Clinical trial NCT03987191
Conditions: Type 1 Diabetes
Sponsor: University of Colorado, Denver
Start date: 2020-01-10; Completion date: 2020-10-08
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized controlled, two arms, investigator initiated, intervention study is aimed to examine an investigational approach in contrast to the clinical standard of 1:1 dose basal insulin conversion in an attempt to lower the incidence and/or duration of hyperglycemia after transition from insulin pump to multiple daily injections in adults with type 1 diabetes.

Detailed description:
Second generation long acting insulin, insulin degludec, has been shown to improve glycemic control and reduce hypoglycemia in patients with type 1 diabetes and insulin treated type 2 diabetes. However, it takes about 48 hours before glycemic benefits are noticeable. Therefore, transition from insulin pump to multiple daily injection using insulin degludec is associated with hyperglycemia during first 48 hours of transition. Considering this, this study proposes to evaluate an investigational strategy to improve glycemic control during transition from insulin pump to multiple daily injections using insulin degludec and insulin aspart.

Arms: arm 1: Stopping of insulin pump on the day of randomization and starting insulin degludec in 1:1 ratio (same units as total basal insulin on pump) and insulin Aspart for meals and corrections arm 2: Administration of insulin degludec in 1:1 ratio (same units as total basal insulin on pump) on the day of randomization AND concomitant use of the insulin pump for 48 hours from transition, where insulin pump basal rate will be reduced by 50% during the first 24 hours from transition and by 75% during 24 to 48 hours from transition. Insulin pump will be disconnected after 48 hours from transition
Interventions: intervention 1: Multiple daily ijnection using Insulin Degludec and Insulin Aspart
Intervention descriptions: intervention 1: Drug: Insulin Degludec and insulin Aspart Pharmaceutical form: Solution for injection Route of administration: Subcutaneous

Protocol documents:
Prot_SAP_000.pdf: 
Version  08-31-2020_R 
 
   Page 1 of 44 
 
SUCCESSFUL TRANSITION FROM INSULIN PUMP TO MULTIPLE DAILY 
1 
INJECTIONS USING INSULIN DEGLUDEC IN ADULTS WITH TYPE 1 DIABETES 
2 
(TRANSITION CLINICAL TRIAL) 
3 
 
4 
 
5 
 
6 
 
7 
INVESTIGATOR-SPONSORED STUDY PROPOSAL 
8 
 
9 
UNIVERSAL TRIAL NUMBER (UTN) 
10 
(U1111-1214-1853) 
11 
 
12 
CINICAL TRIAL NUMBER: NCT03987191 
13 
 
14 
 
15 
 
16 
 
17 
 
18 
 
19 
Barbara Davis Center for Diabetes 
20 
University of Colorado Denver 
21 
1775 Aurora Ct, Room M20-1318 
22 
Aurora, CO 80045 
23 
 
24 
 
25 
 
26 
Correspondence 
27 
 
28 
 Viral Shah, MD 
29 
Assistant Professor of Medicine & Pediatrics 
30 
Barbara Davis Center for Diabetes, Adult Clinic 
31 
School of Medicine 
32 
University of Colorado Anschutz Medical Campus 
33 
1775 Aurora Ct,  Room M20-1318 
34 
Aurora, CO 80045 
35 
Phone:303-724-8186 
36 
Fax: 303-724-6784 
37 
viral.shah@cuanschutz.edu 
38 
 
39 
 
40 
 
41 
 
42 
 
43 


Version  08-31-2020_R 
 
   Page 2 of 44 
 
Table of contents 
44 
 
45 
 
46 
1. 
BACKGROUND AND SIGNIFICANCE:........................................................................... 4 
47 
2. 
SPECIFIC OBJECTIVES: ................................................................................................... 6 
48 
3. 
RESEARCH DESIGN AND METHODS: ........................................................................... 6 
49 
3.1. Study Hypothesis .......................................................................................................... 6 
50 
3.2. Endpoints: ..................................................................................................................... 7 
51 
3.3. Study design: ................................................................................................................ 7 
52 
3.4. Rationale for study design ............................................................................................ 9 
53 
4. 
CLINICAL RESEARCH SITES .......................................................................................... 9 
54 
5. 
STUDY POPULATION: ..................................................................................................... 10 
55 
5.1. Inclusion criteria ......................................................................................................... 10 
56 
5.2. Exclusion criteria ........................................................................................................ 10 
57 
5.3. Withdrawal criteria ..................................................................................................... 12 
58 
5.4. Subject replacement .................................................................................................... 12 
59 
5.5. Rationale for study population ................................................................................... 12 
60 
6. 
VISIT PROCEDURES: ....................................................................................................... 13 
61 
6.1. Visit 1, screening and blinded CGM insertion ........................................................... 13 
62 
6.2. Screening Failure ........................................................................................................ 16 
63 
6.3. Visit 2, Randomization visit ....................................................................................... 16 
64 
6.4. Phone call 1 and phone call 2 ..................................................................................... 19 
65 
6.5. Visit 3, end of treatment ............................................................................................. 20 
66 
6.6. Phone call 3, follow-up phone call and end of the study ............................................ 21 
67 
6.7. Table 4: study visit outline ......................................................................................... 22 
68 
6.8. Assessments for Safety: .............................................................................................. 23 
69 
6.9. Assessments for Efficacy: .......................................................................................... 23 
70 
7. 
EVALUABILITY OF SUBJECTS: ................................................................................... 23 
71 
8. 
STATISTICAL CONSIDERATIONS: .............................................................................. 23 
72 
8.1. Sample size calculation .............................................................................................. 23 
73 


Version  08-31-2020_R 
 
   Page 3 of 44 
 
8.2. Statistical Methods ...................................................................................................... 25 
74 
9. 
DATA HANDLING AND RECORD KEEPING: ............................................................. 26 
75 
10. 
ETHICS: ................................................................................................................................ 27 
76 
11. 
STUDY SCHEDULE: .......................................................................................................... 28 
77 
12. 
STUDY DRUGS AND MATERIALS: ................................................................................ 28 
78 
12.1. Study medications(s) /  device(s) ................................................................................ 28 
79 
12.2. Packaging and labelling of study medication(s) ......................................................... 29 
80 
12.3. Storage and drug accountability of study medication(s) ............................................. 29 
81 
12.4. Auxiliary supply .......................................................................................................... 30 
82 
13. 
CONCOMITANT ILLNESS(ES) AND MEDICATION(S) ............................................. 30 
83 
14. 
ADVERSE EVENTS: ........................................................................................................... 30 
84 
14.1. Precautions/over-dosage .............................................................................................. 36 
85 
          14.2 Risks and Discomforts ................................................................................................36 
86 
15. 
PUBLICATION PLAN: ....................................................................................................... 39 
87 
16. 
REFERENCES: .................................................................................................................... 40 
88 
 17.    Appendix 1.............................................................................................................................43 
89 
18.     Protocol Changes...................................................................................................................44 
90 
 
91 
 
92 
 
93 
 
94 
 
95 
 
96 
 
97 
 
98 
 
99 
 
100 
 
101 
 
102 
 
103 
 
104 


Version  08-31-2020_R 
 
   Page 4 of 44 
 
 
105 
1.    BACKGROUND AND SIGNIFICANCE:  
106 
Type 1 diabetes (T1D) is an autoimmune disease characterized by loss of insulin-producing 
107 
pancreatic beta cells [1]. Patients with T1D require lifelong insulin therapy to maintain good 
108 
glycemic control and reduce the risk for microvascular complications [2]. 
109 
Despite many advances in insulin delivery methods, recent data from the Type 1 Diabetes 
110 
Exchange Clinic Registry showed that only about 50% of people with T1D are using an insulin 
111 
pump (continuous subcutaneous insulin infusion, CSII) as their insulin delivery method [3,4]. In 
112 
addition, the overall frequency of pump discontinuation is 3%, being higher in adolescents (4%) 
113 
and young adults (4%) than in young children (3%) or older adults (1%) [5]. Reasons behind pump 
114 
therapy discontinuation, either after a short- or long- standing usage, can be different. The most 
115 
commonly reported ones are issues with wearability, including problems with insertion, pump 
116 
discomfort, skin reactions, adhesive problems, and interference with sports and activities. Other 
117 
common ones included the feeling of anxiety, discontinuation recommended by health care 
118 
practitioner, failure with glycemic control and pump working properly (i.e. infusion set failure) 
119 
[5,6]. Moreover, many T1D patients on CSII treatment often go on a “pump vacation”, periods of 
120 
the year during which the patient decides to temporarily go back on multiple daily insulin 
121 
injections (MDI). Reasons for taking a pump vacation can be very different, the most common 
122 
ones being related to esthetic reasons (i.e. during summer period at the seaside) and during 
123 
holidays [7].  
124 
Insulin degludec is a new ultra-long acting insulin. To date, it is the only insulin analogue to self-
125 
associate into multi-hexamers upon subcutaneous injection, resulting in a soluble depot from 
126 


