X 
CGM Calibrations3 
 
X 
X 
X 
X 
Competency assessment prior to discharge 
home with iAPS 
 
 
X 
 
 
24, 48, and 72 hour contact, then a minimum of 
weekly contact with subjects. 
 
 
 
 
X 
   
1 – Vital signs at admission, Q12 hours, discharge, and per investigator discretion during the closed-loop phase. 
2 – Fingersticks per protocol criteria for hypo and hyperglycemia during closed-loop use. 
 
3 – As required per manufacturer’s instructions. 
4 – A1c and/or fructosamine may be performed via point-of-care or by central laboratory testing every 4 weeks during the extension phase. 
    

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6.4 
Screening Visit 
Subjects must sign the consent form prior to any screening procedures. Each subject will have 
the opportunity to ask questions and receive answers from study personnel prior to signing the 
consent. 
The following will be evaluated/performed and documented during the screening visit: 
1) Informed consent form (signed and dated) 
2) Inclusion and Exclusion criteria 
3) Demographic information (e.g., date of birth, gender, race) 
4) Medical history to include any relevant data related to the current pregnancy, to specifically 
include common conditions in pregnancy such as heartburn, headaches and nausea, asthma, 
diet plan and how subjects are managing this during pregnancy and how they will manage it 
during the closed-loop session. 
5) Diabetes history (diabetes type, diabetes duration, pump use duration, past/current CGM use, 
total daily insulin dose, basal rates, carbohydrate ratios, correction factors). 
6) Current medication use 
7) Vital signs to include blood pressure, heart rate, height and weight. 
8) Physical examination, including skin inspection of potential sensor and infusion set insertion 
sites. 
9) Recording of duration of pregnancy (Gestational Age).  
10) HbA1c via point-of-care or laboratory testing.  
11) Screening liver and renal function testing, if not completed within prior 3 months. 
12) Insulin pump, CGM (if available) and glucometer (if available) data download. 
6.5 
Open Loop Data Collection 
Approximately 1-2 weeks prior to the planned closed-loop session, study subjects will first 
undergo Dexcom G6 training as per the study CGM training form, and then wear Dexcom G6 for 
CGM for 1-2 weeks.  
Study clinicians will evaluate skin prior to sensor placement and upon removal for 
appropriateness of site as well as any skin findings or reactions. Sensors will be worn for up to 
10 days. For the study, clinicians will review that CGM use is not currently approved for 
pregnant women, and that there is no approved wear site in pregnancy. As such, participants will 
be instructed that CGM will be worn in the posterior upper arm during the study, as this site is 
the approved wear site for the clinical study. Staff will also review the need to make all treatment 
decisions based on fingerstick SMBG. 
Subjects with no prior experience with the Dexcom CGM will be taught by study staff on how to 
use the CGM, including how to insert the sensor and transmitter and to calibrate the CGM as 
necessary per manufactures instructions.  

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Participants will be advised to continue daily activities and food consumption as usual and 
continue to make diabetes management decisions (e.g., insulin dosing adjustments, 
hypoglycemic/hyperglycemic management, lifestyle modifications, etc.) as per clinician 
recommendations. Participants who are naïve to CGM will undergo training on CGM use 
(similar to CGM training in nonpregnant person new to CGM), including use of trend arrows, 
alerts, alarms and historical trend information. During this instruction, emphasis will be made on 
the use of fingerstick SMBG to confirm low or high readings before making treatment decisions, 
as well as using fingerstick SMBG to make meal bolus and correction dose decisions. Clinicians 
will decide on an individual basis the appropriate glucose thresholds and alarm settings with the 
aim of safely achieving pregnancy specific glucose targets and reducing hypoglycemia. 
Participants’ CGM data will be reviewed on a daily basis for the first 3 days of wear followed by 
at least two times per week for safety. 
Subjects will also be provided with a glucose meter and test strips for home use. Subjects will be 
instructed that if CGM calibration is required, the best time to calibrate the CGM is when 
glucose levels are not rapidly changing, generally before breakfast and before dinner.  
Subjects will be given a Contour NEXT glucose meter. The glucose test strip bottle given to the 
subject will pass quality control (QC) testing with at least one control solution prior to being 
given out to subjects. A glucose meter and/or test strips will not be used in a study if it does not 
read within the target range of the QC solution testing per manufacturer labeling. 
Study staff may contact the subjects more frequently, use the Dexcom Follow app to monitor 
subjects, and/or simply review their diabetes care on the phone. During this phase, the subjects’ 
basal rates, carbohydrate ratios and/or insulin sensitivity factors may be adjusted as needed based 
on clinician discretion to optimize pump settings prior to entering the hybrid closed-loop phase.  
6.6 
Hybrid Closed-Loop Phase (~48-60 Hours)  
Subjects will be instructed to insert a new CGM sensor at least 24 hours prior to arrival to the 
supervised outpatient environment. Study staff will verify that the subject has changed out their 
CGM sensor at least 24 hours prior to the start of closed-loop session and document this on the 
study case report forms.  
Prior to arriving for the closed-loop visit, subjects will be reminded to bring all their usual 
medication, to include PRN medications especially those needed for asthma and other chronic 
illnesses should an exacerbation occur.  Subjects will also be reminded to stay well hydrated 
even prior to arrival, and to bring their own supportive tools they are already using such as 
pillows or lumbar support to the session. 
Prior to initiating the closed-loop study, fetal  heart rate will be documented using a portable 
Doptone. Vital signs to include blood pressure will also be taken at admission and every 12 
hours, at investigator discretion, and will be performed for development of new symptoms such 
as headache or nausea. 

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During the closed-loop session, subjects will be supervised at all times by study staff who are 
clinically trained in treating hypoglycemic and hyperglycemic emergencies per the clinical study 
protocol. In addition, a clinician (MD/NP) will be present.  
At the start of closed-loop use, subjects will be advised that use of the iAPS, in particular 
entering boluses, may only be performed with direct study staff supervision, until training on the 
system is complete. 
Fingerstick glucose measurements will be performed as required by manufacturer’s instructions 
to calibrate the CGM. Fingerstick glucose measurements will also be performed before all meals, 
2 hours after meals, and at bedtime. In addition, subjects can perform additional fingersticks 
upon their request, upon request of the investigator, when prompted by the HMS, as per 
evaluation and treatment of hyper- and hypoglycemia guidelines in the protocol, during exercise, 
for CGM calibration or for any other reason.  
During the closed-loop phase, subjects will be allowed to snack at any time and bolus 
appropriately per their home routine, with the goal to prebolus 15-30 minutes of ahead of time to 
minimize postprandial hyperglycemia. Each subject will be provided with the same rapid-acting 
insulin (e.g., Novolog or Humalog) as they customarily use. The carbohydrate content of all 
meals/snacks that a subject would normally bolus for will entered into the iAPS by the subjects 
while supervised by the study staff for all meals and snacks requiring insulin.  
If a CGM sensor fails or comes loose at any point during this phase, the sensor will be replaced 
and closed-loop mode will resume once the sensor has completed warm-up. Skin Tac or other 
similar agents may be used to ensure adequate adherence of the CGM sensor to the skin. 
Subjects will be allowed to perform light exercise (e.g., walking, stretching, yoga) per their usual 
home routine at any time during the closed-loop phase, and may take additional carbohydrates 
for exercise as per their usual home routine. Any additional carbohydrates or activity will be 
documented in the subjects’ chart.  
Subjects will eat their usual prescribed diet while using the system. They will be encouraged to 
hydrate well as well. 
In the case of maternal assessment of decreased fetal movement, fetal kick count will be assessed 
(at least 10 movements within 2 hours) if gestational age appropriate (>28w gestation). Research 
medical staff will assess and as needed research staff will stop the session and request subject 
contact her obstetrician and/or send subject to appropriate acute care setting for immediate 
evaluation. 
For new onset vaginal bleeding, hypertension >140/90 mm Hg, uterine cramping (regular and/or 
painful) or contractions, PPROM, headache related to new onset hypertension, nausea with 
significant vomiting and any other medical concern that may cause a safety concern, research 
medical staff will stop the session and request subject contact her obstetrician and/or facilitate 
transport of subject to appropriate acute care setting for immediate evaluation. Fetal doptones 
will also be performed. 

