Conditions: Type 1 Diabetes Mellitus
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

Brief summary:
This clinical trial is a feasibility study to assess the performance of an Artificial Pancreas (AP) device using the Artificial Pancreas System (APS©) platform for subjects with type 1 diabetes using rapid-acting insulin as well as preprandial inhaled insulin (Technosphere® Insulin Inhalation System by MannKind Corporation). The goal of this proposed study is to explore the feasibility of using multiple insulin delivery routes in order to mimic the physiology of both first- and second-phase insulin secretion. The intent is to exploit the rapid action achieved by inhaled insulin to compensate for part of the meals and utilize the conventional subcutaneous route for management of basal insulin and as second-phase meal-related insulin.

Detailed description:

Arms:
arm 1: Adults aged 21-65 years with type 1 diabetes mellitus for at least one year who are using an insulin infusion pump with rapid-acting insulin for at least six months

Interventions: intervention 1: Investigational inhaled insulin (Technosphere) intervention 2: Artificial Pancreas (AP) device (APS©)
Intervention descriptions: intervention 1: by MannKind Corp. IND 61,729 intervention 2: Device includes:

* OneTouch® Ping® Glucose Management System with modified Meter-Remote from Animas® Corp or the OmniPod® Insulin Management System from Insulet Corp.
* Dexcom® G4® CGM System (CGM) from Dexcom® Corp
* Control algorithm: zone-Model Predictive Control (zone-MPC) with safety Health Monitoring System (HMS)

Protocol document:
Prot_SAP_000.pdf: 
NCT01874392   Unique Protocol ID: JDRF 17-2010-765 
Brief Title: 
Feasibility Study Using Zone-MPC Controller, HMS and Technosphere® Insulin 
Inhalation System From MannKind Corp 
Date of most recent update: 16NOV2012 


 
CLINICAL PROTOCOL 
Revision 4 
Artificial Pancreas Device 
 
Feasibility Study using Zone-MPC Controller 
(Zone-Model Predictive Control) and Health 
Monitoring System (HMS) and Technosphere® Insulin 
Inhalation System from MannnKind Corp. 
 
Name 
Function/ 
Title 
Signature 
Date 
Prepared 
by 
Dr. Howard 
Zisser, MD 
Director of Clinical Research and 
Diabetes Technology 
Sansum Diabetes Research Institute 
 
 
Approved 
by 
Dr. Eyal 
Dassau, PhD 
Senior Investigator & Diabetes Team 
Research Manager Department of 
Chemical Engineering University of 
California, Santa Barbara 
 
 
 
SPONSOR 
Sansum Diabetes Research Institute 
Principal Investigator: Howard Zisser, M.D. 
Director of Clinical Research and Diabetes Technology 
2219 Bath Street 
Santa Barbara, CA 93105 
Ph: 805-682-7638 
Fax: 805-682-3332 


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TABLE OF CONTENTS 
 
EXECUTIVE SUMMARY ........................................................................................................... 4 
1. 
DESCRIPTION OF THE DEVICES .................................................................................. 11 
1.1. 
OVERVIEW AND HARDWARE ........................................................................................... 11 
1.2. 
CONTINUOUS GLUCOSE MONITOR (CGM)....................................................................... 15 
1.3. 
INSULIN PUMP .................................................................................................................. 15 
1.4. 
CONTROL ALGORITHM .................................................................................................... 16 
2. 
STUDY OBJECTIVES ........................................................................................................ 17 
2.1. 
STUDY’S CHALLENGES .................................................................................................... 17 
2.2. 
PRIMARY AND SECONDARY ENDPOINTS .......................................................................... 18 
3. 
BACKGROUND INFORMATION .................................................................................... 19 
3.1. 
ETHICAL BACKGROUND .................................................................................................. 19 
3.2. 
SUMMARY OF KNOWN RISKS AND BENEFITS ................................................................... 20 
3.3. 
SUMMARY OF PAST FINDINGS .......................................................................................... 20 
3.3.1. Overview .................................................................................................................. 20 
3.3.2. Necessary future development .................................................................................. 21 
3.3.3. Overview of recent results: IDE G090129 ............................................................... 21 
3.3.4. Overview of most recent results: IDE G110093 with same AP device as in this 
proposed protocol ................................................................................................................. 23 
3.4. 
DESCRIPTION OF POPULATION STUDIED .......................................................................... 27 
3.5. 
LITERATURE DATA REFERENCES ..................................................................................... 28 
4. 
TRIAL DESIGN ................................................................................................................... 29 
4.1. 
OVERVIEW OF CLINICAL STUDY ...................................................................................... 29 
4.2. 
SCREENING VISIT: PHYSICAL EXAM................................................................................. 33 
4.3. 
SUBJECT PREPARATION TO INITIATE TRIAL: OUTPATIENT ............................................... 33 
4.4. 
IN-PATIENT: AT THE CRC (2-DAYS) ................................................................................ 35 
4.4.1. Arrival ...................................................................................................................... 35 
4.4.2. Monitoring ............................................................................................................... 37 
4.4.2.1. 
On-going monitoring ..................................................................................................................... 37 
4.4.2.2. 
Blood volume requirements ........................................................................................................... 39 
4.4.2.3. 
Safety ............................................................................................................................................. 40 
4.4.3. Unannounced meals during closed-loop .................................................................. 43 
4.4.3.1. 
Dinner ............................................................................................................................................ 43 
4.4.3.2. 
Breakfast ........................................................................................................................................ 43 
4.4.3.3. 
Snack before exercising ................................................................................................................. 43 
4.4.3.4. 
Snack after exercising .................................................................................................................... 43 
4.4.4. Exercising ................................................................................................................. 43 
4.4.5. Discharge from the CRC .......................................................................................... 46 
4.5. 
FOLLOW-UP CALL ............................................................................................................ 46 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..................................................... 46 
5.1. 
INCLUSION CRITERIA ....................................................................................................... 46 


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5.2. 
EXCLUSION CRITERIA ...................................................................................................... 47 
5.3. 
STARTING RULES ............................................................................................................. 49 
5.4. 
STOPPING RULES.............................................................................................................. 50 
5.4.1. Criteria for individual subject withdrawal ............................................................... 50 
5.4.2. Criteria for suspending / stopping the study ............................................................ 51 
6. 
EXPECTED SAMPLE SIZE ............................................................................................... 51 
7. 
DESCRIPTION OF THE CLINICAL CENTER .......................................................... 5251 
8. 
ASSESSMENT OF EFFICACY .......................................................................................... 52 
9. 
ASSESSEMENT OF SAFETY ............................................................................................ 52 
9.1. 
REPORTING TO REGULATORY AGENCIES ......................................................................... 52 
9.2. 
DEFINITIONS .................................................................................................................... 53 
9.2.1. Adverse Event (AE) .................................................................................................. 53 
9.2.2. Serious Adverse Event (SAE) ................................................................................... 53 
9.2.3. Unanticipated Adverse Device Effect (UADE) ........................................................ 54 
9.2.4. Device complaints .................................................................................................... 54 
9.2.5. Anticipated adverse events ....................................................................................... 55 
9.3. 
ADVERSE EVENT REPORTING AND PROTOCOL MONITORING ........................................... 57 
10. DATA ANALYSIS ............................................................................................................... 58 
10.1. 
OVERVIEW..................................................................................................................... 58 
10.2. 
CONTROL VARIABILITY GRID ANALYSIS ..................................................................... 58 
10.3. 
PRIMARY END-POINTS ................................................................................................... 60 
10.4. 
SECONDARY END-POINTS .............................................................................................. 61 
10.4.1. Analyses ................................................................................................................. 61 
10.4.2. Details for calculations .......................................................................................... 62 
11. ACCESS TO SOURCE DATA / DOCUMENT ................................................................. 63 
11.1. 
ELECTRONIC DATA ........................................................................................................ 63 
11.2. 
HARD COPY RECORDS ................................................................................................... 64 
12. RECORD KEEPING ........................................................................................................... 64 
13. ETHICS COMMITTEE ...................................................................................................... 64 
14. FINANCIAL DISCLOSURE .............................................................................................. 65 
15. INVESTIGATOR’S BROCHURE ..................................................................................... 65 
16. INVESTIGATOR’S CONTACT INFORMATION .......................................................... 65 
17. LIST OF TABLES ............................................................................................................... 67 
 
 
 


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EXECUTIVE SUMMARY 
This clinical trial is a feasibility study to assess the performance of an Artificial Pancreas 
(AP) device using the Artificial Pancreas System (APS©) platform for subjects with type 
1 diabetes using rapid acting insulin as well as pre-prandial inhaled insulin 
(Technosphere® Insulin Inhalation System by MannKind Corporation).  This is a follow-
up study to the approved feasibility study IDE G110093.  The new proposed study and 
IDE G110093 use the same device and follow the same clinical protocol with the addition 
of the pre-prandial inhaled insulin in this new proposed feasibility study.  The CGM for 
this proposed study is the next generation of Dexcom CGMs, the G4® System which was 
recently approved by the FDA.  The goal of this proposed study is to explore the 
feasibility of using multiple insulin delivery routes in order to mimic the physiology of 
both 1st and 2nd phase insulin secretion.  The intent is to exploit the rapid action achieved 
by inhaled insulin to compensate for part of the meals and utilize the conventional 
subcutaneous route for management of basal insulin and as second phase meal-related 
insulin.  Preliminary analysis of the results of IDE G110093 have been very encouraging 
and are supportive of this new proposed study using inhaled insulin to reduce the post-
prandial peak.  The AP device is a closed-loop between a Dexcom® G4® System 
(Dexcom® Incorporated, San Diego, CA) continuous glucose monitor (CGM) and a 
OneTouch® Ping® Glucose Monitoring System (Animas Corp, Westchester, PA) 
subcutaneous insulin delivery pump (CSII).  The AP device is controlled by a zone-
Model Predictive Control (zone-MPC) algorithm augmented by a safety algorithm named 
the Health Monitoring System (HMS).  The clinical study will include 12 to 20 adults 
subjects aged 21 to 65 years old. 
 
The study consists of an evaluation of the Artificial Pancreas device during a 24-hour 
closed-loop in a clinic environment (Sansum Diabetes Research Institute, Santa Barbara, 
CA).  The 24-hour period includes: 
 2 unannounced meals (evening dinner and breakfast of 50 g CHO each) preceded 
with a nominal dose of Technosphere® inhaled insulin; 
 1 period of 30 minutes of exercise at 50% of the predicted heart rate reserve 
(HRR) preceded with a snack and followed by a snack 3 hours later (on Day 2); 
 complete night from 12:00 am to 7:00 am; 
The subject will arrive at approximately 4:00 pm to the CRC (clinical research center), 
the closed-loop will be initiated at approximately 4:30 pm that same day and continued 
until 4:30 pm the next day.  A physician will be monitoring the patient with the artificial 
Pancreas (AP) device at all time. 
 


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The proposed study will evaluate the performance of the AP device combined with 
Technosphere® Insulin Inhalation Powder in predicting the fall and rise of glucose values 
and in regulating insulin delivery to mitigate extreme blood glucose variations during the 
following challenges: 
 following unannounced meals,  
 during a nocturnal period, and  
 during a period of active exercise. 
The goal is to demonstrate that the AP device is able to maintain the subject blood 
glucose within a safe range at all times.  One of the objectives of the study will be to 
measure the percent of time spent in the following zones: 
 [80-140] mg/dL at all times unless described otherwise 
 [80-140] mg/dL during the nocturnal period 
 [70-180] mg/dL postprandial, for 5 hours following the unannounced meals 
 [70-150] mg/dL during and for 3 hours following exercise 
In particular, an analysis will report on 1-hour and 2-hour postprandial glucose level and 
6-hour area-under-the-curve (AUC) when compared to G110093 to evaluate the impact 
of the Technosphere® insulin (only for those subjects who enrolled in both clinical 
studies). 
It is anticipated that following the planned challenges, glucose value might increase 
temporarily beyond those ranges.  These excursions will be reviewed and analyzed (value 
and duration) and the study will determine how the AP device mitigates those excursions 
and maintains glucose levels within a safe and acceptable range.  The clinical study will 
also review any event that occurs during the course of the 24-hour closed-loop: 
hypoglycemic events, hyperglycemic events, outside intervention, other Adverse Event, 
Serious Adverse Events, Unanticipated Adverse Device Effect, and device complaints for 
the commercial devices used.  A root cause analysis of the event will be performed to 
determined if it is related to the device or the drug and if the drug, which drug 
(subcutaneous or Technosphere® Insulin).  Safety of the patient will remain the primary 
goal.  The goal of the AP device combined with the Technosphere® Insulin Inhalation 
Powder (with Gen2C inhaler) is to operate without outside intervention even when 
challenged by meals or exercise unless the outside intervention is requested by the Health 
Monitoring System (HMS).  The subject will just inhale one 10U dose prior to meals.  
This is approximately 4U of subcutaneous insulin. 
 
The table below is a synopsis of the proposed clinical protocol. 


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Title of the 
protocol 
Feasibility Study using Zone-MPC Controller 
(Zone-Model Predictive Control) and Health Monitoring System (HMS) and 
Technosphere® Insulin Inhalation System from MannKind Corp. 
Sponsor 
Sansum Diabetes Research Institute (SDRI) 
Investigational 
Device 
Artificial Pancreas (AP) device: 
Artificial Pancreas System platform (APS©) from the University of California, 
Santa Barbara and SDRI with: 
 
OneTouch® Ping® Glucose Management System with modified Meter-
Remote from Animas® Corp or the OmniPod® Insulin Management 
System from Insulet Corp. 
 
Dexcom® G4® CGM System (CGM) from Dexcom® Corp 
 
Control algorithm: zone-Model Predictive Control (zone-MPC) with safety 
Health Monitoring System (HMS) 
Drug 
Approved rapid acting insulin (subcutaneous): Humalog®, Apidra® or Novolog® 
Investigational inhaled insulin: Technosphere® Insulin Inhalation System (Gen2C 
inhaler) by MannKind Corp. IND 61,729 
Study Purpose 
Primary objective of this feasibility study: 
To evaluate the performance of the AP device while the subject is under close 
medical supervision in the Clinical Research Center (CRC) setting. 
 
This objective will be assessed by subjecting the AP device (combined with the 
Technosphere® Insulin Inhalation Powder) and the subject to several challenging 
situations, such as meals, exercise, and nocturnal period.  The study will evaluate the 
percent of time the glucose level of the subject remains within pre-specified target 
ranges: 
 
Target range (unless described otherwise): [80-140] mg/dL 
 
Overnight target range: [80-140] mg/dL 
 
Target range 5 hours after meal: [70-180] mg/dL 
 
Target range during exercise: [70-150] mg/dL 
 
Target range 3 hours after exercise: [70-150] mg/dL 
 
The study will also evaluate the glucose level at 1- and 2-hour postprandial and the 
area-under-the-curve (AUC) at 6-hour post-prandial. 
 
Secondary objectives: 
To evaluate the performance of the AP device combined with the Technosphere® 
Insulin Powder System: 
 
when glucose values are outside of the desirable ranges,  
 
in analyzing the values and duration of the extremes, in particular if <70 
mg/dL and <60 mg/dL. 
 
in analyzing adverse events, 
 
in analyzing outside interventions not following the recommendation of the 
HMS, 
 
if the same subjects were enrolled in this study and the original IDE 
G110093 study (protocol revision 2.2): comparing the glucose profile 
between the two clinical studies with and without the Technosphere® 
Insulin. 
Study Design 
Non-randomized, uncontrolled, feasibility study conducted in the United-States at 
one clinical site, with one principal investigator. 
 
Overview of the procedures: 


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Following the successful screening and informed consent process: 
 
During the week prior to the CRC visit, the subject will review glucose control and 
insulin pump settings with study staff, with goal to aim for optimal glucose control. 
(Subject’s basal rate settings are used for insulin delivery during closed-loop mode 
when glucose is predicted to be within determined glucose zones, and insulin to 
carbohydrate ratios are used in study test meal calculations). 
 
