The Efficacy and Safety of Faster Insulin Aspart (Fiasp®) Compared to Conventional Insulin Aspart (NovoLog®) as Correction Bolus in Patients With Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion (CSII) and Continuous Glucose Monitoring (CGM): a Cross-over Controlled Trial
Phase: PHASE4
Conditions: Type 1 Diabetes Mellitus
Sponsor: Mountain Diabetes and Endocrine Center

1 
 
 
Version 4.0  updated  01/07/2019 
 
 
The efficacy and safety of faster insulin aspart (Fiasp) compared to conventional insulin aspart as 
1 
correction bolus in patients with type 1 diabetes using continuous subcutaneous insulin infusion (CSII) 
2 
and continuous glucose monitoring (CGM): a cross-over controlled trial 
3 
INVESTIGATOR-INITIATED STUDY PROPOSAL 
4 
UTN: U1111-1207-7424 
5 
Protocol: GPP2019 
6 
 
7 
Wendy Lane MD 
8 
Mountain Diabetes and Endocrine Center 
9 
1998 Hendersonville Rd 
10 
Asheville, NC 28803 
11 
 
12 
Correspondence to: 
13 
Wendy Lane MD 
14 
Phone: (828) 684-9588 
15 
Fax: (828) 684-9626 
16 
Email: mountaindiabetes@msn.com 
17 
 
18 
 
19 
Background and significance: 
20 
 
21 
Patients with type 1 DM using CSII require bolus insulin for two purposes: first, to cover carbohydrate 
22 
intake to control postprandial glucose, and second, to correct episodes of hyperglycemia.  The latter 
23 
function is referred to as a “correction dose” or “correction bolus”.  Insulin pumps have bolus calculators 
24 
which calculate correction doses based on the patient’s individualized BG target and insulin sensitivity 
25 
factor (ISF).  Rapid-acting insulin analogues delivered by pump typically require 2 to 4 hours to fully 
26 
correct an acute hyperglycemic episode, and sometimes multiple correction doses are needed to 
27 
normalize the blood glucose level.  This can be frustrating for patients, particularly when a correction 
28 
bolus is necessary in addition to a meal bolus; frequently, patients must wait for the correction bolus to 
29 
take effect and delay eating until the blood glucose has begun to normalize to avoid severe postprandial 
30 
hyperglycemia. There is consequently an unmet need in insulin delivery, and in particular in CSII, for an 
31 
insulin which can correct a hyperglycemic episode more rapidly than is currently possible with rapid-
32 
acting insulin analogues.   
33 
 
34 
Faster insulin aspart (Fiasp) is a novel formulation of insulin aspart with an accelerated time-action 
35 
profile which results in twice the exposure to insulin and 74% greater insulin action within the first 30 
36 
minutes after injection compared to conventional insulin aspart (1). This results in twice-as-fast onset of 
37 
appearance in the bloodstream (4 vs. 9 min compared to conventional insulin aspart) (1) which has been 
38 
demonstrated to reduce postprandial glucose levels in patients with type 1 DM using CSII (2, 3).  
39 
Theoretically, this faster insulin action would be useful in correction dosing during acute episodes of 
40 
hyperglycemia to normalize the blood glucose level more rapidly than is currently possible with 
41 
conventional insulin aspart (NovoLog).   
42 
 
43 

2 
 
 
Version 4.0  updated  01/07/2019 
 
 
Many patients with type 1 DM using CSII now also use continuous glucose monitoring (CGM) for making 
44 
insulin dosing decisions.  Currently the FDA has approved 2 CGM systems for nonadjunctive use in bolus 
45 
insulin dose calculations.  Only one of these systems, the Dexcom, reads continuously to the patient and 
46 
has alarms to warn of impending episodes of hyper- or hypoglycemia, and this is the system used most 
47 
commonly by patients with type 1 DM using open-loop CSII. Patients now incorporate the Dexcom trend 
48 
arrow, which depicts the rate and direction of glucose change, into the correction dose calculation, and 
49 
recommendations on how to incorporate CGM information into correction dose calculations have 
50 
recently been updated based on an expert consensus report (4). However, these guidelines were 
51 
created for use with rapid acting insulin analogues.  How they might need to be modified for use with 
52 
Fiasp (the first and only ultra-rapid insulin analogue) is not known. 
53 
 
54 
The purpose of this investigator-initiated trial is to compare the efficacy in terms of time to recovery 
55 
from hyperglycemia as measured by time to arrest of hyperglycemic excursion (“glucose plateau point”, 
56 
primary endpoint) and return to premeal glucose target if feasible (secondary endpoint) between Fiasp 
57 
and conventional insulin aspart when used as a correction bolus.   These endpoints will be determined 
58 
by CGM (Dexcom) from data exported from the Dexcom Clarity program. 
59 
 
60 
SPECIFIC OBJECTIVES 
61 
 
62 
Primary objective:  
63 
 
64 
To compare time to stabilization of rising blood glucose level after correction bolus between Fiasp and 
65 
NovoLog.  This data point will be referenced to as the “glucose plateau point” (GPP).  The time of each 
66 
correction bolus will be captured from the pump download, and correlated with Dexcom Clarity reports 
67 
to identify the GPP. 
68 
 
69 
 
70 
The time to return to premeal target glucose after use of a correction bolus, if feasible,* to achievement 
71 
of pre-meal target glucose,  which will be individualized per subject (though most subjects will have a 
72 
glucose target of 100 mg/dL). 
73 
 
74 
*This parameter will be analyzed for correction boluses which were isolated and the subject did not 
75 
consume additional carbohydrate until after he/she returned to the premeal target. 
76 
 
77 
Secondary objectives:  
78 
 
79 
1. Incidence of early post-correction hypoglycemia (within 60 minutes and 120 minutes of use of 
80 
correction bolus) with each insulin (key safety endpoint) (5,6). 
81 
2.  To quantify the difference between insulin sensitivity factor (ISF) and insulin-on-board (IOB) 
82 
time, if any, for correction dosing between NovoLog and Fiasp.  
83 
3. Percent time in target range 70-180 mg/dL by CGM for each insulin bolus. 
84 
4. Percent time in hyperglycemic range by CGM for each insulin bolus. Hyperglycemia ranges to be 
85 
captured will include Category 1: 181-250 mg/dL and Category 2: above 250 mg/dL. 
86 
5. Percent time in hypoglycemic range below 70 mg/dL by CGM for each insulin bolus. 
87 
Hypoglycemia ranges to be captured include Category 1: 69-54 mg/dL and Category 2: below 54 
88 
mg/dL. 
89 

3 
 
 
Version 4.0  updated  01/07/2019 
 
 
6. GlycoMark (1,5 anhydroglucitol, a marker of postprandial glucose excursion) during use of each 
90 
insulin. 
91 
7. HbA1c during use of each insulin. 
92 
 
93 
RESEARCH DESIGN AND METHODS 
94 
 
95 
Study hypothesis: 
96 
Compared to conventional insulin aspart, Fiasp will correct hyperglycemia (defined as arrest of rise of 
97 
blood glucose, following correction bolus, ie, GPP ) faster than conventional insulin aspart in subjects 
98 
with type 1 DM using CSII. 
99 
 
