Clinical trial NCT03554486
Conditions: Diabetes Mellitus, Type 1
Sponsor: Stanford University
Start date: 2018-07-23; Completion date: 2019-03-30
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a pilot outpatient study conducted at Stanford to obtain preliminary data on how Fiasp® works in a closed-loop system and to determine if any changes need to be made to the 670G pump to optimize the use of Fiasp®.

Detailed description:
This will be a randomized cross-over blinded study and to see how the 670G pump responds to the introduction of Fiasp® insulin. Subjects enrolled in the study will have a 2 week period of optimization with weekly assessments of their Carelink download before entering the blinded phase of the study. They will use their usual home insulin during the optimization phase. They will then be started on their first blinded insulin (aspart or Fiasp®) which they will use for 2 weeks, before they cross-over to the other insulin.

Arms: arm 1: Following a 2-week run-in period for pump-setting adjustments and monitoring, participants 1 will use Fiasp insulin for 2 weeks, followed by Novolog insulin for 2 weeks. Both the subject and the investigator will be blinded to which group the subject is assigned. arm 2: Following a 2-week run-in period for pump-setting adjustments and monitoring, participants 1 will use Novolog insulin for 2 weeks, followed by Fiasp insulin for 2 weeks. Both the subject and the investigator will be blinded to which group the subject is assigned.
Interventions: intervention 1: Fiasp intervention 2: Novolog
Intervention descriptions: intervention 1: Fiasp insulin will be used for 2 weeks with the 670G hybrid closed-loop system intervention 2: Novolog insulin will be used for 2 weeks with the 670G hybrid closed-loop system

Protocol documents:
Prot_SAP_000.pdf: 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
Evaluation of  Fiasp® (Fast acting insulin aspart)  
9 
in 670G Hybrid Closed-loop Therapy 
10 
 
11 
 
 
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Version 1.0 
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3/30/18 
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NCT: 03554486 
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18 


Table of Contents 
19 
 
20 
CHAPTER 1:  INTRODUCTION ............................................................................... 4 
21 
1.1 Study Objectives: ............................................................................................ 4 
22 
1.2 BACKGROUND INFORMATION ..................................................................... 4 
23 
1.2.1 Fiasp® .......................................................................................................... 4 
24 
1.2.2 Medtronic 670G Hybrid Closed-loop ............................................................ 5 
25 
1.2.3 Use Of A Standard Breakfast To Assess Insulin Pharmacodynamics Data In 
26 
An Outpatient Setting. ........................................................................................... 7 
27 
1.3 Study Overview ............................................................................................. 10 
28 
1.4 Protocol Synopsis: ......................................................................................... 10 
29 
General Considerations ....................................................................................... 12 
30 
CHAPTER 2:  SUBJECT ENROLLMENT AND STUDY INITIATION .................... 13 
31 
Study Enrollment and Duration ........................................................................... 13 
32 
Eligibility and Exclusion Criteria .......................................................................... 13 
33 
Eligibility Criteria ........................................................................................... 13 
34 
Exclusion Criteria .......................................................................................... 13 
35 
Recruitment Plan: ................................................................................................ 14 
36 
Informed Consent Plan and HIPAA Authorizations: ............................................ 14 
37 
Eligibility Assessment and Baseline Data Collection ........................................... 14 
38 
Historical Information and Physical Exam ........................................................... 14 
39 
HbA1c ................................................................................................................. 15 
40 
Authorization Procedures .................................................................................... 15 
41 
CHAPTER 3:   PROTOCOL PROCEDURES ......................................................... 16 
42 
Visit 1:  Informed consent process: ..................................................................... 16 
43 
Informed consent process: .............................................................................. 16 
44 
History and physical exam: .............................................................................. 16 
45 
Part 1:  Randomized, cross-over, blinded study to assess any adaptations of the 
46 
670G pump to Fiasp® and to assess meal pharmacodynamics of Fiasp® 
47 
compared to aspart with a typical breakfast in the home environment ................ 17 
48 
Part 2: Extended Use Optimization Study ........................................................... 18 
49 
CHAPTER 4:  ADVERSE EVENT REPORTING AND PROTOCOL MONITORING
50 
 ................................................................................................................................ 20 
51 
Definition ............................................................................................................. 20 
52 
Recording of Adverse Events .............................................................................. 20 
53 
Reporting Serious or Unexpected Adverse Events ............................................. 21 
54 
Potential Risks and Side Effects ......................................................................... 21 
55 
Risk of Hypoglycemia .......................................................................................... 22 
56 
Risk of Hyperglycemia ......................................................................................... 22 
57 
Protection Against Risks and Treatment of Side Effects ..................................... 22 
58 
Other Risks ......................................................................................................... 22 
59 
CHAPTER 5:  MISCELLANEOUS CONSIDERATIONS ........................................ 23 
60 
Potential Benefits ................................................................................................ 23 
61 
Subject Compensation ........................................................................................ 23 
62 
Subject Withdrawal .............................................................................................. 23 
63 
Confidentiality ...................................................................................................... 23 
64 


Level of Risk ........................................................................................................ 23 
65 
CHAPTER 6:  STATISTICAL CONSIDERATIONS ................................................ 25 
66 
CHAPTER 7:  REFERENCES ................................................................................ 27 
67 
 
 
68 


CHAPTER 1:  INTRODUCTION 
69 
 
70 
1.1 Study Objectives:   
71 
To assess the effect of using Fiasp® in a closed-loop system:  
72 
Part 1:  To assess how the 670G system adapts to the introduction of Fiasp® 
73 
insulin  
74 
Part 2:  To assess changes experienced clinicians will make to the use of Fiasp® 
75 
insulin in the 670G pump 
76 
 
77 
 
78 
1.2 BACKGROUND INFORMATION 
79 
1.2.1 Fiasp®  
80 
Faster-acting insulin aspart (faster aspart or Fiasp®) is insulin aspart in a new formulation 
81 
that contains two well-known excipients generally recognized as safe (GRAS), niacinamide 
82 
and L-arginine. These are both listed in the US Food and Drug Administration inactive 
83 
ingredient database, in products for injection, at higher concentrations than used in Fiasp®.  
84 
With Fiasp®, niacinamide is considered responsible for faster initial absorption after 
85 
subcutaneous administration and L-arginine serves as a stabilizing agent. In subjects with 
86 
type 1 diabetes mellitus (T1DM),  Fiasp® administered by subcutaneous injection had 
87 
twice-as-fast onset of appearance, a 2-fold higher early exposure, and >50% greater early 
88 
glucose-lowering effect compared with insulin aspart 1,2. When Fiasp® is administered by 
89 
subcutaneous insulin infusion pump therapy, the rapid onset of action is even more 
90 
pronounced.  The time to half-maximal activity was reduced by 11.8 minutes, the time to 
91 
peak activity was reduced by 25.7 minutes, and the duration of insulin activity was reduced 
92 
by 35.4 minutes when compared to insulin aspart 3 (see Figure 1 below). 
93 
 