Two to three days prior to the CRC visit, the subject will attend an outpatient visit 
for the insertion, by study staff, of two CGM sensors, as well as to receive training 
and instructions on how to care for the CGM.  The CGM will be in blinded mode 
during the 2-3 days as an outpatient.  The Bayer Contour® NEXT EZ blood glucose 
meter will be used for all CGM calibrations. 
 
Two to three days after this sensor insertion visit, the subject will return to the CRC 
for approximately 25-28 hours, during which the evaluation of the AP device will 
occur.   The CGM will be unblended. 
 
On the first day of the CRC visit, the subject will arrive at approximately 4:00 pm.  
If the subject’s blood glucose is greater than 250 mg/dL at arrival to the clinic, the 
study will be rescheduled.  All times are +/- 30 minutes. 
 
Closed-loop will start at approximately 4:30 pm. 
 
A small evening meal (~50g CHO) will be given at approximately 6:30 pm 
without announcing it to the device, i.e. without providing any information 
to the device.  The meal will be preceded by administering a single dose of 
Technosphere® Insulin (10U) using the Gen2C inhaler. 
 
Night time will be from approximately 12:00 am to 7:00 am. 
 
Another small meal (~50 g CHO) will be given for breakfast at 
approximately 7:00 am.  The meal will be preceded by administering a 
single dose of Technosphere® Insulin (10U) using the Gen2C inhaler. 
 
At 11:00 am, the subject will be given a snack (~16 g CHO) and start 
exercise. 
 
The subject will exercise for 30 minutes at 50% of his/her target heart rate. 
 
At approximately 2:00 pm, the subject will be given another snack (~16 g 
CHO). 
 
At around 4:30 pm, i.e. 24 hrs after starting, closed-loop will end. 
 
During the CRC visit, all diabetes care and use of the AP device will be the 
responsibility of the investigator.  The insulin brand (subcutaneous) used during the 
CRC session will be the same as the brand used by the subject.  Technosphere® 
Insulin will be delivered using the 10U Gen2C cartridge per the Investigator’s 
Brochure manufacturer’s instructions.  A detailed plan for diabetes monitoring and 
for responding to hypoglycemia and hyperglycemia will be in place as described by 
this protocol.  Subject will be monitored closely by trained study staff during the 
entire CRC visit.  A physician will be present at all time. 
 
The CGM will be calibrated as required by the manufacturer, as well as 
approximately 30 minutes before each meal and before bedtime.  Additional 
calibrations may also be performed as required. 
 
Blood glucose will be monitored by YSI at least every 30 minutes.  More frequent 
monitoring may be performed as defined in the protocol to ensure the safety of the 
patient.   
Each time a YSI measurement will be taken, a finger stick measurement using the 
CONTOUR® NEXT EZ blood glucose monitoring system will be performed to 


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collect information, but no decision will be made from the results of the finger stick. 
 
If the HMS recommends giving CHO to the subject, the investigator will follow the 
recommendation.  Any other outside intervention by the investigator will terminate 
the study session for that subject.  If clinical results from a subject are found to be 
suboptimal with excessive hyperglycemia or excessive hypoglycemia alarms, the 
responsiveness factor of the control algorithm may be adjusted for the study of the 
next subject. 
 
Once the glucose level of the patient is back to more than 90 mg/dL for more than 1 
hour, and the glucose level is less than 180 mg/dL with ketones less than 0.6 
mmol/L, the patient will be discharged from the CRC. 
 
On the day following the CRC visit, the study staff will be in contact, by telephone 
or in person with the subject for follow-up. 
 
Subject Population 
Adults aged 21-65 years 
Type 1 diabetes mellitus for at least one year 
Using an insulin infusion pump with rapid acting insulin for at least six months 
Sample Size 
12 to 20 subjects 
Duration of the 
subject 
participation 
Total duration by each subject is expected to be approximately one week from time 
of contact to review glucose control to follow-up after discharge from CRC visit. 
Study Center 
Sansum Diabetes Research Institute, Santa Barbara, CA 
Inclusion Criteria 
 
Clinical diagnosis of type 1 diabetes for at least one year and using an insulin 
pump for at least 6 months with commercially available rapid acting insulin 
 
The diagnosis of type 1 diabetes is based on the investigator’s judgment; C 
peptide level and antibody determinations are not needed.  
 
Age 21 to 65 years 
 
For females, not currently known to be pregnant or nursing 
 
HbA1c between 5.0% and 10%, as measured with DCA2000 or equivalent 
device 
 
Forced expiratory volume in 1 second (FEV1) ≥  70% Third National Health 
and  Nutrition Examination Survey  (NHANES III)  predicted 
 
Forced vital capacity (FVC) ≥70% NHANES III predicted 
 
Forced  expiratory volume in 1 second as a percentage of forced  vital 
capacity(FEVl/FVC)≥NHANES  III lower limit of normal (LLN) 
 
Willing to perform the calibration of the study CGMs using a finger stick only 
and willing to follow instructions for insulin pump and CGM wear. 
 
Willing to use the study CGM and study insulin pump during closed-loop. 
 
Able to and agrees to avoid the following medication starting 24 hours before 
sensor wear through completion of CRC visit: acetaminophen, and 


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pseudoephedrine. 
 
An understanding of and willingness to follow the protocol and sign the 
informed consent. 
Exclusion Criteria 
 
Pregnancy (as determined by a positive blood pregnancy test performed in 
females of childbearing capacity during screening visit and urine test at time of 
admission for in-patient visit) or nursing mother.  
 
Diabetic ketoacidosis in the past 6 months prior to enrollment requiring 
emergency room visit or hospitalization 
 
Severe hypoglycemia resulting in seizure or loss of consciousness in the 12 
months prior to enrollment 
 
Current treatment for a seizure disorder; 
o 
 Subjects with a history of seizures may be included in the study if they 
receive written clearance from their neurologist  
 
Cystic fibrosis 
 
Active infection 
 
A known medical condition that in the judgment of the investigator might 
interfere with the completion of the protocol such as cognitive deficit. 
 
Mental incapacity, unwillingness or language barriers precluding adequate 
understanding or co-operation, including subjects not able to read or write. 
 
Coronary artery disease or heart failure.  
o 
Subjects with a history of coronary artery disease may be included in 
the study if they receive written clearance from their cardiologist 
 
Presence of a known adrenal disorder 
 
Active coronary artery disease or heart failure 
 
Active gastroparesis 
 
If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, 
lack of stability on the medication for the past 2 months prior to enrollment in 
the study 
 
Uncontrolled thyroid disease 
o 
Adequately treated thyroid disease and celiac disease do not exclude 
subjects from enrollment 
 
Abuse of alcohol 
 
A recent injury to body or limb, muscular disorder, use of any medication, any 
carcinogenic disease, or other significant medical disorder if that injury, 
medication or disease in the judgment of the investigator will affect the 
completion of the exercise protocol 
 
Current use of a beta blocker medication 


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 
Laboratory results: 
o 
Hematocrit < 30% or >55% 
o 
A1C > 10% 
o 
Abnormal liver or renal function (Transaminase >2 times the upper 
limit of normal, Creatinine> 1.5 mg/dL) 
o 
Labs drawn at screening visit or within one month prior to screening 
(for other purposes) will suffice for enrollment purposes related to 
hematocrit 
 
Subject has skin conditions that, in the determination of the investigator, would 
preclude wearing the study devices (infusion set and sensor), in the abdomen.   
Examples include but are not limited to: psoriasis, burns, scaring, eczema, 
tattoos, and significant hypertrophy at sites of device wear; any known allergy to 
medical adhesives. 
 
Currently on long-term treatment using prednisone. 
 
If subject had been on short term treatment of prednisone, defer enrollment until 
underlying condition and prednisone treatment have resolved. 
 
Allergy to study drug, food or other study material 
 
History of asthma, COPD (chronic obstructive pulmonary disease), or any other 
clinically relevant chronic lung disease 
 
Respiratory track infection within 4 weeks before screening  
 
Clinically significant screening ECG, physical examination, laboratory test, or 
vital sign abnormality  
 
Exposure to any investigational drug within 30 days. 
 
History of malignancy within the 5 years before screening (other than basal cell 
carcinoma) 
 
Inability, in the opinion of the investigator, to adequately inhale Technosphere® 
Inhalation powder 
 
Abnormal spirometry  
 
Currently smoking or discontinued smoking (including cigarettes, cigars, pipes) 
over the past 6 months. 
 
Highly sensitive to insulin: insulin-to-carbohydrate ratio I:C > 1:12. 
 
Current participation in another investigational trial (unless participation to 
original protocol of IDE G110093) or has previously participated to this study. 
 
 


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1. DESCRIPTION OF THE DEVICES 
1.1. Overview and hardware 
The subject of this application is an Artificial Pancreas device also referred to as 
the AP device.  The AP device is intended for use in people with type 1 diabetes 
and is designed to automatically deliver insulin using a commercially available 
insulin pump and to continuously monitor subcutaneous glucose levels using a 
commercially available continuous glucose monitor (CGM).  The AP device is 
intended to adjust insulin doses only when glucose concentration is, or is 
predicted to be, outside the specified zone [80-140] mg/dL.  It includes a 
redundant safety control that will send warnings of impending hypoglycemia 
and recommend eating carbohydrates immediately to prevent hypoglycemia.  
The Artificial Pancreas device is a closed-loop system linking a subcutaneous 
Continuous Glucose Monitor (CGM) and a subcutaneous insulin delivery pump, 
which is controlled by an algorithm.  The device incorporates a Model 
Predictive Control (MPC) algorithm and a Health Monitoring System (HMS) as 
an additional safety feature.  The AP device is augmented with the use of the 
Technosphere® Insulin Inhalation System (Gen2) that will deliver a fix amount 
of ultra-rapid-acting insulin whose absorption and exposure times are similar to 
that observed in normal physiology.  The inhaled insulin will only be used prior 
to a meal to mimic phase 1 of insulin secretion and reduce the post-prandial 
peak.  The powdered insulin is currently under review (Phase III of IND 61,729) 
 
The AP device is composed of: 
 Artificial Pancreas System (APS©) platform from the University of 
California, Santa Barbara and Sansum Diabetes Research Institute 
(UCSB/SDRI) (MAF-1625).  The APS© is the infrastructure that allows 
the communication between all the elements of the device, i.e, connection 
with: 
o OneTouch® Ping® Glucose Management System (Animas Corp, 
Westchester PA) continuous subcutaneous insulin infusion (CSII) 
pump (K080639 and MAF-1777 for the modified meter remote to 
interface with the APS©) or the OmniPod® Insulin Management 
System (Insulet Corp, Bedford, MA) (CSII) pump (K042792 and 
MAF-1542 for the modified Insulet Personal Diabetes Manager to 
interface with the APS©) 
o Dexcom® G4® System (Dexcom® Inc, San Diego, CA) 
subcutaneous continuous glucose monitor (CGM) monitor 


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(P120005 with Dexcom G4® Receiver DevKit to interface with 
APS© platform). 
 Zone-MPC control algorithm developed in collaboration between UCSB 
and SDRI. 
 Health Monitoring System (HMS) algorithm developed by UCSB which 
issues safety notifications to the subject and support personnel to prevent 
impending hypoglycemia. 
The artificial pancreas device augmented with the Technosphere® Insulin 
Inhalation System is described in Figure 1–1Figure 1–1.  
 
Figure 1–1:  Artificial Pancreas Device 
The Dexcom G4® CGM System, as shown in Figure 1-2 is composed of: 
 Dexcom G4® Receiver 
 Dexcom G4® Transmitter 
 Dexcom G4® Sensor 
 


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Figure 1–2: G4® receiver (left), G4® transmitter (center), G4® sensor (with applicator, 
pod and sensor probe) 
 
The Gen2 Inhalation System consists of the following, as described in Figure 1–3 
and Figure 1-4. 
 Is developed and manufactured by MannKind Corporation (Paramus, NJ).  
The New Drug Application (NDA) file is currently being reviewed by 
FDA (IND 61,729).  Clinical studies are in Phase III.  A letter of 
authorization to access the IND can be found in Appendix 1 of the IDE 
submission Supplement #3. 
 Delivers the Technosphere® Inhalation (TI) Powder to the lung.  It is 
supplied with nominal strength of 10U (blue) and 20U (green) insulin 
cartridges.  The powder consists of 3 units (U) of insulin per milligram. 
 The inhaler does not require manual activation and relies on inspiratory 
flow as the sole source of energy to fluidize and deagglomerate the 
powder for inhalation. 


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Figure 1–3: Gen2 TI inhaler (MannKind Corp) in open position ready to insert, 
remove cartridge, open with cartridge and closed 
 
Figure 1–4:  Gen2 TI inhaler (MannKind Corp) in closed position with cartridge on 
the side 
In addition to YSI measurements as required periodically, a finger stick 
measurement will be obtained using the CONTOUR® NEXT EZ blood glucose 
monitoring system (details provided in Appendix 7 of S005).  This information 
will be collected for information only and no decision will be made on the 
results of the finger stick. 
 
 


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1.2. Continuous glucose monitor (CGM) 
The Dexcom® G4® System Continuous Glucose Monitor (CGM) has been 
approved by FDA under PMA P050012 (S045 on 8/17/2012) and has not been 
modified.  An additional software, the Dexcom G4® Receiver Tool DevKit 
software has been installed on the study laptop to interface with the APS© 
platform. 
The CGM unit consists of an interstitial glucose sensor, inserted under the skin 
of the abdomen into the fatty tissue.  An applicator with a removable needle is 
used to insert the sensor.  The process of insertion is similar to the insertion of 
an insulin infusion set.  The sensor is held in place by adhesive tape, and a small 
transmitter is snapped into place over the sensor.  The transmitter communicates 
every 5 minutes by radiofrequency to a hand-held receiver.  During the CRC 
phase of the study, the receiver is connected to the laptop computer to provide 
the glucose information to the algorithms: zone MPC and HMS.  The CGM will 
require calibration with a fingerstick blood glucose value as stipulated by the 
manufacturer’s instructions as well as before meals and bedtime.  The purpose is 
to ensure the most accurate sensor value for the study to understand the 
effectiveness of the control algorithm.  In this study the calibration will be 
performed with the CONTOUR® NEXT EZ blood glucose meter (commercially 
available, unmodified product k111268).  In order to minimize the risk of 
cancellation of the clinical study due to a sensor problem, the subject will wear 
two sensors, and at the time of the CRC stay, the investigator will select which 
sensor to use, and document the rationale, as noted in the procedure section.  
This will be done before the start of the 24-hour closed-loop.  Should the 
selected CGM fail during the CRC visit, the investigator will be able to switch 
to the backup CGM and continue the study, and will document the reason and 
impact of the change. 
1.3. Insulin pump 
The insulin pump used in this clinical study may be the OneTouch® Ping® 
insulin pump with modified Meter-Remote or the OmniPod™ Insulin 
Management System with the modified Insulet Personal Diabetes Manager 
(PDM).  The pump delivers insulin subcutaneously through an infusion set, in 
this study the Inset® 30 infusion set.  The OneTouch® Ping® insulin pump is 
not modified and has received 510k clearance (K080639).  Only the Meter-
Remote software has been modified to allow the algorithm to send commands 
from the APS© platform to the insulin pump by way of the modified Meter-
Remote.  The Meter-Remote is connected by USB to the laptop and 
communicates to the One Touch® Ping® insulin pump by radiofrequency.  The 