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Treatment for hypo- and hyperglycemia that occur during the closed-loop phase will follow the 
hypo- and hyperglycemia treatment plan as detailed in Table 8.  
6.6.1 Monitoring Frequency in the Closed-Loop Session 
The frequency of glucose monitoring during closed-loop use is described above and summarized 
below:
  Table 7. Frequency of glucose monitoring during Closed Loop 
Measurement 
Device 
When 
Frequency 
CGM 
Entire Closed-Loop 
Session  
• Every 5 minutes 
Fingerstick SMBG 
Calibration of CGM 
During Closed-Loop 
• As required by CGM manufacturer 
instructions.   
Fingerstick SMBG 
Closed-loop 
• Scheduled before all meals, 2 hours after 
meals, and at bedtime 
• Every 15 minutes once BG is below 63 
mg/dL until BG ≥ 63 mg/dL 
• Every 30 minutes once BG > 250 mg/dL 
for at least 1 hour until BG ≤ 250 mg/dL 
At home  
CGM  
 
Every 5 minutes  
 
Multiple visual and auditory alarms are embedded into the iAPS should the system malfunction. 
The control algorithm also includes intrinsic safety limits that trigger alarms should the patient’s 
glucose level go too high or too low and which prevents the system from delivering too much 
insulin. 
Should the HMS predict that the glucose level is going to be <54 mg/dL in the next 15 min, the 
system will alert on the iAPS and send a redundant text message to a predefined list of people, 
which in this study will include the medical staff (who will be on stand-by and in close physical 
proximity to the subject in this study) to notify the subject to consume 4-16 grams of 
carbohydrate, at the discretion of the investigator (Table 8). All warnings issued by the HMS will 
be documented. The study personnel monitoring the study will confirm that the subject has 
responded to the hypoglycemia alert and has taken corrective action. If the subject is asleep or 

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has not heard or noticed the alert, the study medical staff will wake the subject, inform her of the 
alert and confirm that proper action is taken. 
To prevent dehydration secondary to hyperglycemia, the subject will be encouraged to consume 
water or sugar free beverages during the trial if she is thirsty. 
Photographs and/or videos of participants may be used in presentations at conferences and shown to 
potential subjects, as well as research donors. Subjects will be given the option consent to be 
photographed and/or videotaped while participating in the study. Subjects may decline to consent to 
photograph and video, and this will not impact their participation in the study. Photographs and 
videotape will be full body portrait with study devices, and subjects will have the have the option 
upon consent of choosing to have their face blurred. Subject names will not be associated with any 
photograph(s) or video(s) used.  
Upon session completion, prior to discharge, subjects who are not continuing with closed-loop 
use will transition back to their personal diabetes management devices after having been 
determined safe for  discharge by the study clinician. Prior to discharge from the closed-loop 
study, fetal heart rate will be documented using a portable Doptone and vital signs will be 
repeated. 
A follow up phone call will be performed 2 hours after discharge to make sure the subject is 
doing well and  has safely transitioned back to their home pump. 
6.6.2 Extension Phase  
For subjects who wish to continue use beyond the 48- hour observed session, they may continue 
use of the system at home if the following criteria are met: 
1) CGM training refresher completed: At investigator discretion, applicable elements of the 
CGM system training may be completed as refresher training. The participant will be provided 
with a supply of CGM sensors, a backup CGM transmitter, and blood glucose strips to last until 
the next study visit. 
2) Blood ketone meter training completed and supplies issued: The participant will be provided 
with a study blood ketone meter and strips and instructed on the use of this device.   
3) Home Glucagon Emergency Kit: Participants will be required to have a home glucagon 
emergency kit. Participants who currently do not have one will be given a prescription for the 
glucagon emergency kit. 
4) Completion of formal study pump training and study phone training, using the study 
checklists, as per sections 6.6.3 and 6.6.4 below. 
5) No severe hypoglycemic or hyperglycemic adverse events during the 48-hour training visit, as 
defined in sections 8.1.2.1 and 8.1.2.2, respectively. 
6) No UADE’s or reportable device issues, as defined in section 8.2. 
7) Completion of care partner training. 

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6.6.3 Pump Training 
For extension phase continued use of the system, subjects will complete study pump training 
during their 48-hour study session: 
 
• The participant will be fully instructed on the study insulin pump. A member of the study 
research team will conduct the training and in particular discuss differences from their 
home pump in important aspects such as calculation of insulin on board and correction 
boluses. Additional topics not limited to but may include: infusion site initiation, 
cartridge/priming procedures, setting up the pump, charging the pump, navigation 
through menus, bolus procedures including stopping a bolus, etc. 
• The study team will assist the participant in study pump infusion site initiation and will 
start the participant on the study pump. The study pump will be programmed with the 
participant’s usual basal rates and pump parameters. The participant’s personal pump will 
be removed. 
• The participant will be supervised with the study pump during at least one meal or snack 
bolus to ensure participant understanding of the pump features. 
• The participant will be encouraged to review the literature provided with the pump and 
infusion sets after the training is completed. 
• The appropriate study pump training checklist will be used to document and facilitate the 
training process; a physical or electronic copy of the pump user guide will be provided 
for the participant to take home. 
• Participants will be provided with sufficient insulin infusion supplies to last until the 
subsequent visit. 
6.6.4 Study Phone Training 
For extension phase continued use of the system, subjects will complete study phone training 
during their 48-hour study session: 
 
• The study team will confirm the subject’s parameters are entered in the system (APS 
RM) with the study physician. 
• How to switch the system between Pump mode (open-loop, preprogrammed basal insulin 
delivery) and Closed Loop mode depending on circumstances.  
• How to calibrate the CGM unit during the study as per manufacturer’s instructions and 
per clinical need. 
• How to access the CGM trace from the sensor on the phone screen. Study staff will also 
explain the concept of “safe basal” to the subjects which can be activated after CGM 
connectivity is interrupted to the study phone. 