94 
Figure 1-1:  Fiasp®  Pharmacokinetics.  A bolus of 0.15 U/kg of aspart (grey) (n=46) or  
95 
Fiasp®  (blue) (n=44) was given subcutaneously by an insulin pump and serum insulin 
96 
concentrations were measure.
97 
 
98 
In a 6 week double-blind, randomized, crossover active-controlled trial comparing aspart to  
99 


Fiasp®  using continuous subcutaneous insulin infusion (CSII) pump therapy, the  Fiasp®  
100 
two hour post prandial glucose levels were significantly lower following a standardized meal 
101 
test 4 (Figure 1-2) 
102 
 
103 
Figure 1-2: Mean baseline-adjusted plasma glucose levels following either insulin aspart (in 
104 
grey) or  Fiasp®  (in blue) given as an insulin pump bolus at the onset of a standardized 
105 
liquid meal (Boost) which has 102 grams of CHO.  The bolus calculator in their pump was 
106 
used for each meal dose. 
107 
 
108 
The more rapid onset of action and shorter duration could be very beneficial to full closed-
109 
loop control allowing an earlier onset of insulin action to cover the postprandial glucose rise, 
110 
and decreasing the residual insulin after a meal to prevent late hypoglycemia.   Fiasp® has 
111 
not been tested in a hybrid closed-loop system. 
112 
Fiasp® was approved by the FDA on September 29, 2017 for people with type 1 and type 2 
113 
diabetes in a pre-filled FlexTouch® pen and in 10 ml vials.  It was approved to be given by 
114 
injection, but not for use in pumps.  In Europe it was approved for use by injections and in 
115 
insulin infusion pumps.  In both the US and Europe it was approved for use in pregnancy.  
116 
There has been one study published on pump compatibility of Fiasp® 5 which showed a 
117 
premature end of infusion set wear in 10% of 210 Fiasp® infusions, and 4% of 98 aspart 
118 
infusions (p=ns).   
119 
 
120 
1.2.2 Medtronic 670G Hybrid Closed-loop 
121 
The Medtronic 670G hybrid closed loop system is the first fully integrated system designed 
122 
for continuous day and night closed-loop control.  The system requires meal announcement 
123 
with an estimate of carbohydrate intake and a premeal insulin bolus to optimize glucose 
124 
excursions.  We published the first results of using this system in 2015 in adolescents 
125 
attending a diabetes camp 6, and the 670G system was approved for commercial sale by 
126 
the FDA on September 28th, 2016.  We have had adolescents using this system for 2 ½ 
127 
years, 7-14 year olds using the system for 15 months, and 5 to 6 year olds have been using 
128 


this system at Stanford for over 3 months as part of the pivotal trials with extended use of 
129 
the system after the initial 3 month pivotal  phase.  Both the adult and pediatric clinics now 
130 
have patients using the 670G system.   
131 
 
132 
Figure 1-3:  Medtronic 670G system:  Medtronic 670G pump, Guardian 3 continuous 
133 
glucose sensor, and Bayer Link glucose meter. 
134 
 
135 
 
136 
The safety and effectiveness of the in-home use of a hybrid closed-loop (HCL) system was 
137 
investigated in adolescents (n = 30, ages 14–21 years) and adults (n = 94, ages 22–75 
138 
years) with type 1 diabetes in a multicenter pivotal trial 7. The 670G system was used 
139 
during a 2-week run-in phase without HCL control, or Auto Mode, enabled (Manual Mode) 
140 
and then in Auto Mode during a 3-month study phase.  Data from the trial is seen below, in 
141 
Table 1. 
142 
Table 1: Comparison of glucose control and insulin doses from the 2 week baseline 
143 
data compared to the 3 months of 670G hybrid closed loop use 8 
144 
Run In (Baseline) 
3 month Data 
p 
HbA1c 
7.4 ± 0.9 
6.9 ± 0.6 
<0.001 
% <70 mg/dL 
6.4 ± 5.3 
3.3 ± 2.0 
<0.001 
% 71-180 mg/dL 
66.7 ± 12.2 
72.2 ± 8.8 
< 0.001 
% >180 mg/dL 
27.4±13.7 
24.5±9.2 
< 0.001 
Mean Glucose 
150.2±22.7 
150.8±13.7 
NS 
Within Day CV 
33.5±4.3 
30.8±3.3 
< 0.001 
TDI  
47 ± 22 
51 ± 27 
< 0.001 
 
145 


The adolescents used the system for a median 75.8% of the time, and adults used the 
146 
system for a median 88.0% of the time. From baseline run-in to the end of study phase the 
147 
adolescent HbA1c decreased from 7.7% to 7.1% (P < 0.001) and adult HbA1c levels 
148 
decreased from 7.3% to 6.8% (P < 0.001).  The proportion of overall in-target (71–180 
149 
mg/dL) sensor glucose (SG) values increased from 60.4% to 67.2% (P < 0.001) in 
150 
adolescents and from 68.8% to 73.8% (P < 0.001) in adults. Figure 1-4 provides a graph of 
151 
the sensor values for both adolescent and adult subjects comparing their baseline data to 
152 
their data using the 670G.  There were no severe hypoglycemic or diabetic ketoacidosis 
153 
events in either cohort. 
154 
 
155 
Figure 1-4:  Graph of the median and interquartile range sensor values over a 24 hour day 
156 
comparing the values obtain at baseline with regular care (in grey), to the data over 3 
157 
months of using the Medtronic 670G pump for the adult and adolescent patients. The gray 
158 
band and dotted line represent data from the run-in phase; the pink band and solid line 
159 
represent data from the study phase. 7 
160 
 
161 
1.2.3 Use Of A Standard Breakfast To Assess Insulin Pharmacodynamics Data 
162 
In An Outpatient Setting. 
163 
In a study to assess the effect of hyaluronidase administration on insulin 
164 
pharmacodynamics, 14 subjects were instructed to eat the same breakfast meal each day, 
165 
give an insulin bolus based on their usual insulin-to-carbohydrate ratio and correction 
166 
factor, and they were instructed not to eat for at least 3 hours following breakfast.  Subjects 
167 
were required to document their food intake each morning at breakfast and the 
168 
carbohydrate content was verified on the pump download bolus history.  Postprandial 
169 
glucodynamic parameters including peak glucose concentration (Cmax), time to Cmax (tmax), 
170 
A