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Meter-Remote will not be used for blood glucose monitoring or sensor 
calibration in this study. (A separate unmodified CONTOUR® NEXT EZ meter 
will be used for CGM calibrations.).  The OmniPod™ Insulin Management 
system had not been modified and has received 510(k) clearance (K042792).  
Only the Insulet PDM has been modified to communicate with the APS® 
platform.  Both insulin delivery systems, the OneTouch® Ping® and the 
OmniPod™, have been validated as components working with the APS® 
infrastructure (MAF-1625). 
1.4. Control algorithm 
The control algorithm is unique to this application: it combines a zone-Model 
Predictive Control (MPC) algorithm with the added safety feature of the Health 
Monitoring System (HMS) which provides warnings and notifications of 
impending hypoglycemia to request outside intervention, such as absorption of 
fast acting glucose.  The notification is not only available to the subject via the 
AP device, but also to the physician or another person who could be located 
remotely in the future (this IDE exclusively takes place in the clinical research 
setting in presence of a physician).  The HMS algorithm uses the same CGM 
data as the zone-MPC control algorithm but utilizes a separate algorithm for 
trending and predictions of future glucose values.  Using a redundant and 
independent algorithm is an important safety feature of the overall AP device.  
The HMS will send a warning to the AP device and a text message to the 
attending physician (present at all times) whenever it predicts a glucose value 
below 70 mg/dL within the next 15 minutes.  The warning will include a 
recommendation to give the subject approximately 16 g of carbohydrates.  The 
warning must be acknowledged for the pop-up window to close.  The 
acknowledgement gives the choice to “accept” or “ignore” the warning and 
recommendation. 
The zone-MPC control algorithm is at its core a Model Predictive Control 
(MPC), which incorporates an explicit model of human T1DM glucose-insulin 
dynamics.  The model is used to predict future glucose values and to calculate 
future controller moves that will bring the glucose profile into the desired range.  
Software constraints ensure that insulin delivery rates are constrained between 
minimum and maximum values.  The first insulin infusion (out of n steps) is 
then implemented.  At the next time step, k +1, the process is repeated based on 
the new measured glucose value and the last insulin rate.  The algorithm adjusts 
insulin delivery automatically to achieve and maintain the patient’s glucose level 
within a predetermined safe range: 80-140 mg/dL.  The only variable that may 
be adjusted between subjects is the responsiveness factor which is the ration of 
Q/R.  It can be described as the agility of the control algorithm to respond to 


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changes in glucose concentration.   Three levels may be evaluated: Q/R with a 
ratio of 1:12, 1:15 and 1:50 (from most responsive to least responsive).  The 
default setting is considered to be the nominal ratio of Q/R of 1:15.  The first 
subject will be evaluated using that setting.  Then, following results from each 
subject, if results showed poor glucose control, as defined by frequent 
hypoglycemia alerts or excessive hyperglycemia, in the investigator’s opinion, 
the responsiveness factor may be adjusted to the most agile setting of 1:12 or 
most conservative setting of 1:50 for the next subject.  
The total number of subjects will remain 12 to 20 total.  Each subject will only 
be evaluated using one responsiveness factor setting.  Changes to another setting 
will be based on prior clinical results and decision of the investigator for the 
next subject.  This will be a clinical decision to add to the overall safety of the 
study.  All changes of the responsiveness factor between subjects and their 
justifications will be documented. 
2. STUDY OBJECTIVES 
2.1. Study’s challenges 
The purpose of this feasibility study is to evaluate the performance of the AP 
device while the subject is under close clinical supervision in a Clinical 
Research Center (CRC) setting.  The assessment will take place over a 
continuous 24-hour closed-loop period with three types of challenges: 
 Unannounced meals 
The purpose of this challenge is to evaluate the performance of the AP device 
to safely regulate the glucose level when the subject has an unannounced 
meal.  In other words, it will determine whether the AP device auto-regulates 
insulin delivery following the meal and keeps the glucose concentration of the 
subject within the range [70-180] mg/dL for most of the 5 hours following the 
meal. 
 Overnight glucose control  
The purpose of this challenge is to evaluate the performance of AP device 
during the night.  It will determine whether the AP device will safety regulate 
the glucose concentrations of the subject during the night, i.e. if the glucose 
concentrations will remain within the [80-140] mg/dL range during sleep. 
 Exercise 
The purpose of this challenge is to evaluate the performance of the AP device 
when the subject is exercising.  The goal is to determine whether the AP 
device can maintain a safe glucose range or whether there is a need for an 


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exercise detection signal to improve glucose control during the exercise 
period.  The analysis will determine if glucose level remains within the [70-
150] mg/dL range during exercise and for most of the 3 hours following 
exercise. 
2.2. Primary and secondary endpoints 
The assessment of the performance of the device will be based principally on two 
types of metrics: 
 Primary endpoints: percentage of time spent within a specific zone, in 
particular the desired zone [80-140] mg/dL.  Other zones will be defined 
after meal or exercises. 
 Secondary endpoints: review of the extremes of the glucose values of the 
subject, duration of those extremes and the review of any event requiring 
outside intervention to treat hypoglycemia or hyperglycemia. 
 
The primary endpoint of the clinical study is the amount of time spent within a 
specified glucose target range.  In this study there will be different ranges 
depending on both time of day and time after meals and exercise: 
 Target range (unless described otherwise): [80-140] mg/dL 
 Overnight target range: [80-140] mg/dL 
 5 hours postprandial target range: [70-180] mg/dL 
 During exercise: [70-150] mg/dL 
 3 hours post-exercise: [70-150] mg/dL 
 
The secondary endpoints of the clinical study include excursions outside the 
range, the maximum value of the excursion, the duration the subject remains 
outside of the target ranges and whether or not there is any outside intervention to 
treat hypo- or hyperglycemia.  The extremes are defined as follows: 
 For hyperglycemia: any blood glucose value >400 mg/dL (measured by 
YSI)  
 For hypoglycemia: any blood glucose value <60 mg/dL (measured by 
YSI) 
In addition, a secondary end-point will consist in analyzing CGM values that were 
trending beyond the desirable ranges.  The analysis will determine the percent of 
time spent in the following zones: 


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 If glucose value per CGM is ≥300 mg/dL for more than 1 hour; 
 If glucose value is predicted to be ≤70 mg/dL by CGM ; 
 If glucose value per CGM is ≤70 mg/dL; 
 If glucose value per CGM is ≤60 mg/dL; 
The secondary endpoints will also be assessed by evaluating all safety events.  
The levels of hypoglycemia and hypoglycemia are described by Table 15–2Table 
9–2. 
3. BACKGROUND INFORMATION 
3.1. Ethical background 
The study will be conducted in accordance with the Declaration of Helsinki 
(1964), including all amendments, International Conference on Harmonization 
(ICG), Good Clinical Practice (GCP) guidelines and relevant local laws and 
regulations. 
The final protocol and informed consent form will be reviewed and approved by 
Cottage Health System (Santa Barbara, CA) Institutional Review Board (IRB) 
(IRB #10-36) following the approval of this IDE by the FDA and prior to any 
subject screening being conducted.  Any changes to the clinical protocol will be 
communicated to the FDA and the IRB as required by the regulations.  Periodic 
and final study reports will be communicated to both FDA and IRB.  The 
investigator will report Unanticipated Adverse Device Effect (UADE) and 
Serious Adverse Event (SAE) to both the FDA and IRB per reporting 
requirements. 
Each subject will be provided with oral and written information describing the 
nature and duration of the study.  Prior to initiation of any study-related 
procedures, the subject will sign and date a written informed consent to 
participate in the study and will also sign and date, if separate, the authorization 
form required under HIPAA, authorizing the use and disclosure of the subject’s 
protected health information.  The signed original informed consent form (ICF) 
and HIPAA authorization form will be retained with the study center’s records 
and each subject will receive a copy of each form he/she has signed.  The 
subject will also sign the California Bill of Rights.  The investigator must be 
satisfied that the subject has understood the information provided before written 
consent is obtained.  The original informed consent documentation must be 
made available for inspection by the investigator.  Documentation of the 
informed consent form process will be available in the subject’s source 


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documents.  Informed Consent form draft can be found in Appendix 8 of the 
original IDE. 
3.2. Summary of known risks and benefits 
As this is a feasibility study, there are known risks and benefits.  Providing close 
clinical supervision mitigates the risks as much as possible.  Most of the risks 
are not unique to the study and are typical for patients using CGM and insulin 
pumps and who are having their blood glucose level checked using standard 
methods.  The known risks are: 
 Hyper and hypoglycemia brought on by changing the diet and insulin 
regimen and exercise during the trial. 
 Weight gain or loss may be caused by changes in diet and insulin dosing 
during the study. 
 Using the CGM or insulin pump:  risk of bruising, infection, pain and/or 
bleeding at the site of insertion and skin site reaction to adhesive. 
 Blood sampling with finger stick: minor discomfort and risk of infection at 
site of finger stick. 
 Blood sampling with a needle: risk of infection at site of venipuncture, 
fainting, bruising, formation of a blood clot, pain and/or bleeding at the site 
of venipuncture. 
 On rare occasions, the continuous glucose sensor may break and leave a 
small portion of the sensor under the skin that may cause redness, swelling, 
or pain at the insertion site. 
 On rare occasions, heart or lung problem identified during the exercise test. 
However, the benefits of the study are multiple.  Results will support moving 
one step closer toward a future portable autonomous artificial pancreas for type 
1 diabetic patients.  This feasibility will evaluate the performance of a zone-
MPC and HMS algorithms as well as the concept of an overall Artificial 
Pancreas using a subcutaneous glucose monitor and insulin pump with 
unannounced meals, night and exercise. 
3.3. Summary of past findings 
3.3.1. Overview 
Similar studies have been performed in the past using the APS© platform 
and other types of algorithms.  Using a subcutaneous glucose sensor and a 
subcutaneous insulin delivery method presents the advantage of using 
currently available and proven technology, while expanding the intended 


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use of those devices.   The challenge associated with those devices is the 
delay of data from the sensors and the delay of the action of the insulin 
delivered.  Results to date have been very promising.  All closed-loop 
evaluations have been limited to in-clinical settings of 12 to 48 hours 
cycles.  They have shown that, with currently approved CGMs and insulin 
delivery pumps, it is possible to automatically regulate glucose level 
within an acceptable range.  In particular artificial pancreas devices 
reduced and most frequently avoided hyperglycemia during the day and 
nocturnal hypoglycemia.   
3.3.2. Necessary future development 
Future studies need to be designed to address larger challenges of 
unannounced food intakes as well as situations when the patient is under 
stress or exercising.  Generally, additional studies are necessary to identify 
and optimize control algorithms.  Those algorithms, tailored to be optimal 
for each patient will need to include multiple layers of safety mechanisms 
to prevent hyperglycemia and hypoglycemia.  Eventually, it is also 
desirable to expand the testing to offer a choice of CGMs and insulin 
delivery pumps to give flexibility to the patient. 
3.3.3. Overview of recent results: IDE G090129 
IDE G090129 sponsored by UCSB and Sansum Diabetes Research 
Institute (SDRI) was approved by FDA on April 2010.  The study of 10 
subjects evaluated the performance of a closed-loop artificial pancreas 
using the APS© platform with the Dexcom® SEVEN® PLUS (Dexcom®, 
San Diego, CA) CGM, the OmniPod™ (Insulet Corp, Bedford, MA) 
insulin delivery pump and the mpMPC control algorithm and IOB 
(insulin-on-board) constraints.  The control algorithm of that study was a 
control-to-target Model Predictive Control algorithm, i.e. the target was 
110 ± 30 mg/dL.  The algorithm was also referred to as mpMPC with IOB 
constraints.  The algorithm was customized for each patient based on data 
collected during 3 outpatient days prior to the in-clinic day.  The insulin 
delivery of the subjects was entirely controlled by the artificial pancreas 
during the closed-loop in the CRC setting.  The closed-loop lasted for 
approximately 10 hours for each subject and included one unannounced 
meal.  The subject was closely monitored in the CRC setting.  The clinical 
trial took place at the Sansum Diabetes Research Institute (Santa Barbara, 
CA).  The first subject underwent closed loop in August 2010.  To-date, 
10 subjects have been enrolled and completed the trial. 
Early analysis of the preliminary results of IDE G090129 are presented in 
Figure 3–1Figure 3–1.  As can be seen the closed-loop results are all in the 


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A + B zones of the Control Variability Grid Analysis (CVGA) which are 
desirable zone.  Four of the ten subjects were in the A-zone and six in the 
B-zone, trending mostly towards the high end.  This picture analysis 
shows that the controlling algorithm was able to maintain the subject 
within a safe zone automatically even when following an announced meal.  
There was no adverse event reported during the study. 
 
Figure 3–1: CVGA of preliminary results of closed-loop under IDE 
G090129 
Another feasibility study using the same control algorithm (mpMPC with 
IOB constraints), the APS© platform, same CGM (Dexcom® SEVEN® 
PLUS) and same CSII (OmniPod™) has been completed in Israel 
(Schneider Children’s Medical Center).  Glucose control of twelve 
subjects was automated using the closed-loop system for a period of 
approximately 6 hours.  During that time, the system was challenged with 
an unannounced meal of 30 to 40 g of carbohydrate after a starting point 
of low to mild hyperglycemia (180-250 mg/dL).  Results showed that 
glucose level was maintained with the safe range of [80-180] mg/dL 70% 
of the times and the low and high blood glucose indices were 0.12 and 6.9 
respectively.  No hypoglycemia episodes were reported.  Severe 
hyperglycemia was reported in only 3 trials with postprandial peaks of 
275, 288 and 276 mg/dL. 


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3.3.4. Overview of most recent results: IDE G110093 with same AP device 
as in this proposed protocol 
The clinical protocol of this IDE study using the same Artificial Pancreas 
device was originally approved in August 2011 and preliminary results are 
presented below.  Up to this point, thirteen subjects have been enrolled 
and twelve have completed their clinical trial.  The results of the twelve 
study-days are presented in Appendix 9 of the submission (refer to S003 
submission).  Figure 3–2 and Figure 3–3 are examples of snapshots of 
glucose, CGM and YSI profiles of two subjects during the 24-hour closed-
loop.  These are typical of the various profiles, they include post-prandial 
peaks and HMS alerts which effectively prevented hypoglycemia.  The 
ingestion of carbohydrate following the HMS alert is indicated on the 
snapshots.   
Of the 12 enrolled subjects, the first enrolled subject did not complete her 
first study-day as explained hereafter and had to return: before arriving at 
the CRC for the start of the closed-loop session, took 3.35 units of insulin 
to correct for her hyperglycemia (correction factor of 1 to 70) for an 
elevated capillary glucose value of 270 mg/dL at 2:09 pm, approximately 
2 hours before her visit to the CRC.  Upon being connected to the 
Artificial Pancreas during initialization the HMS predictive alarm was 
triggered due to her glucose rate of fall due to the recent outpatient 
correction bolus.  All procedures for glucose rescue were followed.  The 
HMS was triggered an additional 3 times over the next 2 hours.  YSI nadir 
was 44 mg/dL with mild symptoms of hypoglycemia.  The admission was 
stopped at this time.  Additional oral glucose was given.  The subject was 
discharged home once her glucose concentration was stabilized at a safe 
level and was rescheduled for a different study day.  
Overall, the results from the 12 subjects showed that there were no safety 
events.  The HMS safety alert effectively predicted imminent 
hypoglycemia and issued a recommendation, which was followed each 
time to ingest carbohydrate, hence preventing hypoglycemia.  There was 
no CGM or YSI measurements below 60 mg/dL.  The time spent between 
60 and 70 mg/dL was minimal (only 1% of the overall time, on average 
was spent below 70 mg/dL).  
The primary end-points as described by the approved clinical protocol 
were to measure the percent of time the glucose level of the subject 
remains within the following pre-specified target range: 


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 Target (unless described otherwise): [80-140] mg/dL 
 Target overnight: [80-140] mg/dL 
 Target 5 hours after meal: [70-180] mg/dL 
 Target during exercise: [70-150] mg/dL 
 Target 3 hours after exercise: [70-150] mg/dL 
Table 3–1 is a summary of the average time spent in each zone as 
measured by YSI.  The same table for results measured by CGM can be 
found in Appendix 9 of the IDE submission.   
 