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• How to activate the meal bolus screen of the phone system any time insulin will be given 
with a meal or any time additional correction insulin is desired. 
• Specifically, study staff will follow inform the subject that: 
o The bolus screen correction calculation is based on the last CGM value. 
o Fingerstick glucose measurements are required prior to all meals, 2 hours after 
meals, and at bedtime, in addition to confirmatory fingersticks for hyperglycemia 
(> 180 mg/dL) and hypoglycemia (<63 mg/dL) as per the study safety plan. After 
2 weeks, the accuracy of fingerstick measurements will be reviewed as compared 
to CGM, and the requirement for scheduled fingersticks may be able to be 
removed. Fingersticks for the study safety plan will always be required. 
o They can add a fingerstick value into the bolus screen, and this will adjust the 
correction slider calculated correction dose. If there is any concern about the 
accuracy of the current CGM value, a fingerstick is generally more accurate and 
should be performed instead of relying on the current CGM value. 
o They can adjust the correction slider calculated correction dose. 
o They can use the total dose box to adjust the final dose to be delivered, regardless 
of what settings are entered into the other boxes (glucose value, carbohydrates, 
correction). The amount shown in this box will be delivered. 
o CGM trend information is not used in the meal bolus or correction bolus 
calculation. 
o Study staff will observe them using all buttons and boxes on the meal bolus 
screen to show us they understand how to use the meal bolus screen. 
• How to inform the system of hypoglycemia treatment via a hypoglycemia treatment 
button on the phone UI after each hypoglycemic treatment is consumed. 
• What to do when exercising while using the system. 
• The participant will be assessed for understanding of the system interface and how to 
react to safety/alert messages. 
• How to perform blood ketone testing. 
• Review of the iAPS App User Guide; a physical or electronic copy will be provided for 
the participant to take home. 
• The study iAPS training checklist will be used to document and facilitate the training 
process. 
6.6.5 General Usage Training and System Initiation 
For extension phase continued use of the system, subjects will be instructed to use the system in 
closed-loop mode except 1) when no CGM sensor is available or 2) if insulin is delivered by any 
means other than the study pump (e.g. injection of subcutaneous insulin via syringe in the event 

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of infusion site failure). If insulin is delivered by any means other than the study pump, 
participant will be instructed to turn off closed-loop mode for approximately four hours. 
 
The participant will also be instructed to contact study staff during periods of illness with an 
elevated temperature >101.5 degrees Fahrenheit (38.6 degrees Celsius), periods of significant 
illness, or during periods of use of medications such as epinephrine for the emergency treatment 
of a severe allergic reaction or asthma attack in addition to use of oral or injectable 
glucocorticoids to determine if closed-loop use should be temporarily discontinued. 
Participants will be specifically instructed: 
1) Not to upgrade the phone operating system. 
2) Not to plug headphones into the study phone or alerts will be silenced. 
3) Not to put the phone on vibrate mode or alerts will be silenced. 
4) Not to use any manufacturer provided (e.g. Dexcom G6 Mobile App) or third-party 
components for CGM connectivity and monitoring, as this will interfere with 
connectivity to the study phone. 
During the 48 hour training session, the subject’s care partner must be trained on the following: 
- Review device training including the alerts that are sent to the participant. 
- Review study staff contact information. 
- Mixing and giving glucagon, turning subject to the side, and call 9-1-1. 
- Disconnecting the study pump. 
- Review symptoms of hypoglycemia that can include sweating, jitteriness, and not feeling well, 
as well as the possibility of fainting or seizures (convulsions). 
- Review symptoms of hyperglycemia to include increased thirst, urination, headaches, not 
feeling well, nausea, vomiting, and ultimately diabetic ketoacidosis. 
- Review disconnecting the study devices. 
Training of the care partner will be completed either in person or via video visit during a portion 
of the 48-hour study session, prior to discharging the subject home with the system for home use. 
After study system training and the 48-hour closed-loop session has been completed, participants 
will proceed with home use of the study system. Participants may use the study pump and study 
phone without closed-loop and study CGM during periods of component disconnections or 
technical difficulties. In order to continue on in the outpatient extension phase of the study, 
subjects must have a care partner/other responsible adult, willing to share their contact 
information with the study team and who has ready access to the subject, who can be available to 
physically find the subject and assist if the subject does not respond to contacts from the study 
team. 
 
6.7 
Remote Monitoring 

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The study providers on site will monitor all subjects on the web interface for the iAPS (Appendix 
A - Device User Manual) so they can see ongoing data from all current subjects at once. 
Required real-time alerts, for the duration of the outpatient study, are to be set as follows: 
• CGM > 180 mg/dL for more than 1.5 hours 
• CGM > 250 mg/dL for 20 minutes 
• CGM < 54 mg/dL for more than 20 minutes 
• No CGM data for 2 hours. 
• Out of closed loop for 2 hours 
Additional text notifications to providers may be added and continued at investigator discretion 
to assure subject safety. 
7 
ASSESSMENT OF SAFETY 
7.1 
Blood Volume Requirements 
Finger stick: 
Each fingerstick measurement requires 1.5 microliters for accurate measurement. There is no 
significant blood loss. There are only screening blood draws for the study, which require < 10 
mL of blood. Screening Hemoglobin A1c will be performed by fingerstick point-of-care testing 
if not performed as a serum sample as part of routine clinical care. These screening blood draws 
are also the typical evaluation done in the routine care of a pregnant woman with T1D.  
7.2 
Hypoglycemia and Hyperglycemia Prevention and Treatment 
Table 8. Hypoglycemia and Hyperglycemia Prevention and Treatment  
Condition 
Action Taken – Inpatient Study 
Action Taken – Outpatient 
Extension 
HMS alert for 
impending 
hypoglycemia  
Study staff will closely monitor the 
subject’s CGM readings for potential 
hypoglycemia during the 48-hour 
session.  
A confirmatory fingerstick 
measurement will be performed.  
If fingerstick glucose ≥ 63 mg/dL, 
treatment may be initiated by the 
investigator (~4-16 g fast acting 
carbohydrate) per investigator 
discretion. Subjects will then 
perform a follow-up fingerstick 
measurement 15 minutes after 
Subject is instructed to perform a 
confirmatory fingerstick measurement 
for all predictive low alarms.  
If fingerstick glucose ≥ 63 mg/dL, 
treatment may be initiated with ~4-16 
g fast acting carbohydrate. Subjects 
will then perform a follow-up 
fingerstick measurement 15 minutes 
after treatment if CGM < 63 mg/dL. 
This protocol will be repeated until 
the HMS alert stops alarming.  
If fingerstick glucose < 63 mg/dL, 
treatment will be initiated with ~4-16 

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treatment if CGM < 63 mg/dL. This 
protocol will be repeated until the 
HMS alert stops alarming.  
If fingerstick glucose < 63 mg/dL, 
treatment will be initiated by the 
investigator (~4-16 g fast acting 
carbohydrate) per investigator 
discretion. Subjects will then 
perform a follow-up fingerstick 
measurement 15 minutes after 
treatment if CGM < 63 mg/dL. This 
protocol will be repeated until the 
HMS alert stops alarming.  
g fast acting carbohydrate). Subjects 
will then perform a follow-up 
fingerstick measurement 15 minutes 
after treatment if CGM < 63 mg/dL. 
This protocol will be repeated until 
the HMS alert stops alarming. 
 