and estimated average glucose excursions were assessed using sensor glucose values at 
171 
a time interval of 0 to 180 minutes after breakfast bolus.  If a bolus was given between 120-
172 
180 minutes following the breakfast bolus, CGM values were only used up to the time of the 
173 
bolus.  The glucose at the time of the breakfast bolus (Time 0) was set to 0 mg/dL for each 
174 
meal, and the remaining CGM values were adjusted proportionally to allow analysis of 
175 
postprandial glucodynamic parameters.  We utilized a mixed-effects model accounting for 
176 
crossover study design of the study with the sequence of treatment nested within the 
177 
patient, and this was the random effect.  Breakfast meals were excluded from postprandial 
178 
analysis if: 1) the rate of change was greater than 0.5mg/dL/min in the 1 hour prior to 
179 
breakfast, 2) subjects gave a subsequent bolus prior to 120 minutes following the breakfast 
180 
bolus, or 3) subjects deviated from their typical breakfast.  
181 
For the postprandial glucose analysis (Table 2)  there were limited observations available, 
182 
but the estimated average glucose excursion was less for hyaluronidase compared to 
183 
standard weeks on Day 1 of infusion set life (12-24 hours after the first hyaluronidase 
184 
infusion) and Day 3 of infusion set life (immediately after second hyaluronidase infusion).  
185 
This effect was lost on Day 2 of infusion set life (36-48 hours after the first hyaluronidase 
186 
infusion) and Day 4 of infusion set life (24 hours after the second hyaluronidase infusion). 
187 
The study was not powered to show a difference in glucodynamic parameters, but Cmax 
188 
and tmax tended to be lower immediately after hyaluronidase infusions.  Postprandial 
189 
profiles obtained from CGM glucose values are presented in mean ± standard error for 
190 
meals analyzed on Days 1-4 of infusion set life in Figure 3.  There were too few meals 
191 
available for analysis beyond Day 4 of infusion set life to allow postprandial analysis. 
192 
 
193 
Table 2: Postprandial glucodynamic parameters following hyaluronidase injection    
194 
 
195 
 
0 hours post 
Hyaluronidase 
 
12-24 hours post 
Hyaluronidase 
36-48 hours post 
Hyaluronidase 
Standard 
(N=11) 
Hyal 
(N=11) 
Standard 
(N=14) 
Hyal 
(N=10) 
Standard 
(N=11) 
Hyal 
(N=13) 
Estimated 
glycemic 
excursion+ 
24.8 
-6.7 
20.7 
-5.4 
14 
26.9 
P-value 
<0.001* 
<0.001* 
<0.001* 
Cmax° 
 
 
Mean ± SD 
69.5 ± 47.4 
43.5 ± 44.5 
72.0 ± 48.8 
36.9 ± 35.1 
51.6 ± 
32.0 
56.4 ± 
25.9 
Median, IQR 
63 (31,80) 
34 
(7,68) 
77.5 (19,117) 
29 (17,48) 
46 (33,76) 
52 (42,69) 
P-value 
0.296 
0.167 
0.681 
tmax‡ 
 
 
Mean ± SD 
84.5 ± 49.3 
69.1 ± 67.2 
92.9 ± 58.9 
76.5 ± 55.8 
65.4 ± 
32.6 
73.8 ± 
40.2 
Median, IQR 
65 (50,105) 
50 (10,240) 
82.5 (60,130) 
60 (45,120) 
65 (50,95) 
55 (45,90) 
P-value 
0.3 
0.5 
0.591 
 
196 
P-values were obtained using a mixed-effects model accounting for crossover study 
197 
design of the study with the sequence of treatment nested within the patient, and 
198 
this was the random effect.   
199 
+AUC=Area under the Curve (mg/dL) 
200 


°Cmax=Peak glucose concentration (mg/dL) 
201 
‡Tmax=Time to peak glucose concentration (minutes) 
202 
*represents statistical significance (i.e. P<0.05) 
203 
 
204 
Figure 1-5: Postprandial glucose profiles by Day of infusion set wear (and hours 
205 
following hyaluronidase infusion) 
206 
 
207 
 
208 
 
 
209 
Day 1 of Infusion Set
(12-24 hrs s/p 1st Hyal dose)
Time in minutes
-90
-60
-30
0
30
60
90
120
150
180
Glucose mg/dl from baseline
-40
-20
0
20
40
60
80
Hyaluronidase (N=10) 
Standard (N=14)
Day 2 of Infusion Set
(36-48 hrs s/p 1st Hyal dose) 
Time in minutes
-90
-60
-30
0
30
60
90
120
150
180
Glucose mg/dl from baseline
-20
0
20
40
60
Hyaluronidase (N=13) 
Standard (N=11)
Day 3 of Infusion Set
(0 hrs s/p 2nd Hyal dose)
Time in minutes
-90
-60
-30
0
30
60
90
120
150
180
Glucose mg/dl from baseline
-60
-40
-20
0
20
40
60
80
Hyaluronidase (n=11)
Standard (N=11)


1.3 Study Overview 
210 
 
211 
Use of Fiasp®: Fiasp® insulin has been approved for sale in the USA, and has been 
212 
available since February 7th 2018.  Although it is not approved for pumps, it will be used in 
213 
pumps off-label because of it has a more rapid onset of action.  The 670G closed-loop 
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system automatically adjusts basal rates throughout the day and night to minimize hyper 
215 
and hypoglycemia.  Use of the 670G provides a unique opportunity to assess how Fiasp® 
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works in a closed-loop system and to determine if any changes need to be made to the 
217 
670G pump to optimize the use of Fiasp®.  
218 
 
219 
According to the FDA guidelines we do not think this study requires an IND since we meet 
220 
all of the following six conditions:      
221 
i. 
it is not intended to be reported to FDA in support of a new indication for use or to 
222 
support any other significant change in the labeling for the drug; 
223 
ii. 
it is not intended to support a significant change in the advertising for the product; 
224 
iii. 
it does not involve a route of administration (it is still being given subcutaneously) or 
225 
dosage level, use in a subject population, or other factor that significantly increases 
226 
the risks (or decreases the acceptability of the risks) associated with the use of the 
227 
drug product; 
228 
iv. 
it is conducted in compliance with the requirements for IRB review and informed 
229 
consent [21 CFR parts 56 and 50, respectively]; 
230 
v. 
it is conducted in compliance with the requirements concerning the promotion and 
231 
sale of drugs [21 CFR 312.7]; and 
232 
vi. 
it does not intend to invoke 21 CFR 50.24.” 
233 
 
 
234 
 
235 
1.4 Protocol Synopsis: 
236 
 
237 
This is a pilot outpatient study conducted at Stanford to obtain preliminary data on 
238 
how Fiasp® works in a closed-loop system. The plan will be to enroll up to 20 
239 
subjects for each part of the study.  Part 1 is a blinded cross-over study to assess 
240 
how well Fiasp® insulin works when used with the 670G pump compared to aspart 
241 
insulin and will take 6 weeks for a subject to complete.  Part 2 is a Fiasp® 
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optimization phase to assess if making changes to meal coverage with the 
243 
knowledge that Fiasp® is being used can optimize the advantages of the 670G 
244 
pump with Fiasp® use, and to observe longer term use of Fiasp® in the 670G 
245 
pump. This will be a 6 week study.    
246 
 
