Effect of Hybrid Closed-Loop Insulin Delivery on Glucose Counterregulation in Long Standing Type 1 Diabetes: A Proof of Concept, Mechanistic, Single-Arm Clinical Trial
Phase: NA
Conditions: Type1diabetes, Hypoglycemia Unawareness, Nocturnal Hypoglycemia, Hypoglycemia Night, Hypoglycemia
Sponsor: University of Pennsylvania

 
 
 
 
EFFECT OF HYBRID CLOSED-LOOP INSULIN DELIVERY ON GLUCOSE 
COUNTERREGULATION IN LONG STANDING TYPE 1 DIABETES: A PROOF OF 
CONCEPT, MECHANISTIC, SINGLE-ARM CLINICAL TRIAL 
 
Principal Investigator 
Michael R. Rickels, M.D., M.S. 
Professor of Medicine 
Institute for Diabetes, Obesity & Metabolism 
12-134 Smilow Center for Translational Research 
3400 Civic Center Boulevard 
Philadelphia, PA 19104 
215-746-0025 – phone 
215-898-5408 – fax 
rickels@pennmedicine.upenn.edu 
Funding Sponsor 
National Institute of Diabetes and Digestive and Kidney Disease 
Guillermo Arreaza-Rubin, M.D., Program Official 
Democracy II, Room 6101 
6707 Democracy Boulevard 
Bethesda, MD 20892-5460 
(301) 594-4724 – phone 
(301) 480-3503 – fax 
arreazag@mail.nih.gov 
 
 
NIH Grant Number 
2R01-DK-091331 
 
 
Investigational Product: 
Medtronic MiniMed 670G System and Tandem t:slimX2 Basal-IQ and 
 
Control-IQ 
 
Protocol Number: 
IRB Number: 
NERP16-015 (Medtronic Diabetes) 
827557 
IND/ IDE Number: 
Exempt 
 
 
 
ClinicalTrials.gov Number: 
NCT03215914 
 
 
 
 
 
Initial version 
v1.0 May 15, 2017 
Amended 
v2.1 18-Feb-2019  
Amended 
v2.2 25-Sep-2019 
Amended 
v2.3 12-Feb-2020 
Amended 
v2.4 19-Mar-2021

 
 
 
 
Hybrid Closed Loop in Hypoglycemia 
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Table of Contents 
 
 
Contents 
 
LIST OF ABBREVIATIONS............................................................................................................................ III 
STUDY SUMMARY ...................................................................................................................................... 1 
BACKGROUND AND STUDY RATIONALE ............................................................................................... 3 
INTRODUCTION ............................................................................................................................................ 3 
1.1 
BACKGROUND AND RELEVANT LITERATURE ..................................................................................... 3 
1.2 
NAME AND DESCRIPTION OF THE INVESTIGATIONAL PRODUCT ........................................................... 5 
1.2.1 
Clinical Data to Date ................................................................................................................ 5 
2 
STUDY OBJECTIVES ......................................................................................................................... 8 
3 
INVESTIGATIONAL PLAN .................................................................................................................. 8 
3.1 
GENERAL DESIGN .......................................................................................................................... 8 
3.1.1 
Recruitment, Informed Consent and Screening Phase ........................................................... 9 
3.1.2 
Study Intervention Phase ...................................................................................................... 10 
3.2 
STUDY ENDPOINTS ....................................................................................................................... 11 
3.2.1 
Primary Study Endpoints ....................................................................................................... 11 
3.2.2 
Secondary Study Endpoints .................................................................................................. 11 
3.2.3 
Primary Safety Endpoints ...................................................................................................... 11 
4 
STUDY POPULATION AND DURATION OF PARTICIPATION ...................................................... 11 
4.1 
INCLUSION CRITERIA .................................................................................................................... 11 
4.2 
EXCLUSION CRITERIA ................................................................................................................... 12 
4.3 
SUBJECT RECRUITMENT ............................................................................................................... 12 
4.4 
DURATION OF STUDY PARTICIPATION ............................................................................................ 13 
4.5 
TOTAL NUMBER OF SUBJECTS ...................................................................................................... 13 
4.6 
VULNERABLE POPULATIONS .......................................................................................................... 13 
5 
STUDY INTERVENTION (STUDY DRUG, DEVICE, BIOLOGIC, VACCINE, FOOD ETC.) ............. 13 
5.1 
DESCRIPTION ............................................................................................................................... 13 
5.2 
INTERVENTION REGIMEN ............................................................................................................... 14 
5.3 
RECEIPT AND STORAGE ................................................................................................................ 14 
5.4 
ADMINISTRATION AND ACCOUNTABILITY ......................................................................................... 15 
5.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 15 
5.5.1 
Return or Destruction of Investigational Product ................................................................... 15 
6 
STUDY PROCEDURES ..................................................................................................................... 15 
6.1 
SCREENING ................................................................................................................................. 16 
6.2 
STUDY INTERVENTION PHASE ....................................................................................................... 16 
6.2.1 
Visit 1 (run-in visit) ................................................................................................................. 16 
6.2.2 
Visit 2 (baseline visit) ............................................................................................................. 17 
6.2.3 
Visits 3 – 7, Months 1 – 5 ...................................................................................................... 17 
6.2.4 
Visit 8, Month 6 ...................................................................................................................... 17 
6.2.5 
Visit 9, Month 9 ...................................................................................................................... 17 

 
 
 
 
 
 
 
6.2.6 
Visit 10, Month 12 .................................................................................................................. .……...18 
6.2.7 
Visit 11, Month 15 .................................................................................................................. .……...18 
6.2.8 
Visit 12, Month 18 .................................................................................................................. .……...18 
6.3 
SUBJECT WITHDRAWAL ................................................................................................................ . ……..18 
6.3.1 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ . ……..18 
6.4 
EARLY TERMINATION VISITS .......................................................................................................... . ……..18 
7 
STATISTICAL PLAN………………………………………………………………………………………….……..19 
7.1 
PRIMARY ENDPOINT ..................................................................................................................... ….…..19 
7.2 
SECONDARY ENDPOINTS .............................................................................................................. .……..19 
7.3 
SAMPLE SIZE AND POWER DETERMINATION ................................................................................... .……..19 
8 
SAFETY AND ADVERSE EVENTS…………………………………………………...…………………………..19 
8.1 
DEFINITIONS ................................................................................................................................ .……..19 
8.1.1 
Adverse Event ....................................................................................................................... .……..19 
8.1.2 
Serious Adverse Event .......................................................................................................... .……..19 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ .……..21 
8.3 
RELATIONSHIP OF AE TO STUDY ................................................................................................... .……..21 
8.4 
REPORTING OF ADVERSE EVENTS, ADVERSE DEVICE EFFECTS AND UNANTICIPATED PROBLEMS ...... .……..21 
8.4.1 
Follow-up report ..................................................................................................................... .……..22 
8.4.2   INVESTIGATOR REPORTING: NOTIFYING THE PENN IRB ............................................................... .……..22 
8.5 
MEDICAL MONITORING ................................................................................................................. .……..23 
8.5.1 
Data and Safety Monitoring Plan ........................................................................................... .……..23 
8.5.2   DATA SAFETY MONITORING BOARD ........................................................................................... .……..23 
9 
STUDY ADMINISTRATION, DATA HANDLING AND RECORD KEEPING…………………………….…...23 
9.1 
CONFIDENTIALITY ......................................................................................................................... .……..24 
9.2 
DATA COLLECTION AND MANAGEMENT .......................................................................................... ……...24 
9.3 
RECORDS RETENTION .................................................................................................................. .……..25 
10 
STUDY MONITORING, AUDITING, AND INSPECTING………………………………………………….……25 
10.1 
STUDY MONITORING PLAN ............................................................................................................ .……..25 
10.2 
AUDITING AND INSPECTING ........................................................................................................... .……..25 
11 
ETHICAL CONSIDERATIONS……………………………………………………………………………….……25 
11.1 
RISKS .......................................................................................................................................... .……..26 
11.2 
BENEFITS..................................................................................................................................... .……..26 
11.3 
RISK BENEFIT ASSESSMENT ......................................................................................................... .……..26 
12 
STUDY FINANCES……………………………………………………………………………………………..…...27 
12.1 
FUNDING SOURCE ........................................................................................................................ .……..27 
12.2 
CONFLICT OF INTEREST ................................................................................................................ .……..27 
12.3 
SUBJECT STIPENDS OR PAYMENTS ................................................................................................ .……..27 
13 
PUBLICATION PLAN…………………………………………………………………………………………..…...27 
14 
REFERENCES ...............................................................................................................................................28 
15 
ATTACHMENTS………………………………………………………………………………………………..…...31          

Hybrid Closed Loop in Hypoglycemia 
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List of Abbreviations 
 
 
 
AE: Adverse event 
 
BMI: Body mass index 
 
CHPS: Center for Human Phenomic Science 
 
CRF: Case report form 
 
CSII: Continuous subcutaneous insulin infusion 
DCCT: Diabetes Control and Complications Trial 
DSMB: Data and safety monitoring board 
DSMP: Data and safety monitoring plan 
ECG: Electrocardiogram 
 
FDA: Food and Drug Administration 
 
HAAF: Hypoglycemia-associated autonomic failure 
 
IRB: Institutional review board 
 
LGS: Low glucose suspend 
 
PHI: Protected health information 
 
PI: Principal investigator 
 
SAE: Serious adverse event 
SAP: Sensor augmented pump 
T1D: Type 1 diabetes

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Study Summary 
 
 
Title 
 
 
Effect of Hybrid Closed-Loop Insulin Delivery on Glucose Counterregulation in 
Long Standing Type 1 Diabetes: a proof of concept, mechanistic, single-arm 
clinical trial 
 
Short Title 
 Hybrid Closed-Loop for Hypoglycemia 
 
 
IRB Number 
827557 
 
 
Protocol Number 
NERP16-015 (Medtronic Diabetes) 
 
Phase 
Mechanistic 
 
 
 
Methodology 
Open label, single-arm trial of the effect of hybrid closed-loop insulin delivery on 
glucose counterregulatory mechanisms assessed by the stepped- hyperinsulinemic 
hypoglycemic clamp in patients with long standing type 1 diabetes complicated by 
hypoglycemia unawareness. 
 
Study Duration 
4.5 years 
 
 
 
Study Center(s) 
Single-center (Penn) 
 
 
 
 
 
 
 
 
 
 
Objectives 
 
 
 
 
 
 
 
 
Number of 
Subjects 
 
Impaired glucose counterregulation and loss of hypoglycemia symptom recognition 
(hypoglycemia unawareness) develops in long standing type 1 diabetes, in part due 
to repeated exposure to hypoglycemia as a consequence of therapeutic 
hyperinsulinemia, and increases the risk for severe hypoglycemia, an important 
complication in itself and a significant barrier to the attainment of adequate glycemic 
control. This study aims to determine whether hypoglycemia avoidance achieved 
through implementation of hybrid closed-loop insulin delivery can improve glucose 
counterregulation in type 1 diabetic patients with hypoglycemia unawareness. We 
hypothesize that the endogenous glucose production response to insulin-induced 
hypoglycemia will be greater in subjects after 6 months when compared to before 
implementation of hybrid closed-loop insulin delivery. Glucose counterregulatory 
hormone, symptom, and endogenous glucose production responses will be 
measured using the stepped-hyperinsulinemic hypoglycemic clamp before, after 6 
months’ intervention, and after 18 months to assess the durability of any benefit from 
avoidance of hypoglycemia with continued use of the hybrid closed-loop system. 
 
We will screen up to 30 participants in order to enroll 15-18 subjects with type 1 
diabetes and hypoglycemia unawareness to receive hybrid closed loop insulin 
delivery.
 
 
 
 
 
 
 
 
 
 
 

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Investigational  
Product (drug, 
biologic, device, etc.) 
 
 
 
 
 
Duration of 
administration (if 
applicable) 
 
 
 
 
 
Reference therapy 
Medtronic MiniMed 670G system or Tandem t:slimX2 with Basal-IQ and 
Control-IQ technology using the Dexcom G6 sensor. Eligible subjects with type 
1 diabetes will initiate hybrid closed-loop insulin delivery based on interstitial 
glucose monitoring via the MiniMed 670G system or the Tandem t:slimX2 insulin 
pump with the Dexcom G6 sensor according to Medtronic’s and Tandem’s 
labeling. These systems combine subject-delivered pre-meal boluses with 
automatic interprandial insulin delivery that include automated functions for both 
predictive and threshold suspension of insulin delivery intended to minimize 
exposure to glucose levels < 70 mg/dl. 
 