100 
ENDPOINTS 
101 
 
102 
Primary endpoint:  
103 
 
104 
Time (in minutes) to stabilization of rising BG (GPP) by CGM after correction bolus  during the final 2 
105 
week maintenance period.    Two categories of correction dose will be analyzed: 1) those following an 
106 
isolated correction dose (taken independently of a meal dose), and 2) those taken as part of a 
107 
combination bolus with a meal dose. 
108 
 
109 
Secondary endpoints:  
110 
 
111 
1. Incidence of early hypoglycemia (BG < 54 mg/dl within 1 and 2 hours) following correction bolus 
112 
with each insulin (key safety endpoint). 
113 
2. Change in ISF, if any, required for hypoglycemia prevention using Fiasp and quantification of 
114 
same.   
115 
3. Change in IOB, if any, required for prevention of late hyperglycemia using Fiasp and 
116 
quantification of same. 
117 
4. GlycoMark (1,5 anhydroglucitol, a measure of postprandial glucose excursion) on each insulin. 
118 
5. HbA1c on each insulin. 
119 
6. Percent time spent in target range, hyperglycemic range and hypoglycemic range by CGM on 
120 
each insulin during the final 2 weeks of each treatment period. 
121 
7. Standard deviation of mean blood glucose as determined by CGM on each insulin. 
122 
8. Treatment related impact measures on each insulin (TRIM D questionnaire).  
123 
 
124 
Study endpoints will be obtained from each subject’s CGM and insulin pump data during the final 2 
125 
weeks of each treatment period. 
126 
 
127 
STUDY TYPE 
128 
 
129 
This is a 25-week open-label prospective single center 2 arm crossover trial.   
130 
STUDY POPULATION 
131 
45 subjects with type 1 diabetes with good glycemic control who are experienced in the use of CSII (with 
132 
any open loop pump) and CGM (Dexcom) will be randomized either to use Fiasp or conventional insulin 
133 

4 
 
 
Version 4.0  updated  01/07/2019 
 
 
aspart in CSII.  The study population will be derived from established clinic patients at Mountain 
134 
Diabetes and Endocrine Center. 
135 
 
136 
INCLUSION CRITERIA 
137 
1. Male and female patients > 18 years of age  
138 
2. Type 1 DM of > 1 year duration 
139 
3. Use of any open loop insulin pump, Tandem T-Slim with Basal IQ, Insulet Omnipod Dash, or any 
140 
other investigator-approved insulin pumps with Dexcom CGM G5, G6, or newer version for > 6 
141 
months 
142 
4. Good baseline glycemic control (HbA1c < 7.5%; low risk of hypoglycemia by CGM as defined by 
143 
Dexcom Clarity report) 
144 
5. No episodes of severe hypoglycemia in the previous 3 months 
145 
6. Pump download shows regular meal bolusing, accurate carbohydrate counting ability, and 
146 
willingness to use exercise markers in Dexcom 
147 
7. CGM download shows regular use (>85% of time) and regular calibration if using G5 sensor (G6 
148 
requires no calibration) 
149 
8. Females using adequate contraception 
150 
 
151 
EXCLUSION CRITERIA 
152 
1. Use of CGM other than Dexcom G5 or G6 or a newer Dexcom CGM version  
153 
2. Suboptimal baseline glycemic control (HbA1c > 7.5%) 
154 
3. Pump or CGM download shows suboptimal use of devices (lack of meal boluses, frequent 
155 
overrides of pump, excessive pump suspension, inadequate calibration or inconsistent usage of 
156 
CGM) 
157 
4. Serious comorbidities including CVD with recent event, actively treated malignancy, renal 
158 
dysfunction with eGFR < 45 ml/min, or any other condition which in the opinion of the 
159 
investigator would preclude subject’s ability to participate in trial 
160 
5. Females unwilling to use contraception, planning pregnancy or breastfeeding  
161 
6. Use of any other glucose-lowering agents than insulin 
162 
7. Hypersensitivity to insulin aspart or one of the excipients in faster insulin aspart 
163 
8. Known diabetic gastroparesis 
164 
WITHDRAWAL CRITERIA 
165 
Females who become pregnant will be withdrawn from the study.  Any subject may withdraw consent at 
166 
any time.   
167 
SUBJECT REPLACEMENT 
168 
Subjects withdrawn from the study prior to randomization will be replaced; subjects withdrawn after 
169 
randomization will not be replaced. 
170 
RATIONALE FOR STUDY POPULATION 
171 

5 
 
 
Version 4.0  updated  01/07/2019 
 
 
Only subjects with good baseline glycemic control who are experienced in optimal use of CSII and CGM 
172 
will be eligible for this study.  This will minimize the effect of incorrect device usage (omission of meal 
173 
boluses or inaccurate assessment of meal boluses, excessive overrides of the pump’s bolus 
174 
recommendations, excessive time disconnected from the pump, inconsistent CGM use, etc) as a 
175 
confounding factor in the assessment of each insulin’s efficacy.  In other words, these patients have 
176 
already optimized diabetes self-management and device usage; any change in glycemic control can 
177 
therefore be attributed to the difference in pharmacologic profile of the insulin, not to patient behavior. 
178 
 
179 
VISIT PROCEDURES 
180 
Overview: 
181 
45 subjects with type 1 diabetes with good glycemic control who are experienced in the use of CSII (with 
182 
any open loop pump) and CGM (Dexcom G5 or G6) will be randomized either to use Fiasp or 
183 
conventional insulin aspart in CSII.  CSII settings (basal, bolus, and correction factors) will be optimized 
184 
for a 2-week run in period followed by a 10-week period of CSII use with the assigned insulin. After a 12-
185 
week maintenance period, each group will cross over to the other insulin (conventional insulin aspart or 
186 
Fiasp) by CSII for a second 2-week optimization period followed by a 10-week treatment period.  
187 
Subjects will be instructed to enter the premeal interstitial BG (IBG) into the pump as per standard 
188 
practice (for calculation of the correction insulin bolus) and the 1 and 2-hour postprandial IBG following 
189 
each meal which will be captured by Dexcom.  The time to flattening of the BG (GPP) will be captured 
190 
from the raw data report exported from Dexcom Clarity.    The time required from initiation of the 
191 
correction bolus to GPP and from time of correction bolus   to premeal target IBG (if feasible) will be 
192 
captured for each insulin. Hypoglycemic events and their timing, in particular in relation to insulin 
193 
boluses, will also be captured. 
194 
 
195 
Meal Challenge: 
196 
 
197 
Meal challenge protocol to determine Insulin Sensitivity Factor (ISF) (also called Correction Factor (CF)), 
198 
time to GPP, and time to correction of hyperglycemic excursion by CGM 
199 
At the randomization visit and at the insulin crossover visit (Visits 2 and 8), each subject will perform a 
200 
meal challenge to assess the time GPP and to return to premeal glucose target using a Correction Bolus 
201 
(CB) after induction of hyperglycemia following a carbohydrate load from a standard liquid meal 
202 
(consisting of 8 oz Ensure: 32 grams CHO, 9 gm protein, 6 mg fat). This visit may require up to 5 hours of 
203 
observation.  The ISF will be customized for each insulin based on the decline of BG from post-Ensure 
204 
peak BG to nadir to prevent future post-correction hypoglycemia. 
205 
Protocol: 
206 
1. At Visit 2, subject will be randomized to Novolog or Fiasp. At Visit 8, the subject will cross-over 
207 
to the other study insulin from Visit 2.  
208 
2. Prior to randomization or crossover and completion of each meal test, the subject’s blood 
209 
glucose must be < 150 mg/dL.  If the subject’s blood glucose is greater than 150 mg/dL, the visit 
210 
will be rescheduled. 
211 