247 
Part 1:  Randomized cross-over, blinded study which includes assessment of meal 
248 
pharmacodynamics. 
249 
Part 1 will be a randomized cross-over blinded study and will also test to see how  
250 
the 670G pump responds to the introduction of Fiasp® insulin.  Subjects enrolled in 
251 


the study will have a 2 week period of optimization with weekly assessments of their 
252 
Carelink download before entering the blinded phase of the study.  They will use 
253 
their usual home insulin during the optimization phase.  They will then been started 
254 
on their first blinded insulin (aspart or Fiasp®) which they will use for 2 weeks, 
255 
before they cross-over to the other insulin.  During the second week of each arm we 
256 
will: 
257 
1)  Assess CGM measurements of:  
258 
a) time in range (70-180 mg/dl) 
259 
b) percent time <70 mg/dl,  
260 
c) mean glucose, 
261 
d) glucose CV,  
262 
2) Pump data for:   
263 
a) CHO:I ratios at Breakfast, Lunch and Dinner,   
264 
b) total daily insulin dose,  
265 
c) total daily basal insulin,  
266 
d) insulin delivery form MN to 6AM, and 6AM to MN  
267 
3) We will test to see if there is any difference in pharmacodynamics when 
268 
using Fiasp® in the home environment when they are eating their usual 
269 
breakfast.   
270 
4) We will also assess their glucose levels following a high fat meal at dinner of 
271 
at least 30 grams of fat.   
272 
 
273 
Part II:   Extended Use Observational Study. 
274 
This study will consist of 6 weeks of closely monitored home use of the 670G pump 
275 
with review of their pump and sensor downloads every 2 weeks by clinicians who 
276 
are experienced in using the 670G pump.  The goals of this phase of the study are 
277 
to:     
278 
1) Assess how Fiasp® changes meal bolusing, i.e. do adjustments need to be 
279 
made in their carbohydrate to insulin ratios or timing of their boluses when 
280 
they are using Fiasp®  I 
281 
2) Assess how Fiasp® works with the higher fat meals that may occur with 
282 
dinner, i.e. will the dinner dose need to be divided into early and late boluses 
283 
3) Assess how Fiasp® affects infusion sites under usual care conditions, i.e are 
284 
there any local reactions to Fiasp® 
285 
4) Assess if Fiasp® becomes less effective over the life an infusion set (are sets 
286 
changed more frequently)   
287 
5) Assess how the 670G performs when Fiasp® is used:   
288 
a. Do insulin-to-carbohydrate ratios need to be modified 
289 
b. Does duration of insulin action need to be modified 
290 
c. Is more or less basal insulin delivered 
291 
d. Does the total daily dose change 
292 
e. Does the performance of the 670G change overnight (MN to 6AM) 
293 
and during the day (6AM to MN) in terms of time in range, mean 
294 
glucose and % of readings <70 mg/dL. 
295 
 
296 
will include both males and females and an enrollment goal will be to achieve an 
297 


approximately equal sex distribution.  Their total daily insulin dose should be at least 
298 
0.3 units/kg/day and they should be eating at least 60 grams of carbohydrate each 
299 
day. 
300 
 
301 
General Considerations 
302 
The study is being conducted in compliance with the policies described in the study 
303 
policies document, with the ethical principles that have their origin in the Declaration 
304 
of Helsinki, with the protocol described herein, and with the standards of Good 
305 
Clinical Practice. 
306 
 
 
307 


CHAPTER 2:  SUBJECT ENROLLMENT AND STUDY INITIATION 
308 
 
309 
Study Enrollment and Duration 
310 
Part 1: Randomized cross-over, blinded study with assessment of meal 
311 
pharmacodynamics:  up to 20 subjects will be studied and the studies for each 
312 
subject will last 6 weeks.  
313 
Part 2: Long term use of Fiasp®.  We will recruit up to 20 subjects who are using 
314 
Fiasp® insulin,  they are not excluded if they were in Part 1, in fact subjects in part 1 
315 
will be encouraged to continue into part 2 of the study.  Duration is up to 6 weeks, or 
316 
until subject decides to stop using Fiasp®.   
317 
 
318 
Eligibility and Exclusion Criteria 
319 
 
320 
Eligibility Criteria 
321 
To be eligible for the study, a subject must meet the following criteria: 
322 
1. Clinical diagnosis of type 1 diabetes and using 670G pump for at least 1 
323 
month, and willing to have the 670G pump downloaded into a Carelink 
324 
Clinical research database. 
325 
2. The diagnosis of type 1 diabetes is based on the investigator’s judgment; C-
326 
peptide level and antibody determinations are not needed.   
327 
3. Age ≥18 years 
328 
4. Using Novolog or Fiasp® insulin at time of enrollment 
329 
5. Willing to use Fiasp® insulin  
330 
6. Total daily insulin dose is at least 0.3 units/kg/day 
331 
7. Usual carbohydrate intake is at least 60 grams a day, and willing to have at 
332 
least 25 grams of carbohydrates for breakfast 
333 
8. For females, not currently known to be pregnant 
334 
9. An understanding of and willingness to follow the protocol and sign the 
335 
informed consent 
336 
10. Willing to have photographs taken of their infusion sites 
337 
11. Willing to download their 670G pump every 1-2 weeks to a research Carelink 
338 
account 
339 
12. Willingness to answer a brief online questionnaire every 2 weeks  
340 
13. Must be able to understand spoken or written English 
341 
14. For subjects participating in Part 2 of this study they will need to be using 
342 
Fiasp® as part of their usual care 
343 
15. Hemoglobin A1c between 6 and 10% at the time of enrollment 
344 
  
345 
Exclusion Criteria 
346 
The presence of any of the following is an exclusion for the study: 
347 
1. 
Pregnant or lactating females 
348 
2. 
No hypoglycemic seizure or loss of consciousness in the past 6 months 
349 
3. 
Severe episode of DKA in the 6 months prior to study enrollment that was 
350 
unrelated to an infusion set failure 
351 
4. 
No known cardiovascular events in the last 6 months 
352 
5. 
No active proliferative diabetic retinopathy 
353 


6. 
Known tape allergies  
354 
7. 
Current treatment for a seizure disorder  
355 
8. 
Cystic fibrosis  
356 
9. 
Active infection 
357 
10. 
A known medical condition that in the judgment of the investigator might 
358 
interfere with the completion of the protocol 
359 
11. 
Inpatient psychiatric treatment in the past 6 months 
360 
12. 
Presence of a known adrenal disorder 
361 
13. 
If on antihypertensive, thyroid, anti-depressant or lipid lowering 
362 
medication, with lack of stability on the medication for the past 2 months 
363 
prior to enrollment in the study 
364 
14. 
Abuse of alcohol 
365 
15. 
Dialysis or renal failure 
366 
16. 
Known eGFR <60% 
367 
 
368 
Note: Adequately treated thyroid disease and celiac disease do not exclude 
369 
subjects from enrollment.  
370 
 
371 
Recruitment Plan:  
372 
We will contact subjects at our clinic who are using the 670G system and are using 
373 
Novolog or Fiasp® insulin.  A short description of the present study will be given to 
374 
them via email, phone or in-person.  If the subject expresses interest, then the study 
375 
will be presented in detail.  The goal will be to enroll four subjects each week to 
376 
establish cohorts of 4 subjects.  
377 
 