 
Figure 3–2: Snapshot of glucose, CGM and YSI profile or subject 01-002  
HMS alerts


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Figure 3–3: Snapshot of glucose, CGM and YSI profile or subject 01-010 
 
Table 3–1: Overall time in range by YSI for 12 subjects  
 
Entire CL 
CL excl 
meals & 
exercise 
Midnight 
to 7am 
Dinner 
Meal 
Breakfast 
Meal 
30 
minute 
exercise 
Exercise 
+3 hrs 
3 hrs 
post 
exercise 
<70 
1% 
1% 
0% 
0% 
2% 
0% 
3% 
4% 
70-180 
4. 81% 
5. 92% 
6. 92% 
72% 
63% 
92% 
89% 
89% 
>180 
18% 
7% 
8% 
28% 
35% 
8% 
7% 
7% 
<70 
1% 
1% 
0% 
0% 
2% 
0% 
3% 
4% 
70-150 
63% 
83% 
79% 
39% 
45% 
54% 
67% 
68% 
>150 
36% 
16% 
21% 
61% 
53% 
46% 
30% 
28% 
<80 
5% 
4% 
1% 
4% 
7% 
0% 
7% 
13% 
80-140 
7. 52% 
8. 73% 
9. 70% 
30% 
30% 
38% 
56% 
87% 
>140 
43% 
23% 
29% 
66% 
63% 
62% 
36% 
0% 
Note: CL = closed-loop 
HMS Alert
HMS Alerts


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Figure 3–4: CVGA during overnight period (midnight to 7:00 am)  
Over the 24-hour closed-loop period when the AP device monitored 
glucose level and automatically delivered insulin, for 81% of the time by 
YSI, the glucose level was within [70-180] mg/dL range: this included a 
nocturnal period, 2 meals and an exercise period. 
When excluding the periods following the meals and exercise segment, the 
total time spent within the [70-180] mg/dL zone increased to 92% when 
measured by YSI.  Most frequently, when following a meal, the glucose 
level increased.  During the 5-hours following each meal, the subjects 
spent on average 63-72% in the zone [70-180] mg/dL while they spent 
89% in that same zone during the 3-hours following the 30-minutes 
exercise segment at moderate intensity.   The control of the AP device 
during the nocturnal period was particularly effective as, on average, the 
subjects spent 92% of their time within the zone [70-180] mg/dl, 70% of 
the time within the narrower zone [80-140] mg/dL and 0% below 70 
g/mL.  A summary of the nocturnal results is illustrated by CVGA (Figure 
3–4) where all data points are within the A and B zones. 
The actual profile from each subject will vary due to multiple factors 
including the initial glucose level and initial slope (trend) of each subject.  
However, in summary, the data showed that when measured by YSI or 
CGM, the glucose level of the subject was in control the majority of the 


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times with some peaks following meals and valleys following exercise, 
but never reaching values that could affect the safety of the patient.  The 
peaks and valleys are explained by the fact that insulin delivery is 
automatically controlled with no input from the user indicating the start of 
a meal, the size of the meal, or the start of exercise.  Therefore, the 
algorithm must detect the beginning effect of the meal (increased of 
glucose level) or beginning of the exercise (decrease of glucose level) to 
start reacting and anticipating further glucose increase and decrease and to 
adjust insulin delivery above or below basal levels accordingly.   The 
redundant safety alert system (HMS) effectively requested ingestion of 
CHO when predicting hypoglycemia.  Those recommendations were 
followed and hypoglycemia was avoided. 
With those early results, the AP device showed that, for the evening and 
breakfast meals, it was able to detect the meal and prevent excessive post-
prandial peaks and maintained the glucose level within a safe range.  
The glucose level during and after the exercise period has a different 
profile for each subject because of the difference in the trend preceding the 
exercise session.  There was no hypoglycemic event or HMS alert during 
the exercise period 
In conclusions, this preliminary analysis of the results showed that the AP 
device is able to detect meals and react appropriately to prevent excessive 
post-prandial peaks.  It also works effectively in anticipating risks of 
hypoglycemia and alerting the physician / subject to ingest carbohydrate.  
The redundant safety mechanism functioned as anticipated.  
Because of the post-prandial peak, the new clinical study is proposing to 
use a dose of Technosphere® Insulin Inhalation Powder at the beginning 
of each meal.  TI is a very fast acting insulin.  It is anticipated that the TI 
will mimic the early phase of prandial insulin hence, will reduce the post-
prandial peak.  This will allow the AP device to operate more effectively 
as a regulator of glucose level using subcutaneous delivery of insulin.  
Besides the added TI dose at the beginning of each meal, the clinical 
design will remain exactly the same (only the meal size of the breakfast 
will be increased to 50 g of CHO to be the same as the evening meal). 
9.1. Description of population studied 
Although there is no restriction in recruitment of subjects as to race or ethnicity, 
it is expected that the subjects will primarily be non-minority white.  The 
population of Santa Barbara is primarily non-minority Whites and Latinos of 


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predominantly Mexican descent, with African Americans, Asians and America 
Indians comprising less than ten percent of the population.  Because type 1 
diabetes disproportionately afflicts the Northern European population and is rare 
among Latinos of Mexican descent, it is not expected that minorities or non-
English speaking subjects will be enrolled.  Subjects will be recruited using the 
Sansum Diabetes Research Institute database of patients.   
It is expected that the ratio of men to women will be close to 1:1. 
The population studies in this clinical trial eligible is adults aged 21-65 years of 
age with type 1 diabetes mellitus for at least one year.  For more details, refer to 
Sections 11.15.1 and11.25.2. 
The in-clinic portion of the trial will take place at the Sansum Diabetes Research 
Institute (SDRI).  Informed consent will be obtained before the study procedures 
are conducted. 
9.2. Literature data references 
The current treatment method for insulin-dependent diabetic patients requires 
either multiple daily subcutaneous insulin injections or continuous subcutaneous 
insulin injection via a pump.  Both treatment modes necessitate frequent blood 
glucose measurements in order to determine the daily insulin requirements for 
maintaining euglycemia.  Because such frequent monitoring involves patient 
discomfort and is very time consuming, few patients are able to maintain their 
levels of glucose consistently within a safe range.  Mounting evidence suggests 
that euglycemia is necessary to prevent the complications of diabetes.  As a 
result, being able to develop an automated glucose monitoring and insulin 
delivery system has been considered a key priority for improving the life of 
patients with type 1 diabetes. 
In the last two years, at least eight teams have reported results of closed-loop 
feasibility studies: 
 El-Khatib et al.: “A bihormonal closed-loop artificial pancreas for type 1 
diabetes” (2010) 
 Hovorka et al.: “Manual closed-loop insulin delivery in children and 
adolescents with type 1 diabetes: a phase 2 randomised crossover trial” 
(2010) 
 Renard et al.: “Closed-loop insulin delivery using a subcutaneous 
glucose sensor and intraperitoneal insulin delivery: feasibility study 
testing a new model for the artificial pancreas” (2010) 


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 Atlas et al.: “MD-logic artificial pancreas system: a pilot study in adults 
with type 1 diabetes” (2010) 
 Bruttomesso et al.: “Closed-loop artificial pancreas using subcutaneous 
glucose sensing and insulin delivery and a model predictive control 
algorithm: preliminary studies in Padova and Montpellier” (2009) 
 Clarke et al.: “Closed-loop artificial pancreas using subcutaneous 
glucose sensing and insulin delivery and a model predictive control 
algorithm: the Virginia experience” (2009) 
 Dassau et al.: “Real-time hypoglycemia prediction suite using 
continuous glucose monitoring: a safety net for the artificial pancreas” 
(2010) 
 Buckingham et al.: “Prevention of nocturnal hypoglycemia using 
predictive alarm algorithms and insulin pump suspension” (2010) 
The detailed review of those studies can be found in the IDE submission related 
to this clinical protocol.   
Some of the studies used insulin only or insulin combined with glucagon. 
Insulin was most often delivered subcutaneously, but also intra-peritoneally, 
many types of control algorithms were used (proportional-integral-derivative, 
fuzzy logic, model predictive control, hypoglycemic prediction, modified linear 
prediction, Kalman filtering, adaptive hybrid infinite impulse response filter, 
statistical prediction and numerical logical) and studies were performed on 
children or adults.   
Overall, each automated closed-loop system managed to maintain safer levels of 
glucose levels than a non-automated system.  The variety of types of algorithms 
being evaluated indicates how active this field of research is.  It also indicates 
that the algorithm that will be most effective and safe for the physiology of a 
wide range of patients has not been identified yet.  The answer will likely 
consist in using a combination of algorithms.  So far, all controlling algorithms 
showed that they were able to bring glucose level to a safe range and prevent or 
at least reduce the number of hyper and hypoglycemic events. 
10. TRIAL DESIGN 
10.1. Overview of clinical study 
The study design is a non-randomized, uncontrolled, feasibility study enrolling 
12 to 20 adult subjects at one site only.  The Sponsor anticipates that the study 
duration will last up to a year, or until enrollment and testing are completed.  


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The individual subject participation is anticipated to be approximately of one 
week’s duration (or possibly longer if any visits are rescheduled).  The overview 
of the study design for each subject is described by Figure 10–1Figure 4–1. 
 
Figure 10–1:  Overview of the clinical trial 
 Upon successful screening and informed consent process, during the 
week prior to the CRC visit, the subject will review overall glucose 
control and insulin pump settings with study staff to aim for optimal 
glucose control. 
 Two to three days prior to the CRC visit, the subject will attend an 
outpatient visit for the insertion, by study staff, of two CGM sensors, as 
well as to receiving training and study instructions on how to care for 
them.  The two CGMs will be set to their blinded mode.  The Blinded 
Mode Dexcom® CGM documentation is provided in Appendix 14 of the 
original IDE submission.  The subject will be trained on how to calibrate 
and care for the study CGMs for the 2-3 days as an outpatient.  The 
subject will be instructed to manage his/her own glucose levels per the 
method he/she is accustomed to.  The subject will not be able to see 
glucose readings on the blinded receiver of the CGM prior to the CRC 
visit, however other non-glucose related alarms will be functioning. 
Screening /  lab 
work / enrollment 
Visit to review glucose 
management and 
pump settings
Visit to insert the two 
study CGM
Anytime
Approximately 1 week 
before in-patient
2-3 days  
before in-patient
Arrival at Sansum 
Clinic
24 hours
Start closed-loop: 5 pm
Meals, night, exercise, snacks
End closed-loop: 5 pm following day
In-patient
Closed-Loop
Discharge from 
Sansum Clinic
Phone follow-up
Discharge ~ 6:00 pm
Arrive ~ 4:00 pm
24 hours later
{
OUT-PATIENT
IN-PATIENT
{
{
OUT-PATIENT


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 The CRC visit will last approximately 25-28 hours including 
approximately 24 hours, in closed-loop to evaluate the AP device.  
During all that period, blood samples will be analyzed using a YSI 
2300Stat every 30 minutes or more frequently if requested by the study 
physician.  Each time a YSI measurement is taken, a finger stick 
measurement with the CONTOUR® EZ blood glucose monitoring 
system will be used for information purpose only. 
o If the subject’s blood glucose is > 250 mg/dL at arrival at the 
clinical, the clinical study will be rescheduled for that subject. 
o The subject will check in at Sansum Diabetes Research Institute 
at approximately 4:00 pm and have the insulin pump of the study 
inserted by the physician.  Both CGM receivers will be unblinded 
during the CRC visit.  The subject’s own insulin pump will be 
disconnected.  An intravenous catheter will be inserted for blood 
samples and for IV administration of glucose, if necessary.  
o The closed-loop will start at approximately 4:30 pm. 
o Approximately 2 hours later, the subject will be given a small 
unannounced meal consisting of 50 g of CHO. 
o The subject will sleep overnight at the center, while connected to 
the AP device. 
o At 7:00 am, another unannounced meal (breakfast) consisting of 
50 g of CHO will be given. 
o At 11:00 am, a small snack of approximately 16 g CHO if YSI 
value is <120 mg/dL and the subject will start exercising for 
approximately 30 min at 50% of the his/her predicted heart rate 
reserve. 
o Approximately 3 hours after end of exercise, a small snack of 16 
g CHO will be given. 
o Closed-loop will be stopped at approximately 4:30 pm, 24 hours 
after starting. 
o The subject will return to using his/her own insulin pump and 
CGM (open loop), once stable, the subject will be discharged 
from the CRC.  Blood ketones will be measured.  The subject 
will be discharged only if: 
 Blood glucose is greater than 90 mg/dL for 1 hour 


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 Blood glucose is less than 180 mg/dL with ketones less 
than 0.6 mmol/L. 
 The study personnel will contact the subject in person on site or by 
phone approximately 24 hours after the discharge as a follow-up. 
The responsiveness factor used in the control algorithm is decided for each 
patient based on the results from the previous subject.  The default nominal 
setting of the responsiveness factor will be Q/R ratio of 1:15.  Changes of the 
responsiveness factor will be decided upon clinical results from each subject in 
evaluating the frequency and severity of hypoglycemia and the hyperglycemia.  
A subject will only be studied for 1 setting of the responsiveness factor.  The 
decision of changing the responsiveness factor setting will be made by the 
investigator to ensure the overall safety of the study. 
 
Figure 10–2Figure 4–2is a graphical representation of the study design and the 
expected glucose level profile during the 24-hour closed loop. 
 
 
Figure 10–2:  Clinical Study Design 
 
 
50
1 dose of Technosphere®  
Insulin Inhalation Powder
1 dose of Technosphere®  
Insulin Inhalation Powder
If BG < 120 mg/dL


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10.2. Screening visit: physical exam 
Each possible subject must go through a screening visit up to 1 month prior to 
their participation to the study to determine if he/she meets the eligibility criteria 
for the study.   The patient will be asked questions about his/her health and 
medication history as well as authorization to access and review his/her medical 
record.  The subject will be given opportunity to ask questions.  The screening 
visit will also include: 
 A physical examination 
 If the subject is female and of childbearing potential, perform a 
pregnancy blood test.  On admission day at the CRC, a urine pregnancy 
test will be repeated. 
 Vital sign recording: height, weight, temperature, blood pressure, heart 
rate 
 Blood test for routine laboratory evaluation: hemoglobin A1c, thyroid 
function, kidney function, and liver function 
 Description of the clinical trial and food and insulin regimen to follow 
during in-clinic days. 
 Recording of the following: 
o Download of subject’s pump settings including basal profile, 
correction factors and insulin to carbohydrate ratios. 
o Average total daily insulin (TDI) 
o Duration of diabetes 
o Hemoglobin A1c 
 Review and approval of the Informed Consent form (IC). 
All laboratory testing will be performed by an accredited laboratory.  The 
screening evaluation form can be found in Attachment 9 of the IDE.  The 
Informed Consent form can be found in Appendix 8 of the IDE submission. 
10.3. Subject preparation to initiate trial: outpatient 
A day or two prior to the initiation of the outpatient phase of the trial, two 
DexCom G4® glucose sensors will be inserted beneath the skin of the patient 
according to the manufacturer’s recommendations.  The patient will be 
instructed on how to care for the receiver when in the shower or when sleeping 


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and how to enter the blood glucose readings for calibration.  The Dexcom® 
G4® measures the patient’s interstitial glucose level every 5 minutes.  The CGM 
will be in blinded mode and the subject will not be able to see glucose readings 
on the CGM receiver.   
Calibration of the CGM will be performed using CONTOUR® NEXT EZ Blood 
Glucose meter and strips.  Study personnel will perform the Quality Control 
(QC) procedure to check that the glucose meter is working properly.  The QC 
procedure will use the two Control Solutions (low and high).  The results from 
each control solution must be within the acceptable range indicated by the 
Control Solution. This meter and strips will be given to the subject to perform 
all required calibrations of the CGM.  
CGM calibration will be performed according to manufacturer’s instructions and 
before meals and bedtime.  In addition to the Dexcom® G4® Blinded Mode 
User Guide, the subject will be given an instruction sheet called “Subject 
Blinded CGM Instruction Sheet” on how to perform calibration of the CGM 
during the outpatient phase.  During the outpatient phase of the trial, the subject 
will use his/her own CGM if using one, and his/her own insulin delivery pump.  
The subject will rely on finger stick blood values for insulin delivery settings 
and bolus amounts. The subject will be instructed to perform finger-sticks at 
least four times per day for both routine care and for device calibration.  Glucose 
values for calibration should be taken when glucose values are not changing 
rapidly, e.g. before meals.   
During the outpatient phase of the study, the patient will be encouraged to 
contact Sansum Diabetes Research Institute to address any question or concern 
he/she may have.  Should there be any event of hyperglycemia or hypoglycemia, 
the subject would contact the study physician who will determine the safest 
course of action for the subject.  This may include delaying or excluding the 
patient from the closed-loop phase of the trial.   
Subject will be instructed to bring to CRC visit all diabetes care and insulin 
pump supplies, although subject will use study-provided rapid acting insulin (of 
same brand used by subject) during CRC visit.  Subject will be instructed to 
charge the CGM units overnight on the night prior to the CRC visit. 
If the subject is using CGM at time of enrollment, the subject will not use their 
own CGM device from the time of study CGM insertion until the time of 
discharge from the CRC visit. 
In case of illness or cancellation, the visits may be rescheduled at the discretion 
of the investigator.   
 