6 
 
 
Version 4.0  updated  01/07/2019 
 
 
3. On site at Visits 2 and 8, the subject will change infusion site and cartridge and fill the cartridge 
212 
with the designated insulin.  The new site and cartridge will be placed prior to the meal 
213 
challenge so that the designated insulin is used for the meal challenge. 
214 
4. Subject will ingest an 8 oz bottle of Ensure, consuming the meal within 5 minutes, without a 
215 
meal bolus.  Subject will have a calibrated Dexcom sensor in place. 
216 
5. The time to peak post-Ensure hyperglycemic response and the magnitude of hyperglycemia will 
217 
be recorded. 
218 
6. At the time of peak response (flattening of Dexcom trend arrow at highest BG level), a 
219 
correction bolus (calculated using subject’s usual BG target and Insulin Sensitivity Factor (ISF)) 
220 
will be administered in the usual fashion via insulin pump. 
221 
7. The time to achievement of the GPP (flattening of the glucose trend arrow) and return to 
222 
premeal target BG for each insulin will be documented. 
223 
8. The Dexcom display will be observed for 2 to 3 hours post correction bolus.  If the subject 
224 
experiences a BG below 70 mg/dl in that time, the ISF will be modified (increased by 15 to 20%) 
225 
to prevent post-correction hypoglycemia.  
226 
 
227 
STUDY VISIT PROCEDURES 
228 
Visit 1 (Screening Visit), Week -1: Obtain written informed consent; review inclusion/exclusion criteria; 
229 
demography (including child bearing potential and tobacco use); medical history; record concomitant 
230 
medications; vital signs (including height, weight and BMI); diabetes history, pump and Dexcom 
231 
downloads; insulin pump settings adjustments (if needed). Provide and educate subject about diaries; 
232 
review Rule of 15 treatment for hypoglycemia (consume 15 grams of carbohydrate/re-check BG in 15 
233 
minutes) and hypoglycemia assessment; confirmation of consumption of 3 meals daily; collect venous 
234 
sample for HbA1c and GlycoMark (LabCorp); subjects will be instructed to take entire correction dose at 
235 
once and not to repeat correction dose unless 1. No flattening of trend arrow by 2 hours after correction 
236 
dose or 2. Suspected set occlusion; review of infusion site reactions and occlusions; perform urine 
237 
pregnancy test, if applicable; dispensing of trial product 
238 
Visit 2: (Randomization Visit) Week 0: office visit; vital signs; physical exam; subject attends visit fasting; 
239 
completion of Meal Challenge. Randomize subject per protocol. Placement of new infusion site with 
240 
conventional insulin aspart or Fiasp as per randomization. Subject completes TRIM D questionnaire. 
241 
Device downloads; insulin optimization/titration; insulin pump settings adjustments including ISF/CF (if 
242 
needed); subjects will be instructed to take entire correction dose at once and not to repeat correction 
243 
dose unless 1. No flattening of trend arrow by 2 hours after correction dose or 2. Suspected set 
244 
occlusion;  assessment of infusion site reactions and occlusions; troubleshooting; assessment of AEs and 
245 
concomitant medications; review and dispensing of diary; dispensing of trial product; technical 
246 
complaints; review Rule of 15 for hypoglycemia and hypoglycemia assessment; confirmation of 
247 
consumption of 3 meals daily; instruction in designated insulin use 
248 
Visit 3, Week 2: office visit; vital signs; device downloads; insulin optimization/titration; insulin pump 
249 
settings adjustments (if needed); assessment of infusion site reactions and occlusions; troubleshooting; 
250 
confirmation of consumption of 3 meals daily; assessment of AEs and concomitant medications; review 
251 
and dispensing of diary; dispensing of trial product; technical complaints; drug accountability; review 
252 
Rule of 15 for hypoglycemia and hypoglycemia assessment; subjects will be instructed to take entire 
253 
correction dose at once and not to repeat correction dose unless 1. No flattening of trend arrow by 2 
254 
hours after correction dose or 2. Suspected set occlusion 
255 

7 
 
 
Version 4.0  updated  01/07/2019 
 
 
Visit 4, Week 4: phone visit; online Dexcom device download with review; adjust pump settings if 
256 
needed; assess AE’s and concomitant medications; review diary; confirmation of consumption of 3 
257 
meals daily; technical complaints; assessment of infusion site reactions and occlusions; review Rule of 15 
258 
for hypoglycemia and hypoglycemia assessment; subjects will be instructed to take entire correction 
259 
dose at once and not to repeat correction dose unless 1. No flattening of trend arrow by 2 hours after 
260 
correction dose or 2. Suspected set occlusion 
261 
Visit 5, Week 6: office visit; vital signs; device downloads; insulin optimization/titration; insulin pump 
262 
settings adjustments (if needed); assessment of infusion site reactions and occlusions; troubleshooting; 
263 
confirmation of consumption of 3 meals daily; assessment of AEs and concomitant medications; review 
264 
and dispensing of diary; dispensing of trial product; dispense Dexcom CGM sensor; technical complaints; 
265 
drug accountability; review Rule of 15 for hypoglycemia and hypoglycemia assessment; subjects will be 
266 
instructed to take entire correction dose at once and not to repeat correction dose unless 1. No 
267 
flattening of trend arrow by 2 hours after correction dose or 2. Suspected set occlusion 
268 
Visit 6, Week 8: phone visit; online Dexcom device download with review; adjust pump settings if 
269 
needed; assess AE’s and concomitant medications; review diary; confirmation of consumption of 3 
270 
meals daily; technical complaints; train subject how to enter bolus information into Dexcom history, 
271 
assessment of infusion site reactions and occlusions; review Rule of 15 for hypoglycemia and 
272 
hypoglycemia assessment; Subjects will be instructed to take entire correction dose at once and do not 
273 
repeat correction dose unless 1. No flattening of trend arrow by 2 hours after correction dose 2. 
274 
Suspected set occlusion 
275 
Visit 7, Week 10: phone visit; online Dexcom device download with review; adjust pump settings if 
276 
needed; assess AE’s and concomitant medications; review diary; confirmation of consumption of 3 
277 
meals daily; technical complaints; re-educate subject how to enter bolus information into Dexcom 
278 
history; assessment of infusion site reactions and occlusions; review Rule of 15 for hypoglycemia and 
279 
hypoglycemia assessment; subjects will be instructed to take entire correction dose at once and not to 
280 
repeat correction dose unless 1. No flattening of trend arrow by 2 hours after correction dose or 2. 
281 
Suspected set occlusion 
282 
Visit 8 (Treatment Crossover Visit), Week 12: office visit; vital signs; physical exam; subject attends visit 
283 
fasting; completion of Meal Challenge. Placement of new infusion site with the conventional insulin 
284 
aspart or Fiasp as per crossover. Subject completes TRIM D questionnaire. Device downloads; insulin 
285 
optimization/titration; insulin pump settings adjustments including ISF/CF (if needed); assessment of 
286 
infusion site reactions and occlusions; troubleshooting; assessment of AEs and concomitant 
287 
medications; review and dispensing of diary; dispensing of trial product; technical complaints; review 
288 
Rule of 15 for hypoglycemia and hypoglycemia assessment; confirmation of consumption of 3 meals 
289 
daily; instruction in designated insulin use; subjects will be instructed to take entire correction dose at 
290 
once and not to repeat correction dose unless 1. No flattening of trend arrow by 2 hours after correction 
291 
dose or 2. Suspected set occlusion; collect venous sample for HbA1c and GlycoMark (LabCorp); perform 
292 
urine pregnancy test, if applicable 
293 
Visit 9, Week 14: office visit; vital signs; device downloads; insulin optimization/titration; insulin pump 
294 
settings adjustments (if needed); assessment of infusion site reactions and occlusions; troubleshooting; 
295 
confirmation of consumption of 3 meals daily; assessment of AEs and concomitant medications; review 
296 
and dispensing of diary; dispensing of trial product; technical complaints; drug accountability; review 
297 
Rule of 15 for hypoglycemia and hypoglycemia assessment; subjects will be instructed to take entire 
298 
correction dose at once and not to repeat correction dose unless 1. No flattening of trend arrow by 2 
299 
hours after correction dose or 2. Suspected set occlusion 
300 