 
18 months 
 
 
There is no standard reference therapy against which the investigational product 
is being compared. The purpose of this small, proof-of-concept, mechanistic 
study is to determine whether hybrid closed-loop insulin delivery can achieve 
sufficient hypoglycemia avoidance in patients with long standing type 1 diabetes 
experiencing hypoglycemia and symptom unawareness despite receiving 
intensive insulin therapy standard-of-care to improve glucose counterregulation 
against insulin-induced hypoglycemia. The data generated will be available to 
power future randomized clinical trials to determine the comparative efficacy of 
emerging artificial pancreas and β-cell replacement approaches to achieve target 
glycemic control with amelioration of problematic hypoglycemia in type 1 diabetes. 
 
 
 
 
 
Statistical 
Methodology 
 
 
 
 
 
 
 
Safety 
Evaluations 
 
 
 
 
 
Data and Safety 
Monitoring Plan 
 
The difference in glucose counterregulatory responses obtained during the 
hypoglycemic clamp will be compared within subject from before to 6 months after 
implementation of hybrid closed-loop insulin delivery using paired t-tests or 
Wilcoxon matched-pairs tests as appropriate, and significance will be considered 
at P ≤ 0.05 (two-tailed) for the primary outcome measure of the rate of 
endogenous glucose production. 
For the additional measures, multiple 
comparisons are being made without adjustments for multiplicity, and so any 
findings will be hypothesis generating. The additional responses at 18 months will 
be analyzed by repeated measures mixed model for longitudinal measurements 
over time. 
 
Safety evaluations will include direct questioning for the occurrence of severe 
hypoglycemia, defined as an event with symptoms or signs compatible with 
hypoglycemia in which the subject was unable to treat him/herself and which was 
associated with either a blood glucose level < 54 mg/dl [3.0 mmol/L] or prompt 
recovery 
after 
oral 
carbohydrate, 
intravenous 
glucose, 
or 
glucagon 
administration. 
 
The PI will be primarily responsible for monitoring the data quality and the 
ongoing safety of subjects. A study monitor independent from the study team will 
be assigned to oversee the implementation of the data and safety monitoring plan 
(DSMP). This plan will include the establishment of a data and safety monitoring 
board (DSMB). The mission of the DSMB will be to ensure that the risk 
associated with participation in research is being minimized to the extent 
practical. 

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BACKGROUND AND STUDY RATIONALE 
 
This document is a clinical research protocol and the described study will be conducted in compliance 
with the protocol, Good Clinical Practice standards, associated federal regulations, and all applicable 
University research requirements. All episodes of noncompliance will be documented. 
 
Introduction 
 
1.1 
Background and Relevant Literature 
Hypoglycemia is a major barrier to the achievement of adequate glycemic control for most patients with 
insulin-dependent diabetes, both those with type 1 diabetes and advanced type 2 diabetes (Cryer, 2008). 
Inadequate glycemic control can lead to the development of diabetic retinopathy, nephropathy, and 
neuropathy, the leading causes of adult blindness, kidney failure, and non-traumatic amputation in the 
United States. The American Diabetes Association treatment guidelines recommend that adults with type 
1 diabetes target HbA1c levels < 7.0% unless there is a reason, such as significant hypoglycemia or 
hypoglycemia unawareness, to set a higher target (2015). However, even with HbA1c < 7.0% the residual 
risk for cardiovascular and all-cause mortality in patients with type 1 diabetes remains more than twice 
that in nondiabetics (Lind et al., 2014), with the lowest mortality rates seen with HbA1c ≤ 6.5% (Stadler et 
al., 2014). Unfortunately, despite tremendous advances in the technology available for insulin delivery 
and glucose monitoring, only 30% of adults with type 1 diabetes in the United States receiving care at 
specialty diabetes clinics are achieving a HbA1c level < 7.0% (Miller et al., 2015). Despite this low 
proportion of patients reaching target average glycemic control, 8% reported experiencing a severe 
hypoglycemic event resulting in seizure or loss-of-consciousness in the prior 3 months, including 6% of 
those with a HbA1c level < 7.0%, 8% of those with a HbA1c between 7.0 – 9.0%, and 12% of those with a 
HbA1c > 9.0% (Miller et al., 2015). Thus, current recommendations to set a higher HbA1c target for 
patients with significant hypoglycemia or hypoglycemia unawareness (2015) are unlikely to impact the 
burden of severe hypoglycemia in type 1 diabetes, and may not be acceptable to patients striving to avoid 
or mitigate the micro- and macrovascular complications of this disease. 
 
Severe episodes of hypoglycemia are life-threatening, fear of such episodes distressing, and the 
cumulative effects of recurrent hypoglycemia impair neurocognitive function. Diabetes-related death is 
the most frequent cause of mortality among patients under 30 years-of-age (Skrivarhaug et al., 2006; 
Feltbower et al., 2008), and while severe hypoglycemia is documented in only ~ 12% of diabetes-related 
deaths, this is likely an under representation due to the presence of twice as many unexplained diabetes- 
related deaths. Not uncommonly, young people with type 1 diabetes are found “dead-in-bed” (Tanenberg 
et al., 2010; Tattersall and Gill, 1991), an unfortunate consequence of likely severe hypoglycemia 
inducing brain death (Auer, 2004) or a fatal cardiac arrhythmia (Tu et al., 2010). In fact, patients reporting 
an episode of severe hypoglycemia experience a 3.4-fold increase in mortality over the subsequent 5 
years (Mccoy et al., 2012). The risk of experiencing a severe hypoglycemic episode increases with long 
standing disease due to the progressive development of compromised physiologic defense mechanisms 
against a falling blood glucose concentration in the setting of therapeutic hyperinsulinemia. By 15 years 
of disease duration most patients have developed near total loss of functioning β-cells (C-peptide 
negative) (Tsai et al., 2006) resulting in loss of inhibition of endogenous insulin secretion as well as 
activation of glucagon secretion in response to declining blood glucose (Cooperberg and Cryer, 2010), 
which together normally increase endogenous (primarily hepatic) glucose production to circumvent the 
development of hypoglycemia. In the absence of these islet cell responses to hypoglycemia, epinephrine 
secretion and autonomic symptom generation become critical to increase endogenous glucose 
production and alert the individual to ingest food (Figure 1) (Cryer et al., 2003). Unfortunately, these 
sympathoadrenal responses are impaired by recurrent episodes of hypoglycemia leading to a syndrome 
of hypoglycemia unawareness, also known as hypoglycemia-associated autonomic failure (HAAF) (Cryer, 
2013). Hypoglycemia unawareness is associated with a 20-fold increased risk for experiencing life- 
threatening hypoglycemia (Pedersen-Bjergaard et al., 2004). Clearly, new strategies are required to 
restore physiologic defense mechanisms against the development of severe hypoglycemia. 
Technologic strategies with real-time continuous glucose monitoring (CGM) hold promise for the 

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amelioration of hypoglycemia in patients with type 1 diabetes, and particularly when incorporated into to 
an automated closed-loop glucose sensing and insulin delivery system, also known as the artificial 
pancreas. With the establishment of continuous subcutaneous insulin infusion (CSII) or pump therapy 
(Pickup, 2012), and CGM via a subcutaneous glucose sensor (Tamborlane et al., 2008) as viable 
technologies there has been increasing academic and industrial effort to develop a closed-loop artificial 
pancreas system. However, mechanical problems with insulin delivery (Heinemann and Krinelke, 2012), 
the delay and variability of insulin absorption from the subcutaneous space (Heinemann, 2002; 
Heinemann et al., 2009), and variability of insulin action (Hinshaw et al., 2013) coupled to the delay and 
potential inaccuracy of interstitial glucose measurements (Basu et al., 2013; Basu et al., 2015) represent 
key challenges to closed-loop control of blood glucose, particularly in the context of perturbations in 
glucose homeostasis introduced by meals, exercise, and illness. In order to advance component 
development prior to realization of an artificial pancreas system, a roadmap was accepted to include 
sequential steps beginning with automated mitigation of hypoglycemia progressing through control-to- 
range and control-to-target algorithms prior to adopting fully closed-loop control (Kowalski, 2009). 
Unfortunately, patients with long standing type 1 diabetes and defective glucose counterregulation with 
hypoglycemia unawareness, while most in need of new therapeutic strategies, have the most at stake in 
adoption of closed-loop control that can lead to severe hypoglycemia if the sensor overestimates the 
blood glucose and physiologic recognition of the development of low blood glucose is absent. Thus, 
understanding the effects of hybrid closed-loop insulin delivery on physiologic defense mechanisms 
against the development of low blood glucose is critical before fully closed-loop control can be attempted 
in this population. 
 
Support for CGM in adults with type 1 diabetes is based on modest reductions in HbA1c (~0.5%) from a 
baseline ≥ 7.0% with no increase in hypoglycemia for patients ≥ 25 years of age who used their glucose 
sensor during at least 6/7 days per week (Tamborlane et al., 2008). This and most studies of CGM 
excluded patients experiencing problematic hypoglycemia or hypoglycemia unawareness, whereas in 
clinical practice CGM is most often implemented in hopes of reducing hypoglycemia. In a retrospective 
clinic-based analysis, implementation of CGM for one year in patients with problematic hypoglycemia at 
baseline was associated with a reduction, but not elimination, of severe hypoglycemic events, but did not 
improve hypoglycemia awareness (Choudhary et al., 2013). Nocturnal hypoglycemia contributes to the 
development of HAAF (Cryer, 2004), is a frequent setting for experiencing severe hypoglycemia, and is 
an important contributor to mortality in type 1 diabetes (Tanenberg et al., 2010; Tattersall and Gill, 1991). 
Prediction and detection of nocturnal hypoglycemia is not fully addressed by CGM that depends on 
appropriate use and response to devise alerts (vibration) and alarms. Implementation of a strategy for 
hypoglycemia avoidance with the goal of recovery from HAAF will require mitigation of nocturnal 
hypoglycemia. Reduction of nocturnal hypoglycemia may be particularly amenable to automated 
suspension of insulin delivery with a sensor-augmented pump (SAP) (Bergenstal et al., 2013; Ly et al., 
2013). Also known as low glucose suspend (LGS), the automated suspension of insulin delivery by a 
pump informed of the sensor glucose level marked the first step toward a closed-loop system dependent 
on information exchange between the CGM and insulin pump. Importantly, SAP with LGS has been 
shown to reduce nocturnal hypoglycemia by 38% compared to CGM alone without increasing HbA1c 
(Bergenstal et al., 2013). Another trial that included patients with reduced awareness of hypoglycemia 
showed similar results plus a reduction in severe hypoglycemic events with use of LGS, but this study 
included rather young patients with short duration disease (Ly et al., 2013). Whether this strategy may 
similarly benefit patients with long standing type 1 diabetes complicated by hypoglycemia unawareness 
and lead to clinically meaningful improvement of glucose counterregulation is unknown, but will likely 
require even greater reduction in hypoglycemia exposure. In the present study (Figure 1), we will 
determine the effect of hybrid closed-loop insulin delivery on endogenous glucose production during 
insulin-induced hypoglycemia in type 1 diabetic patients with hypoglycemia unawareness using next 
generation systems from Medtronic or Tandem that automates interprandial insulin delivery including 
suspension for predictive hypoglycemia as well as when the glucose crosses a set low threshold, and so 
promises even greater hypoglycemia avoidance that may be required to reverse HAAF and improve 
glucose counterregulation  and  hypoglycemia  symptom  recognition.    Demonstration of improved 
physiologic defense against hypoglycemia is critical to understanding whether protection from 
hypoglycemia may persist when the glucose sensor is not functioning properly. 

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Figure 1. This study will determine the 
effect of hypoglycemia avoidance by hybrid 
closed-loop 
insulin 
delivery 
on 
the 
endogenous glucose production response 
to insulin-induced hypoglycemia. Glucose 
counterregulation will be assessed before 
and after 6 and 18 months’ implementation 
of a hybrid closed-loop system in patients 
with long standing type 1 diabetes and 
hypoglycemia unawareness.  
 