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10.4. In-patient: at the CRC (2-days) 
Figure 10–3Figure 4–3summarizes the key elements of the clinical trial for each 
patient’s CRC visit. 
 
Figure 10–3:  Clinical Study Timeline during Closed-Loop 
 
10.4.1. Arrival 
The subject will arrive to the CRC center at approximately 4 pm with all 
diabetes care supplies and using own insulin pump upon arrival.  If the 
subject’s blood glucose is greater than 250 mg/dL when they arrive at the 
CRC, then, the clinical study will be rescheduled.  If the subject is female 
of child bearing potential, a urine pregnancy test will be performed on 
arrival to the CRC to verify that she is not pregnant.  The investigator will 
also check for any changes in health since the screening visit and the 
insertion of the CGM.  The investigator will determine if any reported 
health changes may have an impact on the enrollment status of the subject.  
The subject will already be wearing two CGMs for the study set to blinded 
mode.  Upon arrival, the study staff will unblind both CGMs.  The study 
staff will also perform the Quality Control process on the glucose meter 
(OneTouch® Ultra®) using two control solutions.  The day of the trial, the 
infusion set of the OneTouch® Ping® Glucose Management System with 
modified meter remote CSII will be inserted subcutaneously.  They will be 
inserted into the abdomen using a non-hypertrophied area, as clinically 
determine by the investigator.  The pump and its modified meter remote 
will have been paired and verified by the manufacturer, i.e. Animas® 
Corporation.  The insulin used for the trial is the same as the insulin used 
Arrives at CRC
Start closed-loop
4pm
4:30pm
6:30pm
12am
7am
11am 11:30am 2:30pm 4:30pm
Unannounced 
meal
Begin night
End night
Snack
Start exercise
Unannounced 
breakfast
End 
exercise
Snack
Discharge 
from CRC
Approximative
time
End 
closed-loop
CLOSED-LOOP IN CLINICAL SETTING


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by the subject.  A full new cartridge of insulin will be used for the closed-
loop phase (same brand as the one normally used by the subject). 
An indwelling catheter will be put in place for frequent blood glucose 
monitoring and for the rapid administration of intravenous glucose if 
necessary.  No heparin and / or heparin lock will be used during the study.   
The investigator determines which one of the two CGM devices will be 
used in the trial and documents the rationale for the decision.  For 
example, the most accurate CGM may be used, and may be determined by 
the closest sensor glucose value to a meter glucose value performed at the 
time.  The second CGM is considered a mitigation factor, a back-up in 
case the first CGM ceases to function properly during the trial.  During the 
study, the physician may switch to using the alternate CGM if there was a 
problem with the radiofrequency communication or any other 
abnormalities affecting the output of the CGM.  The rationale for selecting 
either one of the CGMs to start the trial will be documented on the CRF.  
If a CGM has to be switched, the change will be documented and 
explained.  If both CGMs were performing equally, either one of them 
may be selected.  If both CGMs were to cease to function, the clinical trial 
for the subject would be terminated and the investigator will determine 
whether it will be rescheduled. 
Blood finger stick is performed using the CONTOUR® NEXT EZ Blood 
Glucose meter and strips. 
Once all connections have been verified, the subject will be disconnected 
from his/her insulin pump and will be connected to the AP device.  The 
AP device is connected as a closed-loop per the AP User Manual, but the 
control algorithm will not be turned on until approximately 4:30 pm.  In 
effect, the device will operate as an open-loop until the controlling 
algorithm is turned on, thus closing the loop. 
 
While at the CRC, the subject will calibrate the CGM following the 
manufacturer’s recommendations (~ every 12 hours) and using the 
CONTOUR® NEXT EZ device.  In addition to the recommended 
calibration, the subject will calibrate the CGM approximately 30 minutes 
before each meal and before going to bed. 
 


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10.4.2. Monitoring 
10.4.2.1. On-going monitoring 
During the closed-loop phase of the study, the following personnel 
will be present: 
 Study coordinator 
 Study engineer 
 Study physician  
Blood glucose level will be measured using a YSI 2300 Stat at a 
minimum of every 30 minutes (±10 min) and as described by 
Table 10–1Table 4–1.  The study physician may request more 
frequent measurements for safety.  If the subject reports symptoms 
of hypoglycemia, the blood glucose level will be measured with 
YSI and hypoglycemia guidelines will be followed.  The YSI will 
be used according to manufacturer’s instructions and operated by 
trained study staff.  The YSI will be checked a minimum of every 
2 hours with the 180 mg/dL standard and recalibrated if YSI 
glucose standard reads outside the range of 177-183 mg/dL or as 
needed.  All plasma glucose samples will be read on 2 membranes 
and discrepancies in values that exceed 5 mg/dL will be called to 
attention of the study physician to assess the need for immediate 
recalibration.  
Each time a YSI measurement is taken, a finger stick measurement 
using the CONTOUR® EZ blood glucose monitoring system will 
be taken for information. 
Calibration of the CGM will be performed with a finger stick with 
the CONTOUR® NEXT EZ glucose meter.  On the day of CGM 
insertion and at the beginning of the CRC visit, QC testing of the 
standard solution specific to the CONTOUR® NEXT EZ glucose 
meter will be performed.  QC may be repeated any time there is a 
question about the glucose result from the meter.  The labeling of 
the commercially available standard solution can be found in 
Appendix 13 of the original IDE submission.  The QC testing will 
be performed with at least two different concentrations of control 
solution, including a concentration in the hypoglycemic range if 
the manufacturer provides one.  A glucose meter will not be used 
in a study if it does not read within the target range at each 
concentration per manufacturer labeling. 


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Table 10–1:  Frequency of glucose monitoring during CRC 
Measurement 
When 
Frequency 
CGM 
Closed-loop 
Every 5 min 
Finger stick 
OneTouch® Ultra® 
Calibration of CGM 
Per manufacturer’s guidelines and 
before meals & at bedtime  
YSI + finger stick 
CONTOUR® EZ 
Closed-loop 
Every 30±10 min 
YSI + finger stick 
CONTOUR® EZ 
If subject reports symptoms of 
hypoglycemia 
When subject reports symptoms of 
hypoglycemia 
YSI + finger stick 
CONTOUR® EZ 
Hypoglycemia: BG<70 mg/dL per YSI 
Or  
if AP device (CGM) predicts <70 
mg/dL in the following 15 min 
Every 15±5 min  
until YSI >80 mg/dL 
YSI + finger stick 
CONTOUR® EZ 
Hyperglycemia: BG>400 mg/dL 
Every 15±5 min 
Until YSI<300 mg/dL 
YSI + finger stick 
CONTOUR® EZ 
During exercise 
Every 15±5 min 
and for 1 hour after starting 
exercise 
 
The AP device includes multiple visual and auditory alarms that 
are embedded into the APS© software should the system 
malfunction.  The control algorithm also includes intrinsic safety 
limits that trigger alarms should the patient’s glucose level go too 
high or too low and which prevents the system from delivering too 
much insulin. 
Should the HMS predict that the glucose level is going to be <70 
mg/dL in the next 15 min, the system will alert on the AP device 
and send a redundant text message to a predefined list of people, 
which in this study will be only the physician (who will be next to 
the subject in this study) to notify the subject to eat 16 g of CHO.  
All warnings issued by the HMS will be documented. 
To prevent dehydration secondary to hyperglycemia, the subject 
will be allowed to consume sugar free beverage during the trial if 
he/she is thirsty. 
Each adverse event will be graded as mild, moderate, or severe as 
described by Table 15–1Table 9–1.  Should there be any Serious 
Adverse Event or Unanticipated Adverse Device Effect, immediate 
action for the safety and welfare of the patient will be taken.  An 
investigation will be promptly conducted and reported to the safety 


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officer of the IRB.  All adverse events will be documented as 
described in section 159. 
10.4.2.2. Blood volume requirements 
Maximum amounts: 
All subjects are adults between the age of 21 and 65 years old.  At 
the time of admission, the maximum number of blood draws that 
can be safely performed based on the subject’s age, weight, blood 
draw history and volume per draw will be determined.  The 
amount of blood that may be drawn should not exceed 10.5 mL/kg 
or 550 mL, whichever is smaller, over any eight week period.  It is 
anticipated that the number of protocol-defined blood draws will 
not exceed this subject limit and no single blood draw will exceed 
1.5 cc.  However, if the required number of draws for the 
admission is determined to exceed the recommended limit for the 
subject, the admission will be cancelled.  If the blood draw limit is 
reached during the admission for any reason, the admission will be 
terminated. 
Worst case estimate: 
It is anticipated that at a minimum, 51 blood draws will be 
necessary during the admission.  The frequency of YSI 
measurement may be increased following HMS warnings or for 
any other reason.  As a worst case, if the HMS were raising 9 to 10 
warnings, hence increasing the frequency of YSI measurements, it 
would require to perform approximately 80 blood draws.  Blood 
sparing methods will be used.  Therefore, each blood draw 
measurement will require approximately 1.2 cc.  However, for the 
worst case estimate, the calculation will consider that a blood draw 
may require 1.5 cc.  Therefore, if there were between 51 and 80 
YSI readings, the total amount of blood drawn would be between: 
 
51draws x 1.5 cc = 77 cc 
 
80draws x 1.5 cc = 120 cc 
Finger stick: 
Each fingerstick measurement requires 1.5 microliters.  As these 
are minimal, they are not included in the impact of total blood 
draw volume. 


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Screening laboratory: 
Sampling for screening laboratory will require approximately 10 
cc.  The laboratory testing is likely going to take place 1 to 8 
weeks prior to the CRC clinical session. 
10.4.2.3. Safety 
The site maintains appropriate equipment for mitigating severe 
Adverse Events that may occur during this study.  The safety 
equipment at the CRC includes: 
 An automated defibrillator 
 A standard crash cart including glucagon, intravenous and 
oral dextrose, oxygen with ambubag. 
Sansum Diabetes Research Institute, where the trial will take place, 
is located 1/2 block from Santa Barbara Cottage Hospital, less than 
30 seconds by car, should there be any Serious Adverse Event. 
The Sponsor and Principle Investigator of this study is a physician 
certified in Internal Medicine for more than 19 years.  For the last 
10 years, he has been part of or led more than seventy clinical 
studies in the diabetes therapeutic area.  All studies were 
conducted per FDA regulations and ICH/GCP guidelines.  These 
credentials have been summarized in the IDE submission.  The 
Principle Investigator is also the developer of this clinical protocol.   
 
 


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Table 10–2Table 4–2 describes which actions will be taken for the 
safety of the patient.   
All actions taken will be documented in the CRF.  For example, if 
the investigator initiates a correction bolus or if the patient ingest 
carbohydrates.  Any outside intervention not requested by the 
device will lead to the termination of the trial for that subject, that 
day.  The trial may be repeated another day after adjustment of the 
safety factor.  If the subject is required to ingest carbohydrates 
following warnings generated by the HMS, these will not be 
considered a failure of the device and the trial will continue.  All 
outside intervention, requested by the HMS or not, will be 
documented in the CRFs. 
 
 


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Table 10–2: Safety action to take in case of hypoglycemic and hyperglycemic events 
based on YSI values 
CONDITION 
ACTION 
Hyperglycemia 
 
Asymptomatic and serum glucose > 
250 mg/dL more than 2 hours 
Or if subject develops nausea, 
vomiting or abdominal pain 
Test the blood for serum ketones. Check the pump, if not running, 
change pump. 
If blood ketones exceed 1.0 mmol/L, the study for this subject will be 
terminated. 
If a correction bolus needs to be administered by the study staff, it 
will be administered with a syringe. 
Mild polyuria and polydipsia;  
serum glucose > 250 mg/dL more 
than 3 hours 
If blood ketones were less than 0.6 mmol/L at 2 hours, recheck blood 
ketones and check the pump. If pump not running or catheter 
occluded or leaking, change the pump.  
If blood ketones > 1.0 mmol/L, then the study for this subject will be 
terminated. 
If a correction bolus needs to be administered by the study staff, it 
will be administered with a syringe. 
Glucose level ≥300 mg/dL for more 
than 1 hour 
Investigator will give a manual correction dose bolus administered 
with a syringe.  The trial will be terminated for this subject. 
Emesis, but with a normal 
sensorium and glucose > 350 mg/dL 
The study for this subject will be terminated.  Intravenous fluids 
would be given at a rate of 3,000 cc/M2/day.  A manual correction 
dose of a short acting insulin analog would be given. The insulin 
infusion set would be changed.  The subject would remain in the 
CRC until serum glucose is < 200 mg/dL. 
Subject will be monitored for at least 2 hours post treatment by study 
investigator.  In case of reoccurring symptoms the subject shall be 
transferred to the emergency room by paramedics. 
If a correction bolus needs to be administered by the study staff, it 
will be administered with a syringe. 
Decreased sensorium (sleepy, 
difficult to arouse) with or without 
emesis: glucose > 350 mg/dL 
The study will be terminated for this subject.  The subject will be 
transferred to the emergency room for evaluation with electrolytes 
and pH and monitoring for possible further deterioration of 
neurological status as a decrease sensorium may be indicative of 
electrolyte and/or pH abnormalities that could lead to respiratory or 
cardiac depression if not detected and treated appropriately. 
Blood glucose >400 mg/dL 
The study is terminated for this subject. The investigator will give a 
manual (with a syringe) correction bolus. 
No heart rate, no blood pressure 
Perform resuscitation. If this occurred all studies would be put on 
holding pending an investigation of the circumstances leading to this 
very adverse outcome. Call 911 and transfer the treated subject to 
emergency room. 
Hypoglycemia 
 
If CGM prediction is <70 mg/dL in 
The AP device notifies the physician.  The physician treats the 