Version  08-31-2020_R 
 
   Page 5 of 44 
 
which it is slowly and continuously absorbed into the circulation [8-9]. In the pharmaceutical 
127 
formulation, i.e. in the presence of phenol and zinc, the insulin degludec hexamers adopt a 
128 
conformation where only one of the ends is available to interact with the side chain of another 
129 
hexamer and thus forms stable di-hexamers. Upon diffusion of phenol following injection, the 
130 
insulin degludec di-hexamers open at both ends and lead to the formation of multi-hexamers. The 
131 
gradual diffusion of zinc from the ends of the multi-hexamers causes terminal insulin degludec 
132 
monomers to slowly and steadily dissociate, resulting in a slow and gradual delivery of insulin 
133 
degludec from the subcutaneous injection site into the circulation [8-10]. This is the major 
134 
difference with insulin glargine which, following subcutaneous injection, forms microprecipitates 
135 
that must re-dissolve prior to absorption and which renders its absorption inherently variable [8-
136 
10]. 
137 
The longer duration of action and the lower day-to-day insulin degludec variability makes it an 
138 
appealing choice when patients want to start multiple daily injections. In addition, when compared 
139 
to insulin glargine, insulin degludec is associated with lower incidence of nocturnal and overall 
140 
hypoglycemia in insulin requiring patients with diabetes [11].  
141 
However, differently from insulin glargine, the time needed from first dose of insulin degludec to 
142 
reach steady state, defined as serum concentration exceeding 90% of the final plateau, is about 2 to 
143 
3 days, being at 60% of steady state within at day 1 and 85% at day 2 [12-13]. This results in an 
144 
increased risk of hyperglycemia, during the initial 48-72 hours of CSII to MDI transition using 
145 
insulin degludec. 
146 


Version  08-31-2020_R 
 
   Page 6 of 44 
 
Current CSII to MDI transition strategy is to stop CSII and initiate long acting insulin (such as 
147 
glargine or detemir 1:1) from day 1 of stopping insulin pump [14-17]. However, the standard of 
148 
care strategy has not been successful at the Barbara Davis Center for Diabetes, a leading T1D 
149 
center in the world (unpublished observation), due to significant hyperglycemia during the first 48-
150 
72 hours of this transition. Hyperglycemia for initial 2-3 days makes transition from CSII to MDI 
151 
difficult and frustrating for the patients. Therefore, there is a need to have a standardized approach 
152 
to transitioning patients from CSII to MDI using insulin degludec. 
153 
Considering the lack of evidence and knowledge gap, this study is proposed to examine an 
154 
investigational approach in contrast to the clinical standard of 1:1 dose conversion in an attempt to 
155 
lower the incidence and/or duration of hyperglycemia after transition from insulin pump. 
156 
2. SPECIFIC OBJECTIVES: 
157 
The primary objective of this study is to evaluate the efficacy and safety of an alternative CSII to 
158 
MDI transition strategy using insulin degludec compared to the standard of care in adults with 
159 
T1D. 
160 
3. RESEARCH DESIGN AND METHODS: 
161 
3.1. Study Hypothesis 
162 
We hypothesize that, as compared to the actual standard of care transition strategy (1:1 dose 
163 
conversion at the day of CSII to MDI transition), an alternative transition strategy will result in 
164 
lower time spent in hyperglycemia without increasing the risk for hypoglycemia. The alternative 
165 
strategy being (overlap transition strategy): 
166 
• Administration of insulin degludec at a 1:1 basal dose conversion dosage at day 0, with the 
167 
concomitant use of the insulin pump for 48 hours from transition, where CSII basal rate 
168 


Version  08-31-2020_R 
 
   Page 7 of 44 
 
will be reduced by 50% during the first 24  hours from transition and by 75% during 24 to 
169 
48 hours from transition. CSII will be disconnected after 48 hours from transition.  
170 
3.2. Endpoints: 
171 
Primary and secondary endpoints will be analyzed from 1-week of blinded CGM use during 
172 
randomization phase.  
173 
Primary endpoint: 
174 
1. Time spent in CGM glucose levels >180mg/dl 
175 
Secondary endpoints: 
176 
1. Time spent in CGM-measured “time-in-range”(glucose levels  ≥70 mg /dl and ≤180 mg/dl) 
177 
2. Time spent in CGM-measured hypoglycemia < 70 mg/dl 
178 
3. Frequency of severe hypoglycemia as defined by the ADA (severe cognitive impairment 
179 
requiring external assistance for recovery) and severe hyperglycemia (BG≥250 needing 
180 
hospitalization) 
181 
4. Number of boluses (correction boluses) between groups during first 72 hours of 
182 
randomization 
183 
5. Patient-Reported Outcomes (PRO) using validated questionnaires; insulin delivery 
184 
satisfaction survey (IDSS) and Work Productivity and Activity Impairment Questionnaire: 
185 
Specific Health Problem V2.0 (WPAI: SHP) [18,19]  
186 
3.3. Study design: 
187 
• This is a 3-week, randomized control, open label, single center clinical trial with two study 
188 
arms comparing the efficacy and safety of the ‘standard of care transition’ and an ‘overlap 
189 
transition’ strategy 
190 


Version  08-31-2020_R 
 
   Page 8 of 44 
 
• The study consists of a screening phase, one week of run-in phase (blinded CGM 
191 
monitoring), one week of the experimental protocol following randomization phase and 
192 
one week of follow-up phase.  
193 
• Overall, the study will last 3 weeks that includes four clinical trial phases (Figure 1): 
194 
o Screening phase (Week 0): After informed consent, inclusion and exclusion, blinded CGM 
195 
will be inserted.  
196 
o Run-in phase (Week 0 to end of week 1): Subjects will wear blinded CGM and continue to 
197 
use CSII.  
198 
o Randomization phase (Week 1 to week 2): Subjects will be randomly allocated to one of 
199 
two transition protocols (1:1 randomization). 
200 
o Follow-up phase (Week 2 to week 3): Subjects will return to their preclinical trial CSII 
201 
regimen. 
202 
Figure 1: Study Design 
203 
 
204 


Version  08-31-2020_R 
 
   Page 9 of 44 
 
3.4. Rationale for study design 
205 
The rationale behind the overlap protocol strategy is linked to insulin degludec pharmacokinetic 
206 
and pharmacodynamics. Indeed, insulin degludec steady state concentration reaches 60% and 85% 
207 
respectively at day 1 and 2, and 100% steady state is reached on day 3 from the first day of insulin 
208 
degludec injection [12-13]. 
209 
Therefore, 50% and 75% dose reduction proposed in the overlap transition strategy of the first 2 
210 
days will cover for the slow rise of insulin degludec concentration the first 2 days, and the 100% 
211 
insulin pump discontinuation on day 3 will correspond to the time needed for insulin degludec to 
212 
reach the steady state. This would reduce time spent in hyperglycemia post-CSII discontinuation. 
213 
Rationale for blinded CGM: Since the primary outcome is time spent in hyperglycemia (CGM 
214 
glucose >180 mg/dl), it is necessary to have CGM during randomized phase. Real-time CGM 
215 
would interfere with the primary and secondary outcomes as patients will have ability to see CGM 
216 
glucose trend and adjust insulin accordingly. Therefore, blinded CGM would be appropriate for 
217 
this research protocol. In addition, the time in range (and percentage of hypoglycemia) also 
218 
depends on person’ ability to manage diabetes and therefore, baseline CGM will provide the data 
219 
about time-in-range and time spent in hyper-and hypo-glycemia. The information from blinded 
220 
CGM during run-in-phase will be useful for analysis of primary and secondary outcomes that will 
221 
be adjusted for baseline CGM glucose metrics.  Blood glucose fluctuations are greatest during the 
222 
first week of insulin pump to MDI transition and therefore, 1 week CGM period is enough for 
223 
comparison of primary and secondary outcomes between the groups.  
224 
4. CLINICAL RESEARCH SITES 
225 
The study will be conducted at a single site, Barbara Davis Center for Diabetes. 
226 
 
227 


Version  08-31-2020_R 
 
   Page 10 of 44 
 
5. STUDY POPULATION: 
228 
We plan to enroll 34 participants with the expectation that 30 will be randomized and complete the 
229 
study.  
230 
5.1. Inclusion criteria 
231 
 
232 
1) Age ≥18 years and ≤ 65 years  
233 
2) Patients with T1D diagnosed for at least 12 months 
234 
3) Point-of-care HbA1c levels between ≥6.5% and ≤ 8.5%  
235 
4) Patients on CSII (any insulin pump) for at least past 6 months 
236 
5) Willing and able to wear a blinded CGM during the time of study period 
237 
6) Willing to perform self-monitoring of blood glucose (SMBG) at least 4 times a day 
238 
7) Ability to provide informed consent before any trial-related activities 
239 
8)  Not willing to or plan any travel out of Colorado during the 3 weeks of study period  
240 
9) Willing to use insulin degludec in the morning once a day  
241 
5.2. Exclusion criteria 
242 
 