1.2 
Name and Description of the Investigational Product 
In the present study, we will assess the effect of hypoglycemia avoidance by hybrid closed-loop insulin 
delivery on endogenous glucose production during insulin-induced hypoglycemia in type 1 diabetic 
patients with hypoglycemia unawareness to determine its potential for restoring defective glucose 
counterregulation and protecting patients from experiencing future severe hypoglycemia episodes. The 
first of these advanced systems for automated insulin delivery, including predictive and threshold 
suspension for protection against hypoglycemia, is the latest one from Medtronic, the MiniMed 670G, which 
was approved for use in the US by the FDA in 2016. Medtronic’s predecessor systems, the MiniMed 
530G and MiniMed 630G, are FDA-approved and commercially available in the United States. All of 
these systems have a LGS feature based on automated suspension of insulin delivery when the sensor 
glucose crosses below a defined threshold. What is unique to the MiniMed 670G system is the 
automated interprandial insulin delivery (when in “auto” mode) as well as automated suspension of insulin 
delivery when the sensor glucose is predicted to cross below a defined threshold (when in “auto” or 
“manual” mode). This predictive function is more likely to prevent the ultimate development of low blood 
glucose, and so should be more effective in mediating hypoglycemia avoidance required for the reversal 
of HAAF and correction of defective glucose counterregulation and hypoglycemia symptom recognition. 
Thus, we will implement hybrid closed-loop insulin delivery using the MiniMed 670G system in the present 
study.  The second of these advanced systems for automated insulin delivery, including predictive and 
threshold suspension for protection against hypoglycemia is the Tandem t:slimX2 insulin pump integrated 
with the Dexcom G6 continuous glucose monitoring (CGM) system. As stand-alone devices the Dexcom 
G6 and t:slimX2 pump are both FDA-approved and have been commercially available in the United States.  
However; on Dec 13, 2019, the FDA announced the approval of the Control-IQ Hybrid Closed Loop System 
from Tandem Diabetes Care. The approval of the Control-IQ system as a “controller” represents the first-
ever approval of an interoperable algorithm for use in an automated insulin dosing system. 
 
The Medtronic MiniMed 670G system includes the Guardian Sensor 3, Medtronic’s newest and most 
advanced CGM sensor and the first and only sensor approved by the FDA for use in hybrid closed-loop 
insulin delivery, which is driven by SmartGuard technology that varies basal insulin delivery based on 
personalized needs, and that includes a predictive low glucose management algorithm, referred to as 
suspend before low, that suspends insulin delivery when the sensor glucose is predicted to fall within 20 
mg/dl of a preset low glucose limit within 30 minutes, and automatically restarts basal insulin delivery on 
recovery from hypoglycemia. This strategy builds on the previous threshold suspend function that would 
suspend insulin delivery once the sensor glucose is below the preset low glucose limit. While alerts 
(vibration) and alarms may be set for activation of the predictive suspension, they remain mandatory 
should threshold suspension be reached. The user can manually restart basal insulin delivery at any 
time, and basal insulin delivery is automatically resumed after 2 hours of suspension regardless of the 
sensor glucose. 
 
 
1.2.1   Clinical Data to Date 
A study involving 124 subjects with type 1 diabetes (mean ± SD age 38 ± 14 years, 66% female, mean 

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disease duration 22 years) evaluated the MiniMed 670G system over a 3-month study period (Bergenstal 
et al., 2016). The system was in closed-loop mode for a median (IQR) 87% (75 – 92%) of the study 
period during which HbA1c decreased from 7.4 ± 0.9 to 6.9 ± 0.6% and time spent < 70 mg/dl decreased 
from 5.9 ± 4.1 to 3.3 ± 2.0% with an even greater reduction from 6.4 ± 5.3 to 3.1 ± 2.2% seen overnight. 
There were no episodes of severe hypoglycemia or ketoacidosis observed. Sensor and reference 
glucose values were in good agreement as indicated by an overall mean absolute relative difference of 
10.3 ± 9.0%. There were 28 devise-related adverse events reported that were resolved at home, 
including 17 episodes of severe hyperglycemia (glucose > 300 mg/dl), 11 attributed to the infusion set as 
is expected with insulin pump delivery, 5 attributed to the algorithm controller, and only 1 attributed to the 
sensor. This overwhelmingly positive safety profile led to licensure by the FDA in late 2016. 
 
Another study further tested the safety of the MiniMed 670G system in 8 subjects with type 1 diabetes 
(mean [range] age 18 [14-36] years, 63% female, mean disease duration 8 years) challenged with 
aerobic exercise and a purposefully over-calibrated glucose sensor and observed over 4 days that should 
both increase the risk of hypoglycemia (de Bock et al., 2017). Reassuringly, the system driven insulin 
delivery limits were effective in preventing exercise-induced and nocturnal hypoglycemia even in the 
presence of the over-calibrated glucose sensor over-reading the plasma glucose by 14%. The only 
hypoglycemia observed followed subject delivered meal or correction insulin boluses, with none being 
severe. Whether such protection against hypoglycemia is afforded to patients with long standing disease 
and defective glucose counterregulation will be assessed in the present study. 
 
We have previously evaluated the effect of real time CGM on glucose counterregulation in 11 subjects 
with long standing type 1 diabetes complicated by hypoglycemia unawareness under IRB protocol 
#813094, funded by the previous cycle of the NIH grant sponsoring the current study. Results indicated that 
real time CGM can improve the endogenous glucose production response to insulin-induced hypoglycemia, 
but the effect was not evident until 18 months post-intervention (Figure 2) (Rickels et al., 2018). Autonomic 
symptoms became distinguishable under hypoglycemic vs. euglycemic clamp conditions at 6 and 18- 
month post-intervention; however, the change in autonomic symptom response to insulin-induced 
hypoglycemia was not significantly different over time. 
 
The results of the first large-scale, 6-month randomized (2:1) clinical trial of closed-loop vs. sensor-
augmented pump involved 168 participants ages 14-71 years, and demonstrated an 11 percentage point 
increase of time spent in the glucose range 70 – 180 mg/dl with closed-loop, as well as a 0.88 percentage 
point decrease of time spent with hypoglycemia (< 70 mg/dl) and 0.33 percentage point reduction in HbA1c 
(Brown et al., 2019).  The trial compared the new Control-IQ hybrid closed loop vs. the same t:slimX2 pump 
and CGM without the control-IQ algorithm. Time in closed loop / Control-IQ (like the 670G “automode”) was 
92%. 

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ENDOGENOUS GLUCOSE PRODUCTION 
(mg/kg per min) 
 
AUTONOMIC SYMPTOM SCORE (∆) 
 
T1D pre-RT-CGM 
2.4 
 
T1D 6 months post-RT-CGM 
T1D 18 months post-RT-CGM 
14 
 
12 
         
 
T1D pre-RT-CGM 
T1D 6 mo post-RT-CGM 
T1D 18 mo post-RT-CGM 
2.0 
 
1.6 
Non-diabetic control 
Non-diabetic control 
10 
8 
 
1.2 
6 
 
0.8 
4 
 
0.4 
 
0.0 
 
 
 
 
0 
40 
80 
120 
160 
200 
240 
MINUTES 
 
2 
 
0 
 
0 
40 
80 
120 
160 
200 
240 
MINUTES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2. Results of glucose counterregulation testing from type 1 diabetic patients with hypoglycemia 
unawareness (n = 11) before and after 6 and 18 months’ implementation of real time CGM, and from 
non-diabetic controls (n = 12). There was an improvement in the endogenous glucose production response 
to insulin-induced hypoglycemia by 18 months post-intervention (P < 0.05). The gray shaded region gives 
the 95% CI for results obtained during hyperinsulinemic euglycemic conditions. Autonomic symptoms, 
while not significantly improved, were not statistically different during hypoglycemia compared to 
euglycemia before, and were greater under hypoglycemic vs. euglycemic conditions post-intervention (P < 
0.05 at both 6 and 18 months). 
 
This effect on glucose counterregulation was associated with reductions in both the Clarke score of 
hypoglycemia unawareness and the HYPO score of hypoglycemia severity (Figure 3), indicating clinical 
improvement in hypoglycemia awareness and less problematic hypoglycemia, with a reduction in the 
severe hypoglycemia event rate from 2.2 ± 0.7 per subject-year at baseline to 0.9 ± 0.5 per subject-year at 
18 months (P < 0.01), and importantly no deterioration of glycemic control (HbA1c 7.2 ± 0.2 % at 
baseline and 7.0 ± 0.2 % at 18 months). 

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CLARKE SCORE 
HYPO SCORE 
 
P < 0.01 
6 
 
4000 
 
 
3000 
 
 
 
P < 0.001
 
4 
2000 
 
2 
1000 
 
0 
0 
 
pre 
6 mo 
12 mo 
18 mo 
pre 
6 mo 
12 mo 
18 mo
Figure 3. Measures of hypoglycemia unawareness and severity in response to implementation of real time 
CGM in type 1 diabetic patients with hypoglycemia unawareness (n = 11). The dashed line for the Clarke 
score indicates the cut-off for impaired awareness of hypoglycemia, and the dashed line for the HYPO score 
gives the 90
t h percentile cut off for 100 patients with type 1 diabetes (Ryan et al., 2004). 
 
Interestingly, CGM measures of glycemic control indicated only a trend for improvement in glucose 
variability as measured by the glucose S.D. (P = 0.07), with no significant reduction in time spent 
hypoglycemic (< 60 mg/dl) despite the improvements in hypoglycemia awareness, hypoglycemia events, 
and glucose counterregulation (endogenous glucose production). Importantly, nocturnal hypoglycemia (< 
60 mg/dl) remained present at ~ 5% of time between midnight and 6 a.m. throughout the 18-month study. 
The present study will more specifically target avoidance of nocturnal hypoglycemia by implementation of 
hybrid closed-loop insulin delivery that should significantly reduce time spent in the hypoglycemia range 
in order to affect even greater recovery in endogenous glucose production and autonomic symptom 
generation. 
 
2 
Study Objectives 
This study aims to determine whether hypoglycemia avoidance achieved through implementation of 
hybrid closed-loop insulin delivery can improve glucose counterregulation in type 1 diabetic patients with 
hypoglycemia unawareness. We hypothesize that the endogenous glucose production response to 
insulin-induced hypoglycemia will be greater in subjects after 6 months when compared to before 
intensive implementation of hybrid closed-loop insulin delivery. Glucose counterregulatory hormone, 
symptom, and endogenous glucose production responses will be measured using the stepped- 
hyperinsulinemic hypoglycemic clamp before, after 6 months’ intervention, and after 18 months to assess 
the durability of any benefit from avoidance of hypoglycemia with continued use of the hybrid closed-loop 
system. 
 
3 
Investigational Plan 
 
3.1 
General Design 
Open label, single-arm clinical trial of the effect of hybrid closed-loop insulin delivery using the MiniMed 
670G system (Medtronic Diabetes, Northridge, CA) or the t:slim Basal-IQ and Control-IQ technology 
(Tandem Diabetes, San Diego, CA) on glucose counterregulatory mechanisms in patients with long 
standing type 1 diabetes complicated by hypoglycemia unawareness. Comparisons will be made within 
subject with the primary outcome measure being endogenous glucose production in response to insulin-
induced hypoglycemia after 6 months’ intervention. Secondary outcome measures will include endogenous 
glucose production in response to hypoglycemia after 18 months’ intervention, and glucose 
counterregulatory hormone and symptom responses to hypoglycemia after 6 and 18 months. 
The purpose of this small, proof-of-concept, mechanistic study is to determine whether hybrid closed-loop 

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insulin delivery can achieve sufficient hypoglycemia avoidance in patients with long standing type 1 diabetes 
experiencing hypoglycemia and symptom unawareness despite receiving intensive insulin therapy 
standard-of-care to improve glucose counterregulation against insulin-induced hypoglycemia. As it remains 
critically important to understand the potential physiologic benefits of hypoglycemia avoidance by means of 
a hybrid closed-loop system in this population, studying each well characterized subject as his/her own 
control by a within subject design should serve the study purpose, and has been the standard approach to 
assessing the effects of various approaches to hypoglycemia avoidance in patients with unawareness 
(Fanelli et al., 1993; Cranston et al., 1994; Fanelli et al., 1994; Dagogojack et al., 1994; Liu et al., 1996; 
Rickels et al., 2016). The data generated will be available to power future randomized clinical trials to 
determine the comparative efficacy of emerging artificial pancreas and β-cell replacement approaches to 
achieve target glycemic control with amelioration of problematic hypoglycemia in type 1 diabetes. 
 