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CONDITION 
ACTION 
the following 15 min 
subject with 16 g of oral CHO.  The study is not terminated for this 
subject.  This is an anticipated part of the study.  YSI frequency will 
increase to every 15±5 min until YSI >80 mg/dL. 
Adrenergic/cholinergic symptoms 
without neurocognitive changes;  
YSI<70 mg/dL, but > 60 mg/dL 
Subjects would be closely monitored with glucose levels every 15±5 
minutes until YSI > 80 mg/dL.  The investigator will give CHO if 
directed by HMS. 
Asymptomatic or 
adrenergic/cholinergic symptoms 
with serum glucose < 60 mg/dL 
If the HMS did not raise hypoglycemic warning, the study will be 
terminated for the subject.  Subject will be treated with oral simple 
carbohydrates, such as glucose tablets or juice, and glucose by YSI 
rechecked in 15 minutes, and treatment repeated if glucose remains < 
70 mg/dL.  With second treatment the insulin infusion will be 
suspended until glucose is > 70 mg/dL.  YSI frequency will continue 
every 15±5  min until YSI > 80 mg/dL.  Subject will be monitored 
for at least 2 hours post treatment by study investigator. In case of 
reoccurring symptoms the subject shall be transferred to the 
emergency room by paramedics. 
Moderate neurocognitive change, 
subject is talking but unable to treat 
their hypoglycemia without 
assistance; serum glucose < 50 
mg/dL 
The study will be terminated for this subject.  This is unlikely to 
occur because treatment would have been given with first glucose < 
60 mg/dL and glucose is measured every 15 minutes.  Subjects will 
be treated with oral simple carbohydrates, such as glucose tablets or 
juice, and serum glucose subsequently rechecked in 15 minutes, and 
treatment repeated if glucose remains < 70 mg/dL.  With second 
treatment the insulin infusion will be suspended until glucose is > 70 
mg/dL. Subject will be monitored for at least 2 hours post treatment 
by study investigator. In case of reoccurring symptoms the subject 
shall be transferred to the emergency room by paramedics.   
Moderate neurocognitive changes, 
but subject is incoherent and/or 
refusing treatment and needs 
assistance for hypoglycemia 
treatment; serum glucose < 50 
mg/dL 
 
The study will be terminated for this subject.  This is unlikely to 
occur because treatment would have been given with first glucose < 
60 mg/dL and glucose is subsequently measured every 15 minutes. 
Intravenous glucose would be given (0.5 grams/kg intravenous over 
3 minutes), and insulin delivery suspended until glucose is > 70 
mg/dL. Subject will be monitored for at least 2 hours post treatment 
by study investigator. In case of reoccurring symptoms the subject 
shall be transferred to the emergency room by paramedics. 
Seizure of loss of consciousness; 
serum glucose < 50 mg/dL 
The study will be terminated for this subject.  This is unlikely to 
occur because treatment would have been given with first glucose < 
60 mg/dL and glucose is subsequently measured every 15 minutes. 
Intravenous glucose would be given (0.5 grams/kg intravenous over 
3 minutes), and insulin delivery suspended until glucose is > 70 
mg/dL.  In the event subject experience loss of consciousness or 
seizure he / she will be transferred to the emergency room by 
paramedics. 
No heart rate, no blood pressure 
Perform resuscitation. If this occurred all studies for all subjects 
would be put on holding pending an investigation of the 
circumstances leading to this serious adverse event. Call 911 and 
transfer the treated subject to emergency room. 
 


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10.4.3. Unannounced meals during closed-loop 
During the 24-hour closed-loop, the subject will take two meals (evening 
dinner and breakfast), one snack prior to the exercise segment, and one 
snack 3 hours after exercise.  All meals will be unannounced.  This means 
that the subject will ingest the meal and the AP device will automatically 
regulate insulin delivery without being given any details about the meal.  
Therefore, it will react to the increase of glucose level following the meal.  
Based on the CGM data collected every five minutes, the AP device will 
quickly react to the meal and deliver correction bolus based on the 
predictions of future insulin.  The objective is to observe the controller’s 
ability to detect the meal and make an appropriate control action.  The 
target glucose is to return to and remain in the range of [70-180] 
mg/dLduring the 5 hours post-prandial and then to return to [80-140] 
mg/dL range afterwards. 
10.4.3.1. Dinner 
Approximately 2 hours (±30 min) after starting the closed-loop 
(Day 1), i.e. 6:30 pm, once the subject’s glucose has been 
stabilized by the AP device, the subject will be given an evening 
meal with approximately 50 g of carbohydrates (CHO).  The 
subject will remain under closed-loop control overnight.  
10.4.3.2. Breakfast 
At approximately 7:00 am (±30 min) on Day 2, the subject will be 
given a breakfast with approximately 50 g of CHO. 
10.4.3.3. Snack before exercising 
Just before starting the exercising segment of the trial, at 
approximately 11:00 am, the subject will eat a snack of 
approximately 16 g of CHO if his/her glucose level is <120 mg/dL. 
10.4.3.4. Snack after exercising 
Approximately 3 hours after starting the exercising, at 
approximately 2:00 pm (±30 min) on Day 2, the subject will eat a 
snack of approximately 16 g of CHO if his/her glucose level is 
<120 mg/dL. 
10.4.4. Exercising 
Approximately 5 hours after the breakfast (11:00 am ± 30 min), the 
subject will undergo exercise for 30 minutes (±5 minutes) at 50% of his / 


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her predicted heart rate reserve (HRR).  The subject will be monitored for 
approximately 6 hours following the end of the exercise segment or until 
his/her blood glucose has stabilized within the [80-140] mg/dL range.  
During and for 3 hours after exercise, the subject will be monitored to 
verify that his/her glucose level returns and remains within the range of 
[70-150] mg/dL. 
If the subject’s blood level is >270 mg/dL the subject will not go through 
the exercising segment of the trial, but will continue the closed-loop until 
the end of the 24-hour trial.  Subjects whose glucose level is below 120 
mg/dL at (11:00  30 min) will be given 16 g CHO tablets and will not 
start exercise until glucose is greater than 120 mg/dL. 
Exercise will be done by cycling on a recumbent stationary bicycle or by 
walking on a treadmill for 30 minutes (15 minutes of exercise, 5-minute 
break, followed by15 additional minutes of exercise) at approximately 
50% predicted heart rate reserve (HRR).  HRR is calculated using the 
following formulas.  The calculation is different for men and women.  
HRR: Heart Rate Reserve 
RHR: Resting Heart Rate 
MHR: Maximum Heart Rate 
THRX%: Target heart rate to be at X% of HRR 
Smoking code: “1” if the subject is a smoker and “0” if the subject is not a 
smoker 
Equation 1 provides the MHR for men.  The Target Heart Rate is provided 
by equation 3. 
MHR=203.9 - (0.812 x Age) + (0.276 x RHR) - (0.084 x Weightkg) - (4.5 
x smoking code)         (1) 
Equation 2 provides the MHR for women. 
MHR = 204.8 – (0.718 x Age) + (0.162 x RHR) – (0.105 x Weightkg) – 
(6.2 x smoking code)      (2) 
Target Heart Rate for exercise (at 50%) is provided by equation 3:  
THR50% = [(MHR – RHR) x 50% ] + RHR        (3) 
 


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References: 
Whaley MH, et al, Predictors of over- and underachievement of age-predicted maximal 
heart rate, Med Sci Sports Exerc 1992;24(10):1173-9;  
Karvonen MJ, Kentala E, Mustala O. The effects of training on heart rate; a longitudinal 
study.Ann Med ExpBiolFenn. 1957;35(3):307-15;  
Davis JA, Convertino VA.A comparison of heart rate methods for predicting endurance 
training intensity.MedSci Sports. 1975;7(4):295-8. 
 
Subjects with high risks factors for cardiac disease and Type 1 diabetes, as 
recommended by the American Diabetes Association will be monitored 
with continuous electrocardiography throughout exercise to monitor for 
potential arrhythmias.  The risks factors are: 
 Age > 35 years 
 Type 1 diabetes for > 15 years’ duration 
 Presence of any additional risks factor for coronary artery disease 
 Presence of microvascular disease (proliferative retinopathy or 
nephropathy, including microalbuminuria) 
 Peripheral vascular disease 
 Autonomic neuropathy 
All subjects will wear a Polar RS400 heart rate monitor.  The resistance on 
the bicycle or the speed and grade on the treadmill will be adjusted to keep 
subjects close to the target heart rate. 
Exercise may be discontinued at the request of the subject or at 
investigator discretion if there is concern for the subject’s safety. 
Blood glucose (YSI) will be sampled every 15±5 minutes for one hour 
beginning at the start of exercise.  Additional YSI blood glucose values 
may be requested by the study physician as deemed necessary for safety. 
Exercise will be discontinued and the subject will be given 16 mg CHO if 
the system predicts unavoidable impending hypoglycemia as determined 
by the HMS (i.e. when CGM glucose level is predicted to be <70 mg/dL 
in the following next 15 min).  Treatment with 16 mg CHO may be 
repeated as necessary. 
If the subject feels hypoglycemic subject will perform finger stick and YSI 
measurement will be taken.   If YSI value below 60 mg/dL, juice or 


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glucose tablets will be used to return the glucose to >80 mg/dL and 
exercise may be discontinued.  Closed-loop will be discontinued.  This 
will mark the end of the trial for this subject. 
Following the exercise segment, the subject will be monitored for 
approximately 5-6 hours (end of the 24-hour period).  During that time, 
the insulin delivery for the subject will continue to be controlled by the AP 
device.  The patient may have a snack of 16 g CHO approximately 3 hours 
after the start of exercise.  The patient will not be discharged until blood 
sugar value, based on YSI is >90 mg/dL for at least an hour. 
10.4.5. Discharge from the CRC 
At the end of the 24-hour period and once the glucose level of the subject 
has stabilized within the desired zone (>90 mg/dL for at least 1 hour), the 
AP device will be disconnected.  The IV line and the two CGMs will be 
removed.  The subject will be connected to his/her own insulin pump.  The 
investigator or study staff will verify that the insulin pump of the subject 
has been restarted successfully.  Glucose check will be performed after 
new infusion set or the pump of the subject has been inserted, as per 
standard care.  Subject will return all supplies to study staff.  On the 
subject’s blood glucose is >90 mg/dL and <180 mg/dL with ketones <0.6 
mmol/L, the subject will be discharged from the CRC. 
This marks the end of the study day after using the AP device for 
approximately 24-hour (as a closed-loop). 
10.5. Follow-up call 
A brief contact with the subject, typically by phone, will take place within 24 
hours (±12 hours) to verify that the subject has no further questions or has any 
problems related to his/her participation in the study.  The contact will be 
documented in the subject file.  
11. SELECTION AND WITHDRAWAL OF SUBJECTS 
Twelve to twenty subjects will be enrolled in the study. 
11.1. Inclusion criteria 
To be eligible for the study, a subject must meet the following criteria: 
 Clinical diagnosis of type 1 diabetes for at least one year and using an 
insulin pump for at least 6 months with commercially available rapid acting 
insulin 


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 The diagnosis of type 1 diabetes is based on the investigator’s judgment; C 
peptide level and antibody determinations are not needed.  
 Age 21 to 65 years 
 For females, not currently known to be pregnant or nursing 
 HbA1c between 5.0% and 10%, as measured with DCA2000 or equivalent 
device 
 Willing to perform the calibration of the study CGMs using a finger stick 
only and willing to follow instructions for insulin pump and CGM wear. 
 Willing to use the study CGM and study insulin pump during closed-loop. 
 Able to and agrees to avoid the following medication starting 24 hours 
before sensor wear through completion of CRC visit: acetaminophen, 
prednisone, and pseudoephedrine. 
 Forced expiratory volume in 1 second (FEV1) ≥  70% Third National 
Health and  Nutrition Examination Survey  (NHANES III)  predicted 
 Forced vital capacity (FVC) ≥70% NHANES III predicted 
 Forced  expiratory volume in 1 second as a percentage of forced  vital 
capacity(FEVl/FVC)≥NHANES  III lower limit of normal (LLN) 
 An understanding of and willingness to follow the protocol and sign the 
informed consent. 
11.2. Exclusion criteria 
The presence of any of the following, the subject will be excluded from the 
study: 
 Pregnancy (as determined by a positive blood pregnancy test performed in 
females of childbearing capacity during screening visit and urine test at time 
of admission for in-patient visit) or nursing mother.  
 Diabetic ketoacidosis in the past 6 months prior to enrollment requiring 
emergency room visit or hospitalization 
 Severe hypoglycemia resulting in seizure or loss of consciousness in the 12 
months prior to enrollment 
 Current treatment for a seizure disorder; 
o  Subjects with a history of seizures may be included in the study if 
they receive written clearance from their neurologist  


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 Cystic fibrosis 
 Active infection 
 A known medical condition that in the judgment of the investigator might 
interfere with the completion of the protocol such as cognitive deficit. 
 Mental incapacity, unwillingness or language barriers precluding adequate 
understanding or co-operation, including subjects not able to read or write. 
 Coronary artery disease or heart failure.  
o Subjects with a history of coronary artery disease may be included in 
the study if they receive written clearance from their cardiologist 
 Presence of a known adrenal disorder 
 Active coronary artery disease or heart failure 
 Active gastroparesis 
 If on antihypertensive, thyroid, anti-depressant or lipid lowering medication, 
lack of stability on the medication for the past 2 months prior to enrollment 
in the study 
 Uncontrolled thyroid disease 
o Adequately treated thyroid disease and celiac disease do not exclude 
subjects from enrollment 
 Abuse of alcohol 
 A recent injury to body or limb, muscular disorder, use of any medication, 
any carcinogenic disease, or other significant medical disorder if that injury, 
medication or disease in the judgment of the investigator will affect the 
completion of the exercise protocol 
 Current use of a beta blocker medication 
 Laboratory results: 
o Hematocrit < 30% or >55% 
o A1C > 10% 
o Abnormal liver or renal function (Transaminase >2 times the upper 
limit of normal, Creatinine> 1.5 mg/dL) 
o Labs drawn at screening visit or within one month prior to screening 
(for other purposes) will suffice for enrollment purposes related to 
hematocrit 


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 Subject has skin conditions that, in the determination of the investigator, 
would preclude wearing the study devices (infusion set and sensor), in the 
abdomen.   Examples include but are not limited to: psoriasis, burns, 
scaring, eczema, tattoos, and significant hypertrophy at sites of device wear; 
any known allergy to medical adhesives. 
 Currently on long-term treatment using prednisone. 
 If subject had been on short term treatment of prednisone, defer enrollment 
until underlying condition and prednisone treatment have resolved. 
 Allergy to study drug, food or other study material. 
 History of asthma, COPD (chronic obstructive pulmonary disease), or any 
other clinically relevant chronic lung disease. 
 Respiratory track infection within 4 weeks before screening. 
 Clinically significant screening ECG, physical examination, laboratory test, 
or vital sign abnormality. 
 Exposure to any investigational drug within 30 days. 
 History of malignancy within the 5 years before screening (other than basal 
cell carcinoma). 
 Inability, in the opinion of the investigator, to adequately inhale 
Technosphere® Insulin Inhalation Powder. 
 Abnormal spirometry. 
 Currently smoking or discontinued smoking (including cigarettes, cigars, 
pipes) over the past 6 months. 
 Highly sensitive to insulin: insulin-to-carbohydrate ratio I:C > 1:12 
 Current participation in another investigational trial (unless participation to 
original protocol of IDE G110093) or has previously participated to this 
study. 
11.3. Starting rules 
For the in-clinic days, the subject is to arrive in the clinic around 4 pm.  The last 
meal of the subject, prior to arrival to the clinic should have occurred no later 
that noon of that day.  The subject should not have any insulin bolus after 2:00 
pm or ingest any carbohydrate after the lunch, unless it is for treatment of 
hypoglycemia, i.e. if the subject glucose level is < 70 mg/dL. 


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The clinical staff may reschedule the subject if the above directions are not 
followed.  If the subject has questions on the day of admission, they should 
contact the study staff. 
 