243 
1) Age <18 years and > 65years 
244 
2) HbA1c >8.5 % at screening 
245 
3) Less than 12 months of insulin treatment 
246 
4) Patients on 670G or Tandem Control IQ (Medtronic and Tandem Hybrid Closed-loop 
247 
systems) and not willing use manual mode during the study period 
248 
5) Patients with T1D using any glucose lowering medications other than insulin 
249 
6) Pregnancy, breast feeding, and positive pregnancy test during screening 
250 


Version  08-31-2020_R 
 
   Page 11 of 44 
 
7) Women of childbearing age wanting to become pregnant or not using adequate 
251 
contraceptive measures 
252 
8) Current or recent (< 2 weeks prior to visit 1) use of any steroidal medication, or anticipated 
253 
steroidal treatment, during the study period 
254 
9)  eGFR below 45 ml/min/1.73 m^2 using MDRD formula 
255 
10) History of severe hypoglycemia in the previous 3 months 
256 
11) History of diabetic ketoacidosis (DKA) requiring hospitalization in the past 3 months 
257 
12) History of allergy to any form of insulin or its excipients  
258 
13) History of allergy to adhesives 
259 
14) Unwilling to use blinded CGM during the study period 
260 
15) Unwilling to perform SMPG at least 4 times a day 
261 
16) Known history of alcohol abuse or illicit drug use within 6 months prior to screening 
262 
17) Use of investigational drugs within 5 half-lives prior to screening 
263 
18) Participation to other study trials during the study period 
264 
19) Elevated liver enzymes (AST and ALT) 3 times the upper limit of normal 
265 
20) Hypoglycemia unawareness defined as GOLD score ≥4 [20] 
266 
21) Any comorbidities or medical conditions that make a person unfit for the study at the 
267 
discretion of the investigators 
268 
22) Anticipated travel across different time zones (difference greater than 4 hours) or 
269 
anticipated change in physical activities or diet at the discretion of the investigators.  
270 
 
271 
 
272 


Version  08-31-2020_R 
 
   Page 12 of 44 
 
5.3. Withdrawal criteria 
273 
• Participation in this research is voluntary. Subjects may withdraw at will at any time. When 
274 
withdrawing from the study, the participant should let the research team know that he/she 
275 
wishes to withdraw. A participant may provide the research team with the reason(s) for 
276 
leaving the study, but is not required to provide their reason.  
277 
• Participants will be withdrawn from the study if they become pregnant, actively try to 
278 
become pregnant, develop an allergic reaction to insulin/adhesives, severe episodes of 
279 
hypoglycemia/hyperglycemia, or at the judgement of investigators due to safety concerns, 
280 
such as abnormality in laboratory exam results. 
281 
• After withdrawal, the participant will be given instructions on how to safely stop using 
282 
study medications and, eventually, on how to correctly and safely return to the previous 
283 
insulin regimen. Instructions are also given on who to contact if there are any questions or 
284 
concerns that arise after study withdrawal.  
285 
• At the time of withdrawal, the research participant should let the research team know if 
286 
he/she will allow the use of his/her health information and collected data by the researchers. 
287 
5.4. Subject replacement 
288 
Subject replacement will occur only if withdrawal occurs before the one-week randomization 
289 
phase. Subjects will not be replaced during the one-week randomized phase.  
290 
5.5. Rationale for study population  
291 
In anticipation of screening failure or withdrawal  or anticipated issues due to covid-19 pandemic, 
292 
we plan to screen up to 40 subjects to have 30 complete the clinical trial. 
293 
 
294 
 
295 


Version  08-31-2020_R 
 
   Page 13 of 44 
 
6. VISIT PROCEDURES: 
296 
6.1. Visit 1, week 0, day0,  screening and blinded CGM insertion 
297 
 Subjects will attend a screening visit (Visit 1, week 0) in order to assess eligibility for the 
298 
study. 
299 
 Before screening takes place, subjects will be provided with written information about the 
300 
trial and the procedures involved. Subjects will be fully informed, both orally and in 
301 
writing, about their responsibilities and rights while participating in the trial, as well as 
302 
about possible advantages and disadvantages when participating in this trial. Subjects will 
303 
have the opportunity to ask questions and have ample time to consider participation. The 
304 
informed consent process will take place before the screening visit. Before signing the 
305 
informed consent, the investigator will make sure that has full knowledge of the study 
306 
processes, and the possibility to withdrawal at any time during the study.  
307 
 Subjects who wish to participate in the trial must sign and date the informed consent form 
308 
for the trial before any trial-related procedures. All subjects will be provided with a copy of 
309 
signed informed consent form. 
310 
 At screening, the subjects will be assigned a unique subject number, which will remain the 
311 
same throughout the trial. The subject number will consist of 6 digits (the first 4 digits 
312 
indicating the protocol number and the last 2 digits are unique for the subject). 
313 
 All subjects will undergo review of inclusion and exclusion criteria. If any inclusion 
314 
criteria is answered ‘no’ or any exclusion criteria is answered ‘yes’, the subject is a screen 
315 
failure, and no further assessment will take place.  
316 


Version  08-31-2020_R 
 
   Page 14 of 44 
 
 Patients will be told the importance of compliance in pre-set study visit time schedules. 
317 
This will be true for both visits done at the BDC and phone call visits. After screening visit 
318 
(visit 1, day 0), they will be asked to come at the BDC at visit 2 (day 7±1) and visit 3 (day 
319 
14±1). Furthermore, they must be compliant with phone call 1 (Week 1+24 hours; visit 
320 
2+24 hours), phone call 2 (Week 2+48 hours; P1+24 hours) and phone call 3 (day 21±1) 
321 
 Point of care HbA1c and spot urine pregnancy test (for women in reproductive age group) 
322 
will be done at the time of screening. A non-fasting blood will be drawn for complete 
323 
metabolic panel (CMP). 
324 
 If any clinical pathological condition is detected at physical examination, the investigator 
325 
can decide, at his/her discretion, to withdraw the patient from the study. 
326 
 For laboratory results such as CMP, “results pending” will be selected at Visit 1, week 0. 
327 
 Please refer to Table 1 for a description of items to be performed at the screening visit. 
328 
 All subjects will undergo GOLD questionnaire to exclude patients with hypoglycemia 
329 
unawareness. Subjects with hypoglycemic unawareness defined as a GOLD score of ≥ 4 
330 
[18] will be excluded. 
331 
 All subjects will be assessed for ability to perform SMBG. Participants will be required to 
332 
perform at least 4 SMBG daily using their own glucose meter; with at least one being in a 
333 
fasted state, one pre-prandial and one 2-3 hours post-meal glucose value. In addition, 
334 
participants will be required to check their blood glucose level if they have symptoms of 
335 
hyperglycemia or hypoglycemia. We expect hyperglycemia during first 48-72 hours after 
336 
randomization in group1 (standard of care transition). Therefore, SMBG requirements are 
337 


Version  08-31-2020_R 
 
   Page 15 of 44 
 
necessary to select appropriate patients for this clinical trial for safety reasons. However, 
338 
SMBG data will not be analyzed for primary or secondary endpoints.  
339 
 All subjects will go through a quick review on diabetes self-management, including: 
340 
o Recognition of carbohydrates in commonly eaten foods 
341 
o Ability to count the carbohydrate content in typical portions of simple foods 
342 
o Ability to interpret a nutrition label for carbohydrate content 
343 
o Preventing and treating hypoglycemia using carbohydrate-containing food and/or 
344 
glucagon 
345 
 All subjects will be instructed NOT to make any changes in the basal and bolus pump 
346 
settings during run-in phase unless necessary for safety reasons (i.e. episodes of severe 
347 
hypoglycemia or hyperglycemia) at discretion of investigators. If any therapy change will 
348 
be necessary, it must be recorded. 
349 
 Dexcom G6 will be inserted either on abdomen or upper arm depending on patient’s 
350 
preference and blinded at screening to analyze baseline CGM glucose metrics. The 
351 
participants will not be able to see glucose values from the blinded CGM. All the subjects 
352 
will be trained on function modalities of the blinded CGM. Dexcom G6 does not require 
353 
calibration.  
354 
 Patients on Medtronic 670 G (Medtronic hybrid closed-loop system where insulin pump 
355 
delivers automatic basal rate based on Medtronic Guardian CGM glucose) will be 
356 
instructed to use only pump (the Auto/ hybrid closed-loop mode will be disabled) because 
357 
automatic insulin delivery can alter the primary objective of the study.  
358 


Version  08-31-2020_R 
 
   Page 16 of 44 
 
 Patients using real time (rt) personal CGM (e.g. Freestyle Libre, Dexcom G4, Dexcom G5, 
359 
Medtronic Guardian Connect) will be screened for the study; however, they are not 
360 
allowed to use rt-CGM during the 2 weeks of the study (run-in-phase and randomization). 
361 
They can use rt-CGM during third week of the study while transitioning back to their own 
362 
insulin pump.  
363 
 