3.1.1 Recruitment, Informed Consent and Screening Phase 
Subjects will be recruited from the diabetes practices of the University of Pennsylvania Health System. 
Additional candidates for participation may be referred by their personal physicians, may respond to the 
website for the Penn Institute for Diabetes, Obesity & Metabolism, or may respond to the study posting on 
ClinicalTrials.gov or an IRB-approved secure on-line system iConnect. All inquiries will be subjected to a 
structured telephone interview conducted by a research coordinator to determine potential eligibility; in 
some cases, candidates’ medical records may be reviewed by the PI after a signed release of medical 
records is received. If review of the phone interview and any medical records indicates that the potential 
participant is not eligible, s/he will be notified by the research coordinator and explained why this is so; if 
review indicates potentially unsuitable diabetes care, the potential participant may be referred to Penn’s 
Rodebaugh Diabetes Center for further assessment  and  management;  if review  indicates that the 
potential participant may be eligible, s/he will be contacted by the research coordinator to schedule the 
screening visit and the informed consent form will be mailed to subjects for review. 
 
At the screening visit, the study details and procedures will be discussed with a research coordinator and 
at least one of the PI or the research nurse practitioner. The potential participant is given adequate time 
to ask questions and review the informed consent document. Once satisfied that all questions have been 
answered, the potential participant will either decline to participate or sign the informed consent document. 
This may occur at a subsequent visit if the potential participant desires, in order to think further about 
what participation means and/or to consult with family, friends and/or a personal physician. The consent 
form is signed in the presence of a witness (research coordinator +/- family member). All participants 
must read, sign, and date a consent form before entering the study, undergoing physical examination 
or undergoing any testing. The informed consent form will be revised whenever important new safety 
information is available, whenever the protocol is amended, and/or whenever any new information 
becomes available that may affect participation in the studies. 
 
Subjects will include adult (ages 25 - 70 years) patients with established (C-peptide negative) type 1 
diabetes of equal to or more than 5 years duration complicated by hypoglycemia unawareness (Clarke 
score 4 or more (Clarke et al., 1995)), experiencing severely problematic hypoglycemia and/or marked 
glycemic lability (Ryan et al., 2004; Senior et al., 2015), despite the use of basal-bolus insulin analog 
delivery by multi-dose injection or pump therapy together with frequent blood glucose monitoring (more 
than 3 times daily) and/or CGM under the direction of an endocrinologist. Because modest hypoglycemia 
in the range 50 – 58 mg/dl (Heller and Cryer, 1991) and particularly overnight (Cryer, 2004) impairs 
subsequent counterregulatory responses to hypoglycemia, subjects will require at least 5% of time with a 
sensor glucose < 60 mg/dl including at least one episode occurring overnight in 7 days. Subjects will be 
excluded for severe obesity (BMI ≥ 38 kg/m2), insulin resistance (daily insulin requirement ≥ 1.0 units/kg·d), 
poor glycemic control (HbA1c ≥ 10%), uncontrolled hypertension, active cardiovascular disease, 
abnormal kidney, liver, or thyroid function, anemia, seizure disorder not related to prior severe 
hypoglycemia, pregnancy, and nursing.  Eligibility will be confirmed through the performance of a history 
and physical examination by the PI or the research nurse practitioner, EKG, urine pregnancy test (if 
applicable), serum chemistries, TSH, cell counts, HbA1c and C-peptide, completion of glycemic lability 
and hypoglycemia awareness and hypoglycemia severity questionnaires, placement of a 7 day blinded 

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CGM (iPro 2, Medtronic Diabetes, Northridge, CA) unless  CGM is available for downloading, and 7 day 
accelerometry ( WGT3X-BT, Actigraph LLC, or Actiwatch2) to define the nocturnal period. Only after all 
eligibility criteria (inclusion and exclusion) are met, will a potential subject be enrolled. Repeated clinical 
testing throughout the study (please see Table 1) will ensure the continued safety and minimization of 
risk for the enrolled participants. 
 
3.1.2 Study Intervention Phase 
Eligible subjects will complete a baseline assessment of glucose counterregulation by stepped- 
hyperinsulinemic hypoglycemic clamp prior to starting intervention with the hybrid closed-loop system 
(MiniMed 670G system, Medtronic Diabetes, Northridge, CA) or the t:slim Basal-IQ and Control-IQ 
technology (Tandem Diabetes, San Diego, CA). Unless a system becomes available to the subject via their 
insurance carrier, one will be provided for them or we will cover the upgrade fee as dictated by their 
insurance. In addition, subjects using the Medtronic system will also receive a study glucometer 
(Contour Next Link 2.4, Bayer, Indianapolis, IN) that communicates with the MiniMed 670G insulin pump 
for bolus dosing calculation and glucose sensor calibration. Subjects who cannot maintain > 80% (or 6/7 
day) compliance with the sensor component as assessed at each study visit may be dropped since less 
compliance has not been associated with any benefit of CGM to glycemic control (Tamborlane et al., 2008), 
and limits the potential for benefit from LGS on hypoglycemia avoidance. Accuracy of the sensor will be 
assessed at each visit through devise download and interpretation (Mastrototaro et al., 2008). Study 
visits will occur weekly for the first month, then monthly until month 6, and then every 3 months until 
month 18. Month 1, 2, 4 & 5 visits may be performed via telephone if the device has been 
uploaded to the Care Link Medtronic platform or to the t-connect Tandem platform. This schedule 
will allow for determination of possible benefit from hybrid closed- loop insulin delivery on glucose 
counterregulation after 6 months of intensive provider support, and then for assessment of the durability 
or potential further gains in beneficial effects after another 12 months of more typical provider interaction 
occurring every 3 months. Weekly visits may be performed via telephone with uploading devise data to 
Care Link or t-connect for review and interpretation. Uploaded or downloaded insulin delivery, blood and 
sensor glucose monitoring, insulin dose settings and CGM calibration accuracy, alert settings, time spent 
in auto and manual modes, and LGS threshold and activity will be assessed at each visit, targeting > 
80% CGM and LGS compliance, adjusting basal and bolus insulin dosing in order to minimize glycemic 
excursions while maximizing hypoglycemia (< 60 mg/dl) avoidance, with adjustment of alarms set to alert 
the subject to rapidly increasing or decreasing glucose and predict the occurrence of elevated or low 
blood glucose (Tamborlane, 2008). During manual mode, target glucose ranges will be 90 – 140 mg/dl 
before meals, < 180 mg/dl after meals, and 120 – 160 mg/dl at bedtime, with correction dosing to no 
lower than 100 mg/dl during the day, and 120 mg/dl overnight. Alarm settings may be individualized to 
target these ranges, but the hypoglycemia alarm for LGS will not be set lower than 70 mg/dl (Cryer, 2009). 
During auto mode, the automated interprandial basal insulin delivery will adjust according to the closed-
loop algorithm to target a sensor glucose of 120 mg/dl, which may be temporality increased to 150 mg/dl if 
needed to further minimize exposure to hypoglycemia during exercise or overnight. Prior to each 3 monthly 
visit, subjects will wear an actigraph monitor (WGT3X-BT, Actigraph LLC or Actiwatch2) for three weeks 
in order to define the nocturnal period. Every 6 months’ measures of hypoglycemia awareness (Clarke 
score) and severity (HYPO score), and the glycemic lability index (LI) will be calculated from 
questionnaires, event diaries, and device downloads, respectively (Senior et al., 2015). At 6 months and at 
18 months, subjects will again undergo assessment of glucose counterregulation by stepped-
hyperinsulinemic hypoglycemic clamp testing.

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Screening Baseline Month 17 Month 27 Month 3
Month 47 Month 57 Month 6
Month 9 Month 12 Month 15 Month 18
Consent 
X 
H&P8 
X 
X 
 
 
X 
 
 
X 
X 
X 
X 
X 
EKG1 
X 
HCG2 
X
X
X
X
BMP3 
X
X
X
LFTs4 
X
X
X
TSH5 
X 
CBC3 
X 
X 
X 
HbA1c3 
X 
X 
X 
X 
X 
C-peptide6 
X 
Download
X
X
X
X
X
X
X
X
X
X
X
X
Actigraphy
X
X
X
X
X
X
X
CSM & PSQUI 
X 
 
 
 
ISI & ESS 
X 
X
X 
X
X 
X
X 
Clarke Score 
X 
X 
X 
X 
HYPO Score 
X 
X 
X 
X 
HypoA-Q 
X 
X 
X 
X 
Lability Index 
X 
X 
X 
X 
Table 1. Schedule of Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1EKG, electrocardiogram within 6 months. 
2HCG, human chorionic gonadotropin by serum or urine. 
3BMP, basic metabolic panel, CBC, complete blood count, and HbA1c within 3 months. 
4LFTs, liver function tests within 6 months. 
5TSH, thyroid stimulating hormone within 12 months. 
6Any documented C-peptide < 0.3 ng/ml. 
7Month 1, 2 4 or 5 may be done via phone if participant is comfortable uploading pump to Carelink website 
     8H & P not required monthly 
 
3.2 
Study Endpoints 
 
3.2.1 
Primary Study Endpoints 
The primary outcome measure will be endogenous glucose production in response to insulin-
induced hypoglycemia after 6 months of hybrid closed-loop insulin delivery. 
 
3.2.2 
Secondary Study Endpoints 
Secondary outcome measures will include endogenous glucose production in response to insulin-
induced hypoglycemia after 18 months’ intervention with the hybrid closed-loop system, and glucose 
counterregulatory hormone and symptom responses to hypoglycemia after 6 and 18 months. 
 
3.2.3 
Primary Safety Endpoints 
The primary safety measure will be incidence of severe hypoglycemia, defined as an event with 
symptoms or signs compatible with hypoglycemia in which the subject was unable to treat him/herself 
and which was associated with either a blood glucose < 54 mg/dl or prompt recovery after oral 
carbohydrate, IV glucose, or glucagon administration. 
 
4 
Study Population and Duration of Participation 
The evaluation of the effect of hybrid closed-loop insulin delivery on endogenous glucose production 
during insulin-induced hypoglycemia will involve subjects with long standing type 1 diabetes complicated 
by hypoglycemia unawareness. The inclusion/exclusion criteria are: 
 
4.1 
Inclusion Criteria 
Subjects who meet all of the following criteria are eligible for enrollment: 
• Male and female subjects age 25 to 70 years. 
• Subjects who are able to provide written informed consent and to comply with the procedures of the 
study protocol. 

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• Clinical history compatible with type 1 diabetes with disease onset < 40 years of age and insulin 
dependent for > 5 years. 
• Absent C-peptide (< 0.3 ng/ml). 
• Involvement in intensive diabetes management defined as the use of basal-bolus insulin analog 
delivery by multi-dose injection (MDI) or continuous subcutaneous insulin infusion (CSII) together 
with self-monitoring of blood glucose values more than 3 times daily and /or continuous glucose 
monitoring (CGM) under the direction of an endocrinologist, diabetologist, or diabetes nurse 
practitioner with at least 3 clinical evaluations during the previous 12 months. 
• Hypoglycemia unawareness manifested by a Clarke score of 4 or more AND at least 1 of the 
following: HYPO score greater than or equal to the 90th percentile (1047); OR marked glycemic 
lability defined by a glycemic lability index (LI) score greater than or equal to the 90th percentile 
(433 mmol/l2/h·wk-1); OR a composite of a HYPO score greater than or equal to the 75th 
percentile (423) 
and a LI greater than or equal to the 75th percentile (329) (Senior et al., 2015). 
• Documented > 5% time spent in the hypoglycemic range (glucose < 60 mg/dl) by 7 day real- 
time or blinded CGM; at least one episode of hypoglycemic during the 7 days must occur 
overnight. 
 