8 
 
 
Version 4.0  updated  01/07/2019 
 
 
Visit 10, Week 16: phone visit; online Dexcom device download with review; adjust pump settings if 
301 
needed; assess AE’s and concomitant medications; review diary; confirmation of consumption of 3 
302 
meals daily; technical complaints; assessment of infusion site reactions and occlusions; review Rule of 15 
303 
for hypoglycemia and hypoglycemia assessment; subjects will be instructed to take entire correction 
304 
dose at once and not to repeat correction dose unless 1. No flattening of trend arrow by 2 hours after 
305 
correction dose or 2. Suspected set occlusion 
306 
Visit 11, Week 18: office visit; vital signs; device downloads; insulin optimization/titration; insulin pump 
307 
settings adjustments (if needed); assessment of infusion site reactions and occlusions; troubleshooting; 
308 
confirmation of consumption of 3 meals daily; assessment of AEs and concomitant medications; review 
309 
and dispensing of diary; dispensing of trial product; dispense Dexcom CGM sensor; technical complaints; 
310 
drug accountability; review Rule of 15 for hypoglycemia and hypoglycemia assessment; subjects will be 
311 
instructed to take entire correction dose at once and not to repeat correction dose unless 1. No 
312 
flattening of trend arrow by 2 hours after correction dose or 2. Suspected set occlusion 
313 
Visit 12, Week 20: phone visit; online Dexcom device download with review; adjust pump settings if 
314 
needed; assess AEs and concomitant medications; review diary; confirmation of consumption of 3 meals 
315 
daily; technical complaints; train subject how to enter bolus information into Dexcom history; 
316 
assessment of infusion site reactions and occlusions; review Rule of 15 for hypoglycemia and 
317 
hypoglycemia assessment; subjects will be instructed to take entire correction dose at once and not to 
318 
repeat correction dose unless 1. No flattening of trend arrow by 2 hours after correction dose or 2. 
319 
Suspected set occlusion 
320 
Visit 13, Week 22: phone visit; online Dexcom device download with review; adjust pump settings if 
321 
needed; assess AE’s and concomitant medications; review diary; confirmation of consumption of 3 
322 
meals daily; technical complaints; re-educate subject how to enter bolus information into Dexcom 
323 
history; assessment of infusion site reactions and occlusions; review Rule of 15 for hypoglycemia and 
324 
hypoglycemia assessment; subjects will be instructed to take entire correction dose at once and not to 
325 
repeat correction dose unless 1. No flattening of trend arrow by 2 hours after correction dose or 2. 
326 
Suspected set occlusion 
327 
Visit 14 (End of Study Visit), Week 24: office visit; vital signs; physical exam; Placement of new infusion 
328 
site with post-trial insulin; Subject completes TRIM D questionnaire. Device downloads; insulin pump 
329 
settings adjustments including ISF/CF (if needed); assessment of infusion site reactions and occlusions; 
330 
troubleshooting; assessment of AEs and concomitant medications; review of diary; drug accountability; 
331 
technical complaints; review Rule of 15 for hypoglycemia and hypoglycemia assessment; instruction in 
332 
designated insulin use; collect venous sample for HbA1c and GlycoMark (LabCorp); perform urine 
333 
pregnancy test, if applicable 
334 
 
335 
ASSESSMENTS OF EFFICACY 
336 
These will include the time in minutes as captured by CGM (Dexcom) to arrest of rise in BG (GPP) after 
337 
use of correction dose (primary endpoint); other CGM (secondary) endpoints will include: time to return 
338 
to premeal target blood glucose if feasible, percent time in target range, hyperglycemia, hypoglycemia 
339 
and SD by CGM, HbA1c and GlycoMark (LabCorp assay; Burlington, NC).  
340 
 
341 
ASSESSMENTS OF SAFETY 
342 
The key safety endpoint will be capturing the frequency and timing of hypoglycemic events, defined as 
343 
BG < 54 mg/dl by CGM or by glucose meter or any BG measured by CGM or glucose meter requiring 
344 

9 
 
 
Version 4.0  updated  01/07/2019 
 
 
assistance for treatment.  If a CGM hypoglycemic event is verified by fingerstick BG and the meter and 
345 
CGM BG values are discordant, the meter BG will be considered the accurate reading only for Dexcom 
346 
G5.  
347 
 The reference document, local (US) Prescribing Information, will be used for evaluation of expectedness 
348 
of Adverse Events. All adverse events resulting from incorrect storage or usage of study product as per 
349 
product labelling, if applicable, will be reported to the appropriate institutions (Reference 
350 
ID:4160518).  The investigator will copy Novo Nordisk when expediting SAE information to health 
351 
authorities and will report all SAEs related to Novo Nordisk products to the local Novo Nordisk affiliate 
352 
safety department.  SAE submission to Novo Nordisk will be within 15 days from the investigator’s first 
353 
awareness of the event. 
354 
 
355 
 
356 
 
357 
ASSESSMENTS OF SUBJECT COMPLIANCE 
358 
Compliance of study subjects with use of CSII and CGM will be assessed by review of device downloads 
359 
at each visit. Items assessed on downloaded reports will include percent time devices are used,  number 
360 
and timing of infusion set changes, bolus/basal delivery (as percentages of total daily insulin dose) and 
361 
carbohydrate intake.  Other significant subject assessments will include number of infusion set 
362 
occlusions, and missed boluses. These assessments will be reviewed  in both treatment arms via  CGM 
363 
and insulin pump downloads at each study visit. 
364 
 