11.4. 
Stopping rules 
11.4.1. Criteria for individual subject withdrawal 
The termination of a subject from the study will be documented in the 
subject source documents and on the CRF.  The reason for the termination 
and possible following effects must be documented.  Subjects that have 
discontinued participation will not be replaced.  Should a subject be lost-
to-follow-up (LTF), i.e. no return for the on-site 24-hour closed-loop after 
enrollment, a reasonable effort will be made to contact the subject to 
determine why the subject failed to return.  Any investigator-decided 
outside intervention will trigger termination of the trial for the subject.  If 
the investigator treats the subject with 16 g of carbohydrates following the 
recommendation of the HMS, then the trial will not be terminated, this is 
anticipated and part of the trial.  If a trial is terminated, the same subject 
may be rescheduled and the trial repeated.  Rules for terminating a visit for 
an individual subject are as follows (glucose levels measured by YSI).   
 Outside intervention (bolus or carbohydrate treatment) from the 
investigator that did not follow recommendation from HMS. 
 Gross system malfunctions such as: 
o Pump failure  
o Failure of both study sensors  
o System or controller malfunctions that may have an impact 
on the safety of the subject 
 Any correction bolus initiated by the investigator. 
 Glucose YSI > 250 mg/dL for more than 2 hours and blood 
ketones exceed 1.0 mmol/L. 
 Subject develops nausea, vomiting, or abdominal pain and blood 
ketones exceed 1.0 mmol/L. 
 Glucose YSI > 350 mg/dL with decreased sensorium with or 
without emesis. 
 Glucose level YSI > 400 mg/dL at any point if the investigator 
decides to treat with a correction bolus. 


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 Glucose YSI < 60 mg/dL without having received a HMS warning 
 Glucose YSI < 50 mg/dL. 
 Severe Hypoglycemia or Hyperglycemia as defined by Table 9-2. 
 The subject or physician requests the trial be stopped. 
 Failure of YSI equipment. 
 Subject withdraws his/her consent. 
 Adverse Event which necessitates termination of the study as 
decided by the investigator, such as DKA. 
 Protocol violation: subject is no compliant with procedures, 
becomes pregnant, violates study entry criteria, or use 
unacceptable medication. 
11.4.2. Criteria for suspending / stopping the study 
In case of a recurring system malfunction or subject safety issue observed 
across multiple subject visits, the overall study will be suspended (no 
further subjects at any site) while the problem is diagnosed.   
In the event of a UADE, the Sponsor/investigator will evaluate the event 
and follow-up procedure, including the possible suspension and / or 
termination of the study. 
In the event of a Serious Adverse Event, the Sponsor/investigator will 
evaluate the root cause of the event and will determine appropriate action, 
including termination of the study. 
The study may resume if the underlying problem can be corrected by a 
protocol or system modification that will not invalidate the results 
obtained prior to suspension.  Any change to the protocol or the system 
will need to be approved by the Agency prior to implementation. 
The study may also be suspended or terminated if the FDA, IRB or other 
regulatory authority discontinues the approval of the study protocol or 
Sansum clinical site participation. 
The IRB and FDA will be notified if the study is stopped and permission 
to resume will be obtained from the IRB and FDA prior to restarting. 
12. EXPECTED SAMPLE SIZE 
This is a feasibility clinical study; therefore, only approximately 12 to 20 adult 
subjects will take part to this trial.  


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13. DESCRIPTION OF THE CLINICAL CENTER 
Sansum Research Diabetes Institute, a nonprofit research center founded in 1944 
devoted to the prevention, treatment and cure of diabetes, is located ½ block from 
Santa Barbara Cottage Hospital, approximately 30 seconds by car to the emergency 
room.  It is a research center devoted to the prevention, treatment and cure of 
diabetes.  It is a nonprofit organization that was founded in 1944.  The Institute has 
gained international recognition for its work to develop an artificial pancreas, in 
developing protocols to increase the incidence of healthy babies born to women with 
diabetes, and its work with people at risk for type 2 diabetes.  Physicians and 
researchers continue to develop new treatment protocols for peoples with diabetes.  
New drugs and medical devices are clinically tested to ensure their efficacy and 
safety.   
Sansum Diabetes Research Institute is led by Lois Jovanovič, M.D. who is renowned 
internationally through her work.  She has published extensively in particular in 
relation to developing formulae for insulin dosing in subjects using either insulin 
infusion pumps or multiple daily injections.  Her formulae not only succeeded in 
normalizing blood glucose levels but in a randomized trial, the computer based 
insulin delivery systems fared better than daily interactions with a physician to adjust 
insulin doses.  She has directed multiple clinical trials involving continuous glucose 
monitoring and insulin infusion pumps.  Her expertise and leadership have brought 
Sansum Research Diabetes Institute to the frontline of diabetes research, nutrition, 
education and diabetes prevention.  Her research has already, and will continue to 
improve the lives of people worldwide who suffer from this serious disease. 
Sansum Diabetes Research Institute 
2219 Bath Street 
Santa Barbara, CA 93105 
Ph: 805-682-3332 
Email: info@sansum.org 
14. ASSESSMENT OF EFFICACY 
The goal of the study is to evaluate the feasibility of the artificial pancreas device, not 
to measure its efficacy.  However, as described in the statistical section, several 
outcomes will be measured that may give some indication of the possible efficacy of 
the device. 
15. ASSESSEMENT OF SAFETY 
15.1. Reporting to regulatory agencies 
The study will be conducted after receiving IDE approval by FDA and Cottage 
Health System IRB approval.   


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 All anticipated Adverse Events will be reported in details to both the IRB 
and FDA with the results of the study within 3 months of the completion 
of the trial. 
 Unanticipated Adverse Device Effects (UADE) will be thoroughly 
investigated and as required by 21 CFR 812.46, they will be reported to 
FDA and IRB no later than 10 working days after the sponsor first 
receives notice of the effect, i.e. 10 days after it occurs since the Sponsor 
is also the investigator (Sansum). 
 The CGM Dexcom® G4® or the insulin pump (OneTouch® Ping®) 
malfunctions which are not related to the modifications of the interface to 
include them as components of the AP device or the glucose meter 
(OneTouch ®Ultra® blood glucose meter) will be reported to their 
respective manufacturers as a complaint per MDR requirements (Animas 
Corp for the insulin pump and the glucose meter and Dexcom for the G4® 
CGM). 
 Malfunctions related to the interfaces of the CGM or insulin pumps with 
the APS© platform will also be reported to their respective manufacturers. 
15.2. Definitions 
15.2.1. Adverse Event (AE) 
An Adverse Event (AE) is any untoward medical occurrence in a study 
subject, irrespective of the relationship between the adverse event and the 
device(s) under investigation.  Anticipated adverse events, such as skin 
irritation from sensor wear will be recorded in specific sections of the case 
report forms.  However, a severe skin irritation is not anticipated and 
would be reported on the AE form. 
All adverse events may be graded from mild to severe as defined by Table 
15–1Table 9–1. 
15.2.2. Serious Adverse Event (SAE) 
A Serious Adverse Event (SAE) is any untoward occurrence that is: 
 Results in death. 
 Life threatening, even if temporary in nature; 
 Results in permanent impairment of a body function or permanent 
damage to a body structure; 


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 Necessitates medical or surgical intervention to preclude 
permanent impairment of a body function or permanent damage to 
a body structure.  “Permanent impairment” means irreversible 
impairment or damage to a body structure or functions, excluding 
trivial impairment damage. 
15.2.3. Unanticipated Adverse Device Effect (UADE) 
An Unanticipated Adverse Device Effect (UADE) is any serious adverse 
effect on health or safety, any life-threatening problem or death caused by, 
or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity or degree of incidence in the 
application; or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects. 
15.2.4. Device complaints 
Those only apply to the approved devices used in the AP device, i.e. the 
CGM and the insulin pump.  Those devices are not being used as they 
were intended to be used.  Effectively, these devices are being used 
beyond their original intended use when included in a closed-loop.  
However, their intended output and performance specifications are not 
being modified: the purpose of the CGM in the closed-loop is still to 
provide subcutaneous glucose values, while the purpose of the pump in the 
closed-loop is still to deliver controlled amount of insulin.  A device 
complaint also applies to CONTOUR® NEXT EZ Glucose meter used to 
calibrate the CGM.  It is used per the manufacturer’s instructions. 
A complaint means any written, electronic or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, 
safety, effectiveness, or performance of a device after it is released for 
distribution.  The complaint may or may not be associated with an adverse 
event. 
Should there be any malfunction of the device related to the original 
intended use for which the device is marketed for, it will be reported to the 
manufacturer per 21 CFR 803.3.  For example, problems with the infusion 
set (Inset®), or the subcutaneous needle would be independent of the 
closed-loop trial and will be reported. 
Because both Dexcom® and Animas are close partners in the development 
of an artificial pancreas, they will informally be notified of any other 
malfunction of their device related to their use in the AP device.  This will 


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be valuable information for further product development of an artificial 
pancreas. 
 
15.2.5. Anticipated adverse events 
Each adverse event is graded for its severity from mild to severe as 
described by Table 15–1Table 9–1.  This is a measure of intensity only.  
An adverse event may be severe, but not clinically serious. 
Table 15–1: Severity of adverse events 
Intensity level 
Description 
Mild 
Usually transient, requires no special treatments, and does not 
interfere with the subject’s daily activities 
Moderate 
Usually causes a low level of inconvenience or concern to the 
subject and may interfere with daily activities, but is usually 
ameliorate by simple therapeutic measures. 
Severe 
Interrupts a subject’s usual daily activities and generally requires 
system drug therapy or other treatment. 
 
Hypoglycemia and hyperglycemia are intrinsic risks and adverse events 
associated with type 1 diabetes.  The level of severity of such events 
follows a more detailed description as described by Table 15–2Table 9–2: 
it varies from negligible, mild, moderate, severe and very severe.  Only 
hyperglycemia or hypoglycemia that is rated moderate or worse will be 
documented in a CRF. 
 
 
 


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Table 15–2: Levels of hyperglycemia and hypoglycemia as defined by YSI 
Severity 
YSI 
Clinical symptoms 
Description 
Hyperglycemia 
 
 
 
Negligible 
200<BG<300 mg/dl for 
<1 hr 
or 
BG>300 mg/dl for <1 hr 
Asymptomatic  
Little or no potential injury, pain or 
discomfort 
Mild 
200<BG<300 mg/dl  
Mild polydipsia and mild 
polyuria 
Potential of minor injury, pain, or 
user discomfort 
Moderate 
BG> 300 mg/dl 
Symptoms of ketosis 
(nausea, polyuria, 
polydipsia, vomiting) 
with normal mental 
status 
Potential of non-life threatening 
injury, pain, or direct or indirect 
exacerbation of existing non-life 
threatening condition 
Severe 
BG>300 mg/dL 
requiring intravenous 
fluids to correct 
Altered mental state 
Subject in critical 
condition 
Major injury requiring medical 
intervention 
Very severe 
N/A 
No heart rate, no blood 
pressure 
Subject in critical 
condition 
Potential of death or serious injury 
Hypoglycemia 
 
 
 
Negligible 
60<BG<70 mg/dL 
Asymptomatic  or 
adrenergic/cholinergic 
symptoms without 
neurocognitive changes 
Little or no potential injury, pain or 
discomfort 
Mild 
BG<60 mg/dL 
Or 
HMS indicates impending 
hypoglycemia (<70mg/dL 
in the next 15 min per 
CGM measurements) 
Asymptomatic or 
adrenergic / cholinergic 
symptoms without 
neurocognitive changes 
Potential of minor injury, pain, or 
user discomfort 
Moderate 
BG<60 mg/dL 
Subject is talking, but 
early neurocognitive 
changes such as slow 
speech, mild affect 
changes 
Non-life threatening injury, pain, or 
direct or indirect exacerbation of 
existing non-life threatening 
condition 
Severe 
BG<60 mg/dL 
Require assistance of 
another individual due to 
loss of consciousness, 
seizure or the inability to 
administer treatment to 
self due to 
neuroglycopenia 
Major injury requiring medical 
intervention 
Very Severe 
N/A 
No heart rate, no blood 
pressure 
Subject in critical 
condition 
Potential of death or serious injury 
 


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Table 15–3Table 9–3 is a list of anticipated adverse events.  These will be 
reported on the CRF found in Appendix 9 of the IDE submission. 
Table 15–3: Anticipated Adverse Events 
Adverse event 
Description 
Hypoglycemia 
Refer to details in Table 9-2.  Only report if moderate or worse. 
Hyperglycemia 
Refer to details in Table 9-2.  Only report if moderate or worse. 
Skin irritation 
From sensor wear or insulin pump infusion set. 
Only considered an AE if the irritation is severe or meets definition of 
SAE 
Bruising at the side of insertion 
of CGM, infusion set, IV 
Only considered an AE if bruising is severe or meets definition of 
SAE. 
Infection at the side of insertion 
of CGM, infusion set, IV 
Only considered an AE if infection is severe or meets definition of 
SAE. 
Pain or bleeding at the side of 
insertion of CGM or infusion set 
Only considered an AE if pain or bleeding is severe or meets definition 
of SAE. 
Infection at side of finger stick 
Only considered an AE if infection is severe or meets definition of 
SAE 
Glucose sensor break 
Glucose sensor rupture leaves a small portion of the sensor under the 
skin that may cause redness, swelling or pain at the insertion site 
 
15.3. Adverse event reporting and protocol monitoring 
The first concern will be the safety of the subject, and appropriate medical 
intervention will be made to address any adverse event.   
All adverse events will be recorded on the CRF (Appendix 9 of the IDE), 
including those that may have occurred during the outpatient phase of the trial 
(the investigator will elicit reports of adverse events from the subject).   
In case of a Serious Adverse Event, the study will be put on hold until a thorough 
investigation is performed and documented to determine the root cause of the 
event.  Based on the results, the Sponsor/investigator will determine appropriate 
action, including changes to the protocol or termination of the study, and notify 
the appropriate regulatory authorities if required.   
Intensity:  The intensity of the adverse event will be recorded based on Table 15–
1Table 9–1.  The term severe is a measure of intensity, not clinical severity.  A 
severe AE is not necessarily a serious AE.  For example, itching for several days 
may be rated as severe, but may not be clinically serious. 
Causality:  The study investigator will assess the relationship of any adverse 
event to be related or unrelated to participation in the protocol by determining if 


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there is a reasonable possibility that the adverse event may have been caused by 
the study device or study procedures.   
Outcome: Adverse events that continue after the participant’s discontinuation or 
completion of the study will be followed until their medical outcome is 
determined or until no further change in the condition is expected.  
16. DATA ANALYSIS 
16.1. Overview 
This section presents the statistical analysis that will be used to evaluate the 
primary and secondary end-points of the non-randomized feasibility study.  
These are based on CGM data.  The primary endpoints consist in measuring the 
percentage of time the glucose level of the subject is in the safe zone [80-140] 
mg/dL, including overnight and excluding 5 hours postprandial and during 
exercises and 3 hours post-exercise.  The expected glucose levels during those 
periods are: 
 5 hours postprandial: [70-180] mg/dL 
 During exercise and for 3 hours after exercise: [70-150] mg/dL 
The secondary endpoints consist in measuring the glucose extremes and the 
need for outside intervention to address hypoglycemia and hyperglycemia.  The 
restoration of glucose level to a safe range, i.e. within [80-140] mg/dL after the 
two unannounced meals and the exercise without the need of intervention to 
address hypo- or hyperglycemia, i.e. no physician override to inject insulin or 
give carbohydrate to the subject, will be considered a successful outcome.   
If outside intervention is the result of notification from the Health Monitoring 
System algorithm (HMS), then it will be considered a successful outcome as 
well. 
There is no control group since the patient is his/her own control.  In addition, a 
more refined data analysis will be performed as discussed below. 
16.2. Control Variability Grid Analysis 
The overall performance of the control algorithm will be visualized via the 
Control Variability Grid Analysis (CVGA), which is built on a mix/max plot of 
glucose values.  For each subject , a point is plotted with the X-coordinate 
defined as the minimum blood glucose and the Y-coordinate defined as the 
maximum blood glucose level for an observation period.  In this trial, the 


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observation period is the 24-hour closed-loop including the unannounced meals 
and exercise segments.   
In order to reject sensor errors, the minimum glucose level is set at the 2.5th 
percentile and the maximum glucose level is set at the 97.5th percentile of the 
glucose level distribution, in other words, the Y-X coordinate difference 
corresponds to the 95% spread of the observed distribution.  The plot is then 
split into zones defined by their X and Y coordinate ranges as follows.  The 
zones are color coded to facilitate the visual interpretation of the results:  
 the green zone is safe and acceptable,  
 the orange/yellow zone is not desirable, and  
 the red-zone would be considered failure of the safety of the Artificial  
Pancreas device.   
Numerically, the information contained in the CVGA, can be described as the 
percentages within each zone.  For example, in Figure 3–1Figure 3–1 which 
present the preliminary results of IDE G090129, there were 40% of the data 
points in zone A, 60% in zone B and 0% in zones C or D.  In other words, the 
CVGA can be interpreted as a display of event-based clinical characteristics of 
the control algorithm.  Table 16–1Table 10–1 shows the interpretation of the 
various zones in the CVGA representation. 
 