4.2 
Exclusion Criteria 
Subjects who meet any of these criteria are not eligible for enrollment: 
• 
BMI ≥ 38 kg/m2. 
• 
Insulin requirement of ≥ 1.0 units/kg·day. 
• 
HbA1c ≥ 10%. 
• 
Untreated proliferative diabetic retinopathy. 
• 
Uncontrolled hypertension: systolic blood pressure > 160 mmHg or diastolic blood pressure > 
100 mmHg. 
• 
Active cardiovascular disease 
• 
Abnormal kidney function: eGFR < 60 ml/min/1.73 m2. 
• 
Abnormal liver function: persistent elevation of liver function tests > 1.5 times the upper limit of 
normal. 
• 
Untreated hypothyroidism, Addison’s disease, or Celiac disease. 
• 
Anemia: baseline hemoglobin concentration < 11 g/dl in women and < 12 g/dl in men. 
• 
Presence of a seizure disorder not related to prior severe hypoglycemia. 
• 
Use of glucocorticoids greater than 5 mg of prednisone daily, or an equivalent physiologic dose 
of hydrocortisone. 
• 
For female participants of child-bearing potential: Positive pregnancy test, presently breast-
feeding, or unwillingness to use effective contraceptive measures for the duration of study 
participation. Oral contraceptives, intra-uterine devices, Norplant®, Depo-Provera®, and 
barrier devices with spermicide are acceptable contraceptive methods; condoms used alone 
are not acceptable. 
• 
Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment. 
• 
Use of any investigational agents within 4 weeks of enrollment. 
• 
Any medical condition that, in the opinion of the PI, will interfere with the safe completion of 
the study. 
 
4.3 
Subject Recruitment 
Subjects will be recruited from the diabetes practices of the University of Pennsylvania Health System. 
Potentially eligible patients will be referred by their diabetes providers, may respond to IRB approved 
recruitment flyers placed in the diabetes practices, or may be identified by EPIC chart review conducted 
by the research team, in which case permission to contact a patient will be obtained from the diabetes 
provider. Subjects who have either participated in a prior research study of the PI, or may be screened but 
are either not interested in or not eligible for another research study of the PI, may also be approached 
for consideration of participation in this study. Additional candidates for participation may be referred by 
their personal physicians, may respond to the study listing on the website for the Penn Institute for 

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Diabetes, Obesity & Metabolism, or may respond to the study posting on ClinicalTrials.gov or an IRB-
approved secure on-line system iConnect. 
 
If physicians at our Diabetes Center attend a Diabetes conference, a slide with contact information for 
research participation will be included. We will also include a phrase in the Diabetes Center’s newsletter. 
 
We also plan on using the full Trial X iConnect platform in order to take advantage of everything they have 
to offer including but not limited to their social media campaigns such as the “ClinicalResearch@Penn” 
Facebook page.  This Facebook page posted by the Office of Clinical Research via a Redcap application 
will link to various websites such as the Diabetes Center, CT.gov, iConnect and Clinical Trials at Penn page.  
By utilizing iConnect we will be able to track our recruitment advertisement, and enhance recruitment using 
the platform features such as flyer build, recruitment tracker, volunteer registry and mobile app creation.  
Through iConnect we can manage volume by creating pre-screeners in the system and we can also promote 
our diabetes clinical research initiatives using their “cure talks” platform, a social initiative that organizes bi-
weekly online talk shows. 
 
Subjects recommended by physicians or indicating interest in research participation to their physicians will 
be contacted using the myPennMedicine portal, @pennmedicine email and/ or via telephone. In addition, 
we will be contacting departed Endocrine physicians whom have completed their fellowship at UPenn and 
practice within a commutable distance. 
 
We may also use the UPenn Clinical Trials Unit (CTU) to assist with recruitment.   Their methods for 
attracting potential subjects may also include local IRB-approved flyers, email blasts, Craig's List posts, 
Septa ads, social media ads including Facebook, community outreach, radio, internet and newspaper 
advertisements targeting the Delaware Valley region. All ads used will have IRB approval before use. 
Subjects may also be recruited from PennSeek, Pennomics, iConnect research portal, and Bio-Bank 
queries. They plan to use Facebook ads, specifically Facebook - Boosted Posts, Unpublished Posts, and 
Instagram. Penn Medicine Marketing has referred the CTU team to use the ad agency named Evariant. This 
is the vendor which they use to place all of their ads, and Evariant already has access to the Penn Medicine 
Facebook page. 
 
4.4 
Duration of Study Participation 
Study subjects’ participation will involve at least 1 month for the screening phase that includes the 
collection of 4 weeks of glucose monitoring and diary data, and once baseline testing is scheduled, the 
anticipated 18-month intervention phase. Thus, subjects can anticipate involvement in the study for an 
approximately 20-month time period. 
 
4.5  Total Number of Subjects 
This is a single-site study being conducted at Penn that will involve the enrollment of up to 30 subjects to 
ensure a minimum of 15 and maximum of 18 subjects complete the primary outcome assessment at 6 months, 
all of whom will be anticipated to complete the 18 months of intervention and secondary outcome assessments. 
 
4.6 Vulnerable Populations 
Children, pregnant women, fetuses, neonates, or prisoners are not included in this research study. 
 
 
5 Study Intervention (Study drug, device, biologic, vaccine, food etc.) 
 
5.1 
Description 
The Medtronic MiniMed 670G system is comprised of a MiniMed 670G insulin pump containing closed- loop 
algorithm software, insulin reservoirs, and infusion sets required for standard continuous subcutaneous 
insulin infusion (CSII) therapy, and new Guardian Sensor 3 and Guardian Link 3 transmitters for 
communication of the subcutaneously placed interstitial glucose sensor to the insulin pump for display, 
and triggering of alerts (vibration), alarms, and according to a predictive low glucose management 

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algorithm, referred to as suspend before low, automated suspension of insulin delivery when the sensor 
glucose is predicted to fall within 20 mg/dl of a preset low glucose limit within 30 minutes, and when in 
auto mode, automated interprandial basal insulin delivery. 
Following automated suspension of insulin delivery, the system automatically restarts basal insulin delivery on 
recovery from hypoglycemia. This strategy builds on the previous threshold suspend function that would 
suspend insulin delivery once the sensor glucose is below the preset low glucose limit. While alerts (vibration) 
and alarms may be set for activation of the predictive suspension, they remain mandatory should threshold 
suspension be reached. The user can manually restart basal insulin delivery at any time, and basal insulin 
delivery is automatically resumed after 2 hours of suspension regardless of the sensor glucose. This 
protects against subsequent hyperglycemia should the sensor glucose be erroneously low, and the user 
unresponsive to the alerts and alarms (e.g. due to sleep) that would otherwise prompt the user to obtain a 
confirmatory blood glucose level. The MiniMed 670G insulin pump also communicates with the Contour Next 
Link 2.4 glucometer (Bayer, Indianapolis, IN) that will be provided to subjects for bolus dosing calculation 
and glucose sensor calibration. 
 
The Control-IQ uses the TypeZero/Dexcom hybrid closed loop algorithm which is based on standard insulin 
pump settings.  The t:slimX2 insulin pump is comprised of the t:slimX2 pump, the t:slim 3mL cartridge and a 
compatible infusion set.  The Dexcom G6 continuous glucose monitor is comprised of the Dexcom transmitter, 
the Dexcom sensor and a receiver. The Control-IQ system aims to keep users between 70-180mg/dl as much 
as possible using a combination of strategies. The Basal-IQ is equivalent to “predict before low” mode and the 
Control-IQ is equivalent to “auto” mode in the closed loop system.  
 
Tandem and Dexcom G6 information, user guides and support can be found at: 
https://www.dexcom.com/guides and https://www.tandemdiabetes.com/support/documents 
 
Medtronic 670G information, user guides and support can be found at: 
https://www.medtronicdiabetes.com/products/minimed-670g-insulin-pump-system 
 
5.1 
Intervention Regimen 
At the baseline visit, the research nurse practitioner will train subjects in the use of the system the 
participant has selected, and set individualized insulin dosing and glucose monitoring alerts, with the low 
glucose limit not set less than 70 mg/dl. Target glucose ranges will be 90 – 140 mg/dl before meals, < 180 
mg/dl after meals, and 120 – 160 mg/dl at bedtime, with correction dosing to no lower than 100 mg/dl 
during the day, and 120 mg/dl overnight. Basal and bolus insulin dosing will be adjusted at every visit, or 
as necessary in response to subject inquiry, in order to minimize glycemic excursions while maximizing 
hypoglycemia (< 60 mg/dl) avoidance, with adjustment of alarms set to alert the subject to rapidly increasing 
or decreasing glucose and predict the occurrence of elevated or low blood glucose (Tamborlane, 2008). 
Study visits will occur weekly for the first month, then monthly until month 6, and then every 3 months until 
month 18. Weekly visits, as well as any interim visits, may be performed via telephone with uploading 
devise data to Medtronic Care Link or Tandem t-Connect website for review and interpretation. 
 
5.2 Receipt and Storage 
Unless a MiniMed 670G system becomes available to the subject via their insurance carrier, one will be 
provided for them together with a Contour Next Link 2.4 study glucometer. The research team will 
receive the MiniMed 670G system and associated supplies directly from Medtronic Diabetes for  a 
discounted research rate under an investigator-initiated research support  agreement  NERP16-015. Study 
devices and supplies will be maintained under double lock in the research staff office, and given to eligible 
subjects at the time of training during the baseline visit. Additional supplies will be provided to subjects at 
scheduled or interim visits as necessary to ensure optimal compliance with use of the system for the duration 
of the study. Subjects will be encouraged to receive associated supplies available through insurance, 
for example glucose test strips, via their carrier. If a participant prefers the t:slim Basal-IQ and Control-IQ 
system, study will cover the cost of the insulin pump upgrade as dictated by each individual’s insurance and 
the length of time the current pump has been used. 
 

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2
2
2
5.3 Administration and Accountability 
The research coordinator will track the ordering and dispensing of all study related devices and supplies on 
a per subject basis using a standardized, dated form throughout the study period. Upon receipt of the study 
treatment supplies, an inventory will be performed and a supply receipt log filled out and signed by the 
person accepting the shipment. The research coordinator will count and verify that the shipment contains 
all the items noted in the shipment inventory. Any damaged or unusable devices or sensors in a given 
shipment will be documented in the study files and returned to the manufacturer. 
 
5.4 Subject Compliance Monitoring 
Compliance will be assessed at each visit through device download and interpretation of insulin dosing, 
sensor glucose, and blood glucose data (Mastrototaro et al., 2008). Visits month 1, month 2, month 4 and 
month 5 may take place via telephone if the participant is comfortable uploading their system to the Medtronic 
Carelink or the Tandem t-Connect website. The downloaded sensor and blood glucose monitoring data will 
be used both for assessing CGM calibration accuracy, as well as durations of CGM and LGS use, targeting 
> 80% CGM and LGS compliance, or 6/7 days, and time spent in manual and auto mode. Reasons for 
less compliance will be assessed, and if addressable, re-evaluated at the next scheduled visit. If compliance 
remains under target, or if the reason for sub-optimal compliance is not addressable, the subject will be 
considered non-compliant with the product regimen and withdrawn from participation in the study. In the 
case of subject withdrawal, the subject will be asked to return the study MiniMed 670G system and related 
supplies at a final study visit when they will be returned to their pre-study insulin delivery and glucose 
monitoring regimen. 
 
5.5.1   Return or Destruction of Investigational Product 
Upon completion of study participation, all subjects maybe asked to return the study MiniMed 670G 
system and related supplies at their final study visit when they will be returned to their pre-study insulin 
delivery and glucose monitoring regimen. If the MiniMed 670G system becomes available to any subject via 
their insurance carrier at any time during the study, they will be able to return the study MiniMed 670G system 
and continue in the study using their own MiniMed 670G system. Any usable devices or supplies remaining 
at the termination of the study will be donated to study participants for their ongoing use to offset out-of-
pocket expenses. 
 
6   Study Procedures 
Stepped-Hyperinsulinemic Hypoglycemic Clamp 
Glucose counterregulation will be assessed using the hypoglycemic clamp technique (Rickels et al., 
2005). Subjects will be admitted to the Penn Center for Human Phenomic Science (CHPS) the evening 
prior to each study day after avoiding strenuous exercise for 3 days. Following 12-hours of overnight 
fasting, at t = -120 min a primed (5 mg/kg · fasting plasma glucose/90 for 5 min) continuous (0.05 
mg/kg·min for 355 min) infusion of 6,6-2H -glucose (99% enriched; Cambridge Isotopes Laboratories, 
Andover, MA) will be administered to assess endogenous glucose production before and during the 
induction of hypoglycemia (Bernroider et al., 2005).  After baseline blood samples at t = -20, -10, and -1 
min, at t = 0 min a continuous infusion of insulin (1.0 mU/kg·min for 240 min) will be administered to 
produce hyperinsulinemia. Subsequently, a variable rate infusion of 20% glucose will be initiated to 
achieve hourly plasma glucose steps of 80, 65, 55, and 45 mg/dl.   To reduce changes in plasma 
enrichment of 6,6-2H2-glucose during the clamp, the variable glucose infusion will be enriched to ~ 2.0 % 
with 6,6-2H2-glucose (Bernroider et al., 2005). 
 