365 
Other assessments: TRIM D 
366 
TRIM D questionnaires will be completed at the beginning of the trial and at the end of each treatment 
367 
period for the assessment of quality of life measures using each insulin. 
368 
STATISTICAL CONSIDERATIONS 
369 
This is a 25-week prospective 2 arm crossover trial. 
370 
45 subjects with type 1 diabetes with good glycemic control who are experienced in the use of CSII (with 
371 
any open loop pump) and CGM (Dexcom) will be randomized either to use Fiasp or NovoLog in CSII.  CSII 
372 
settings (basal, bolus, and correction factors) will be optimized for a 2-week run-in period followed by a 
373 
10-week period of CSII use with the assigned insulin. After a 10-week maintenance period, each group 
374 
will cross over to the other insulin (NovoLog or Fiasp) by CSII for a second 2-week optimization period 
375 
followed by a 10-week treatment period.  Assuming a SD of 50 mg/dl for a well-controlled population of 
376 
subjects with type 1 DM, a sample size of 45 subjects should be adequate to show a trend in the 
377 
glycemic response time by CGM after an insulin bolus in this exploratory (pilot) study).  
378 
Subjects will be instructed to record from their personal Dexcom the pre-meal interstitial blood glucose 
379 
(IBG) (for calculation of the correction insulin bolus). These values will be entered into the insulin pump 
380 
at the time of initiation of the correction bolus as per standard practice. The postprandial IBG at the 
381 
point when the titration arrow changes from 2-3mg/dL/min upward to 1 mg/dL/min (flat) or downward 
382 
will be captured from the raw data report exported from Dexcom Clarity.    The point at which the trend 
383 
arrow changes will be referred to as the point of glucose plateau point (GPP).   Severe hypoglycemic 
384 

10 
 
 
Version 4.0  updated  01/07/2019 
 
 
events and their timing, in particular in relation to insulin boluses, will also be captured in the subject 
385 
diary.  
386 
Dependent Variables (recorded for each 12-week trial/insulin) repeated measures: 
387 
Primary dependent variable: 
388 
The primary dependent variable is time for recovery from hyperglycemia (defined earlier) to premeal 
389 
glucose target (defined earlier). 
390 
For each hyperglycemia event (Category 1 and 2) the date/time of start and the time for recovery will be 
391 
recorded. Since these can both be determined by CGM downloads there should be no missing data. 
392 
Depending on the extent of events observed, the number of events will be converted to a convenient 
393 
ratio, e.g., events/week. For the times for recovery a mean will be computed. These variables will be 
394 
computed separately for isolated correction boluses and correction boluses taken as part of a meal 
395 
dose. 
396 
 
397 
Secondary dependent variables (recorded for the last 2 weeks of each 12-week trial/insulin): 
398 
1. Time to levelling off of a rising directional arrow (which signifies arrest of rising blood glucose = 
399 
the glucose plateau point, or GPP) after each correction bolus. The date/time for each event and 
400 
time will be recorded. For the number of events, a ratio will be computed. For the time to 
401 
levelling off, a mean will be computed.  
402 
 
403 
2. Incidence of early post-correction hypoglycemia (defined earlier) within 60 minutes of use of 
404 
correction bolus. The date/time for each event and time will be recorded. For the number of 
405 
events, a ratio will be computed. For the time to levelling off, a mean will be computed. 
406 
 
407 
3. Incidence of early post-correction hypoglycemia (defined earlier) within 120 minutes of use of 
408 
correction bolus. – Count incidences - nominal or ratio depending on range of values obtained. 
409 
The date/time for each event and time will be recorded. For the number of events, a ratio will 
410 
be computed. For the time to levelling off, a mean will be computed.  
411 
 
412 
4. Whether any modification in insulin sensitivity factor is required (for optimal correction dosing 
413 
and hypoglycemia avoidance) when switching from conventional insulin aspart to Fiasp (i.e., will 
414 
the sensitivity factor need to be increased when using Fiasp). For each patient this will be yes/no 
415 
response. This value will be obtained during patient visits.  
416 
 
417 
5. TRIM-D scores will be obtained at the end of each 12-week period. 
418 
 
419 
6. To determine whether there is a late (3 to 4 hour) rise in BG as determined by CGM when using 
420 
Fiasp as compared to conventional insulin aspart, and to see whether a change in insulin-on-
421 
board (IOB) factor for subsequent correction dosing will need to be modified (e.g, reduced from 
422 
3 hours for aspart to 2 hours for Fiasp in patients with normal renal function). For the events 
423 
recorded, a daily or weekly rate and a mean change will be computed. 
424 
 
425 
7. A GlycoMark value will be obtained at the end of each 12-week period. 
426 

11 
 
 
Version 4.0  updated  01/07/2019 
 
 
 
427 
8. An HbA1c value will be obtained at the end of each 12-week period. 
428 
 
429 
9. Percent time spent in target range during each 12-week period. 
430 
 
431 
10.  Percent time spent in hyperglycemic range during each 12-week period. 
432 
 
433 
11.  Percent time spent in hypoglycemic range during each 12-week period. 
434 
 
435 
12.  Standard deviation of BG as determined by CGM for each 12-week period. 
436 
  
437 
 
438 
 
439 
Independent Explanatory Variable 
440 
 
441 
Whether the patient is using Fiasp or conventional insulin aspart for CSII and bolus injections when 
442 
independent, control and dependent variable measures are obtained. Patients will be randomly 
443 
assigned at the beginning of the study to one of the treatments for 12 weeks and then switch to the 
444 
other treatment for the final 12 weeks. 
445 
 
446 
Other Explanatory Variables (recorded at visit 1): 
447 
 
448 
1. Gender of patient - nominal variable 
449 
 
450 
2. Age of patient at start of study. 
451 
 
452 
3. Time since diagnosis with Type 1 DM 
453 
 
454 
4. First treatment – Fiasp or NovoLog 
455 
 
456 
Statistical Analysis 
457 
All statistical analyses will be completed using R version 3.5.0 or higher. 
458 
A linear mixed-effects model with repeated measures will be used for the analysis. Specifically, the 
459 
“lme” function provided in the nonlinear mixed effects models (nlme) package, authored by José 
460 
Pinheiro and Douglas Bates, will be used.  
461 
POWER CONSIDERATIONS 
462 
To estimate power, the analysis was simulated under varying conditions.  
463 
Simulation Assumptions: 
464 