Table 16–1:  Interpretation of the CVGA zones 
Zone ID 
Clinical impact 
X coordinate 
Y coordinate 
A-zone 
Accurate control 
110-90 mg/dL 
110-180 mg/dL 
Lower B 
Benign deviations 
from hypoglycemia 
90-70 mg/dL 
110-180 mg/dL 
B-zone 
Benign control 
deviation 
90-70 mg/dL 
180-300 mg/dL 
Upper B 
Benign deviation into 
hyperglycemia 
110-90 mg/dL 
180-300 mg/dL 
Lower C 
Over-correction of 
hypoglycemia 
<70 mg/dL 
110-180 mg/dL 
Upper C 
Over-correction of 
hypoglycemia 
110-90 mg/dL 
>300 mg/dL 
Lower D 
Failure to deal with 
hypoglycemia 
<70 mg/dL 
180-300 mg/dL 
Upper D 
Failure to deal with 
hyperglycemia 
90-70 mg/dL 
>300 mg/dL>300 
mg/dL 
E-zone 
Erroneous control 
<70 mg/dL 
 
 


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16.3. Primary end-points 
Table 16–2Table 10–2 is an outline of the analysis of the performance of the AP 
device primary end-points some of which are more qualitative than quantitative.  
All measures will be performed using CGM values.  Below the table, the listed 
questions will be used as a guidance to perform the qualitative review of the AP 
device. 
Table 16–2: Primary end-point measures 
Measure 
Description 
Review qualitatively profile of predictions 
and actual CGM values 
Ability of the zone-MPC and HMS algorithms to predict fall 
and rise of glucose value beyond the zone [80-140] mg/dL (1) 
Review qualitatively actual data of insulin 
pump delivery 
Capacity of the control algorithm to command the pump to 
increase or decrease the insulin pump to keep the subject 
within the zone [80-140] mg/dL (2) 
Review all warning events of HMS.   
Review of events that required outside 
intervention but was not raised by HMS. 
Capacity of the HMS in raising appropriate warnings and 
alarms to require outside intervention to prevent hypoglycemia 
(3) 
% of time within zone [80-140] mg/dL 
except 5 hours post-prandial and during 
exercise and 3 hours post-exercise 
Measures ability of AP device to maintain glucose level within 
a safe zone and to return to save zone following unannounced 
meals and exercises. 
% of time within zone [80-140] mg/dL 
during night between 12:00 am and 7:00 
am 
Measures ability of AP device to maintain glucose level with a 
safe zone during the night and prevent hypoglycemia. 
% of time within zone [70-180] mg/dL 
5 hours after unannounced evening meal, 
and breakfast 
Measures ability of AP device to react to small meal and to 
prevent glucose level from dangerous excursions. 
% of time within zone [70-150] mg/dL 
during the 30 min exercise 
Measures ability of AP device to maintain safe glucose level 
during 30 minutes of non-strenuous exercise 
% of time within zone [70-150] mg/dL 
during the 3 hours following exercise 
Measures ability of AP device to address exercise and to 
prevent glucose level from dangerous excursions 
 
Guiding questions: 
(1) Did the algorithm deliver insulin in a pattern conducive to causing or 
maintaining within-zone CGM measurements? 
(2) Did the algorithm deliver reasonable size insulin amounts?  Did the algorithm 
deliver the basal amount of insulin in quiescent, within-zone period?  When 
CGM measurements were predicting values higher than the upper zone limit 
of [80-140] mg/dL, did the algorithm increase insulin infusion?  When CGM 
measurements predicted values lower than the lower zone limit of [80-140] 
mg/dL, did the algorithm decrease insulin infusion? After glucose excursion 
above the upper zone limit or below the lower zone limit, when the CGM 


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measurements predicted measurement was reentering the zone, did the 
algorithm resume the basal amount of insulin infusion? 
(3) When prediction of BG glucose was to be <70 mg/dL in the following 15 
minutes, did the HMS send a warning text to physician?  Did the HMS system 
send unnecessary warning text messages when the BG was not predicted to be 
<70 mg/dL?  Did the investigator need to give CHO to the subject without 
receiving notification from the HMS either because of CGM failure or HMS 
system failure? 
16.4. Secondary end-points 
16.4.1. Analyses 
In addition to the qualitative evaluation of the performance of the AP 
device, the percentage of time spent in each zone, and the visual 
evaluation provided by CVGA plots, other quantitative measures will be 
reported, analyzed and interpreted.  They are presented in Table 16–
3Table 10–3.  Unless indicated otherwise, the calculations are performed 
using CGM values. 
Table 16–3: Secondary end-points measures 
Measure 
Description 
Averages 
 
Mean glucose level during the 24-hour 
closed-loop 
Computed from CGM and then YSI values 
Mean-pre meal glucose value 
Computed 0-60 minutes before unannounced evening and 
morning meal 
Mean-post meal glucose value 
Computed 0-5 hrs after the evening and morning meal  
Mean exercise glucose value 
Computed value during the 30 min of exercise 
Mean-pre-exercise glucose value 
Computed 0-60 minutes before exercise 
Mean-post exercise glucose value 
Computed 0-3 hrs after end of exercise 
Extremes 
 
% of time of glucose > 400 mg/dL 
Computed from CGM and YSI values: analysis during 24 hour 
closed-loop, during night (12:00 am to 7:00 am) and during 
exercise 
% of time of glucose ≥ 300 mg/dL 
Computed from CGM and YSI values if duration is more than 
1 hour: analysis during 24 hour closed-loop, during night 
(12:00 am to 7:00 am) and during exercise 
% of time of glucose < 60 mg/dL 
Computed from CGM and YSI values: analysis during 24 hour 
closed-loop, during night (12:00 am to 7:00 am) and during 
exercise 
% of time of glucose ≤ 70 mg/dL 
Computed from CGM and YSI values if duration is more than 
1 hour: analysis during 24 hour closed-loop, during night 
(12:00 am to 7:00 am) and during exercise 
Area under the curve per gram CHO 
Computed from the beginning of a meal and continued for 5 


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Measure 
Description 
hours 
Area under the curve during exercise 
Computed during exercise and for 3 hours following exercise 
Area between the curve and nearest zone 
limit when outside the range [80-140] 
mg/dL 
This will measure how much deviation from the zone.  The 
analysis may be performed for the 24-hour closed-loop, for the 
night (12:00 am to 7:00 am), and during/following exercise and 
meals. 
Total amount of insulin delivered and 
standard deviation of delivery amounts 
during the 24-hour closed-loop 
Correspondence of total insulin delivered to total daily insulin 
(TDI) 
Variability and risk assessment (*) 
 
Interquartile range 
It measures the spread around the center of the desired zone, 
i.e. 110 mg/dL 
LBGI: Low blood glucose index 
Measures the frequency and extend of low blood glucose 
readings using CGM data 
HBGI: High blood glucose index 
Measures the frequency and extend of high blood glucose 
readings using CGM data 
Blood glucose index: LBGI+HBGI 
Measure the overall variability and the associated risk with 
hypoglycemia and hyperglycemia. 
Standard deviation of glucose rate of 
change 
Measures the stability of the closed-loop over time 
(*) See details of calculations in section 16.4.210.4.2. 
The review of the secondary end-points will also include the review of all 
AEs, SAEs, UADE, and complaints.  It will also include the review of the 
need of outside intervention to safely manage the subject. 
Data will be presented in table or graphs or both.  Data of all subjects may 
be pooled together or may be presented individually.  Should it be 
warranted, data may also be pooled in different sub-groups. 
16.4.2. Details for calculations 
Inter-quartile range (IQR):  It is a measure of the glucose variability.  It is 
more appropriate than the glucose standard deviation because the glucose 
distribution is highly asymmetric; the hypoglycemic range is numerically 
narrower than the hyperglycemic range, so the distribution of the glucose 
values of a subject is typically skewed.  The standard deviation of glucose 
values would be predominantly influenced by hyperglycemic excursion 
and would not be sensitive to hypoglycemia.  Therefore, the inter-quartile 
range will be calculated.  It is also called the mid-spread or middle fifty.  It 
is a statistical dispersion being equal to the difference between the third 
and first quartile.  It is a robust statistic. 
IQR = Qa – Q1      (1) 


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Where: Q3 is the 75th percentile and Q1 is the 25th percentile 
 
Risk index (LBGI and HBGI):  In order to capture the glucose variability 
and its associated risks for hypoglycemia and hyperglycemia, the low 
blood glucose index (LBGI) and high blood glucose index (HBGI) will be 
calculated as follows: 
Compute (2):  
f(BG) = 1.509 x [(ln(BG)) 1.084 – 5.381]     (2) 
The BG risk function is r(BG) using equation (3):  
r(BG) = 10 x f(BG)2          (3) 
The left and right branches are separated as described by (4) and (5):  
rl(BG) = r(BG)   if f(BG) < 0 and    0 otherwise    (4)  
rh(BG) = r(BG)   if f(BG) > 0 and   0 otherwise     (5) 
Given a series of CGM readings BG1, BG2, ….BGn, the Low and High BG 
indices (LBGI and HBGI) are computed as the average of rl(BG) and 
rh(BG) respectively. 
 
 
The BG risk index is then defined as: 
BGRI = LBGI + HBGI        (8) 
In essence, the LBGI and the HBGI split the overall glucose variation into 
two independent sections related to excursions into hypo- and 
hyperglycemia, and at the same time equalize the amplitude of these 
excursions with respect to the risk they carry.   
17. ACCESS TO SOURCE DATA / DOCUMENT 
17.1. Electronic data 
After the insertion of the 2 CGMs, the subject will be an outpatient for 2 to 3 
days before the CRC closed-loop trial.  Data from the CGM and insulin data 
during those few days will be collected for information purpose only.  
There are two types of data collected from the in-patient phase of the study: 


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 Manually entered data in APS© MATLAB® file:  
 Time stamps meal, exercise, other events 
 YSI values transferred from paper print out 
 Automatically generated: 
 
 APS© generated MATLAB® file with continuous glucose CGM 
and insulin data. 
The MATLAB® file generated during the closed-loop, including the time 
stamped events can be converted into Excel for analysis once the trial has been 
completed.  Patients are identified by numbers, and only the study coordinator is 
able to correlate the electronic file with the name of the patient.  Data analysis is 
blind to the patient’s name.  There will be a Master Patient Log. 
At the end of each trial with each subject, the electronic file is copied onto a 
Sansum computer which is backed up daily to an outside location.  The Sansum 
computer is password protected and all the data are saved to a dedicated folder.  
Data are saved with an appropriate filename.  Access to the data is controlled via 
password.  Only restricted personnel has access to the data and there is an audit 
trail associated with all data entry, data changes and manipulations.  Raw data 
are protected and cannot be altered.  Hard copy print-out of the data are also 
generated as a back up at the time of completion of the trial (prior to conversion 
of the file into Excel). 
17.2. Hard copy records 
All forms for the screening visit, the monitoring form, the clinical research 
forms (CRFs) and the informed consent are completed using a hard copy 
document.  The record is the original hard copy document.  All records are kept 
at Sansum in the study file.  The records are kept indefinitely.  
18. RECORD KEEPING 
All clinical hard copy forms and records are maintained by Sansum Diabetes 
Research Institute.  They are locked and kept indefinitely. 
All electronic records will be stored both on the study computer and will be 
transferred to a Sansum computer that is connected to a backup server at the end of 
each closed-loop session. 
19. ETHICS COMMITTEE 
Sansum Diabetes Research Institute uses the Cottage Health System IRB for this 
study.  IRB approval for the initial design of this clinical study was obtained under 


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the reference number #10-36 prior to this submission.  Any change resulting from this 
IDE will be resubmitted to the IRB before proceeding to the initiation of the clinical 
trial. 
Cottage Health System IRB 
Chair, CHS IRB:  Laurel J. Mehler, M.D. 
Post Office Box 689 
Pueblo at Bath Street 
Santa Barbara, CA 93102-0689 
20. FINANCIAL DISCLOSURE 
This clinical trial is partly funded by the JDRF grant #17-2010-765.  It is also actively 
supported by the Chemical Engineering department of the University of California, 
Santa Barbara, and Sansum Diabetes Research Institute. 
Subjects will be paid $400 to participate in this study; and there will be no cost to the 
subjects to participate in this study. 
Study supplies are provided at no cost by Dexcom® Corporation for CGMs 
(Dexcom® G4® System) and Animas Corporation for insulin delivery pumps 
(OneTouch® Ping®) and finger stick glucose meter (OneTouch® Ultra®). 
Financial disclosure of the Principle Investigator will be kept in the study file. 
21. INVESTIGATOR’S BROCHURE 
The AP device User Manual to be used by the investigator can be found in Appendix 
1 of the IDE application.  
22. INVESTIGATOR’S CONTACT INFORMATION 
The Sponsor is SDRI and the Principal Investigator is Howard Zisser, M.D.  He is the 
Director of Clinical Research and Diabetes Technology at the Sansum Diabetes 
Research Institute (SDRI) where he conducts clinical trials on new and innovative 
therapies for type 1, type 2 and gestational diabetes.  He is also an Adjunct Professor 
in the Department of Chemical Engineering of the University of California, Santa 
Barbara.  Dr. Zisser has been recognized worldwide for his work with continuous 
glucose sensors, insulin delivery systems and intensive glucose management.  He has 
directed numerous clinical studies. 
 
 
 


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Principal Investigator: 
Howard Zisser, M.D. 
Sansum Diabetes Research Institute 
Director of Clinical Research and Diabetes Technology 
2219 Bath Street 
Santa Barbara, CA 93105 
 
Email: hzisser@sansum.org 
Phone: 805-682-7640, X255 
Fax: 805-682-3332 
 
The co-investigators are: 
Francis Doyle III, Ph.D.  
Associate Dean for Research, Engineering 
Duncan and Suzanne Mellichamp Chair in Process Control 
UCSB-MIT-Caltech/ARO Institute of Collaborative Biotechnologies 
 
Eyal Dassau, Ph.D. 
Senior Investigator & Diabetes Team Research Manager 
 
University of California 
Department of Chemical Engineering 
Santa Barbara, CA 93106-5080 
 
Email: doyle@engineering.ucsb.edu 
Email: dassau@engineering.ucsb.edu 
Phone: 805-893-8133 
Fax: 805-893-4731 
 
Lois Jovanovič, M.D. 
Sansum Diabetes Research Institute 
Chief Scientific Officer 
2219 Bath Street 
Santa Barbara, CA 93105 
 
Email: ljovanovic@sansum.org 
Phone: 805-682-7640, X227 
Fax: 805-682-3332 
 


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23. LIST OF TABLES 
Table 4–2: Safety action to take in case of hypoglycemic and hyperglycemic events based 
on YSI values ............................................................................................................ 41 
Table 9–1: Severity of adverse events .............................................................................. 55 
Table 9–2: Levels of hyperglycemia and hypoglycemia as defined by YSI .................... 56 
Table 9–3: Anticipated Adverse Events ........................................................................... 57 
Table 10–1:  Interpretation of the CVGA zones ............................................................... 59 
Table 10–2: Primary end-point measures ......................................................................... 60 
Table 10–3: Secondary end-points measures .................................................................... 61