364 
6.2. Screening Failure 
365 
Screening failure form must be completed. Resampling/ rescreening is not allowed if person failed 
366 
any of inclusion or exclusion criteria except for the laboratory criteria, where one-time rescreening 
367 
will be permitted at discretion of the investigator. 
368 
 
369 
6.3. Visit 2, Week 1, Day 7±1, Randomization visit 
370 
 Blood glucose meter download and review of SMBG. 
371 
 Subject’s blinded CGM will be removed and downloaded. 
372 
 Review of previous CMP lab data with patient. 
373 
 
Look for any local skin reaction at the site of previous CGM. 
374 
 
If glucose meter or CGM download shows a glucose value <54mg/dl, patient will be asked 
375 
if they experienced symptoms of hypoglycemia, if any assistance was required, and if there 
376 
were circumstances that possibly contributed to or resulted in hypoglycemia.  
377 
 Reporting of AE/ SAE if any  
378 
 Exclusion criteria (after review of CMP laboratory and glucose meter data): 
379 
o AST/ALT > 3 times the upper limit of normal 
380 


Version  08-31-2020_R 
 
   Page 17 of 44 
 
o eGFR <45 ml/min/1.73 m^2 using MDRD formula 
381 
o Abnormal laboratory results or allergic reaction at CGM site, which at the view of 
382 
investigator makes subject unsafe to continue the study. In that case, the 
383 
investigator has to explain the reason of his choice to the patient. 
384 
o Non-compliance defined as SMBG less than 4 times a day for at least 4 out of 7 
385 
days and use of CGM less than 5 out of 7 days during the run-in-phase 
386 
 If no exclusion criteria was met, and the patient is still willing to continue the study, 
387 
randomization process can start. 
388 
 Second, blinded CGM (Dexcom G6) will be inserted.  
389 
 Subjects will receive 1 pen of insulin degludec U-100 and 1-2 pen of insulin aspart U-100 
390 
depending on calculated insulin requirement during randomization phase.   
391 
 Diabetes self-management training including treatment of hypoglycemia and 
392 
hyperglycemia will be reassessed.   
393 
 Subjects will be trained on the use of insulin pen and administration of correct dose of 
394 
insulin degludec U-100 in the morning once a day and correct dose of insulin aspart U-100 
395 
based on carbohydrate ratio and correction factor.  
396 
 Randomization 
397 
Subjects will be randomized equally into one of the two possible treatment arms. 
398 
o Group 1 (standard of care): subjects will stop using CSII on the randomization day, 
399 
and will start insulin degludec injection (1:1 dose conversion) once a day in the 
400 
morning.   
401 


Version  08-31-2020_R 
 
   Page 18 of 44 
 
o Group 2 (overlap transition): Subjects will receive insulin degludec in full dose (1:1 
402 
dose conversion) at randomization, and CSII basal rate will be reduced by 50% 
403 
during the first 24 hours of the transition and by 75% during 24 to 48 hours of the 
404 
transition.  CSII will be discontinued on day 3 of the transition.  
405 
The insulin degludec initiation and CSII basal reduction over 72 hours has been summarized in 
406 
Table 2;  
407 
Table 2: CSII changes and MDI initiation by randomization groups  
408 
 
409 
Randomization  
Treatment 
Change 
V2 (Day 7±1) 
P1 (V2+24 hours) 
P2 (P1+24 hours) 
Group 1(n=15) 
Standard of care  
CSII 
Discontinuation 
 
 
Insulin 
degludec 
Once a day in the morning (1:1 dose conversion) 
 
 
Insulin aspart 
Based on carbohydrate ratio and correction factor 
 
Group 2(n= 15) 
Overlap transition  
CSII 
50% basal rate 
reduction 
75% basal rate reduction Discontinuation 
 
Insulin 
degludec 
Once a day in the morning (1:1 dose conversion) 
 
 
Insulin aspart 
 
No insulin aspart 
injections as patients 
will be using 
boluses through 
insulin pump 
No insulin aspart 
injections as patients 
will be using boluses 
through insulin pump 
Insulin aspart 
injections based on 
carbohydrate ratio 
and correction 
factor 
 
410 
o Insulin degludec dose conversion guidance:  
411 
• On the day of randomization, CSII will be downloaded and information on average basal 
412 
insulin for the last 3 days, carbohydrate ratio and correction factor will be recorded.  
413 
• The average basal insulin for last 3 days will be used to calculate insulin degludec U-100 
414 
starting dose. For example; average basal insulin during last 3 days of CSII is 20 units/day, 
415 
the insulin degludec U-100 starting dose will be 20 units/day. The dose will be rounded up or 
416 
down as needed. E.g. if patient’s total daily dose is 32.4 units, it will be rounded to 32 units 
417 


Version  08-31-2020_R 
 
   Page 19 of 44 
 
per day. All subjects will be instructed to use insulin degludec once a day in morning only. 
418 
The first dose of insulin degludec will be given in the clinics at Visit 2.  
419 
• The dose of insulin aspart will be based on patient’s own carbohydrate ratio and correction 
420 
factor. Carbohydrate ratio is defined as the number of carbohydrates covered by each unit of 
421 
rapid acting insulin. Correction factor (aka insulin sensitivity factor) is defined as how much 
422 
one unit of rapid acting insulin will drop blood glucose. For example; a patient with 
423 
carbohydrate ratio of 1:15 and correction factor of 1:50 >150 will take 3 units if preprandial 
424 
blood glucose is ~200 mg/dl for 30 grams of meal (2 units for 30 grams of carbs + 1 unit for 
425 
correction). Subjects randomized to group 2 will be instructed to start insulin aspart 48 hours 
426 
after randomization; i.e. when they disconnect their insulin pump.  
427 
 It is likely that patients randomized to standard-of-care group may experience 
428 
hyperglycemia during first 48-72 hours. Therefore, both groups will be given a diary 
429 
(Appendix 1) to record any correction made during the randomization phase to count extra 
430 
insulin injections needed to correct blood glucose during first 72 hours.  
431 
6.4. Phone call 1 [P1, week 2, visit 2+24hrs] and phone call 2 [P2, week 2, P1+24hrs ] 
432 
 
As a safety measures, there will be 2 phone calls 24 and 48 hours after randomization, 
433 
respectively.   
434 
 Phone call 1 (P1) will be done 24 hours (±6 hours in case if patient does not respond to first 
435 
phone call) after visit 2.  
436 
 Phone call 2 (P2) will be done 24 hours (±6 hours in case if patient does not respond to first 
437 
phone call) after P1.  
438 
 
All subjects will be asked/assessed for 
439 


Version  08-31-2020_R 
 
   Page 20 of 44 
 
o 
Any episodes of severe hyperglycemia requiring hospitalization or hypoglycemia 
440 
requiring third person’ assistance. These events will be recorded as SAE and insulin 
441 
dose modification will be done at discretion of the investigator for safety reasons.  
442 
o 
Correct insulin dose and administration will be reassessed.  
443 
o 
Maintenance of glucose and insulin injection dairy.  
444 
o 
Any skin reaction at CGM site.  
445 
 
For Group 2 (overlap transition):  
446 
o 
Instructions to change in basal rate (75% basal reduction) will be done at P1 
447 
o 
Instructions for CSII discontinuation and initiation of insulin aspart based on 
448 
carbohydrate ratio and correction factor at P2  
449 
6.5. Visit 3, week 2, day 14±1: end of treatment  
450 
 Blood glucose meter download and review of SMBG. 
451 
 Subject’s blinded CGM will be removed and downloaded. 
452 
 Look for any local skin reaction at the site of CGM insertion. 
453 
 Subjects will return all the remained study-related products (CGM device components, 
454 
insulin degludec and aspat pens, and any auxiliary supplies) 
455 
 
Report any AE/SAE if any. 
456 
 
Subjects will be transitioned back to their preclinical trial insulin pump regimen. The same 
457 
basal and bolus settings will be used as of preclinical trial insulin pump settings. However, 
458 
there may be changes made to basal and bolus insulin doses depending on blood glucose 
459 
control during the study period at the discretion of investigators.  To reduce the risk of 
460 


Version  08-31-2020_R 
 
   Page 21 of 44 
 
hypoglycemia, subjects will be advised to set a 50% temporary basal insulin rate for 24 hrs 
461 
following insulin degludec transition.  
462 
6.6. Phone call 3, week 3, day 21±1: follow-up phone call and end of the study 
463 
 The intention of phone call 3 is to make sure that subjects are not experiencing major 
464 
hypoglycemia or hyperglycemia events. The study coordinator will make a phone call to 
465 
assist subjects if they require insulin dose adjustments. AE/ SAE will be recorded, if any, 
466 
during third week of clinical trial. However, they would not be a part of statistical analysis.  
467 
 