CGM reading 
<63 mg/dL 
Same as above treatment. This 
protocol will be repeated until the 
fingerstick is >63 mg/dL per 
standard clinical treatment for 
hypoglycemia. 
Same as above treatment. This 
protocol will be repeated until the 
fingerstick is >63 mg/dL per standard 
clinical treatment for hypoglycemia. 
During the first two weeks of 
outpatient use, study investigators 
will receive alerts for prolonged states 
of hypoglycemia. 
Any time a 
subject has 
subjective 
symptoms of 
hypoglycemia  
A fingerstick blood glucose 
measurement will be performed. 
Fast-acting carbohydrates may be 
given to any subject who is 
symptomatic or requests treatment.  
Subject is instructed to perform a 
fingerstick blood glucose 
measurement for symptoms of 
hypoglycemia. Fast-acting 
carbohydrates may be taken at any 
time for hypoglycemia symptoms.  
CGM reading 
is >180 mg/dL 
for more than 
1 hour  
A confirmatory fingerstick 
measurement will be performed.  
If the subject’s BG is confirmed to 
be >180 mg/dL, then ketones will be 
checked using the study-approved 
ketone meter. 
Subject is instructed to perform a 
fingerstick blood glucose 
measurement. 
If the subject’s BG is confirmed to be 
>180 mg/dL, then ketones will be 
checked using the study-approved 
ketone meter. 
Study investigators will receive alerts 
for prolonged states of 
hyperglycemia. 
BG confirmed 
>180 mg/dL 
for more than 
1 hour and 
A manual correction bolus with a 
target of 140 mg/dL may be 
delivered via the pump. Fingerstick 
BG and ketone measurements will be 
repeated after 1 hour. The correction 
Subject will deliver a manual 
correction bolus with a target of 140 
mg/dL via the pump. Fingerstick BG 
and ketone measurements will be 
repeated after 1 hour. The correction 

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ketones are 
<1.0 mmol/L 
dose given may be adjusted by the 
investigator, or by the subject during 
extended use of the system at home. 
If BG fails to decrease by a 
minimum of 50 mg/dL in 1-2 hours, 
then study staff will replace the 
subject’s infusion set with a new 
infusion set and the correction bolus 
will be repeated per the 
investigator’s discretion. Subjects 
will change out their own infusion 
set during extended use of the system 
at home. 
dose given may be adjusted by the 
subject during extended use of the 
system at home. 
If BG fails to decrease by a minimum 
of 50 mg/dL in 1-2 hours, then 
subject will replace their infusion set 
with a new infusion set and the 
correction bolus will be repeated as 
needed.  
During the first two weeks of 
outpatient use, study investigators 
will receive alerts for prolonged states 
of hyperglycemia. 
BG confirmed 
>180 mg/dL 
for more than 
1 hour and 
ketones are 
>1.0 mmol/L 
A manual correction bolus with a 
target of 140 mg/dL may be 
delivered via injection to assure 
proper absorption in the setting of 
likely infusion set failure. 
Fingerstick BG and ketone 
measurements will be repeated after 
1 hour. The correction dose given 
may be adjusted by the investigator, 
or by the subject during extended use 
of the system at home. 
The study staff will replace the 
subject’s infusion set with a new 
infusion set and the correction bolus 
will be repeated per the 
investigator’s discretion. Closed-
loop will be disabled by the 
investigator for the next 2-4 hours 
and until BG has returned to < 180 
mg/dL.  Subjects will change out 
their own infusion set and stop 
closed-loop use during extended use 
of the system at home. 
Subject is instructed that with positive 
ketones, a manual correction bolus 
with a target of 140 mg/dL is to be 
given via injection to assure proper 
absorption in the setting of likely 
infusion set failure. Fingerstick BG 
and ketone measurements will be 
repeated after 1 hour. The correction 
dose given may be adjusted by the 
subject during extended use of the 
system at home. 
The subject will replace their infusion 
set infusion with a new infusion set 
and the correction bolus will be 
repeated as needed. Closed-loop will 
be disabled for the next 2-4 hours and 
until BG has returned to < 180 
mg/dL. Subjects will report all 
positive ketone measurements to the 
investigators. 
Study investigators will receive alerts 
for prolonged states of 
hyperglycemia. 
Subject loses 
consciousness 
or has a 
seizure, or 
subject is 
unable to take 
1 mg of glucagon will be 
administered and 911 will be called. 
The study will be stopped 
immediately until sponsor conducts a 
full investigation to determine the 
root cause for the compromised 
system performance and is able to 
1 mg of glucagon will be 
administered by the subject’s care 
partner/other responsible adult and 
911 will be called. The study will be 
stopped immediately until sponsor 
conducts a full investigation to 
determine the root cause for the 

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Study staff will monitor the subject’s sensor glucose and insulin delivery throughout the study 
using the iAPS on the subject’s phone, the web interface and CGM. All blood glucose 
measurements will be performed with the study-approved glucometer. 
Manual correction boluses may also be administered via the iAPS as needed throughout the 
hybrid closed loop phase. 
For the extension phase (at home use) of the study device, study staff will follow the following 
detailed plan in response to notifications from the study system or contacts from subjects. Failure 
to document these actions in response to a notification or subject contact will be considered a 
protocol deviation. 
Safety Monitoring Contact Plan for At Home Portion of Study   
Plan  
Team notifications  
Plan  
Hyperglycemia Mitigation 
plan  
 
The study team will receive real 
time text alerts for CGM values:  
>180 mg/dL for >1.5 hours or 
>250 mg/dL for >20 minutes. 
 
A study team member will 
contact participant to review 
fingerstick and ketone values, 
discuss etiology of 
hyperglycemia, and review 
with participant mitigation 
strategies including insulin 
coverage for hyperglycemia, 
ketone testing, set change, 
and/ or subcutaneous injection 
as indicated based on clinical 
scenario. A licensed 
oral 
carbohydrates  
address all issues. Sponsor will also 
communicate the results of this root 
cause investigation to FDA and to 
study investigators.  
compromised system performance 
and is able to address all issues. 
Sponsor will also communicate the 
results of this root cause investigation 
to FDA and to study investigators. 
No heart rate, 
no blood 
pressure  
Perform resuscitation, call 911, and 
transfer subject to ER.  
Study will be stopped immediately 
until sponsor conducts a full 
investigation to determine the root 
cause for the compromised system 
performance and is able to address 
all issues. Sponsor will also 
communicate the results of this root 
cause investigation to FDA and to 
study investigators.  
Perform resuscitation, call 911, and 
transfer subject to ER.  
Study will be stopped immediately 
until sponsor conducts a full 
investigation to determine the root 
cause for the compromised system 
performance and is able to address all 
issues. Sponsor will also 
communicate the results of this root 
cause investigation to FDA and to 
study investigators. 