Blood samples will be taken every 5 min, centrifuged, and measured at bedside with an automated 
glucose analyzer (YSI 2300; Yellow Springs Instruments, Yellow Springs, OH) to adjust the glucose 
infusion rate and achieve the desired plasma glucose concentration. Additional blood samples will be 
taken at t = 20, 40, 60, 80, 100, 120, 140, 160, 180, 200, 220, and 240 min for biochemical analysis and 
verification of the plasma glucose levels. The total amount of blood sampled will be 168 ml. A 
questionnaire will be administered every 20 min during the study in order to quantitate autonomic 
symptoms as the sum of scores ranging from 0 (none) to 5 (severe) for each of the following symptoms: 
anxiety, palpitations, sweating, tremor, hunger, and tingling (Towler et al., 1993). 

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Biochemical Analysis: Plasma glucose and lactate will be determined in duplicate by the oxidase method using 
an automated glucose/lactate analyzer (YSI 2900). Plasma free fatty acid levels will be measured in duplicate 
using enzymatic colorimetrics (Wako Chemicals, Richmond, VA). Plasma insulin, glucagon, and pancreatic 
polypeptide will be measured in duplicate by double-antibody radioimmunoassays (Millipore, Billerica, MA, or 
for pancreatic polypeptide, ALPCO Diagnostics, Windham, NH), and plasma epinephrine and norepinephrine 
will be measured by high-performance liquid chromatography (HPLC) with electrochemical detection, by the 
Penn Diabetes Research Center Radioimmunoassay and Biomarker Core. Enrichment of 6,6-2H2-glucose will 
be measured by gas chromatography-mass spectrometry analysis by the Penn Institute for Diabetes, Obesity 
& Metabolism Metabolic Tracer Resource. Samples for radioimmunoassay and HPLC from before and 6 
months after intervention will be assayed simultaneously using the same assay kit. 
 
Calculations: Basal rates of endogenous glucose production (EGP) will be calculated using the formula:  
basal EGP = IR ([enrichmentinf /enrichmentplasma] – 1), where IR is the basal 6,6-2H2-glucose infusion rate in 
mg/kg per min, enrichmentinf i s  t h e  percent enrichment of the 6,6-2H2-glucose infusate, and 
enrichmentplasma is the percent basal plasma 6,6-2H2-glucose enrichment.  The rate of appearance (Ra) of 
glucose during the clamps will be calculated using Steele’s non-steady state equation modified for the 
use of stable isotopes: Ra = F-(V[((C2+C1)/2)] [(E2-E1)/(t2-t1)]/(E2-E1)/2) where C2 and C1 are the glucose 
concentrations at the times (t) 2 and 1 respectively; V is the effective volume of distribution of glucose (40 
ml/kg), F is the tracer infusion rate, and E represents the isotopic enrichment at the respective time 
points. EGP during the clamps will be calculated from the difference between the rate of appearance of 
glucose in the plasma and the infusion rate of exogenous glucose. We will determine counterregulatory 
responses from the hypoglycemic clamp as the glucagon, pancreatic polypeptide, epinephrine, 
norepinephrine, incremental autonomic symptom, and endogenous glucose production values obtained 
during the last 60 min of hypoglycemia. 
 
Sleep Questionnaires: 4 short sleep/activity-related questionnaires will assist in the analysis of sleep / wake 
data obtained from the participants. 2 of the questionnaires will be administered as a baseline and 2 at the 
various protocol time-points when the participants wear the Actigraph watch or Actiwatch 2.   These 
questionnaires would be administered either via paper or electronically into Redcap.   
 
6.1 
Screening 
Once informed consent is obtained as described above, subjects will undergo a history and physical 
examination and review of their glucometer download, insulin pump download (if applicable), CGM 
download (if applicable), EKG, fasting serum biochemistries (glucose, C-peptide, electrolytes, creatinine, 
and liver function tests), HbA1c, TSH, complete blood count, HCG (females), and retinal status. Subjects will 
have a blinded 7 day CGM (iPro 2) placed (to be returned by mail) unless on CGM available for 
downloading, undergo 7 day accelerometry (Actigraph wGT3X-BT monitor or Actigraph2) to define the 
nocturnal period, and be given a glucose log for recording 4 times daily monitoring for a 4-week period in 
order to calculate a lability index. Subjects who may experience difficulty affording a sufficient supply of test 
strips for their glucometer, or whose glucometer is not suitable for downloading, will be provided a 
OneTouch device for use during the screening period. Subjects will complete hypoglycemia questionnaires 
required to calculate HYPO and Clarke scores. 
 
6.2 
Study Intervention Phase 
 
6.2.1 Visit 1 (run-in visit) 
Eligible subjects will return to download their glucometer, insulin pump (if applicable), and CGM (if 
applicable), and confirm that all eligibility criteria (inclusion and exclusion) are met, and if so, will then 
undergo standard Medtronic training on the MiniMed 670G system and Contour Next Link 2.4 study 
glucometer or standard Tandem t:slim training on the t:slimX2 pump and Dexcom G6 CGM. Subjects will 
use the MiniMed 670G system or the t:slimX2 Basal-IQ and Control-IQ s ystem without the 
automated features for a 2 week period to ensure understanding of and compliance with the devices. 
Subjects will receive a follow-up phone call the next morning, and then at one-week to inquire about any 
difficulties with MiniMed 670G system or the t:slimX2 Basal-IQ and Control-IQ system until the 

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next visit. 
 
6.2.2  Visit 2 (baseline visit) 
Subjects will return after 2 weeks in the afternoon to download their MiniMed 670G system and Contour 
Next Link 2.4 study glucometer or their t:slimX2 pump with Basal-IQ and Control-IQ system, and confirm 
tolerability of, compliance with, and willingness to continue the system, and if so, will then be admitted to 
the CHPS where they will receive dinner and then fast overnight after 8 p.m. After 9 p.m. subcutaneous 
insulin therapy will be held and the blood glucose will be maintained in the normoglycemic range overnight 
by a low-dose i.v. insulin infusion according to CHPS protocol. At 7 a.m. a stepped-hyperinsulinemic 
hypoglycemic clamp will be performed as described above under Study Procedures.  Once the clamp 
test is completed, subjects will receive lunch, and undergo further training on the MiniMed 670G system 
or t:slimX2 pump with Basal-IQ and Control-IQ system in order to enable the automated features. Once 
training is complete, and the automated system is operational in manual mode, the subject will be 
discharged. Subjects will receive a follow-up phone call the next morning, and then weekly phone calls to 
inquire about any difficulties with MiniMed 670G system or t:slimX2 pump with Basal-IQ and Control-IQ 
system until the next visit. At the first weekly phone call the system will be switched in to auto mode or 
Control-IQ. During the weekly phone calls, subjects will upload their insulin dosing, glucose sensor, and 
glucometer data to Care Link or t-Connect for review and interpretation with the research nurse practitioner. 
 
6.2.3 Visits 3 – 7, Months 1 – 5 
Subjects will return at month 3 for a history and targeted physical examination by the research nurse 
practitioner. At months 1,2, 4 and 5 if subjects are comfortable uploading their device to the Carelink platform, 
the visits may be done over the phone. At all 5 visits their MiniMed 670G system and Contour Next Link 2.4 
study glucometer or the t:slimX2 pump with Basal-IQ and Control-IQ system will be downloaded and reviewed 
in order to assess compliance with their use of CGM and LGS, time spent in auto and manual modes, re-
educate as necessary, interpret their glucose data, and adjust their insulin dosing. At the Month 3 Visit 5, 
subjects will wear the actigraph / Actiwatch2 monitor for the preceding three weeks, and an HbA1c will be 
checked. At each visit a decision will be made whether to continue weekly phone contact with data upload to 
Care Link or t-Connect. At the Month 5 Visit 7, subjects will receive a glucose log for recording 4 times daily 
blood glucose monitoring for a 4week period. 
 
6.2.4  Visit 8, Month 6 
Subjects will return for a history and targeted physical examination, to turn in their glucose log and actigraph 
/Actiwatch2monitor, and complete hypoglycemia questionnaires, download their MiniMed 670G system and 
Contour Next Link 2.4 study glucometer or or t:slimX2 pump with Basal-IQ and Control-IQ system as for regular 
monthly visits, return the actigraph / Actiwatch 2 monitor after three weeks of wear, and check fasting serum 
biochemistries (glucose, electrolytes, creatinine, and liver function tests), HbA1c, complete blood count, and 
HCG (females). Subjects will be admitted to the CHPS where they will receive dinner and then fast overnight 
after 8 p.m. After 9 p.m. subcutaneous insulin therapy will be held by suspending the MiniMed 670G system, 
and the blood glucose will be maintained in the normoglycemic range overnight by a low-dose i.v. insulin 
infusion according to CHPS protocol. At 7 a.m. a stepped-hyperinsulinemic hypoglycemic clamp will be 
performed as described above. Once the clamp test is completed, subjects will receive lunch, resume the 
MiniMed 670G system or the t:slimX2 pump with Basal-IQ and Control-IQ system, and be discharged. 
 
6.2.5 Visit 9, Month 9 
Subjects will return for a history and targeted physical examination, download their MiniMed 670G system and 
Contour Next Link 2.4 study glucometer or the t:slimX2 pump with Basal-IQ and Control-IQ system in order to 
assess compliance with their use of CGM and LGS, time spent in auto and manual modes, interpret their 
glucose data, and adjust their insulin dosing as may be appropriate, return the actigraph / Actiwatch2 monitor 
after 3 weeks of wear, and check an HbA1c.Visit 10, Month 12 
 
6.2.6  Visit 10, Month 12 
Subjects will return for a history and targeted physical examination, to turn in their glucose log and 
complete hypoglycemia questionnaires, download their MiniMed 670G system and Contour Next Link 2.4 
study glucometer or the t:slimX2 pump with Basal-IQ and Control-IQ system in order to assess 

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compliance with their use of CGM and LGS, time spent in auto and manual modes, interpret their glucose 
data, and adjust their insulin dosing as may be appropriate, return the actigraph / Actiwatch2 monitor after 
three weeks of wear, and check an HbA1c. 
 
6.2.7  Visit 11, Month 15 
Subjects will return for a history and targeted physical examination, download their MiniMed 670G system and 
Contour Next Link 2.4 study glucometer or the t:slimX2 pump with Basal-IQ and Control-IQ system in order 
to assess compliance with their use of CGM and LGS, time spent in auto and manual modes, interpret their 
glucose data, and adjust their insulin dosing as may be appropriate, return the actigraph / Actiwatch2 monitor 
after three weeks of wear, and check an HbA1c. 
 
6.2.8  Visit 12, Month 18 
Subjects will return for a history and targeted physical examination, to turn in their glucose log and actigraph / 
Actiwatch 2  monitor, and complete hypoglycemia questionnaires, download their MiniMed 670G system and 
Contour Next Link 2.4 study glucometer or t:slimX2 pump with Basal-IQ and Control-IQ system as for regular 
monthly visits, return the actigraph/ Actiwatch 2  monitor after three weeks of wear, and check fasting serum 
biochemistries (glucose, electrolytes, creatinine, and liver function tests), HbA1c, complete blood count, and 
HCG (females). Subjects will be admitted to the CHPS where they will receive dinner and then fast overnight 
after 8 p.m. After 9 p.m. subcutaneous insulin therapy will be held by suspending the MiniMed 670G system 
or the t:slimX2 pump with Basal-IQ and Control-IQ system, and the blood glucose will be maintained in the 
normoglycemic range overnight by a low-dose i.v. insulin infusion according to CHPS protocol. At 7a.m. a 
stepped-hyperinsulinemic hypoglycemic clamp will be performed as described above. Once the clamp test is 
completed, subjects will receive lunch, resume their pre-study insulin delivery and glucose monitoring regimen 
unless they have obtained their own MiniMed 670G system that would resume, and be discharged. 
 