468 
 
469 
 
470 
 
471 
 
472 
 
473 
 
474 
 
475 
 
476 
 
477 
 
478 
 
479 
 
480 
 
481 
 
482 


Version  08-31-2020_R 
 
   Page 22 of 44 
 
6.7. Table 4: study visit outline 
483 
V1, V2, V3 stand respectively for visit 1, 2 3; P1, P2, P3 stand respectively for phone call 1, 2, 3 
484 
SMBG; self-monitoring of blood glucose, BMI; body mass index, DSM; diabetes self-
485 
management education, POC; point-of-care.  
486 
*pregnancy test only for women in reproductive age.  
487 
 
488 
 
489 
Period 
Screening 
and Run-
In-Phase 
Randomization 
End of 
treatment  
Follow-up 
Visits 
V1 
V2 
P1 
P2 
V3 
P3 
Day/time from last visit 
0 
7 
V2 + 24hrs 
P1 +24hrs 
14 
21 
Time window 
 
±1 day 
±6hrs  
±6 hrs 
±1 day 
±1 day 
Subject related info/assessment 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
Screen fail/withdrawal criteria 
X 
X 
 
 
 
 
Demography and medical history 
X 
 
 
 
 
 
Diabetes history 
X 
 
 
 
 
 
GOLD questionnaire 
X 
 
 
 
 
 
IDSS, and WPAI questionnaire 
X 
X 
 
 
X 
 
Concomitant illnesses 
X 
 
 
 
 
 
Review of current medications 
X 
 
 
 
 
 
Vital signs  
X 
 
 
 
 
 
BMI  
X 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
Report AE/SAE 
X 
X 
X 
X 
X 
X 
Trial material/steps 
 
 
 
 
 
 
Dispensation of study drugs 
X 
X 
SMBG and DSM education 
X 
Glucose and insulin diary  
 
X 
X 
X 
 
 
Blinded CGM insertion/training 
X 
X 
Blinded CGM removal/download 
X 
X 
SMBG profile 
X 
X 
MDI initiation and training 
X 
Randomization 
X 
Transition back to CSII 
 
 
 
 
X 
 
Compliance check 
 
X 
 
 
 
 
Blood Draw  
 
X 
 
 
 
X 
 
POC A1c, urine pregnancy test* 
X 
 
 
 
 
 
CMP (blood sampling) 
X 
 
 
 
 
 


Version  08-31-2020_R 
 
   Page 23 of 44 
 
 
490 
6.8. Assessments for Safety: 
491 
The following safety assessments will be performed; 
492 
 Time spent in CGM measured hypoglycemia (< 70 mg/dl) and time spent in hyperglycemia 
493 
( ≥250 mg/dl) 
494 
 AE/SAE 
495 
 Documented hypoglycemic episodes 
496 
 Height, weight, vitals and physical examination 
497 
 Baseline laboratory assessment 
498 
 Hypoglycemia unawareness assessment (using GOLD questionnaire) 
499 
 Pregnancy test at screening 
500 
6.9. Assessments for Efficacy:  
501 
The assessment for efficacy is time spent in CGM glucose time-in-range (min/ 24 hours, 70-180 
502 
mg/dl) during the 7 days of randomization period.  
503 
7. EVALUABILITY OF SUBJECTS: 
504 
The data for a subject with minimum of 5 out of 7 days of blinded CGM prior to randomization 
505 
and 5 out of 7 days of blinded CGM after randomization will be evaluable and included for the 
506 
analysis of primary and secondary objectives. 
507 
8. STATISTICAL CONSIDERATIONS: 
508 
8.1. Sample size calculation 
509 
In a study by Garg and colleagues, the subjects with T1D on MDI and blinded CGM for first 4 
510 
weeks of the study spent average of 8.8 hours/day (~528 min/ 24 hours) in CGM defined glucose 
511 
above 180 mg/dl [21]. Similarly, in the recently published DIAMOND study, subjects on MDI 
512 
using CGM experienced average of 601 minutes (~10 hours/ day, IQR; 467-793 min) per 24 hours 
513 


Version  08-31-2020_R 
 
   Page 24 of 44 
 
of time spent in hyperglycemia [22].  We assume that subjects in standard of care group would 
514 
have more hyperglycemia than subjects in overlap transition group. Therefore, the expected CGM 
515 
hyperglycemia is ~ 650 minutes/24 hours in standard of care and ~ 500 minutes/24 hours in 
516 
overlap transition group with the differences in CGM glucose by150 minutes/day between the 
517 
groups.  
518 
This study is powered based on the primary endpoint, which is time spent in CGM-measured 
519 
glucose levels >180mg/dl (hyperglycemia). We have based the sample size on minimal relevant 
520 
differences between the two treatment groups, using a Type I error rate of 5% and a Type II error 
521 
rate of 20%.  We hypothesize that the primary endpoint, time in minutes spent with glucose levels 
522 
>180 mg/dl, will be higher in the standard treatment group than in the experimental group (overlap 
523 
transition group), but we will use a two-sided test to assess differences in hyperglycemia by 
524 
treatment group.  We hypothesize a standard deviation (SD) for time spent in hyperglycemia of 
525 
140 minutes (2.3 hours, or ~10% of the day) based on data from our clinic and previous 
526 
publications.  We will have 80% power to detect a difference of 148.4 minutes (just under 2.5 
527 
hours) between groups, which is a clinically meaningful difference in time spent hyperglycemia, 
528 
with a sample size of 15 participants completing the study per group (total N=30).  We have also 
529 
calculated the detectable difference for larger SD estimates, in case the SD in the study population 
530 
is larger than in our clinic in general, and for 90% power.  The effect sizes detectable with a final 
531 
sample size of 15 patients per group at 80% and 90% power are 1.06 and 1.23, respectively, for all 
532 
endpoints.  
533 
 
534 
 
535 


Version  08-31-2020_R 
 
   Page 25 of 44 
 
 
536 
SD 
Detectable difference (minutes) 
Effect size 
Power 
140 min 
148.4 min 
1.06 
 
80% 
160 min 
169.6 min 
80% 
180 min  
190.8 min 
80% 
140 min 
171.7 min 
1.23 
90% 
160 min 
196.2 min 
90% 
180 min  
220.8 min 
90% 
 
537 
Detectable differences in secondary CGM endpoints, including time in range (70-180 mg/dl) and 
538 
time spent hypoglycemic (<70 mg/dl) have also been considered in our power analysis.  
539 
Parameter 
SD 
Detectable difference 
(minutes) 
Power 
Time in range (70-180 mg/dl) 
160 min 
169.6 min 
80% 
Time in range (70-180 mg/dl) 
180 min 
190.8 min 
80% 
Time in range (70-180 mg/dl) 
200 min  
212.0 min 
80% 
Time spent hypoglycemic (<70 mg/dl) 
45 min 
47.7 min 
80% 
Time spent hypoglycemic (<70 mg/dl) 
60 min 
63.6 min 
80% 
Time spent hypoglycemic (<70 mg/dl) 
75 min 
79.5 min 
80% 
 
540 
8.2. Statistical Methods 
541 
The proposed study includes two groups, one undergoing standard treatment and the other using a 
542 
novel protocol of overlapping doses when transitioning from pump to MDI.  Primary and 
543 
secondary endpoints were described earlier.  
544 
Study participants will be randomized using block randomization, but no stratification will be used 
545 
since this is a small, single center trial.   
546 
Our primary outcome is time spent hyperglycemic (CGM glucose values >180 mg/dl), which we 
547 
will compared between randomized treatment groups (standard of care vs. novel overlap protocol) 
548 


Version  08-31-2020_R 
 
   Page 26 of 44 
 
during the transition from pump to MDI.  We hypothesize that the time spent hyperglycemic will 
549 
be reduced in the experimental group, using the novel overlap protocol, when compared to the 
550 
standard treatment group.  This hypothesis will be tested using a student’s t-test to compare 
551 
univariate differences between the standard care group and the experimental group for each of the 
552 
outcomes.  Secondary endpoints include time in range (70-180 mg/dl), time spent hypoglycemic 
553 
(<70 mg/dl), frequency of severe hypoglycemia, number of correction boluses, and patient 
554 
reported outcomes as defined on the page 7 of the protocol.  Secondary endpoints will be 
555 
examined using student’s t-test to compare these outcomes univariately between the standard care 
556 
and experimental groups.  In a sensitivity analysis, CGM metrics will be evaluated in the first 72 
557 
hours vs entire 1 week as we expect that differences in hyperglycemia and time-in-range will be 
558 
more pronounced between the two groups in the first 72 hours. For both primary and secondary 
559 
endpoints, linear regression analysis will be used to examine outcomes by treatment group while 
560 
adjusting for potential residual confounders, such as age and sex, which may not be fully 
561 
addressed by randomization.  All testing will be two-sided.   The analysis will be conducted as an 
562 
intention-to-treat analysis.  
563 
9. DATA HANDLING AND RECORD KEEPING: 
564 
 All data generated during the study will be retained by the investigator. Safety events will 
565 
be reported to Colorado Multiple Institutional Review Board (COMIRB) in a timely 
566 
manner as described under “Adverse Events”. 
567 
 Data management is the responsibility of the investigator. All paper and electronic data 
568 
will be saved in a de-identifiable manner.  The data will be stored on BDC computers 
569 
which are secured by the University of Colorado servers. The data will be accessible only 
570 