 
378 
Informed Consent Plan and HIPAA Authorizations:  
379 
The subject will be allowed sufficient time to read over the IRB approved consent 
380 
form, and given opportunity to have all questions answered.  The consent will 
381 
contain a brief description of the research project, as well as the procedures and 
382 
treatments to be undertaken, and the risks of each treatment and procedure.  
383 
Consent form will be obtained by delegated research staff. The PI and study staff 
384 
will be available to fully discuss consent with the subjects as needed.  Subjects 
385 
have the right to withdraw at any time during the study.  The subject will be provided 
386 
with the Informed Consent Form to read and will be given the opportunity to ask 
387 
questions.  If the subject agrees to participate, the Informed Consent Form will be 
388 
signed.  A copy of the consent form will be provided to the subject and another copy 
389 
will be added to the subject’s clinic chart.    Written informed consent must be 
390 
obtained from the subject prior to performing any study-specific procedures that are 
391 
not part of the subject’s routine care.   
392 
 
393 
Eligibility Assessment and Baseline Data Collection 
394 
Potential subjects will be evaluated for study eligibility through the elicitation of a 
395 
medical history, performance of a physical examination by study personnel. 
396 
  
397 
Historical Information and Physical Exam 
398 
A history will be elicited from the subject and/or extracted from available medical 
399 


records with regard to the subject’s diabetes history, current diabetes management, 
400 
other past and current medical problems, past and current medications, and drug 
401 
allergies.  A study focused physical exam (including height, weight measurements 
402 
and infusion site assessments) will be performed by the study investigator or 
403 
designee (an attending physician, fellow, nurse practitioner or a physician 
404 
assistant).  
405 
 
406 
HbA1c 
407 
A point of care HbA1c level will be obtained at the time of enrollment, at the start of 
408 
the 3 month observational study and at the end of the observational study.   
409 
 
410 
Authorization Procedures 
411 
As part of the informed consent process, each subject will be asked to sign an 
412 
authorization for release of personal information.  The investigator, or his or her 
413 
designee, will review what study specific information will be collected and to whom 
414 
that information will be disclosed.  After speaking with the subject, questions will be 
415 
answered about the details regarding authorization. 
416 
 
 
417 


CHAPTER 3:   PROTOCOL PROCEDURES 
418 
 
419 
 
420 
Visit 1:  Informed consent process:    
421 
Informed consent process:  The protocol will be reviewed with the subjects, they will 
422 
be given time to read the informed consent and ask any questions about the study.   
423 
 
424 
History and physical exam: Including age at diagnosis of diabetes, duration of 
425 
diabetes, any retinal, renal or cardiac conditions.  Height, weight, and examination 
426 
of skin where infusion sets are inserted.   
427 
 
428 
Laboratory tests:  Point of care A1c will be obtained and urine pregnancy test will be 
429 
obtained on all women who are pre-menopausal.  
430 
 
431 
Training on home procedures: 
432 
 
433 
Blood glucose monitoring:  Subjects will test blood glucose using a Bayer Contour 
434 
Next Link home glucose meter at least 3 times daily.  Subjects will be instructed to 
435 
check blood ketones using a blood ketone meter if there is unexplained sensor 
436 
hyperglcyemia and the blood glucose meter reading is greater than 250 mg/dL.  
437 
 
438 
Calibration of Guardian Sensor:  They will be instructed to calibrate the Guardian 
439 
sensor before breakfast and before dinner each day when there are no rate of 
440 
change arrows and after washing their hands or using the second drop of blood.  
441 
They will also be instructed to calibrate if the Guardian is showing more than a 20% 
442 
error when compared to their Contour Next blood glucose reading and the Guardian 
443 
is not showing a rapid rate of change. 
444 
 
445 
Replacement of Guardian Sensor:  If the Guardian sensor stops functioning during 
446 
the study, the subjects will insert a new sensor.   
447 
 
448 
Determination of an infusion set failure:   
449 
They will be instructed to replace the infusion set if: 
450 
1. Their ketone level is greater than 0.6 mmol/L,  
451 
2. There is evidence of infection at the infusion site 
452 
3. Their blood glucose (meter) does not decrease by at least 50 mg/dL within 1 
453 
hour of a correction bolus for unexplained hyperglycemia with  a blood 
454 
glucose greater than 250 mg/dL.  
455 
4. There is a pump occlusion alarm. 
456 
 
457 
Documentation of infusion site reactions:  At home they will exam the infusion set 
458 
site at time of infusion set failure for signs of infection.  They will record bleeding, 
459 
redness, induration, and bruising in mm, and call one of the investigators if there is 
460 
more than 10 mm of erythema or induration.  They will be given a ruler for making 
461 
these measurements. If there is more than 3 mm of induration or redness they will 
462 
be asked to take a picture and enter these measurments into a text to the study 
463 


coordinator or submit the information directly into RedCap.   
464 
 
465 
The goal will be to have sensor wear at least 80% of the time and in automode at 
466 
least 70% of the time.  There pump will be uploaded to a research Carelink account 
467 
each week.  While in the blinded phase of the study the clinical staff will refrain from 
468 
making changes to 670G pump settings unless requested by the subject or for 
469 
safety reasons such as an episode of severe hypoglcyemia (unconscousness or 
470 
seizure), >10% time <70 mg/dl, or >20% of the time over 250 mg/dl.   
471 
 
472 
Part 1:  Randomized, cross-over, blinded study to assess any adaptations of 
473 
the 670G pump to Fiasp® and to assess meal pharmacodynamics of Fiasp® 
474 
compared to aspart with a typical breakfast in the home environment 
475 
 
476 
Participants will have a 2 week run-in on their usual home insulin (aspart of Fiasp®).  
477 
During the run-in, there pump will be downloaded weekly, reviewed by the clinical 
478 
staff and adjustments will be made to their settings as needed to optimize their 
479 
glycemic control.  Participants will then be randomly assigned to 2 sequences of 
480 
testing starting with either aspart or Fiasp®.  They will use each insulin for two 
481 
weeks.  The participants and the investigators will be blinded to the insulin.  During 
482 
the second week of using a blinded insulin they will have the meal 
483 
pharmacodynamics testing.  They will then cross-over to the other insulin and 
484 
during the second week they will repeat meal pharmacodynamics testing.  At the 
485 
end of each week they will upload their 670G pump to a Carelink clinical (research) 
486 
account and it will be reviewed by the research staff for safety purposes.   
487 
 