12 
 
 
Version 4.0  updated  01/07/2019 
 
 
• 
Effect size: -20 minute reduction in time until stabilization following a correction bolus dose for 
465 
the treatment group relative to the control group. 
466 
• 
Participants are assumed to have three correction bolus events per day. This determines the 
467 
number of data points collected per person. While in reality the number of events will vary 
468 
considerably by person and by day, this is believed to be a conservative estimate (i.e. 
469 
participants will typically have more than three correction doses per day). 
470 
• 
Each patient will contribute 28 days worth of data. This corresponds to two two-week periods 
471 
for each patient, with the first in the treatment arm and the second in the control arm or vice 
472 
versa, depending on randomization. 
473 
• 
No changing of treatment assignment for patients within each arm. 
474 
• 
No dropout of patients. Dropout will not affect the ability to conduct the analysis or violate any 
475 
modeling assumptions, but will reduce the study’s power commensurate with the degree of 
476 
data loss observed. 
477 
• 
No period effect. Times until stabilization are not expected to increase or decrease during the 
478 
second phase of the cross-over trial due to fact that the first arm has already been conducted. 
479 
Alternately, any effect of the first phase is expected to have washed out by the time of data 
480 
collection during the second phase. Given the time between data collection periods in the two 
481 
arms, the existence of a period effect seems unlikely. 
482 
• 
No time trend. On average, participants are not expected to increase or decrease their time 
483 
until stabilization within each trial period (e.g. patients stabilize faster in response to a 
484 
stabilization dose at the end of the data collection period during the first trial arm than they do 
485 
at the beginning). Since data collection occurs during a relatively short window (two weeks) at 
486 
the end of each period, this assumption is likely also easily met. 
487 
• 
Treatment arms are assumed to have an equal number of patients. This is not an assumption of 
488 
the model, merely how the simulations were conducted. Consequently, sample sizes are 
489 
considered in increments of 2. Minor violations of balance between groups after data collection 
490 
can be expected to have a negligible impact on the results. 
491 
Simulation Parameters 
492 
• 
The standard deviation of the random effect distribution, tau. Conceptually, each person has an 
493 
innate average time until glucose stabilization following a correction bolus dose. Tau describes 
494 
the variation of that distribution, indicating the distance between the participant with the 
495 
fastest average time and the participant with the slowest average time. This distance between 
496 
the average stabilization time for the fastest and slowest patient is evaluated at 1, 2, and 3, 
497 
hours. Since the distribution is assumed to follow a normal distribution, for which the width of a 
498 
95% confidence interval is approximately 4 standard deviations, we evaluate values of tau = 15, 
499 
30, 45, corresponding to 60 min, 120 min, and 180 min divided by 4. 
500 
• 
The standard deviation of the error distribution, sigma. This parameter describes the random 
501 
variation in time until stabilization for each participant about their own personal average. 
502 
Where tau described the between-person variation in times, sigma describes the variation 
503 
within each person’s measurements. Sigma is assumed to equal 20 min, suggesting, by the same 
504 
logic as for tau, that we expect most (95%) of the measurements for each person to fall within 
505 
+/- 40min of their individual average values. 
506 

13 
 
 
Version 4.0  updated  01/07/2019 
 
 
• 
The correlation between individual averages on control and treatment assignments, rho. Where 
507 
some participants can be expected to have average times until stabilization that are higher than 
508 
the group average when assigned to the control group, it is reasonable to think that they will 
509 
likewise have a higher average time than the group when assigned to the treatment group. A 
510 
value of rho = 1 indicates perfect correlation between individual averages on treatment and 
511 
control assignments, while a value of rho = 0 indicates no correlation. Both extreme values are 
512 
considered. A value of rho = 0 is the more conservative estimate, however. 
513 
For each value of Tau (15, 30, 45), 2000 simulations, corresponding to 2000 randomly generated 
514 
datasets, were performed. The simulation margin of error is +/- 0.026. With rho = 0, tau = 30, sigma = 
515 
20, and the above assumptions, 80% power is achieved at approximately 23 subjects, while a power of 
516 
100% is achieved with a sample size of approximately 32 or greater. A value of 20 for sigma is based on 
517 
previous studies (Russell-Jones, et al). If subjects bolus more than three times per day then power is 
518 
increased. Further, smaller values of tau also increase power.  
519 
DATA HANDLING AND RECORD KEEPING 
520 
The study data (CGM data and laboratory endpoints including HbA1c and GlycoMark) will be uploaded 
521 
and stored in the cloud in HIPAA-compliant electronic files.  Pertinent data for endpoint safety and 
522 
efficacy analyses will be entered into and electronically filed in password-protected Excel spreadsheets.  
523 
Hypoglycemia diaries will be on paper and stored as source documents along with paper CRF’s capturing 
524 
study-related procedures (history, physical exam, vital signs, con meds, AE’s) at each visit.  Patients will 
525 
complete TRIM-D questionnaires, and responses will be tabulated into Excel spreadsheets for statistical 
526 
analysis. 
527 
All paper source documents and CRFs will be stored on site. All electronic data will be stored in the cloud 
528 
in HIPAA-compliant electronic files. 
529 
 
530 
ETHICS 
531 
The sponsor (Mountain Diabetes and Endocrine Center), its investigators and site staff will comply with 
532 
all applicable regulatory and legal requirements, ICH GCP guidelines and the Declaration of Helsinki in 
533 
obtaining and documenting the informed consent. 
534 
Informed consent will be obtained by a medically qualified site member (MD or RN) after each subject 
535 
has had time to review the informed consent document and have any questions about the study 
536 
answered.  This is performed in a conference room at the study site in a private and unhurried fashion.  
537 
The subjects may bring family members with them to witness the informed consent process.  The 
538 
informed consent documents will be paper documents that will be retained at the site, signed by the 
539 
subject and investigator, and a copy will be provided to each subject. 
540 
Upon approval of the study protocol, the study will be submitted for approval to IntegReview IRB in 
541 
Austin, Texas for review and approval.  The informed consent document will include information about 
542 
the IRB and contact information for the IRB, the site, and the study principal investigator. 
543 
The study will be conducted in accordance with ICH GCP guidelines and the Declaration of Helsinki. 
544 

14 
 
 
Version 4.0  updated  01/07/2019 
 
 
 
545 
STUDY SCHEDULE   
546 
Planned recruitment period: 48 weeks 
547 
FPFV: Upon approval of sponsor and IRB approval (within 6 weeks of sponsor approval) 
548 
LPLV: Within 52 weeks of FPFV 
549 
Final study report: within 4 weeks of LPLV 
550 
Manuscript submission of study results: within 12 weeks of study completion 
551 
 
552 
 
553 
STUDY DRUGS AND MATERIALS  
554 
Study medications: Fiasp, NovoLog (Novo Nordisk) 
555 
Study CGM: Dexcom G5 or G6 
556 
Insulin pumps: Medtronic MiniMed 523, 723, 630G & 670G (used in open loop “manual” mode), 
557 
Tandem T-Slim and Omnipod 
558 
 
559 
PACKAGING AND LABELLING OF STUDY MEDICATION 
560 
Study insulin (conventional insulin aspart and insulin Fiasp) will be distributed at in-person study visits to 
561 
each subject from the site. Conventional insulin aspart and Fiasp will be supplied in vials because all 
562 
insulin will be administered via insulin pump. Subjects will use their own insulin pumps and pump 
563 
supplies during the study.  1 Dexcom G6 sensor or 2 Dexcom G5 sensors, as applicable, will be provided 
564 
by the site during the last 2 weeks of each treatment arm.  All other Dexcom sensors will be supplied by 
565 
the subjects. Dexcoms will be downloaded at each visit (see study visit flow sheet). 
566 
STORAGE AND DRUG ACCOUNTABILITY OF STUDY MEDICATION 
567 
Study insulins will be received in temperature-controlled containers and the temperature of the 
568 
medication upon receipt will be recorded.  Study insulins will be stored at the study site in refrigerators 
569 
maintained between 2 and 8 degrees Celsius; the temperature will be monitored and recorded daily.  
570 
Fiasp vials will not be stored in or near a freezing compartment, and will not be exposed to excessive 
571 
heat or light and will never be frozen.  No trial medication will be dispensed to any individual not 
572 
enrolled in the study.  All medication used in the study will be recorded in the CRF at each study 
573 
dispensing visit. Subjects will be provided with sufficient study insulin for study completion. 
574 
AUXILIARY SUPPLY 
575 
Subjects will use their own insulin pumps, pump supplies, and Dexcom CGM/sensors, except for Dexcom 
576 
G5 or G6 sensor(s) provided during the last 2 weeks of each treatment arm. 
577 
RANDOMIZATION AND BLINDING 
578 
This is an open-label crossover trial.  Subjects will be randomized to treatment sequence (Fiasp then 
579 
NovoLog or NovoLog then Fiasp), each for a 12-week treatment period, by CSII.  Randomization 
580 
sequence will be determined by computerized randomization program.  All patients will receive both 
581 