Version  08-31-2020_R 
 
   Page 27 of 44 
 
by the study team and if transfer of data needed, appropriate measures, including 
571 
encryption of data files will be used to ensure security and subject confidentiality. 
572 
 The records will be stored securely and kept for minimum of 10 years per the Standards 
573 
Operating Procedures (SOP) of the University of Colorado [23]. 
574 
[http://www.ucdenver.edu/research/Research%20Administration%20Documents/COMIRB
575 
-Policy-and-Procedures-Document.pdf] 
576 
10. ETHICS: 
577 
 The trial will be conducted in compliance with this protocol, ICH GCP, the University of 
578 
Colorado COMIRB research policy and in accordance with the Declaration of Helsinki 
579 
[23-25]. 
580 
 The clinical trial protocol, consent form and appropriate study documents will be submitted 
581 
to COMIRB for the approval before the start of any study related activity. 
582 
 Once the protocol is approved by the COMIRB, the study team will contact potential 
583 
subjects from the BDC Adult clinic. 
584 
 Before any trial-related activity, the investigator will give the subject verbal and written 
585 
information about the trial and the procedures involved in a form that the subject can read 
586 
and understand. 
587 
 The subjects will be fully informed of their rights and responsibilities while participating in 
588 
the trial as well as possible disadvantages of being treated with the trial products. 
589 
 The investigator will ensure the subject ample time to come to a decision whether to 
590 
participate in the trial. 
591 


Version  08-31-2020_R 
 
   Page 28 of 44 
 
 A voluntary signed and personally dated informed consent will be obtained from the 
592 
subject before any trial-related activity. 
593 
 The process of informed consent process will occur in a clinical research room located on 
594 
level 1, Barbara Davis Center for Diabetes Adult Clinic. The subject will sign the informed 
595 
consent process in the presence of the investigator and witness. The confidentiality and 
596 
HIPAA will be handled per the University of Colorado research policy. 
597 
11. STUDY SCHEDULE: 
598 
Trial registration: 4 weeks 
599 
Trial will be registered at Clinicaltrials.gov as soon as the study is funded. 
600 
Colorado Multiple Institutional Review Board (COMIRB): 2-3 months 
601 
The protocol, consent form, and appropriate trial materials will be submitted to COMIRB for 
602 
approval. 
603 
Planned duration of recruitment period: 7 months 
604 
Study duration from screening to the end of the study per subject- 3 weeks 
605 
Data cleaning and Statistical analysis: 2 months 
606 
Data presentation and publications: 6-12 months 
607 
12. STUDY DRUGS AND MATERIALS: 
608 
12.1. Study medications(s) /  device(s) 
609 
Insulin: 
610 
 Insulin degludec 100 units/ ml prefilled-pen 
611 
 Insulin Aspart 100 units/ml prefilled-pen 
612 
 Insulin degludec and Aspart will be provided by NovoNordisk.  
613 
Blinded CGM: 
614 


Version  08-31-2020_R 
 
   Page 29 of 44 
 
 Dexcom G6 that will be blinded for the display. We would like to use Dexcom G6 as it 
615 
does not require calibration and is most accurate CGM [26] amongst all marketed CGM. 
616 
Freestyle Libre is relatively inexpensive compared to Dexcom G6; however, Libre takes 12 
617 
hours to warm- up and provide CGM values. The first 12 hours of CSII to MDI transition 
618 
is crucial for primary outcomes. 
619 
 Instructions to use Dexcom G6  
620 
Insulin pump and pump related supplies would be patients own. Similarly, patients will use their 
621 
own blood glucose meter for SMBG.  
622 
12.2. Packaging and labelling of study medication(s) 
623 
All the subjects will be provided sufficient study products including insulin pens, and pen needles. 
624 
Direction of use of insulin pen will be provided as outlines in the protocol. 
625 
Documentation of the study drugs/devices will be documented for each subject in accordance with 
626 
drug and device standard operating procedure of the Barbara Davis Center for Diabetes and the 
627 
University of Colorado Denver. 
628 
12.3. Storage and drug accountability of study medication(s) 
629 
 The drug (Insulin degludec and Aspart) will be stored according to approved label. The 
630 
temperature log will be monitored at the site and any temperature fluctuation will be reported as 
631 
deviation. 
632 
Subjects will be provided educational material(s) on direction of use of insulin and the storage. 
633 
Subjects will be instructed to store insulin in outer carton to protect from the light and cap should 
634 
be kept on the pen when not in use. Each insulin pump should be used within 26 days from the day 
635 
of opening. 
636 


Version  08-31-2020_R 
 
   Page 30 of 44 
 
CGM (sensor and transmitters) will be stored per manufacturer’ recommendation. 
637 
12.4. Auxiliary supply 
638 
The following will be supplied to study participants for the duration of clinical trial; 
639 
Needles for insulin pen, lancets, instruction for the use of insulin pens, instruction of CGM use and 
640 
calibration.    
641 
13. CONCOMITANT ILLNESS(ES) AND MEDICATION(S) 
642 
Concomitant illness is any illness that is present at the start of the trial (i.e. at the first visit). For 
643 
each concomitant illness, date of onset, date of resolution or continuing, at a minimum, should be 
644 
recorded. 
645 
Concomitant medication is any medication other than the trial product(s) that are consumed during 
646 
the trial, including the screening and run-in periods. The information collected for each 
647 
concomitant medication includes, at a minimum, dosage, start date, stop date or continuing, and 
648 
indication. 
649 
Details of all concomitant illnesses and medication will be recorded at trial entry (i.e. at the first 
650 
visit). Any changes in concomitant medication must be recorded at Visit 6 at the time of 
651 
randomization. If the change influences the subject’s eligibility to continue in the trial, the 
652 
investigator may withdraw the subject from the clinical trial. 
653 
14. ADVERSE EVENTS: 
654 
An adverse event (AE) is any untoward medical occurrence associated with the use of a drug in 
655 
humans, whether considered drug related or not. AE can be unfavorable symptoms, sign 
656 
(abnormality on physical exam or laboratory findings) or disease temporarily associated with the 
657 
use of products whether or not related to the products. 
658 


Version  08-31-2020_R 
 
   Page 31 of 44 
 
Few examples (but not limited) of AEs are clinically significant worsening of concomitant illness, 
659 
a new illness, clinically significant radiological or laboratory abnormalities suggesting a disease or 
660 
organ toxicity. 
661 
The following three definitions are used when assessing an AE:  
662 
• Severity assessment  
663 
 Mild - no or transient symptoms, no interference with the subject's daily activities.  
664 
 Moderate - marked symptoms, moderate interference with the subject's daily 
665 
activities.  
666 
 Severe - considerable interference with the subject's daily activities; unacceptable.  
667 
• Causality assessment  
668 
The following terms are used when assessing the relationship between an AE and the 
669 
relevant study product(s): 
670 
 Probable - Good reason and sufficient documentation to assume a causal 
671 
relationship. 
672 
 Possible - A causal relationship is conceivable and cannot be dismissed. 
673 
 Unlikely - The event is most likely related to etiology other than the study product. 
674 
•     Final outcome of an AE 
675 
 
676 
 
Recovered/resolved - The subject has fully recovered, or by medical or surgical 
677 
treatment, the condition has returned to the level observed at the first trial-related 
678 
activity after the subject signed the informed consent. 
679 


Version  08-31-2020_R 
 
   Page 32 of 44 
 
 
Recovering/resolving - The condition is improving and the subject is expected to 
680 
recover from the event. This term is only applicable if the subject has completed the 
681 
trial or has died from another AE. 
682 
 
Recovered/resolved with sequelae - The subject has recovered from the condition, 
683 
but with lasting effect due to a disease, injury, treatment or procedure. If a sequela 
684 
meets an SAE criterion, the AE must be reported as an SAE. 
685 
 
Not recovered/not resolved - The condition of the subject has not improved and 
686 
the symptoms are unchanged, or the outcome is not known. 
687 
 
Fatal - This term is only applicable if the subject died from a condition related to 
688 
the reported AE. Outcomes of other reported AEs in a subject before he/she died 
689 
should be assessed as "recovered/resolved", "recovering/resolving", 
690 
"recovered/resolved with sequelae" or "not recovered/not resolved". An AE with 
691 
fatal outcome must be reported as an SAE. 
692 
 