488 
Procedure for meal testing.  For each week of meal testing they will be asked to 
489 
have 3 days with a consistent breakfast that is the same for all 6 days they are 
490 
doing a meal test (3 days on each insulin).  The breakfast studies should ideally 
491 
occur on standard work days (not holidays or weekends).  On these three days they 
492 
will be asked to have a dinner with at least 30 grams of fat and no additional food in 
493 
the evening (unless they are treating hypoglycemia).  They will be asked to take a 
494 
picture of the dinner meal and identify their food and portion sizes.  If they have a 
495 
smart phone (Android or Apple), they may download Calorie Mamma® or Calorie 
496 
King® to help them in calculating carbohydrates, protein and fat from the meal.  
497 
They will do this for each of their dinner meals on each of the days they are doing 
498 
the breakfast study, and for the breakfast meals they are eating each morning as 
499 
part of the pharmacodynamic testing.  They will change their infusion set before 
500 
dinner prior to the first day of starting a standard breakfast, i.e., if they work from 
501 
Monday to Friday, this could be done on Sunday.  
502 
 
503 
They are blinded to the insulin and the insulin dose decisions for these meals is also 
504 
not under their control since:  1) The overnight insulin delivery is not under their 
505 
control, 2) The timing of the meal bolus will be the same for all mornings, the dose 
506 
will be given immediately before eating, 3) They dose of insulin will be determined 
507 
by their pump using their preset insulin-to-carbohydrate ratio and they will be eating 
508 
the same amount of carbohydrates each morning.  They also will not be getting a 
509 


correction dose of insulin in the morning because they are using the closed-loop 
510 
controller overnight.  If they required a correction dose of insulin, we will not use the 
511 
data from that morning in our data analysis.  We will assess during each of these 
512 
four weeks the time in-range (70-180 mg/dl), mean glucose, CV, and time <70 
513 
mg/dl.   
514 
 
515 
At the end of each two week period of blinded insulin use the participants and the 
516 
health care providers will be given a questionnaire asking them which insulin they 
517 
thought they were using, and if they had noticed any advantages to disadvantages 
518 
while they were using this insulin, and whether they would have wanted to make 
519 
any changes to their insulin delivery settings while using the insulin. 
520 
 
521 
 
522 
Part 2: Extended Use Optimization Study  
523 
 
524 
To be eligible for Part 2 one of the inclusion criteria will be that the subject is 
525 
currently using Fiasp® insulin under their usual care.  Subjects for Part 1 may 
526 
participate in part 2, and we will also recruit subjects outside of part 2 who are 
527 
currently using a 670G pump and taking Fiasp insulin.  They will download their 
528 
670G pump to a research Carelink account every 2 weeks.  Their data will be 
529 
reviewed within 3 days by the clinicians managing the study at each research 
530 
clinical site.  An email, text or phone call will be made to the subject after reviewing 
531 
their pump/sensor data.  Recommendations for dosage changes will be recorded on 
532 
a case report form or directly into RedCap.  The study investigators will meet every 
533 
2 to 4 weeks during the study to review clinical issues and insights that have been 
534 
observed.   
535 
 
536 
To assess the long term effect of using Fiasp® on infusion sites and insulin action, 
537 
they will be asked to use Fiasp® as long as they see benefit in using it after the 
538 
initial meal boluses testing is completed.  Each time they change their infusion set, 
539 
we will ask them to examine the site for any bleeding, redness or induration, and 
540 
measure these changes and take a picture if there are any findings.  (See 
541 
Documentation of infusion site reactions).  We will have them download to a 
542 
CareLink research data base every two weeks to look at their total daily insulin 
543 
requirements, glucose values, and basal insulin requirements with extended use of 
544 
Fiasp®.  They will have an email sent to them every 2 weeks by RedCap to assess 
545 
for issues they have observed while using Fiasp®.   
546 
 
547 
Documentation of infusion site reactions:  At home subjects will exam their infusion 
548 
set site when they are changing an infusion set and assess for bleeding, signs of a 
549 
local tissue reaction or infection.  They will record redness, induration, and bruising 
550 
in mm, and call one of the investigators if there is more than 10 mm of erythema or 
551 
induration.  They will be given a ruler for making these measurements. If there is 
552 
more than 3 mm of induration or redness they will be asked to take a picture and 
553 
enter these measurements and send a text to the study coordinator or submit the 
554 
information directly into RedCap.   
555 


 
556 
They will be instructed to replace the infusion set if: 
557 
1. Their ketone level is greater than 0.6 mmol/L,  
558 
2. There is evidence of infection at the infusion site 
559 
3. Their blood glucose (meter) does not decrease by at least 50 mg/dL within 1 
560 
hour of a correction bolus for unexplained hyperglycemia with a blood 
561 
glucose greater than 250 mg/dL.  
562 
4. There is a pump occlusion alarm. 
563 
 
 
564 


CHAPTER 4:  ADVERSE EVENT REPORTING AND PROTOCOL MONITORING 
565 
 
566 
Definition 
567 
A reportable adverse event is any untoward medical occurrence that meets criteria 
568 
for a serious adverse event or any unexpected medical occurrence in a study 
569 
subject that is study or device-related.  Skin irritation from sensor wear will be 
570 
recorded in specific sections of the case report forms.  An adverse event form is 
571 
only completed if skin irritation is severe or antibiotics are required.   
572 
 
573 
Hypoglycemic events are recorded as Adverse Events if the event required 
574 
assistance of another person due to altered consciousness to actively administer 
575 
carbohydrate, glucagon, or other resuscitative actions.  This means that the subject 
576 
was impaired cognitively to the point that he/she was unable to treat him or herself, 
577 
was unable to verbalize his or her needs, was incoherent, disoriented, and/or 
578 
combative, or experienced seizure or coma.  These episodes may be associated 
579 
with sufficient neuroglycopenia to induce seizure or coma.  If plasma glucose 
580 
measurements are not available during such an event, neurological recovery 
581 
attributable to the restoration of plasma glucose to normal is considered sufficient 
582 
evidence that the event was induced by a low plasma glucose concentration.   
583 
 
584 
Hyperglycemic events are recorded as Adverse Events if the event involved diabetic 
585 
ketoacidosis (DKA), as defined by the DCCT, and had all of the following:  
586 
1) Symptoms such as polyuria, polydipsia, nausea, or vomiting 
587 
2) Serum ketones greater than 1.6 mM,  or large/moderate urine ketones 
588 
3) Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15 
589 
4) Treatment provided in a health care facility 
590 
 
591 
Recording of Adverse Events 
592 
Throughout the course of the study, all efforts will be made to remain alert to 
593 
possible adverse events or untoward findings.  The first concern will be the safety of 
594 
the subject, and appropriate medical intervention will be made. 
595 
 
596 
The investigator will elicit reports of adverse events from the subject at each visit 
597 
and complete all adverse event forms online.  Each adverse event form is reviewed 
598 
by the Coordinating Center to verify the coding and the reporting that is required.      
599 
 
600 
The study investigator will assess the relationship of any adverse event to be 
601 
related or unrelated by determining if there is a reasonable possibility that the 
602 
adverse event may have been caused by the study device or study procedures.    
603 
 
604 
The intensity of adverse events will be rated on a three-point scale: (1) mild, (2) 
605 
moderate, or (3) severe.  It is emphasized that the term severe is a measure of 
606 
intensity: thus a severe adverse event is not necessarily serious.  For example, 
607 
itching for several days may be rated as severe, but may not be clinically serious.   
608 
 