15 
 
 
Version 4.0  updated  01/07/2019 
 
 
treatments unless they drop out. Dropouts are unlikely since the participants are all regular continuing 
582 
patients of the site’s clinical practice.  
583 
 
584 
CONCOMITANT ILLNESSES AND MEDICATIONS 
585 
Definitions: 
586 
Concomitant illness: any illness that is present at the start of the trial (at the first study visit). 
587 
Concomitant medication: any medication other than the trial product(s) that is taken during the trial, 
588 
including the screening and run-in periods. 
589 
Details of all concomitant illnesses and medication will be recorded at trial entry (at the first study visit). 
590 
Any changes in concomitant medication will be recorded at each visit.  
591 
The information collected for each concomitant medication will include start date, stop date or 
592 
continuing, and indication. 
593 
For each concomitant illness, date of onset, date of resolution or continuing, will be recorded. 
594 
 
595 
ADVERSE EVENTS 
596 
Adverse events will be captured at each study visit and recorded on CRF’s.  Special AE and SAE reporting 
597 
forms have been created to capture these events.  SAE’s will be reported within 24 hours of discovery to 
598 
appropriate local and federal authorities as well as to the IRB when appropriate.  The study site will 
599 
comply with all local legal, regulatory, and IntegReview IRB requirements.  In addition, any other events 
600 
that have been submitted to the health authorities according to local regulatory requirements will be 
601 
sent to Novo Nordisk at time of submission to health authorities, at the latest. 
602 
Mountain Diabetes and Endocrine Center, its investigators, and site staff will be responsible for 
603 
reporting of all adverse events including serious adverse events (SAE),  and serious adverse drug 
604 
reactions (SADRs) to the competent authority and independent ethics committee/institutional review 
605 
board based upon federal regulations and local/IRB policies.  
606 
Mountain Diabetes and Endocrine Center, its investigators, and site staff will report to Novo Nordisk all 
607 
SAEs,  and SADRs at the same time such events are reported to regulatory authorities or within 15 days 
608 
from the site becoming aware of such adverse events, whichever comes first.  
609 
Mountain Diabetes and Endocrine Center, its investigators, and site staff will collect the following 
610 
information at minimum for each of these events: 
611 
1. Study name 
612 
2. Patient identification  
613 
3. Event (with appropriate diagnosis) 
614 
4. Drug  
615 
5. Reporter identification  
616 
Also 6) Causality, and 7) Outcome might be reported, if appropriate. 
617 
 
618 
DEFINITIONS 
619 

16 
 
 
Version 4.0  updated  01/07/2019 
 
 
 
620 
Adverse Event (AE): 
621 
An AE is any undesirable medical event occurring to a subject in a clinical trial, whether or not related to 
622 
the trial product(s). This includes events reported from the first trial related activity after the subject has 
623 
signed the informed consent and until post treatment follow-up period as defined in the protocol. The 
624 
following will not be recorded as AEs, if recorded as medical history/concomitant illness on the CRF at 
625 
screening: 
626 
• Pre-planned procedure, unless the condition for which the procedure was planned has    worsened 
627 
from the first trial related activity after the subject has signed the informed consent 
628 
• Pre-existing conditions found as a result of screening procedures  
629 
Clinical Laboratory Adverse Event: 
630 
A clinical laboratory AE is any clinical laboratory abnormality regarded as clinically significant, i.e. an 
631 
abnormality that suggests a disease and/or organ toxicity and is of a severity which requires active 
632 
management, (i.e. change of dose, discontinuation of trial product, more frequent follow-up or 
633 
diagnostic investigation). 
634 
 
635 
Serious Adverse Event (SAE): 
636 
A serious AE is an event that results in any of the following: 
637 
• Death 
638 
• A life-threatening* experience 
639 
• In-patient hospitalization or prolongation of existing hospitalization 
640 
• A persistent or significant disability/incapacity 
641 
• A congenital anomaly/birth defect 
642 
• Important medical events that may not result in death, be life-threatening*, or require 
643 
  hospitalization may be considered an SAE when, based upon appropriate medical judgement, they may 
644 
jeopardise the subject and may require medical or surgical intervention to prevent one of the 
645 
outcomes listed in this definition 
646 
*The term life-threatening in the definition of SAE refers to an event in which the subject was at risk of 
647 
death at the time of the event. It does not refer to an event which hypothetically might have caused 
648 
death if it was more severe. 
649 
 
650 
Serious Adverse Drug Reaction (SADR):  
651 
An adverse drug reaction (ADR) is an adverse event for which a causal relationship (Possible/Probable 
652 
relation) between the study drug and the occurrence of the event is suspected. The ADR will be 
653 
classified as serious if it meets one or more of the seriousness criteria.  
654 
 
655 
Medical Events of Special Interest (MESI): A MESI is (1) a medication error (e.g. wrong drug 
656 
administration or wrong route of administration) or (2) a suspected transmission of an infectious agent 
657 
via the product 
658 
 
659 
Non-Serious Adverse Event: 
660 
A non-serious AE is any AE which does not fulfil the definition of an SAE. 
661 
 
662 
Severity Assessment Definitions: 
663 
• Mild: Transient symptoms, no interference with the subject’s daily activities 
664 

17 
 
 
Version 4.0  updated  01/07/2019 
 
 
• Moderate: Marked symptoms, moderate interference with the subject’s daily activities 
665 
• Severe: Considerable interference with the subject’s daily activities, unacceptable 
666 
 
667 
The Glucose Plateau Point (GPP): 
668 
The point of arrest on the Dexcom CGM when the glucose trend arrow changes from upwards to 
669 
horizontal after each correction bolus and/or meal bolus with insulin.  
670 
 
671 
Relationship to study medication Assessment Definitions:  
672 
• Probable: Good reason and sufficient documentation to assume a causal relationship 
673 
• Possible: A causal relationship is conceivable and cannot be dismissed 
674 
• Unlikely: The event is most likely related to an ethology other than the trial product 
675 
 
676 
Outcome Categories and Definitions: 
677 
 
678 
• Recovered: Fully recovered or by medical or surgical treatment the condition has returned to the level 
679 
observed at the first trial related activity after the subject signed the informed consent 
680 
• Recovering: The condition is improving, and the subject is expected to recover from the event. This 
681 
term should only be used when the subject has completed the trial 
682 
• Recovered with sequelae: As a result of the AE, the subject suffered persistent and     significant 
683 
disability/incapacity (e.g. became blind, deaf, paralysed). Any AE recovered with sequelae will be rated 
684 
as an SAE 
685 
• Not recovered 
686 
• Fatal 
687 
• Unknown 
688 
 
689 
Collection, Recording and Reporting of Adverse Events 
690 
 
691 
All events meeting the definition of an adverse event will be collected and reported from the first trial-
692 
related activity after the subject has signed the informed consent and until the end of the post-
693 
treatment follow-up period as stated in the protocol.  
694 
 