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professional on the study team 
(MD or NP) will make these 
clinical decisions.  
A study team member will 
recheck CGM remotely in 1 
hour to ensure reduction in 
hyperglycemia.    
Severe hyperglycemia 
mitigation plan  
The study team will receive real 
time text alerts for CGM values:  
>180 mg/dL for >1.5 hours or 
>250 mg/dL for >20 minutes. 
 
 
A study team member will 
speak with the participant.  If 
ketones are >1.5 mmol/L, or 
>0.6mmol/L for more than 90 
minutes, and not decreasing 
after an injection of insulin, 
the site PI or delegated 
investigator will ascertain 
whether the participant has the 
capacity to care adequately for 
themselves with guidance. If 
based on clinical expertise and 
judgement, it appears the 
participant may not be 
adequately able to care for 
themselves without assistance, 
then the investigator will 
either directly communicate 
with someone on the scene 
whom they judge to have that 
capacity, or call 911, or both.  
Hypoglycemia Mitigation 
Strategy  
The study team will receive 
real time text alerts for CGM 
values <54 mg/dL for >20 
minutes 
A study team member will 
contact participant to review 
fingerstick values, discuss 
etiology of the hypoglycemia, 
and review with participant 
the appropriate treatment of 
the hypoglycemic episode 
based on glucose level and 
active insulin on board. A 
licensed professional on the 
study team (MD or NP)  will 
direct these clinical decisions.  
Severe Hypoglycemia 
mitigation plan  
The study team will receive 
real time text alerts for CGM 
values <54 mg/dL for >20 
minutes  
If the investigator upon 
contacting a participant due to 
hypoglycemia notes that she is 
unable to treat herself or she is 
unable to be contacted, the 

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study investigator will contact 
her care partner to evaluate 
the participant and administer 
glucagon 1mg IM if needed. 
The investigator or care 
partner will call 911.  
Emergency Care plan 
Study team contacts 
participant or care partner 
because of alert or study team 
is contacted by the study 
participant or care partner or 
another individual onsite for 
an emergent glucose event or 
a potential ADE or UADE 
event with a study device  
 
The event will be reviewed by 
a licensed professional (MD 
or NP) on the study team. If 
the investigator concludes that 
the participant needs 
emergency care, the 
participant will be told to go 
to an emergency department. 
Study staff will determine 
which emergency department 
the participant will be taken to 
and follow up within 15 
minutes of the expected 
arrival time to ensure the 
participant arrived.  
 
If the study staff (MD or NP) 
calls 911, they will remain on 
the telephone with the 
participant until the 
ambulance arrives and speak 
to the Emergency Medical 
Technician to provide history 
and determine where the 
participant will be taken.  
Emergency room visit plan 
Study team contacts 
participant or care partner 
because of alert or study team 
is contacted by the study 
participant or care partner or 
another individual onsite. 
The PI or designated 
investigator will speak 
directly to the emergency 
room staff caring for the 
participant.   
The PI or designated 
investigator will inform the 
participant’s obstetrician of 
the emergency room visit  
Loss of CGM connectivity 
Team will receive a real time 
text alert for lack of CGM 
data for > 2 hours 
A study team member will 
speak with the participant. A 
fingerstick will be performed 
and troubleshooting will be 

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performed as needed to 
resume CGM 
activity/connectivity. During 
this time, the insulin pump 
with automatically deliver 
insulin according the pump’s 
programmed basal insulin 
delivery settings. 
Insulin pump malfunction  
Participant will be alerted by 
loud beeps from the insulin 
pump if there is a pump 
malfunction or a low pump 
battery. Participant will 
contact study team if 
malfunction cannot be 
remedied within 30 minutes. 
Real time text alerts will also 
be sent to study staff for out 
of closed-loop for 2 hours for 
any reason. 
Participant will perform a 
fingerstick. Troubleshooting 
will be performed by the 
study team as needed to 
resume pump functioning. If 
the malfunction is not 
resolved, participant will be 
instructed to resume her 
personal pump or initiate 
subcutaneous insulin 
treatment as guided by the 
study MD or NP until the 
pump is replaced.   
 
 
 
7.3 
Potential Risks and Benefits of the Investigational Device 
Risks and Benefits are detailed below. Loss of confidentiality is a potential risk; however, data 
are handled to minimize this risk. Hypoglycemia, hyperglycemia and ketone formation are 
always a risk in participants with T1D and participants will be monitored for this. As subjects 
will be pregnant, there are also potential unknown risks to the mother or fetus. Since no new 
medications are being used, and subjects are already actively managing their type 1 diabetes 
during their pregnancy, we believe any additional risk from using the study devices is minimal. 
7.3.1 
Known Potential Risks 
7.3.1.1 Venipuncture Risks 
A hollow needle/plastic tube will be placed in the arm for taking blood samples. Blood draws 
can cause some common reactions like pain, bruising, or redness at the sampling site. Less 
common reactions include bleeding from the sampling site, formation of a small blood clot or 
swelling of the vein and surrounding tissues, and fainting. 

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7.3.1.2 Fingerstick Risks 
About 1 drop of blood will be removed by fingerstick for measuring blood glucose and 
sometimes Hemoglobin A1c (HbA1c) or other tests. This is a standard method used to obtain 
blood for routine hospital laboratory tests. Pain is common at the time of lancing. In about 1 in 
10 cases, a small amount of bleeding under the skin will produce a bruise. A small scar may 
persist for several weeks. The risk of local infection is less than 1 in 1000. This should not be a 
significant contributor to risks in this study as fingersticks are part of the usual care for people 
with diabetes. 
7.3.1.3 Subcutaneous Catheter Risks (CGM) 
Participants using the CGM will be at low risk for developing a local skin infection at the site of 
the sensor needle placement. If a catheter is left under the skin for more than 24 hours, it is 
possible to get an infection where it goes into the skin, with swelling, redness and pain. There 
may be bleeding where the catheter is put in and bleeding under the skin causes a bruise (1 in 10 
risk). 
Study staff should verbally alert the participant that on rare occasions, the CGM may break and 
leave a small portion of the sensor probe under the skin that may cause redness, swelling or pain 
at the insertion site. The participant will be instructed to notify the study coordinator 
immediately if this occurs. 
7.3.1.4 Risk of Hypoglycemia 
As with any person having T1D and using insulin, there is always a risk of having a low blood 
sugar (hypoglycemia). The frequency of hypoglycemia should be no more and possibly less than 
it would be as part of daily living. Symptoms of hypoglycemia can include sweating, jitteriness, 
and not feeling well. Just as at home, there is the possibility of fainting or seizures (convulsions) 
and that for a few days the participant may not be as aware of symptoms of hypoglycemia. A 
CGM functioning poorly and significantly over-reading glucose values could lead to 
inappropriate insulin delivery.  Fetal growth restriction or small for gestational neonates has been 
reported in pregnant women with excessive hypoglycemia using multiple daily injections or 
sensor augmented or standard insulin pump therapy.    
7.3.1.5  Risk of Hyperglycemia 
Hyperglycemia and ketonemia could occur if insulin delivery is attenuated or suspended for an 
extended period or if the pump or infusion set is not working properly. Stress can also induce 
hyperglycemia. A CGM functioning poorly and significantly under-reading glucose values could 
lead to inappropriate suspension of insulin delivery. In this study, subjects will take full insulin 
boluses for all their meals, whether or not they are using the closed-loop system. In addition, 
subjects will be medically supervised when undergoing stress assessments, with medical staff 
present who will increase insulin doses as needed if this proves necessary during the stress 
assessments. All subjects will be issued a ketone meter and ketone strips to use to carefully 
monitor for hyperglycemia and be given instructions on how to mitigate hyperglycemia should it 
occur.  Chronic hyperglycemia can increase the risk of fetal macrosomia or large for gestational 
age neonate, polyhydramnios and neonatal hypoglycemia in the newborn fetus at the time of 
delivery. These are the same risks occur in pregnant women utilizing MDI or sensor augmented 
or standard insulin pump therapy.   Acute hyperglycemia can lead to DKA that puts the fetus at 