6.3    Subject Withdrawal 
Subjects may withdraw from the study at any time without impact to their care. They may also be 
discontinued from the study at the discretion of the PI for lack of adherence to intervention or study 
procedures or visit schedules, AEs, or due to persistent insufficient compliance with CGM and LGS use 
that should be targeted to > 80% or 6/7 days. Reasons for less compliance will be assessed, and if 
addressable, re-evaluated at the next scheduled visit. If compliance remains under target, or if the 
reason for sub-optimal compliance is not addressable, the subject will be considered non-compliant with the 
product regimen and withdrawn from participation in the study. In the case of subject withdrawal, the subject 
will be asked to return the study MiniMed 670G system or t:slimX2 pump with Basal-IQ and Control-IQ 
system and related supplies at a final study visit when they will be returned to their pre-study insulin delivery 
and glucose monitoring regimen. The PI may also withdraw subjects who violate the study plan, or to 
protect the subject for reasons of safety or for administrative reasons. It will be documented whether or 
not each subject completes the clinical study. Subjects who withdraw early will have one final visit to collect 
the investigational supplies and to follow up regarding adverse events. 
 
6.3.1   Data Collection and Follow-up for Withdrawn Subjects 
Subjects who withdraw consent to participate in the study will be seen for one final visit to collect the 
investigational supplies and to be returned to their pre-study insulin delivery and glucose monitoring 
regimen. 
 
6.4    Early Termination Visits 
Early termination visits will include a history and targeted physical examination to assess for adverse 
events, download of the MiniMed 670G system and Contour Next Link 2.4 study glucometer or t:slimX2 
pump with Basal-IQ and Control-IQ system in order to interpret glucose data, and inform return to pre-
study insulin delivery and glucose monitoring, and measurement of an HbA1c. 
 
7  Statistical Plan 
 

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7.1  Primary Endpoint 
The primary outcome measure of this study will be the rate of endogenous glucose production in 
response to insulin-induced hypoglycemia after 6 months of intervention. This measure will be calculated 
from the final hour of the stepped-hyperinsulinemic hypoglycemic clamp test, and compared between the 
month 6 and baseline study visits using a paired t-test or the Wilcoxon matched-pairs tests as appropriate, 
with significance considered at P ≤ 0.05 (two-tailed). 
 
7.2 
Secondary Endpoints 
Secondary outcome measures will include the rate of endogenous glucose production in response to 
insulin-induced hypoglycemia after 18 months of intervention, and counterregulatory hormone and symptom 
responses to hypoglycemia after 6 and 18 months. For the additional measures, multiple comparisons 
are being made without adjustments for multiplicity, and so any findings will be hypothesis generating. The 
additional responses at 18 months will be analyzed by repeated measures mixed model for longitudinal 
measurements over time. 
 
7.3 
Sample Size and Power Determination 
Based on our preliminary work in 11 subjects completing 18 months intervention with real time CGM 
alone, the mean ± S.D. endogenous glucose production response pre-intervention was 0.42 ± 0.28 
mg/kg·min and increased marginally to 0.54 ± 0.24 mg/kg·min at 6 months and further to 0.84 ± 0.50 
mg/kg·min at 18 months. To detect a 0.42 mg/kg·min difference from before to 6 months after intervention 
with the hybrid closed-loop system will require 15 subject completers to have > 80% power at α = 0.05 (two-
tailed) using a paired t-test. We plan on enrolling up to 18 subjects to ensure at least 15 subjects complete 
the 6 month assessment. 
 
8 Safety and Adverse Events 
 
8.2 
Definitions 
 
8.1.1 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study. Intercurrent illnesses or injuries should be regarded as adverse events. 
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
• results in study withdrawal 
• is associated with a serious adverse event 
• is associated with clinical signs or symptoms 
• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
For FDA regulated studies the FDA defines an adverse event as the following: 
 
Adverse event means any untoward medical occurrence associated with the use of a device in humans 
whether or not considered device related. 
 
8.1.2 Serious Adverse Event 
Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event is any AE that is: 
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
• a congenital anomaly or birth defect 
• an important medical event 

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Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance. They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above. For example, drug overdose or abuse, a seizure that did not result in 
in-patient hospitalization or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious. 
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events. 
 
Adverse Event Reporting Period 
The study period during which adverse events will be reported is the period from the initiation of study 
procedures to the end of the study treatment follow-up. For this study, the study treatment follow-up is 
defined as 30 days following the completion of study treatment. 
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study. A preexisting condition will be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during the 
study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality will be recorded as a preexisting condition. At the end of 
the study, any new clinically significant findings/abnormalities that meet the definition of an adverse event 
will also be recorded and documented as an adverse event. 
 
Post-study Adverse Event 
All unresolved adverse events will be followed by the PI until the events are resolved, the subject is lost to 
follow-up, or the adverse event is otherwise explained. At the last scheduled visit, an investigator will 
instruct each subject to report any subsequent event(s) that the subject, or the subject’s personal 
physician, believes might reasonably be related to participation in this study. 
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met: 
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
• The abnormality suggests a disease and/or organ toxicity 
• The abnormality is of a degree that requires active management; e.g. change of dose, discontinuation 
of the drug, more frequent follow-up assessments, further diagnostic investigation, etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization will be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol. Any 
condition responsible for surgery will be documented as an adverse event if the condition meets the 
criteria for an adverse event. 
 
• 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances: Hospitalization or prolonged hospitalization for 
diagnostic or elective surgical procedures for a preexisting condition. Surgery should not be 
reported as an outcome of an adverse event if the purpose of the surgery was elective or diagnostic 
and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it is 
a worsening or increase in frequency of hospital admissions as judged by the PI. 
 
Unanticipated Problems Involving Risk to Subjects or Others 

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Any incident, experience, or outcome that meets all of the following criteria: 
• Unexpected in nature, severity, or frequency (i.e. not described in study-related documents such as 
the IRB-approved protocol or consent form, the investigators brochure, etc). 
• Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience or outcome may have been caused by the 
procedures involved in the research). 
• Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
8.2 
Recording of Adverse Events 
At each contact with the subject, an investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination. Information on all adverse events will be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF). All clearly related signs, symptoms, and abnormal diagnostic procedures results will be 
recorded in the source document, and will be grouped under one diagnosis. 
 
All adverse events occurring during the study period will be recorded. The clinical course of each event will 
be followed until resolution, stabilization, or until it has been determined that the study intervention or 
participation is not the cause. Serious adverse events that are still ongoing at the end of the study period will 
be followed up to determine the final outcome. Any serious adverse event that occurs after the study period 
and is considered to be possibly related to the study intervention or study participation will be recorded 
and reported immediately. 
 
8.3 
Relationship of AE to Study 
The relationship of each adverse event to the study procedures will be characterized by the PI and 
classified as definitely related, probably related, possibly related, unlikely or unrelated. 
 
8.4 
Reporting of Adverse Events, Adverse Device Effects and Unanticipated Problems 
Investigators will conform to the adverse event reporting timelines, formats and requirements of the 
various entities to which they are responsible, but at a minimum those events that must be reported are 
those that are: 
• related to study participation, 
• unexpected, and 
• serious or involve risks to subjects or others 
(see definitions, section 8.1). 
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of the 
initial report includes: 
• 
Study identifier 
• 
Study Center 
• 
Subject number 
• 
A description of the event 
• 
Date of onset 
• 
Current status 
• 
Whether study treatment was discontinued 
• 
The reason why the event is classified as serious 
• 
Investigator assessment of the association 
between the event and study treatment
 
 
Additionally, all other events (unanticipated problems, adverse reactions, unanticipated adverse device 
effects and subject complaints will be recorded and reported with respect to institutional and federal policies 
as described in the Penn Manual and below. 
 
 

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8.4.1 Follow-up report 
 
If an AE has not resolved at the time of the initial report and new information arises that changes the 
investigator’s assessment of the event, a follow-up report including all relevant new or reassessed 
information (e.g., concomitant medication, medical history) will be submitted to the IRB. The investigator 
will be responsible for ensuring that all SAE are followed until either resolved or stable. 
 
8.4.2 Investigator Reporting: Notifying the Penn IRB 
This section describes the requirements for safety reporting by investigators who are Penn faculty, 
affiliated with a Penn research site, or otherwise responsible for safety reporting to the Penn IRB. The 
University of Pennsylvania IRB (Penn IRB) requires expedited reporting of those events related to study 
participation that are unforeseen and indicate that participants or others are at increased risk of harm. 
The Penn IRB will not acknowledge safety reports or bulk adverse event submissions that do not meet 
the criteria outlined below. The Penn IRB requires researchers to submit reports of the following 
problems within 10 working days from the time the investigator becomes aware of the event: 
• Any adverse event (regardless of whether the event is serious or non-serious, on-site or off-site) 
that occurs any time during or after the research study, which in the opinion of the principal 
investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately reflected 
in the protocol-related documents, such as the IRB-approved research protocol, any applicable 
investigator brochure, and the current IRB-approved informed consent document and other relevant 
sources of information, such as product labeling and package inserts.) 
AND 
Related to the research procedures (An event is “related to the research procedures” if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be caused by 
the research procedures.) 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the Penn 
IRB using the form: “Unanticipated Problems Posing Risks to Subjects or Others Including Reportable 
Adverse Events” or as a written report of the event (including a description of the event with information 
regarding its fulfillment of the above criteria, follow-up/resolution and need for revision to consent form 
and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the study’s 
regulatory binder. 
 
Reporting Deaths: more rapid reporting requirements 
Concerning deaths that occur during the course of a research study, the following describes the more 
rapid reporting requirement of the Penn IRB for specific situations: 
• Report the event within 24 hours when the death is unforeseen (unexpected) and indicates 
participants or others are at increased risk of harm. 
• Report the event within 72 hours, for all other deaths, regardless of whether the death is related to 
study participation. 
 
For reportable deaths, the initial submission to the Penn IRB may be made by contacting the IRB Director 
or Associate Director. The AE/Unanticipated Problem Form is required as a follow up to the initial 
submission. 
 
Other Reportable events: 
For clinical trials, the following events are also reportable to the Penn IRB: 
• Any adverse event that would cause the sponsor to modify the investigators brochure, protocol or 
informed consent form, or would prompt other action by the IRB to assure protection of human 
subjects. 

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• Information that indicates a change to the risks or potential benefits of the research, in terms of 
severity or frequency. For example: 
– An interim analysis indicates that participants have a lower rate of response to treatment than 
initially expected. 
– Safety monitoring indicates that a particular side effect is more severe, or more frequent than 
initially expected. 
– A paper is published from another study that shows that an arm of your research study is of no 
therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic used in 
a research protocol. 
• Breach of confidentiality. 
• Change to the protocol taken without prior IRB review to eliminate apparent immediate hazard to a 
research participant. 
• Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study. 
• Complaint of a participant when the complaint indicates unexpected risks or the complaint cannot 
be resolved by the research team. 
 
Protocol violation (meaning an accidental or unintentional deviation from the IRB approved protocol) that 
in the opinion of the investigator placed one or more participants at increased risk, or affects the rights or 
welfare of subjects. 
 
8.5 
Medical Monitoring 
 
8.5.1 Data and Safety Monitoring Plan 
The PI will oversee the safety of the study. This safety monitoring will include careful assessment and 
appropriate reporting of adverse events as noted above. In addition, medical monitoring will be conducted 
by a study monitor and data and safety monitoring board (DSMB) as described in the data and safety 
monitoring plan (DSMP). 
 
8.5.2 Data Safety Monitoring Board 
A data and safety monitoring board (DSMB) will be established. The mission of the DSMB is to ensure 
that risk associated with participation in research is being minimized to the extent practical. This mission 
will be accomplished by charging the DSMB to determine safe and effective conduct of the study and to 
recommend conclusion of the trial when significant benefits or risks have developed or the trial is unlikely 
to be concluded successfully. The DSMB will consist of 3 members independent from the trial and the 
study team and having no conflicts of interest with any company developing insulin pumps, glucose 
sensors or related technology, with at least one being a clinical investigator and at least one an 
endocrinologist experienced in the care of subjects with type 1 diabetes. A CV for each member will be 
obtained and updated annually. The CVs will be kept on file in the Sponsor section of the Regulatory 
Binder to document the qualifications of the DSMB members. One member will serve as chair for 
meetings of the DSMB. 
 