Unknown - This term is only applicable if the subject is lost to follow-up. 
693 
Serious adverse event 
694 
An adverse event or suspected adverse reaction is considered "serious" if, in the view of the 
695 
investigator, it results in any of the following outcomes: 
696 
 Results in death, or, 
697 
 Is life-threatening, or, 
698 
 Requires inpatient hospitalization or prolongation of existing hospitalization, or, 
699 
 Results in persistent or significant disability/incapacity, or, 
700 
 Is a congenital anomaly/birth defect, 
701 


Version  08-31-2020_R 
 
   Page 33 of 44 
 
 Is a medically important event that may not result in death, be life threatening or require 
702 
hospitalization may be considered an SAE when - based on appropriate medical judgement 
703 
-they may jeopardize the subject and may require medical or surgical intervention to 
704 
prevent one of the outcomes listed in the definition of SAE 
705 
Suspected transmission of an infectious agent should be considered as an SAE.  
706 
Non-serious AE 
707 
Any AE that does not fulfill the definition of SAE. 
708 
Medical event of special interest (MESI)  
709 
A MESI is an event which, in the evaluation of safety, has a special focus. A MESI is an AE (SAE 
710 
or non-serious AE) which fulfils one or more of the below defined MESI criteria. 
711 
 Medication errors concerning trial products: 
712 
– Administration of wrong drug 
713 
– Wrong route of administration, such as intramuscular instead of subcutaneous 
714 
– Accidental administration of a lower or higher dose than intended, however the      
715 
administered dose must deviate from the intended dose to an extent where clinical 
716 
consequences for the trial subject were likely to happen as judged by the investigator, 
717 
although not necessarily did happen. 
718 
Overdose and missed insulin injection resulting in severe hypoglycemia or hyperglycemia are 
719 
considered as AE or SAE depending on severity.  
720 
Suspected Unexpected Serious Adverse Reactions (SUSAR)  
721 
An unexpected adverse reaction (UAR) is an adverse reaction that is not consistent with the 
722 
product information in the summary of product characteristics (SPC, i.e.US prescribing 
723 


Version  08-31-2020_R 
 
   Page 34 of 44 
 
information). The current version or any updated if available during the clinical trial for US 
724 
prescribing information for study drugs will be used as SPC. If UAR is severe enough to define as 
725 
SAE is called as SUSAR.  
726 
Technical complaint 
727 
A technical complaint is any written, electronic, or oral communication that alleges product 
728 
(medicine or device) defects. The technical complaint may be associated with an AE, but does not 
729 
concern the AE itself. 
730 
Reportable Device Issues 
731 
AE and Unexpected Adverse Device Events (UADE) arising from the use of blinded CGM 
732 
(Dexcom G6) will be reported irrespective of severity, except in following cicumstances:  
733 
The following device issues are anticipated and will not be reported unless the criteria for AE 
734 
reporting described above are met 
735 
• Component disconnections   
736 
• CGM sensors lasting fewer than 7 days  
737 
• CGM tape adherence issues  
738 
• Battery lifespan deficiency due to inadequate charging or extensive wireless 
739 
communication  
740 
• Intermittent device component disconnections/communication failures not leading to 
741 
system  replacement  
742 
• Device issues clearly addressed in the user guide manual that do not require additional 
743 
troubleshooting  
744 
• Skin reactions from CGM sensor placement that don’t meet criteria for AE reporting  
745 


Version  08-31-2020_R 
 
   Page 35 of 44 
 
 
746 
Safety Monitoring Officer  
747 
A safety-monitoring officer (Aaron Michels, MD) will independently monitor the study, including 
748 
adverse events and study drug or device issues with potential to impact participant safety. A 
749 
monthly meeting will be held between study team and the safety officer to review any adverse 
750 
events. Following each safety review, a summary recommendation from the safety monitoring 
751 
officer will be collected.  
752 
Reporting and follow-up of adverse events 
753 
 
754 
All events meeting the definition of an AE must be collected and reported. This includes events 
755 
from the first trial-related activity after the subject has signed the informed consent until the end of 
756 
the post-treatment follow-up period. 
757 
During each contact, the trained professional research associate will ask the subject about AEs and 
758 
technical complaints, for example by asking: "Have you experienced any problems since the last 
759 
contact?". All AEs will be recorded by the investigator on an AE form. SAE will be recorded 
760 
within 24 hours of the investigator’s first knowledge of the SAE. 
761 
The investigator is responsible for reporting all AE to COMIRB within five business days per the 
762 
University of Colorado Denver policy 
763 
(http://www.ucdenver.edu/research/Research%20Administration%20Documents/Unanticipated-Problem-
764 
Reporting-Policy.doc). All non-severe and severe AE will be followed by till the end of the study 
765 
and will be reported to the COMIRB.  
766 
If a subject becomes pregnant during the study, the subject will be dropped from the study and 
767 
followed until the pregnancy outcomes. Pregnancy will be reported as AE (or SAE if fulfills the 
768 


Version  08-31-2020_R 
 
   Page 36 of 44 
 
criteria of SAE) and it will be reported to the study sponsor (NovoNordisk). Pregnancy 
769 
complications will be recorded as adverse events and if the infant has a congenital abnormality or 
770 
birth defect, it will be reported and notified to the COMIRB and the sponsor.  
771 
All SAE and SUSAR will be reported to NovoNordisk within 15 days from the investigator 
772 
becoming aware of such adverse events.  The following information will be provided to the 
773 
sponsor; study name, patient identification (e.g. initials, sex, age), event (preferably a diagnosis), 
774 
drug name, reporter identification (e.g. Name, or initials), causality, and outcome. 
775 
14.1. Precautions/over-dosage 
776 
Insulin over or under dose can cause severe hypoglycemia or hypoglycemia. All subjects will be 
777 
explained on the insulin dose and instructed on insulin pen use as a precautionary measures. The 
778 
education on recognition of hypoglycemia or hyperglycemia and its treatment will be provided at 
779 
screening and as needed during the study. 
780 
14.2 Risks and Discomforts  
781 
a) Blood Drawing Risks  
782 
The risks of drawing blood from a vein include temporary discomfort from the needle stick 
783 
(common), bruising (common), excessive bleeding (unlikely), lightheadedness (rare), infection 
784 
(rare), and fainting (rare).   
785 
b) Fingerstick Risks (for A1c and finger stick glucose monitoring)  
786 
It may hurt when the lancet goes into a participant’s finger but not for long. In about 1 in 10 cases, 
787 
a small amount of bleeding under the skin will produce a bruise. A small scar may persist for 
788 
several weeks. The risk of an infection is less than 1 in 1,000 people.  
789 
c) Related to CGM  
790 


Version  08-31-2020_R 
 
   Page 37 of 44 
 
Wearing sensors can cause adverse skin reactions such as pain at the site sensor insertion. The 
791 
adhesive pads may cause skin erythema for 1 to 2 days or more. An allergic reaction to 1 or more 
792 
parts of CGM devices may occur which can be mild, moderate, or severe (rare). In rare cases, an 
793 
infection at the sensor site may occur. In rare cases, the sensor or needle may break inside the body 
794 
and would require a minor surgical procedure to remove it. We will also screen out individuals 
795 
with a history of serious skin reactions to adhesives.  
796 
d) Risk of Hypoglycemia (Low Blood Sugar)  
797 
As with any person with diabetes who uses insulin, there is always a risk of having low blood 
798 
sugar (hypoglycemia). Symptoms of low blood sugar can include sweating, jitteriness, and not 
799 
feeling well. There is also the possibility of fainting or seizures (convulsions), brain damage, or 
800 
death with a very low blood sugar. Since we will be closely monitoring participants during this 
801 
study, a serious low blood sugar is less likely to occur in any study participant. Even if a low blood 
802 
sugar does occur, it usually goes away quickly with treatment (carbohydrates) that raises the blood 
803 
sugar. A severe low blood sugar may require that a participant get an injection of glucagon and/or 
804 
have emergency services to help raise his/her blood glucose level. 
805 
e) Risk of Hyperglycemia (High Blood Sugar)  
806 
Hyperglycemia usually does not cause many obvious symptoms, but participants may become 
807 
thirsty, fatigued, or have a higher level of sugar in their urine. In severe cases of hyperglycemia, 
808 
diabetic ketoacidosis (DKA) or coma may occur. Hyperglycemia leading to DKA can lead to renal 
809 
failure (kidney failure), cardiac arrhythmia (irregular heartbeat), myocardial infarction (heart 
810 
attack), rhabdomyolysis (muscle breakdown), and even death. A serious effect from 
811 