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acute risk of acidosis and demise. Furthermore, DKA in pregnancy can occur at lower glucose 
levels than in the non-pregnant state, hence the need to be vigilant and intervene when the 
glucose level approaches 180 mg/dL  
7.3.1.6 Risk of Device Reuse 
The study CGM system is labeled for single use only. The sensor (the component of the system 
that enters the skin) will be single use only. The transmitter and receiver may be reused during 
the study after cleaning the device using a hospital-approved cleaning procedure. The transmitter 
is attached to the sensor but does not enter the skin and the receiver is a handheld device. 
Participants will be informed that Food & Drug Administration (FDA) or relevant national 
authorities have approved these devices for single use and that by using them among multiple 
patients, bloodborne pathogens (i.e. Hepatitis B) may be spread through the use of multiple 
users. 
 
The study insulin pump is labeled for single-patient use. During the study, this device may be 
reused after cleaning adhering to a hospital-approved cleaning procedure. All infusion set 
equipment will be single patient use only (infusion set insertion kits, tubing, cartridges etc.).  
 
Participants will be informed that FDA or relevant national authorities typically approve the 
insulin pump device for single use and that by using them among multiple patients, bloodborne 
pathogens (i.e. Hepatitis B) may be spread through the use of multiple users. 
 
The study phone may be reused after cleaning adhering to a hospital-approved cleaning 
procedure. 
 
The study blood glucose meter and blood ketone meter are labeled for single-patient use. 
During the study, only one person can use each device as there are rare risks that bloodborne 
pathogens (i.e. Hepatitis B) may be spread through the use of multiple users. 
 
7.3.1.7 Cleaning Procedure 
All devices being reused in this study as noted above (i.e. the Tandem t:AP pump, the CGM 
receiver and transmitter, and the phone running the iAPS App) will be thoroughly cleaned prior 
to reuse. The person performing the cleaning will sanitize their hands and then put on gloves 
prior to cleaning. 
CGM receivers/CGM Transmitters and/or Insulin pumps/Cellular Devices: Sanitize hands, and 
then put on gloves before opening 70% isopropyl alcohol pads. Thoroughly wipe the device with 
the alcohol pad. Then use 2 Clorox Healthcare®35309 Bleach Germicidal Wipes, one for pre-
cleaning and one for disinfecting. After pre-cleaning wipe the device thoroughly and wet the 
exterior with a 2nd wipe. Allow the surface to stay wet for 3 minutes and then let air dry. 
Dispose of used pad and gloves. Equipment will be stored in a clean Ziploc bag. 
Equipment will be allowed to dry completely. All cleaned equipment will be stored in a clean 
zipped bag until ready for reuse. 
 

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8 
ADVERSE EVENTS, DEVICE ISSUES, AND STOPPING RULES 
8.1 
Adverse Events 
8.1.1 
Definitions 
Adverse Event (AE): Any untoward medical occurrence in a study participant, irrespective of the 
relationship between the adverse event and the device(s) under investigation (see section 8.1.2 
for reportable adverse events for this protocol). 
 
Serious Adverse Event (SAE): Any untoward medical occurrence that: 
• Results in death of the mother or the fetus. 
• Is life-threatening; (a non-life-threatening event which, had it been more severe, might have 
become life-threatening, is not necessarily considered a serious adverse event). 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity or substantial disruption of the ability 
to conduct normal life functions (sight threatening). 
• Is a congenital anomaly or birth defect. 
• Is considered a significant medical event by the investigator based on medical judgment (e.g., 
may jeopardize the participant or fetus or may require medical/surgical intervention to 
prevent one of the outcomes listed above). 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or safety or 
any life-threatening problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of participants (21 CFR 812.3(s)). 
 
Adverse Device Effect (ADE): Any untoward medical occurrence in a study participant which 
the device may have caused or to which the device may have contributed (Note that an Adverse 
Event Form is to be completed in addition to a Device Deficiency or Issue Form). 
 
Device Complaints and Malfunctions: A device complication or complaint is something that 
happens to a device or related to device performance, whereas an adverse event happens to a 
participant. A device complaint may occur independently from an AE, or along with an AE. 
An AE may occur without a device complaint or there may be an AE related to a device 
complaint. A device malfunction is any failure of a device to meet its performance specifications 
or otherwise perform as intended. Performance specifications include all claims made in the 
labeling for the device. The intended performance of a device refers to the intended use for 
which the device is labeled or marketed. (21 CFR 803.3). Note: for reporting purposes, sites 
will not be asked to distinguish between device complaints and malfunctions. 

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8.1.2 
Reportable Adverse Events 
For this protocol, a reportable adverse event includes any untoward medical occurrence that 
meets one of the following criteria: 
1. A serious adverse event 
2. An Adverse Device Effect as defined in section 8.1.1, unless excluded from reporting in 
section 8.2 
3. An Adverse Event occurring in association with a study procedure 
4. Hypoglycemia meeting the definition of severe hypoglycemia as defined below  
5. Diabetic ketoacidosis (DKA) as defined below or in the absence of DKA, a 
hyperglycemic or ketosis event meeting the criteria defined below 
Hypoglycemia and hyperglycemia not meeting the criteria below will not be recorded as adverse 
events unless associated with an Adverse Device Effect. Skin reactions from sensor placement 
are only reportable if severe and/or required treatment.  
8.1.2.1 Hypoglycemic Events 
Hypoglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
event when the following definition for severe hypoglycemia is met: 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. 
8.1.2.2 Hyperglycemic Events/Diabetic Ketoacidosis 
Hyperglycemia not associated with an Adverse Device Effect is only reportable as an adverse 
event when one of the following 4 criteria is met:  
• the event involved DKA, as defined by the Diabetes Control and Complications Trial 
(DCCT) and described below 
• evaluation or treatment was obtained at a health care provider facility for an acute event 
involving hyperglycemia or ketosis 
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 

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All reportable Adverse Events—whether volunteered by the participant, discovered by study 
personnel during questioning, or detected through physical examination, laboratory test, or other 
means—will be reported on an adverse event form online. Each adverse event form is reviewed 
by the Medical Monitor to verify the coding and the reporting that is required. 
8.1.3 
Relationship of Adverse Event to Study Device 
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 device. 
 