695 
Follow-up of Adverse Events 
696 
 
697 
During and following a subject’s participation in this clinical trial, Mountain Diabetes and Endocrine 
698 
Center, its investigators and site staff, will provide adequate medical care to the study subject for any 
699 
study-related adverse events, including clinically significant laboratory values related to the study. 
700 
This medical care for study subjects will be provided regardless of their insurance status. 
701 
 
702 
All adverse events classified as serious or severe or possibly/probably related to the trial product will 
703 
be followed until the subject has recovered and all queries have been resolved. For cases of chronic 
704 
conditions, follow-up until the outcome category is “recovered” is not required, as these cases can be 
705 
closed with an outcome of “recovering” or “not recovered”. 
706 
All other adverse events will be followed until the outcome of the event is “recovering” (for chronic 
707 
conditions), or “recovered” or until the end of the post-treatment follow-up stated in the protocol, 
708 
whichever comes first, and until all queries related to these AEs have been resolved. 
709 
 
710 

18 
 
 
Version 4.0  updated  01/07/2019 
 
 
Pregnancy 
711 
Study subjects will be instructed to notify the site and study physician immediately if they become 
712 
pregnant.  
713 
 
714 
Mountain Diabetes and Endocrine Center, its investigators and site staff, will report to Novo Nordisk 
715 
any pregnancy occurring during the trial period. Reporting of pregnancy by the site will occur within 
716 
the same timelines described above for reporting of Adverse Events.  
717 
  
718 
Pregnancy complications will be recorded as adverse event(s). If the infant has a congenital 
719 
anomaly/birth defect this must be reported and followed up as a serious adverse event. 
720 
 
721 
Precautions/ Insulin Over-dosage 
722 
Study subjects will be prescribed glucagon kits and treatment of hypoglycemia will be reviewed with 
723 
subjects upon enrolment into the study.  
724 
 
725 
LIABILITY AND SUBJECT INSURANCE 
726 
During and following a subject’s participation in trial, Mountain Diabetes and Endocrine Center and 
727 
the study physicians will provide adequate medical care to the study subject for any study-related 
728 
adverse events, including clinically significant laboratory values related to the study. This medical care 
729 
for study subjects will be provided regardless of their insurance status. 
730 
 
731 
Mountain Diabetes and Endocrine Center and its investigators will be responsible for the conduct of 
732 
the study and agree to defend, indemnify, and hold harmless Novo Nordisk, any of its parent 
733 
companies, affiliates, or subsidiaries, and their respective officers, directors, employees, agents, 
734 
representatives, distributors, salespersons, customers, licensees, and end-users from and against any 
735 
claim, suit, demand, loss, damage, expense or liability imposed by any third party arising from or 
736 
related to: (a) any breach of sponsor-investigator's obligations or representations; or (b) sponsor-
737 
investigator’s negligent or grossly negligent use or willful misuse of the study drug, the results, or 
738 
services derived therefrom.  This indemnification shall not apply in the event and to the extent that a 
739 
court of competent jurisdiction or a duly appointed arbiter determines that such losses or liability 
740 
arose as a result of Novo Nordisk’s gross negligence, intentional misconduct, or material breach of its 
741 
responsibilities.  
742 
 
743 
EVALUABILITY OF SUBJECTS  
744 
Only the principal investigator has the authority to exclude any subjects or data observations after the 
745 
initiation of the study, initial selection of subjects, and beginning of data collection. Possible reasons for 
746 
such actions might be (1) questionable validity or reliability of data collection or measurement 
747 
techniques for a particular subject, (2) misrepresentation of initial selection criteria by a subject, or (3) 
748 
changes in the health conditions of subjects that might affect the reliability or validity of measurements 
749 
or accuracy of data collection procedures. The reasons for any such action will be carefully documented 
750 
by the principal investigator and kept on file for the actionable subject. 
751 
 
752 

19 
 
 
Version 4.0  updated  01/07/2019 
 
 
PREMATURE TERMINATION OF STUDY 
753 
The study will only be discontinued prematurely in the unlikely event of an unforeseen safety concern 
754 
arising from the study protocol.   
755 
 
756 
 
757 
 
758 
PUBLICATION PLAN 
759 
Within 12 weeks of study completion and data analysis, the results of this study (which will be registered 
760 
with clinicaltrials.gov) will be submitted in abstract form for oral or poster presentation at a diabetes 
761 
conference (either ADA or EASD) and a manuscript of the complete study results will be submitted to a 
762 
peer-reviewed journal focused on clinical diabetes for publication. 
763 
REFERENCES 
764 
1. Heise T, Pieber TR, Danne T, et al. : Diabetes 2016;65(Suppl 1):A239 
765 
2. Bode B, Johnson J, Hyveled L, et al.: Diabetes Technol Ther. 2017 Jan 1; 19(1): 25–33. Published 
766 
online 2017 Jan 1. doi:  10.1089/dia.2016.0350 
767 
3. ONSET5 NN1218-3854, unpublished data 
768 
4. Aleppo G, Laffel L, Ahmann A, et al.: Journal of the Endocrine Society, Volume 1, Issue 12, 1 
769 
December 2017, Pages 1445–1460,https://doi.org/10.1210/js.2017-00388 
770 
5. Heise T, Pieber TR, Danne T, et al.: Clin Pharmacokin (2017)56: 551-559 
771 
6. Russell-Jones D, Bode BW, De Block C, et al.: Diabetes Care (2017)40: 950 
772 
7. Full Prescribing Information document, Reference ID:4160518, revised09/2017 
773 
8. Bergenstal R et al. JAMA. 2016; 316(13):1407-1408  
774 

20 
 
 
Version 4.0  updated  01/07/2019 
 
 
Trial Procedures 
Screening 
Treatment Period 1 (First Treatment Group) 
Treatment Period 2 (Second Treatment Group) 
Visit (V), Phone (P) 
V1 
V2 
(Randomization) 
V3 
PV4 
V5 
PV6 
PV7 
V8 
(Crossover) 
V9 
PV10 
V11 
PV12 
PV13 
V14 
(EOT) 
Timing of Visit (Weeks) 
-1 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
Visit Window (Days) 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
In/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography & Tobacco Use 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Concomitant Illness 
/Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Child Bearing Potential 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test, Urine 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Vital Signs 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
CGM Download 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Dexcom Sensor(s) 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Insulin Pump Download 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Insulin Optimization 
X 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
Meal Challenge 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
BLOOD SAMPLING 
 
HbA1C (central laboratory) 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 

21 
 
 
Version 4.0  updated  01/07/2019 
 
 
GlycoMark 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hypoglycemia Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Technical Complaints 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infusion Site Reactions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Infusion Site Occlusions 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensing of Trial Product 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 
 
Drug Accountability 
 
 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Treatment Crossover 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Questionnaires/Surveys 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
REMINDERS 
 
Insulin Instruction 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Dispense Diary 
X 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 
 
Collect Diary 
 
X 
X 
 
X 
 
 
X 
X 
 
X 
 
 
X 
Review Diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Confirmation of 
Consumption of 3 Meals 
Daily 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Fasting Visit 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Instruction on Dexcom 
Bolus Entry 
 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
CRC Data Collection and 
Data Validation 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X