609 
Adverse events that continue after the participant’s discontinuation or completion of 
610 


the study will be followed until their medical outcome is determined or until no 
611 
further change in the condition is expected.   
612 
 
613 
Adverse events will be coded using the MedDRA dictionary.  
614 
 
615 
Definitions of relationship and intensity are listed on the website data entry form.   
616 
 
617 
Adverse events that continue after the subject’s discontinuation or completion of the 
618 
study will be followed until their medical outcome is determined or until no further 
619 
change in the condition is expected.   
620 
  
621 
Reporting Serious or Unexpected Adverse Events 
622 
A serious adverse event is any untoward occurrence that:  Results in death; is life-
623 
threatening (a non life-threatening event which, had it been more severe, might 
624 
have become life-threatening, is not necessarily considered a serious adverse 
625 
event); requires inpatient hospitalization or prolongation of existing hospitalization; 
626 
results in a disability or permanent damage which causes a substantial disruption of 
627 
a person's ability to conduct normal life functions; results in a congenital 
628 
anomaly/birth defect;  requires intervention to prevent permanent impairment or 
629 
damage (Devices); or any other serious (Important Medical Event) which may 
630 
jeopardize the patient and may require medical or surgical intervention (treatment) 
631 
to prevent a serious adverse event. 
632 
 
633 
An Unanticipated Adverse Device Event is defined as an adverse event caused by, 
634 
or associated with, a device, if that effect or problem was not previously identified in 
635 
nature, severity, or degree of incidence. 
636 
 
637 
Serious or unexpected adverse events must be reported to the Principal 
638 
Investigator immediately.  
639 
Bruce Buckingham, M.D. 
640 
Division of Endocrinology and Diabetes 
641 
780 Welch Road, Room CJ320H 
642 
Palo Alto, CA 94305 
643 
Office Phone 650-725-6549 
644 
Office Fax 650-736-6690 
645 
 
646 
The principle investigator will notify all participating investigators of any adverse 
647 
device event that is both serious and unexpected. Notification will be made within 
648 
10 days after becoming aware of the event.  
649 
 
650 
Dr. Buckingham will inform the IRB of serious study-related adverse events and 
651 
abide by any other reporting requirements specific to their IRB.  
652 
 
653 
Potential Risks and Side Effects 
654 
There may be a higher frequency of hypoglycemia immediately following a meal bolus.  
655 
There may be prolonged hyperglycemia following a high fat meal. There may be local tissue 
656 


reactions at the FIASP® infusion sites.  Infusion sites may need to be changed more 
657 
frequently than usual when infusing FIASP®.  As with any insulin, there is a risk for both 
658 
high and low blood glucose levels occurring if there is a mismatch between your insulin 
659 
needs and the insulin levels provided by the insulin.  See hypoglycemia and hyperglycemia 
660 
risks below.  It is very rare, but allergic reactions to insulin may occur.   
661 
 
662 
Risk of Hypoglycemia 
663 
As with any person having insulin-dependent diabetes, there is always a risk of 
664 
having a low blood sugar (hypoglycemia).  The frequency of nocturnal 
665 
hypoglycemia should be no more than it would be as part of daily living with 
666 
diabetes.  Symptoms of hypoglycemia can include sweating, jitteriness, and not 
667 
feeling well.  Just as at home, there is the possibility of loss of consciousness or 
668 
seizures (convulsions) and that for a few days you may not be as aware of 
669 
symptoms of low blood sugar.  Even if severe low blood sugar does occur, it almost 
670 
always goes away quickly with treatment to raise the blood sugar. 
671 
 
672 
Risk of Hyperglycemia 
673 
As with any person having insulin-dependent diabetes, there is always a risk of 
674 
having a high blood sugar (hyperglycemia).  The frequency should be no more than 
675 
it would be as part of daily living with diabetes.   
676 
 
677 
Protection Against Risks and Treatment of Side Effects:  
678 
Subjects will be given descriptions of possible side effects from wearing an infusion 
679 
set, and local side effects with insulin infusion sets or Guardian sensor insertion 
680 
sets. They will be told to contact the study staff if they see any signs of a skin 
681 
reaction.  Based on the severity of local skin reaction, topical anti-inflammatory 
682 
medications can be used (such as topical steroids). 
683 
 
684 
Other Risks 
685 
Some subjects may develop skin irritation or allergic reactions to the adhesives 
686 
used to secure the CGM sensor, or to secure the insulin infusion sets for the 
687 
Continuous Subcutaneous Insulin Infusion (CSII).  If these reactions occur, different 
688 
adhesives or “under-taping” (such as with IV 3000, Tegaderm, etc.) will be tried, 
689 
sites will be rotated frequently, and a mild topical steroid cream or other medication 
690 
may be required. 
691 
 
692 
Whenever the skin is broken there is the possibility of an infection.  The CGM 
693 
sensor and insulin infusion set sites are inserted under the skin.  It is possible that 
694 
any part that is inserted under the skin may cause an infection.  These occur very 
695 
infrequently, but, if an infection was to occur, oral and/or topical antibiotics can be 
696 
used.  The risk of skin problems could be greater if a sensor or infusion set is used 
697 
for extended periods of time.  Therefore participants will be carefully instructed 
698 
about daily inspection of their sensor and infusion set sites. 
699 


 
700 
Data downloaded from the CGM sensor, insulin pump, and the home glucose and 
701 
ketone meters will be collected for the study as measures of diabetes self-
702 
management behaviors.  Some people may be uncomfortable with the researchers' 
703 
having such detailed information about their daily diabetes habits.   
704 
 
705 
CHAPTER 5:  MISCELLANEOUS CONSIDERATIONS 
706 
 
707 
Potential Benefits 
708 
Fiasp® may provide a more rapid onset of insulin action and improved post-prandial 
709 
glycemic control. 
710 
 
711 
Subject Compensation 
712 
For Part 1, participants will be compensated $50 for each visit, $15 for completing 
713 
weekly uploads to Carelink for a maximum payment of $245.  For part 2, subject will 
714 
receive $50 for each visit, and $20 for uploading to Carelink and contact with the 
715 
investigators every two weeks they are in the extension phase.   Maximum payment 
716 
of $160.  Compensation of partial participation will be prorated.   
717 
 
718 
Subject Withdrawal 
719 
Participation in the study is voluntary, and a subject may withdraw at any time.  The 
720 
investigator may withdraw a subject who is not complying with the protocol. For 
721 
subjects who withdraw, their data will be used up until the time of withdrawal. 
722 
 
723 
Subject Discontinuation Criteria 
724 
Subjects who become pregnant will be discontinued from the study.  The 
725 
investigator may withdraw a subject who is not complying with the protocol. 
726 
Withdrawal of a subject will be considered for the following reasons:  1) Failure to 
727 
monitor their sensor and infusion sites on a daily basis; 2) developing >1.0 mmol/L 
728 
ketones on 2 or more occasions and failing to change their infusion set or a single 
729 
episode of diabetic ketoacidosis due to an infusion site failure.  For subjects who 
730 
withdraw or who are withdrawn, their data will be used for analysis purposes up until 
731 
the time of withdrawal. 
732 
 