To ensure consistency of adverse event causality assessments, investigators should apply the 
following general guideline when determining whether an adverse event is related: 
 
Yes 
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. 
 
No 
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. 
8.1.4 
Intensity of Adverse Event 
The intensity of an adverse event will be rated on a three point scale: (1) mild, (2) moderate, or 
(3) severe. It is emphasized that the term severe is a measure of intensity: thus a severe adverse 
event is not necessarily serious. For example, itching for several days may be rated as severe, but 
may not be clinically serious. 
• MILD: Usually transient, requires no special treatment, and does not interfere with the 
participant’s daily activities. 
• MODERATE: Usually causes a low level of inconvenience or concern to the participant and 
may interfere with daily activities, but is usually ameliorated by simple therapeutic measures. 
• SEVERE: Interrupts a participant’s usual daily activities and generally requires systemic 
drug therapy or other treatment. 

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8.1.5 
Coding of Adverse Events 
Adverse events will be coded using the MedDRA dictionary. The Medical Monitor will review 
the investigator’s assessment of causality and may agree or disagree. Both the investigator’s and 
Medical Monitor’s assessments will be recorded. The Medical Monitor will have the final say in 
determining the causality. 
 
Adverse events that continue after the participant’s discontinuation or completion of the study 
will be followed until their medical outcome is determined or until no further change in the 
condition is expected. 
8.1.6 
Outcome of Adverse Event 
The outcome of each reportable adverse event will be classified by the investigator as follows: 
• RECOVERED/RESOLVED – The participant recovered from the AE/SAE without sequelae. 
Record the AE/SAE stop date. 
• RECOVERED/RESOLVED WITH SEQUELAE – The event persisted and had stabilized 
without change in the event anticipated. Record the AE/SAE stop date. 
• FATAL – A fatal outcome is defined as the SAE that resulted in death. Only the event that 
was the cause of death should be reported as fatal. AEs/SAEs that were ongoing at the time 
of death; however, were not the cause of death, will be recorded as “resolved” at the time of 
death. 
• NOT RECOVERED/NOT RESOLVED (ONGOING) – An ongoing AE/SAE is defined as 
the event was ongoing with an undetermined outcome. 
• An ongoing outcome will require follow-up by the site in order to determine the final 
outcome of the AE/SAE. 
• The outcome of an ongoing event at the time of death that was not the cause of death, 
will be updated and recorded as “resolved” with the date of death recorded as the stop 
date. 
• UNKNOWN – An unknown outcome is defined as an inability to access the participant or 
the participant’s records to determine the outcome (for example, a participant that was lost to 
follow-up). 
All clinically significant abnormalities of clinical laboratory measurements or adverse events 
occurring during the study and continuing at study termination should be followed by the 
participant’s physician and evaluated with additional tests (if necessary) until diagnosis of the 
underlying cause, or resolution. Follow-up information should be recorded on source documents. 
If any reported adverse events are present when a participant completes the study, or if a 
participant is withdrawn from the study due to an adverse event, the participant will be contacted 
for re-evaluation within 2 weeks. If the adverse event has not resolved, additional follow-up will 
be performed as appropriate. Every effort should be made by the Investigator or delegate to 
contact the participant until the adverse event has resolved or stabilized. 

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8.2 
Reportable Device Issues 
All UADEs, ADEs, device complaints, and device malfunctions will be reported irrespective of 
whether an adverse event occurred, except in the following circumstances. 
The following device issues are anticipated and will not be reported on a Device Issue Form but 
will reported as an Adverse Event if the criteria for AE reporting described above are met: 
• Component disconnections 
• CGM sensors lasting fewer than the number of days expected per CGM labeling 
• CGM tape adherence issues 
• Pump infusion set occlusion not leading to ketosis 
• Battery lifespan deficiency due to inadequate charging or extensive wireless communication 
• Intermittent device component disconnections/communication failures not leading to system 
replacement 
• Device issues clearly addressed in the user guide manual that do not require additional 
troubleshooting 
• Skin reactions from CGM sensor placement or pump infusion set placement that do not meet 
criteria for AE reporting 
8.3 
Timing of Event Reporting 
SAEs and UADEs must be recorded within 24 hours via completion of the serious adverse event 
form. 
 
Other reportable adverse events, device malfunctions (with or without an adverse event), and 
device complaints should be reported promptly by completion of the relevant case report form, 
but there is no formal required reporting period. 
 
Each principal investigator is responsible for reporting serious study-related adverse events and 
abiding by any other reporting requirements specific to his/her Institutional Review Board or 
Ethics Committee. 
 
Upon receipt of a UADE report, the study principal investigators will investigate the UADE and 
if indicated, report the results of the investigation to the sites’ IRBs, and the FDA within ten 
working days of becoming aware of the UADE per 21CFR 812.46(b) (2). The Medical Monitors 
must determine if the UADE presents an unreasonable risk to participants. If so, the Medical 
Monitors must ensure that all investigations, or parts of investigations presenting that risk, are 
terminated as soon as possible but no later than 5 working days after the Medical Monitors 
makes this determination and no later than 15 working days after first receipt notice of the 
UADE. 
 
In the case of a device system component malfunction (e.g. pump, CGM, control algorithm), 
information will be forwarded to the responsible company by the site personnel, to be handled 
by its complaint management system. 

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8.4 
Stopping Criteria 
8.4.1 
Participant Discontinuation of Study Device 
Rules for discontinuing study device use are described below. 
• 
The investigator believes it is unsafe for the participant to continue on the intervention. This 
could be due to the development of a new medical condition or worsening of an existing 
condition for the mother or fetus; or participant behavior contrary to the indications for use of 
the device that imposes on the participant’s safety 
• Significant deterioration of glycemic control as determined at any time or during the 
scheduled weekly contacts, leading to a significant worsening time in range compared to 
baseline (10% or more worsening of time in target range) and time in range consistently 
below 50%. 
• The participant requests that the treatment be stopped 
• One distinct episode of DKA related to system function (includes infusion set 
failure/occlusion leading to DKA) 
• One episode of severe hypoglycemia related to system function  
• Subject’s must discontinue all investigation device (to include study phone and pump) should 
glucocorticoids be administered to the subject (i.e., Betamethasone for fetal lung maturity). 
• Investigation device use (to include study phone and study pump) will be discontinued upon 
hospital admission for any reason, to include for labor and delivery, and subjects will return 
to their standard of care or IV insulin drip per hospital protocols and hospital team directed 
management.  
8.4.2 
Criteria for Suspending or Stopping Overall Study 
In the case of a system malfunction resulting in a severe hypoglycemia or severe hyperglycemia 
event (as defined in section 8.1.2.2), use of the study device system will be suspended while the 
problem is diagnosed. 
 
Further, study enrollment will be stopped, and all investigation device use will be immediately 
discontinued, if: 
• Two subjects have an episode of DKA related to system function (includes infusion set 
failure/occlusion leading to DKA)  
• Two subjects have an episode of severe hypoglycemia related to system function 
• Two subjects have at any time met criteria to stop the study by showing significant 
deterioration of glycemic control as determined at any time or during the scheduled weekly 
contacts, leading to a significant worsening time in range compared to baseline (10% or more 
worsening of time in target range) and time in range consistently below 50%. 
 