The DSMB will meet either by teleconference, or if possible, in person, at least annually and more often if 
requested due to the appearance of unexpected and possibly related serious adverse events, or an 
unexpected number of serious adverse events regardless of their relatedness. Each member will receive 
a monitoring manual including the current protocol, most recent approved consent form, CRF, and DSMP. 
The annual DSMB meeting will be scheduled as soon as possible following submission of the annual 
report to the IRB, and that report containing all adverse events will be reviewed by the DSMB together 
with any available interim efficacy data. All unexpected and possibly related serious adverse events will 
be reported expeditiously to both the IRB and the DSMB chair; all other serious adverse events regardless 
of their relatedness will be reported expeditiously to the DSMB chair. Based on such reporting, the 
DSMB chair may convene a meeting of the board at any time. 
 

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The annual DSMB meeting will be scheduled as soon as possible following submission of the annual 
report to the IRB, and that report containing all adverse events will be reviewed by the DSMB together 
with any available interim efficacy data. All unexpected and possibly related serious adverse events will 
be reported expeditiously to both the IRB and the DSMB chair; all other serious adverse events regardless 
of their relatedness will be reported expeditiously to the DSMB chair. Based on such reporting, the 
DSMB chair may convene a meeting of the board at any time. 
 
Each DSMB meeting will start as an open meeting including the PI and any co-investigators and study 
personnel, where the PI will present the safety and efficacy materials for review to the DSMB and be 
available to answer any and all questions from the Board. The meeting will then be conducted as a 
closed meeting of the DSMB members for any further discussion and voting as to whether the study 
should continue or be placed on hold with 2/3 votes being required for a recommendation. In addition to 
study safety and efficacy data, the DSMB will consider participant recruitment, accrual and retention, 
participant risk versus benefit, and any scientific or therapeutic developments that may have an impact on 
the safety of the participants or the ethics of the study. The research coordinator will keep minutes on the 
open meeting, and the Board chair will keep minutes on the closed meeting; the research coordinator will 
compile both sets of minutes and the recommendation into a report for approval by the DSMB prior to 
submission to the PI and the IRB. 
 
9 
Study Administration, Data Handling and Record Keeping 
 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a 
signed subject authorization informing the subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study; 
• Who will have access to that information and why; 
• Who will use or disclose that information; and 
• The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the PI, by regulation, retains the 
ability to use all information collected prior to the revocation of subject authorization. For subjects that 
have revoked authorization to collect or use PHI, attempts will be made to obtain permission to collect at 
least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
 
9.2     Data Collection and Management 
Participants’ privacy and confidentiality will be respected throughout the study. Each participant is 
assigned a sequential identification number, and these numbers rather than names are used to collect, 
store, and report participant information. Source data is all information, original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation 
of the trial. The University of Pennsylvania will be the only site where the research will be performed. 
Screening visits will involve the documentation of medical history, vital signs, and objective physical 
examination findings, and collection of urine and blood specimens as occurs routinely during standard 
care for patients with type 1 diabetes. Medical history, laboratory, and other reports will be reviewed in 
the electronic medical record (EPIC®) or upon written consent of the potential study participant to obtain 
outside medical records. Specimens will consist of blood and urine samples, to be assayed for metabolic 
and hematological parameters, and to exclude pregnancy. Clinical laboratory test results may be made 
available to each subject’s personal physicians upon their consent and written release of information. 
Additional data collected will include glucose diaries, hypoglycemia questionnaires, adverse event logs, 
insulin pump, glucometer, CGM, and actigraph / Actiwatch 2 monitor downloads, and symptom 
questionnaires and metabolic response data derived from the hyperinsulinemic hypoglycemic clamp 
experiments conducted before and at 6 and 18 months following implementation of hybrid closed-loop 
insulin delivery. Paper source documents and medical and research records, as well as the code 
linking subjects and ID numbers are maintained under lock and key at Penn until data analysis is 

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complete at which point they are archived appropriately. Clinical specimens are assayed promptly. 
The study case report form (CRF) is the primary data collection instrument for the study. All data 
requested on the CRF will be recorded. All missing data must be explained. If a space on the CRF is left 
blank because the procedure was not done or the question was not asked, it will be marked “N/D”. If the 
item is not applicable to the individual case, it will be marked “N/A”. All entries will be printed legibly in 
black ink. If any entry error has been made, to correct such an error, a single straight line will be drawn 
through the incorrect entry and the correct data entered above it. All such changes will be initialed and 
dated. For clarification of illegible or uncertain entries, clarification will be printed above the item, then 
initialed and dated. Data culled from source documents will be transferred directly to a password 
protected database containing only the subject identification number. Subject ID numbers are assigned 
sequentially to each participant and these numbers rather than names are used to collect, store, and 
report participant information. None of the 18 biometric identifiers are entered into the database, however, 
date of birth, and dates of visits and adverse events are maintained under lock and key in the source 
documents for monitoring and analysis purposes. Specimens that are archived or that may be sent out for 
future analyses are coded with subject ID numbers and do not contain any of the 18 biometric identifiers. 
 
All research samples are identified by code only. Only authorized research personnel will have access to 
source documents and research records. Additionally, regulatory personnel from the University (Office of 
Regulatory Affairs and the Office of Human Research) will have access to these records as part of the 
quality assurance and legal responsibilities of the investigation. Unless required by the laws that permit 
copying of records, only the coded identity associated with documents or with other participant data may 
be copied (and all personally identifying information must be obscured). The study database will not 
contain any protected health information, and even so, the database at Penn is user ID and password 
protected. Each user is provided with a unique personal ID and password. 
 
9.3    Records Retention 
The PI will retain all essential study documents for at least 2 years after acceptance of the final 
manuscript for publication related to this protocol. 
 
 
10 Study Monitoring, Auditing, and Inspecting 
 
10.1 Study Monitoring Plan 
This study will be monitored according to the monitoring plan in the Attachments. The PI will allocate 
adequate time for such monitoring activities. The PI will also ensure that the monitor or other compliance 
or quality assurance reviewer is given access to all the above noted study-related documents and study 
related facilities (e.g. Investigational Drug Service pharmacy, Center for Human Phenomic Science, etc.), 
and has adequate space to conduct the monitoring visit. 
 
10.2 Auditing and Inspecting 
The PI will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, government 
regulatory bodies, and University compliance and quality assurance groups of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.). 
The PI will ensure the capability for inspections of applicable study-related facilities (e.g. Investigational 
Drug Service pharmacy, Center for Human Phenomic Science, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
 
11 Ethical Considerations 
This study is to be conducted in accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
This protocol and any amendments will be submitted to a properly constituted independent Institutional 

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Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the study conduct. 
The decision of the IRB concerning the conduct of the study will be made in writing to the 
investigator/sponsor before commencement of this study. 
 
11.1 Risks 
The risks of hybrid closed-loop insulin delivery include local discomfort, skin irritation, bruising, bleeding, 
or rarely infection at the site of insulin infusion cannula or glucose sensor insertion. These risks are 
minimized through proper instruction in insertion technique, including sterile procedures, by our diabetes 
research nurse practitioner. While the use of a hybrid closed-loop system has been shown to reduce time 
spent in the hypoglycemic range, there is a risk of severe hypoglycemia if an inaccurate sensor glucose 
reading is used to make dosing adjustments to insulin delivery. This risk is minimized through intensive 
education that includes prohibiting insulin dose decisions on the basis of a sensor glucose recording, and 
safety measures that are built-in to the closed-loop algorithm during auto mode that monitors for extreme 
sensor discordance and will automatically exit the closed-loop function. There is also a risk of marked 
hyperglycemia should an insulin infusion set become occluded or when inaccurate sensor glucose 
triggers suspension of insulin delivery; rarely diabetic ketoacidosis could develop. This risk is minimized 
through intensive education that includes recognition of faulty insulin cannulas, rotating insertion sites 
every 2-3 days, and appropriate calibration of the glucose sensor at least 3 times daily. Also, the 
automated suspension of insulin delivery is programmed to last no more than 2 hours, less if delivery is 
resumed by the patient. Finally, acceleration of retinopathy with acute correction in glycemic control was 
seen in the Diabetes Control and Complications Trial (DCCT), although the subjects studied here will 
already be receiving intensive insulin therapy as implemented in the DCCT, and so this risk is probably 
not significant. Nonetheless, all subjects will be required to have stable retinopathy documented by their 
ophthalmologist or retinologist prior to participation as exclusion of patients with unstable retinopathy 
should minimize this risk. 
 
Blood drawn for standard of care plus research labs including for the stepped-hyperinsulinemic 
hypoglycemic clamp test will not exceed 450 ml in any six-week period. Nonetheless, blood counts will be 
checked at the time of each clamp test to monitor for the development of anemia, and the exclusion of 
subjects with anemia at baseline should minimize this risk. Additional procedural risks include those 
pertaining to blood draws, maintenance of intravenous catheters, and the delivery of test substances 
(glucose and insulin) during the clamp procedures. Blood draws and intravenous line placement for 
clamp testing may cause the subject to experience some discomfort or bruising at the site of the 
needle/catheter entry. The risks of intravenous line placement for clamp testing include bleeding, 
displacement, and interstitial infusion of fluids; rarely local vein thrombosis, infection or thrombophlebitis 
may develop. The administration of insulin intravenously during the clamp procedures may lead to a 
greater degree of hypoglycemia than expected, but would be rapidly corrected with intravenous glucose. 
The stable isotope of glucose infused during the glycemic clamps is tested for identity, sterility, and 
absence of pyrogens by the Penn Investigational Drug Service, and so carries no additional risks. The 
conduct of these study procedures in the CHPS by experienced research nurses and nurse practitioners 
greatly minimizes the risks of needle/catheter placement and administration of test substances. 
 
11.2 Benefits 
The type 1 diabetic subjects participating in this study will benefit from close follow-up, and may also 
benefit from the guaranteed access to a hybrid closed-loop system and the intensive education and 
support required that is not presently fully reimbursed by insurance carriers. Indeed, if the proposed 
studies demonstrate an improvement in glucose counterregulation with use of hybrid closed-loop insulin 
delivery, then the selected subjects here with long standing disease complicated by hypoglycemia 
unawareness may benefit from a significant reduction in risk of experiencing severe episodes of 
hypoglycemia. 
 
11.3 Risk Benefit Assessment 
The alternative to participation is on-going standard management of type 1 diabetes with available insulin 
delivery and glucose monitoring technologies, which may include SAP with LGS utilizing a threshold 

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suspension of insulin delivery only, and not the predictive suspension and automated delivery available 
through the MiniMed 670G system or the t:slimX2 pump with Basal-IQ and Control-IQ system being used 
in this study. Given the inclusion criteria that selects subjects with type 1 diabetes experiencing 
hypoglycemia unawareness and problematic hypoglycemia and/or marked glycemic lability at increased 
risk for experiencing severe hypoglycemia despite compliance with standard management, the risks of 
participating in the study are outweighed by the potential benefit of reduced exposure to hypoglycemia 
and decreased risk of experiencing a severe hypoglycemia episode from participating in the study. 
 
 
12 Study Finances 
 
12.1 Funding Source 
This study is financed through Public Health Services research grant 2R01-DK-091331 to the PI from the 
National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. 
 
12.2 Conflict of Interest 
No participating investigator has a conflict of interest with this study.   All University of Pennsylvania 
Investigators will follow the University of Pennsylvania Policy on Conflicts of Interest Related to Research. 
 
12.3 Subject Stipends or Payments 
Subjects will receive $150 compensation for each CHPS inpatient visit for clamp testing and $50 
compensation for each outpatient visit to either the Rodebaugh Diabetes Center or CHPS, as well as 
reimbursement for parking and travel related expenses in order to encourage study completion and 
compliance with all study visits. No compensation will be provided for injury that may be incurred as a 
result study participation. Subjects will receive a Greenphire Clincard which the study team will load after 
visit completion. Cash will be given at each visit for parking and travel related expenses. 
 
13 Publication Plan 
Publication and presentation of the data derived from this protocol will be the responsibility of the PI. 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed 
on to any third party without the consent of the study investigator/sponsor.

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15  Attachments 
• Data and Safety Monitoring Plan 
• Informed Consent