733 
Confidentiality 
734 
For security and confidentiality purposes, subjects will be assigned an identifier that 
735 
will be used instead of their name.  De-identified subject information may also be 
736 
provided to Medtronic Diabetes.   
737 
 
738 
Level of Risk 
739 
This research proposal in children is consistent with United States Department of 
740 
Health and Human Services, Protection of Human Subjects, Subpart D, Section 
741 
46.404 (Research not involving more than minimal risk).   
742 
 
743 
Planned Duration of the Entire Study 
744 
Planned duration of the entire study will be 6 months.   
745 


 
 
746 


CHAPTER 6:  STATISTICAL CONSIDERATIONS 
747 
 
748 
This is a pilot study to determine if there are any clinical issues with using Fiasp® in 
749 
the 670G hybrid closed-loop system.  These studies are not statistically powered.  
750 
 
751 
In the blinded cross-over studies (Part I) we will use data obtained during the 
752 
second week of each arm to compare the following measurements using a mixed-
753 
effects model accounting for crossover study design of the study with the sequence 
754 
of treatment nested within the patient: 
755 
a) time in range (70-180 mg/dl) 
756 
b) percent time <70 mg/dl,  
757 
c) mean glucose, 
758 
d) glucose CV,  
759 
e) total daily insulin dose,  
760 
f) total daily basal insulin,  
761 
g) insulin delivery form MN to 6AM, and 6AM to MN   
762 
 
763 
We will test to see if there is any difference in pharmacodynamics when using 
764 
Fiasp® in the home environment when they are eating their usual breakfast.   
765 
Insulin pharmacodynamics following the standard breakfast will be assessed by 
766 
measuring the peak glucose concentration (Cmax), time to Cmax (tmax), and estimated 
767 
average glucose excursions were assessed using sensor glucose values at a time 
768 
interval of 0 to 180 minutes after breakfast bolus.  If a bolus was given between 
769 
120-180 minutes following the breakfast bolus, CGM values were only used up to 
770 
the time of the bolus.  The glucose at the time of the breakfast bolus (Time 0) will be 
771 
set to 0 mg/dL for each meal, and the remaining CGM values were adjusted 
772 
proportionally to allow analysis of postprandial glucodynamic parameters.  We will 
773 
utilize a mixed-effects model accounting for crossover study design of the study with 
774 
the sequence of treatment nested within the patient.  Breakfast meals are excluded 
775 
from postprandial analysis if: 1) the rate of change was greater than 0.3mg/dL/min 
776 
in the 1 hour prior to breakfast, 2) subjects gave a subsequent bolus prior to 120 
777 
minutes following the breakfast bolus, or 3) subjects deviated from their typical 
778 
breakfast.  Dinner meals will be assessed when there has been no additional food 
779 
intake after dinner.  The duration of insulin delivery to cover the meal will be 
780 
determined by the time it takes the post prandial glucose to reach 160 mg/dL 
781 
beyond 1 hour of eating.  The peak glucose will also be recorded. 
782 
 
783 
During the 6 week optimization study (Part II) we will use data obtained during the 
784 
first two weeks of the study (before data was reviewed and changes made by the 
785 
investigators) to data obtained during the last two weeks of the 3 month optimization 
786 
period.  We will compare the following measurements using paired t-tests for data 
787 
with a normal distribution and a Mann-Whitney rank sum test for data that is not 
788 
normally distributed: 
789 
a) time in range (70-180 mg/dl) 
790 
b) percent time <70 mg/dl,  
791 
c) mean glucose, 
792 


d) glucose CV,  
793 
e) total daily insulin dose,  
794 
f) total daily basal insulin,  
795 
g) insulin delivery form MN to 6AM, and 6AM to MN 
796 
h) CHO:I ratios at breakfast, lunch and dinner 
797 
i) Active insulin time 
798 
j) Number of days between infusion set changes 
799 
k) Erythema (mm) and induration (mm) at infusion sites when they are changed 
800 
l) Average daily insulin, and mean glucose for each day of infusion set wear 
801 
m) Number of episodes of unexplained hyperglycemia in the first month vrs the 
802 
last month 
803 
 
804 
  
805 
 
806 
 
 
807 


CHAPTER 7:  REFERENCES 
808 
 
809 
1. 
Heise T, Hovelmann U, Nosek L, Sassenfeld B, Thomsen KMD, Haahr H. 
810 
Pharmacokinetic Properties of Fast-acting Insulin Aspart Administered in Different 
811 
Subcutaneous Injection Regions: Response to the commentary by Nuggehally R. Srinivas. 
812 
Clinical drug investigation 2017. 
813 
2. 
Heise T, Hovelmann U, Brondsted L, Adrian CL, Nosek L, Haahr H. Faster-acting 
814 
insulin aspart: earlier onset of appearance and greater early pharmacokinetic and 
815 
pharmacodynamic effects than insulin aspart. Diabetes Obes Metab 2015;17:682-8. 
816 
3. 
Heise T, Zijlstra E, Nosek L, Rikte T, Haahr H. Pharmacological properties of faster-
817 
acting insulin aspart vs insulin aspart in patients with type 1 diabetes receiving continuous 
818 
subcutaneous insulin infusion: A randomized, double-blind, crossover trial. Diabetes Obes 
819 
Metab 2017;19:208-15. 
820 
4. 
Bode BW, Johnson JA, Hyveled L, Tamer SC, Demissie M. Improved Postprandial 
821 
Glycemic Control with Faster-Acting Insulin Aspart in Patients with Type 1 Diabetes Using 
822 
Continuous Subcutaneous Insulin Infusion. Diabetes Technol Ther 2017;19:25-33. 
823 
5. 
Zijlstra E, Demissie M, Graungaard T, Heise T, Nosek L, Bode B. Investigation of 
824 
Pump Compatibility of Fast-Acting Insulin Aspart in Subjects With Type 1 Diabetes. J 
825 
Diabetes Sci Technol 2017:1932296817730375. 
826 
6. 
Ly TT, Roy A, Grosman B, et al. Day and Night Closed-Loop Control Using the 
827 
Integrated Medtronic Hybrid Closed-Loop System in Type 1 Diabetes at Diabetes Camp. 
828 
Diabetes Care 2015;38:1205-11. 
829 
7. 
Garg SK, Weinzimer SA, Tamborlane WV, et al. Glucose Outcomes with the In-
830 
Home Use of a Hybrid Closed-Loop Insulin Delivery System in Adolescents and Adults 
831 
with Type 1 Diabetes. Diabetes Technol Ther 2017;19:155-63. 
832 
8. 
Bergenstal RM, Garg S, Weinzimer SA, et al. Safety of a Hybrid Closed-Loop 
833 
Insulin Delivery System in Patients With Type 1 Diabetes. JAMA 2016;316:1407-8. 
834 
 
835