In addition, study activities could be similarly suspended if the manufacturer of any constituent 
study device requires stoppage of device use for safety reasons (e.g. product recall). The affected 

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study activities 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. 
 
The medical monitor for the study 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 medical monitor will request suspension of study activities or 
stoppage of the study if deemed necessary based on the totality of safety data available. The 
study medical monitor 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 medical monitor may request suspension of study activities or stoppage of 
the study if deemed necessary based on the totality of safety data available. 
8.5 
Independent Safety Oversight 
The medical monitor will review all reported adverse events and adverse device events. 
Additionally the engineering team at Harvard University will be informed of any UADEs that 
require FDA reporting as defined in section 8.3.  
 
The medical monitor for the study is Dr. Carl Rose, Maternal Fetal Medicine at Mayo Clinic. 
 
For the extension phase of the study, we have convened a Data and Safety Monitoring Board 
(DSMB). The DSMB will provide safety oversight. The DSMB will be informed of all cases of 
severe hypoglycemia and diabetic ketoacidosis irrespective of device relationship, all device-
related SAEs, and all UADEs at the time that they occur during the study and will review 
compiled safety data at periodic intervals. The DSMB also will be informed of any ADEs not 
meeting criteria for a UADE if the Medical Monitor requests the DSMB review. The DSMB can 
request modifications to the study protocol or suspension or outright stoppage of the study if 
deemed necessary based on the totality of safety data available. Details regarding the DSMB’s 
role will be documented in a separate DSMB charter. 

 
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9 
MISCELLANEOUS CONSIDERATIONS 
9.1 
Drugs Used as Part of the Protocol 
Participants will use either lispro or aspart insulin for the closed-loop session. 
9.2 
Prohibited Medications, Treatments, and Procedures 
Treatment with any non-insulin glucose-lowering agent (including GLP-1 agonists, Pramlintide, 
DPP-4 inhibitors, SGLT-2 inhibitors, biguanides, sulfonylureas and naturaceuticals) or Afrezza 
will not be permitted during the trial. 
 
The investigational study devices (study insulin pump, study phone, study CGM systems) must 
be removed before Magnetic Resonance Imaging (MRI), Computed Tomography (CT) or 
diathermy treatment. Participants may continue in the trial after temporarily discontinuing use if 
requiring one of the treatments above.. 
9.3 
Participant Compensation 
Participant compensation will be specified in the informed consent form. 
9.4 
Participant Withdrawal 
Participation in the study is voluntary, and a participant may withdraw at any time. 
For participants who withdraw, their data will be used up until the time of withdrawal. 
9.5 
Confidentiality 
For security and confidentiality purposes, participants will be assigned an identifier that will 
be used instead of their name. Protected health information gathered for this study will be 
securely stored at the study clinic sites. De-identified participant information may also be 
provided to research sites involved in the study.  
 
10 
DATA COLLECTION AND MONITORING 
10.1 
Study Records Retention 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents should 
be retained for a longer period, however, if required by local regulations. No records will be 
destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the 
sponsor to inform the investigator when these documents no longer need to be retained. 
10.2 
Quality Assurance and Monitoring 
Designated personnel from the study clinical center will be responsible for maintaining quality 
assurance (QA) and quality control (QC) systems to ensure that the clinical portion of the trial is 
conducted and data are generated, documented and reported in compliance with the protocol, 

 
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Good Clinical Practice (GCP) and the applicable regulatory requirements. Adverse events will be 
prioritized for monitoring. Study conduct and monitoring will conform with 21 Code of Federal 
Regulations (CFR) 812. 
10.3 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or procedure 
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
the study site staff. As a result of deviations, corrective actions are to be developed by the site 
and implemented promptly. 
 
The site PI/study staff is responsible for knowing and adhering to their IRB requirements.  
 
Further details about the handling of protocol deviations will be included in the monitoring plan. 
 
11 
ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
11.1 
Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
21 CFR Part 56, and/or the ICH E6. 
11.2 
Institutional Review Boards 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether previously consented participants need to be re-consented. 
11.3 
Informed Consent Process 
11.3.1 Consent Procedures and Documentation 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation will be provided to the participants and their families. 
Consent forms will be IRB-approved, and the participant will be asked to read and review the 
document. The investigator will explain the research study to the participant and answer any 
questions that may arise. All participants will receive a verbal explanation in terms suited to their 
comprehension of the purposes, procedures, and potential risks of the study and of their rights as 
research participants. Participants will have the opportunity to carefully review the written 
consent form and ask questions prior to signing. 
 
The participants should have the opportunity to discuss the study with their surrogates or think 
about it prior to agreeing to participate. The participant will sign the informed consent document 
prior to any procedures being done specifically for the study. The participants may withdraw 

 
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consent at any time throughout the course of the trial. A copy of the informed consent document 
will be given to the participants for their records. The rights and welfare of the participants will 
be protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. 
11.3.2 Participant and Data Confidentiality 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB or 
authorized representatives from Sansum Diabetes Research Institute, Mt. Sinai Hospital, Mayo 
Clinic or Harvard University may inspect all documents and records required to be maintained 
by the investigator, including but not limited to, medical records (office, clinic, or hospital) for 
the participants in this study. The clinical study site will permit access to such records.  
 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by local IRB and Institutional regulations. 
 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted from Sansum Diabetes Research Institute, Mt. Sinai Hospital and 
Mayo Clinic and sent to and stored at Harvard University. This will not include the participant’s 
contact or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study management 
systems used by the clinical site will be secured and password protected. At the end of the study, 
all study databases will be de-identified and archived at Sansum Diabetes Research Institute, 
Mayo Clinic, Mt. Sinai and Harvard University. Permission to transmit data will be included in 
the informed consent. 
 
 
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Nimri R, Jovanovič L, Doyle III FJ. Clinical Evaluation of a Personalized Artificial Pancreas. 
Diabetes Care 2013;36:801-809 
2. Dassau E, Brown SA, Basu A, Pinsker JE, Kudva YC, Gondhalekar R, Patek S, Lv D, 
Schiavon M, Lee JB, Dalla Man C, Hinshaw L, Castorino K, Mallad A, Dadlani V, McCrady-
Spitzer SK, McElwee-Malloy M, Wakeman CA, Bevier WC, Bradley PK, Kovatchev B, Cobelli 
C, Zisser HC, Doyle III FJ. Adjustment of Open-Loop Settings to Improve Closed-Loop Results 
in Type 1 Diabetes: A Multicenter Randomized Trial. J Clin Endocrinol Metab 2015;100:3878-
3886 
3. Dassau E, Pinsker JE, Kudva YC, Brown SA, Gondhalekar R, Dalla Man C, Patek S, 
Schiavon M, Dadlani V, Dasanayake I, Church MM, Carter RE, Bevier WC, Huyett LM, Hughes 
J, Anderson S, Lv D, Schertz E, Emory E, McCrady-Spitzer SK, Jean T, Bradley PK, Hinshaw 
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