Version  08-31-2020_R 
 
   Page 38 of 44 
 
hyperglycemia is not expected to occur in any study participant, as we will be monitoring blood 
812 
glucose levels frequently. 
813 
f) Psychosocial Questionnaires  
814 
Answering questionnaires about thoughts, concerns, and distress related to diabetes and general 
815 
quality of life assessments may result in undesired thought processes and/or emotions. These 
816 
feelings may be transitory, recurrent, or permanent though most risks are minimal/transitory.  
817 
g) Unknown Risks  
818 
In any study, there may be additional risks that we do not know about at this time. This is not 
819 
likely but is always a possibility. If we become aware of any new risks, participants will be told 
820 
about them. They will be able to decide if they want to continue to participate in this study. If a 
821 
treatment or procedure has increased risks because it was not done according to study procedures 
822 
due to error, participants will be informed, and the necessary steps will be taken to care for them.  
823 
h) Confidentiality 
824 
There is a risk of a breach in confidentiality. Thus, a confidential subject database will be 
825 
established to maintain study data. Data will be entered into REDCap (Research Electronic Data 
826 
Capture). REDCap is an internal secure, computerized database system at the University of 
827 
Colorado Denver. This system allows data entry, survey/questionnaire building, data exportation 
828 
to statistical packages, and is HIPAA compliant. Each subject will be assigned an identification 
829 
number, which will be used to code and identify all of that subject’s records. This will avoid the 
830 
continual use of subject names. REDCap surveys can be sent to study participants via e-mail for 
831 
direct input into the database. All study data will be locked in the PIs’ offices and all relevant 
832 
computer study files will be input on staff computers, which are password protected and contain 
833 


Version  08-31-2020_R 
 
   Page 39 of 44 
 
encryption software. Data storage will be on a secured server maintained by the University of 
834 
Colorado. The server is backed up nightly and a copy of the back-up file is kept off site in a secure 
835 
facility. Data access will be limited to study personnel. Study results may be presented in the form 
836 
of posters, abstracts, oral presentations, or publications at academic meetings or in journals. In all 
837 
forms of study result reporting, subject identification will not be disclosed. A study subject may 
838 
access his/her protected health information at any time by requesting said information in writing of 
839 
the investigator. The investigative team has been trained in IRB and HIPAA compliance issues 
840 
and will maintain confidentiality and protect health information. The above-stated procedures have 
841 
been highly effective in preventing breaches of patient confidentiality for the prior and current 
842 
research studies in which the PI has been and continues to be involved. 
843 
 
844 
15. PUBLICATION PLAN: 
845 
We plan to present the data at ADA and/or EASD depending on the time of completion of the 
846 
analysis. The study will be published in a peer-reviewed scientific journal. The data will be 
847 
publically assessable through clinicaltrial.gov. Authorship of publications will be in accordance 
848 
with the Uniform Requirements of the International Committee of Medical Journal Editors. 
849 
 
850 
 
851 
 
852 
 
853 
 
854 
 
855 


Version  08-31-2020_R 
 
   Page 40 of 44 
 
16. REFERENCES 
856 
1. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383:69-
857 
82.PMID: 23890997  
858 
2. Shah VN, Moser EG, Blau A, Dhingra M, Garg SK. The future of basal insulin. Diabetes 
859 
Technol Ther. 2013 Sep;15(9):727-32. 
860 
3. Miller KM, Foster NC, Beck RW, Bergenstal RM, DuBose SN, DiMeglio LA, Maahs 
861 
DM, Tamborlane WV; T1D Exchange Clinic Network. Current state of type 1 diabetes 
862 
treatment in the U.S.: updated data from the T1D Exchange clinic registry.  Diabetes 
863 
Care. 2015 Jun;38(6):971-8 
864 
4. Maahs D, Horton LA, Chase HP. The use of insulin pumps in outh with Type 1 diabetes. 
865 
Diabetes Technol Ther. 2010 Jun; 12(Suppl 1): S-59–S-65. 
866 
5. Wong JC, Boyle C, DiMeglio LA, et al. Evaluation of Pump Discontinuation and 
867 
Associated Factors in the T1D Exchange Clinic Registry. Journal of Diabetes Science 
868 
and Technology. 2017;11(2):224-232. doi:10.1177/1932296816663963. 
869 
6. Shah, V.N., et al., Human factors associated with insulin pump and continuous glucose 
870 
monitor discontinuation among adults with type 1 diabetes. . Diabetes Technol Ther, 
871 
2016. 18(S1): p. A18. 
872 
7. Allison Blass. Taking a Pump Vacation, diabetes mine, 2017. Available at 
873 
https://www.healthline.com/diabetesmine/taking-a-pump-vacation  
874 
8. Kurtzhals P, Heise T, Strauss HM, et al. Multi-hexamer formation is the underlying basis 
875 
for the ultra-long glucose-lowering effect of insulin degludec. Diabetologia. 
876 
2011;54(suppl 1):S426. 
877 
9. Jonassen I, Havelund S, Hoeg-Jensen T, et al. Design of the novel protraction mechanism 
878 
of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012;29:2104–2114. 
879 
doi: 10.1007/s11095-012-0739-z. 
880 
10. Heise T, Heinemann L. Rapid and long-acting analogues as an approach to improve 
881 
insulin therapy: an evidence-based medicine assessment..Curr Pharm Des. 2001 Sep; 
882 
7(14):1303-25. 
883 


Version  08-31-2020_R 
 
   Page 41 of 44 
 
11. Lane W, Bailey TS, Gerety G, et al. Effect of Insulin Degludec vs Insulin Glargine U100 
884 
on Hypoglycemia in Patients with Type 1 Diabetes: The SWITCH 1 Randomized 
885 
Clinical Trial. JAMA. 2017; 318(1):33-44. doi:10.1001/jama.2017.7115. 
886 
12. Coester H-V, Heise T, Nosek L, et al. Steady state is reached within 2 to 3 days of once-
887 
daily administration of ultra-long-acting insulin degludec. Diabetologia. 2012;55 (suppl 
888 
1):373. 
889 
13. Haahr H, Heise T. A review of the pharmacological properties of insulin degludec and 
890 
their clinical relevance. Clin Pharmacokinet 2014;53:787-800 
891 
14. Kaufman FR. Insulin Pumps and Continuous glucose monitoring- A user’s guide to 
892 
effective diabetes management. Editor 1. Publisher American Diabetes Association. 
893 
15. Walsh J, Roberts R. Pumping insulin. Third edition. Torrey Pine Press. 
894 
16. Bolderman KM. Putting your patients on the pump. American diabetes Association. 
895 
17. Chase P. Understanding Insulin pumps and continuous glucose monitors. 1st edition. 
896 
Children’s Diabetes Foundation, Denver, CO. 
897 
18. Polonsky WH, Fisher L, Hessler D, Edelman SV. Development of a New Measure for 
898 
Assessing Insulin Delivery Device Satisfaction in Patients with Type 1 and Type 2 
899 
Diabetes. Diabetes Technol Ther 2015;17:773-9. 
900 
19. Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work 
901 
productivity and activity impairment instrument. Pharmacoeconomics 1993;4:353-65. 
902 
20. Gold AE, MacLeod KM, Frier BM: Frequency of severe hypoglycemia in patients with 
903 
type 1 diabetes and impaired awareness of hypoglycemia. Diabetes Care 17:697–703, 
904 
1994 
905 
21. Garg SK, Voelmle MK, Beatson CR, Miller HA, Crew LB, Freson BJ, Hazenfield RM. 
906 
Use of continuous glucose monitoring in subjects with type 1 diabetes on multiple daily 
907 
injections versus continuous subcutaneous insulin infusion therapy: a prospective 6-
908 
month study. Diabetes Care. 2011 Mar;34(3):574-9. 
909 
22. Beck RW, Riddlesworth TD, Ruedy KJ et al for DIAMOND Study Group. Effect of 
910 
initiating use of an insulin pump in adults with type 1 diabetes using multiple daily 
911 


Version  08-31-2020_R 
 
   Page 42 of 44 
 
insulin injections and continuous glucose monitoring (DIAMOND): a multicentre, 
912 
randomised controlled trial. Lancet Diabetes Endocrinol. 2017 Sep;5(9):700-708. 
913 
23. University of Colorado Denver. Colorado Multiple Institutional Review Board 
914 
(COMIRB) policies and procedures. Available at 
915 
http://www.ucdenver.edu/research/research%20administration%20documents/comirb-
916 
policy-and-procedures-document.pdf. Accessed on March 19, 2018  
917 
24. World Medical Association. World Medical Association Declaration of Helsinki: ethical 
918 
principles for medical research involving human subjects. JAMA. 2013;310(20):2191-
919 
2194. 
920 
25. International Conference on Harmonisation. ICH Harmonized Tripartite Guideline. Good 
921 
clinical Practice 01 May 1996.  
922 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/
923 
E6_R1_Guideline.pdf. Accessed on March 19, 2018 
924 
26. Shah VN, Laffel LM, Wadwa RP, Garg SK. Performance of a Factory-Calibrated Real-
925 
Time Continuous Glucose Monitoring System Utilizing an Automated Sensor 
926 
Applicator. Diabetes Technol Ther. 2018 Jun;20(6):428-433. 
927 
 
928 
 
929 
 
930 
 
931 
 
932 
 
933 
 
934 
 
935 
 
936 
 
937 
 
938 
 
939 
 
940 


Version  08-31-2020_R 
 
   Page 43 of 44 
 
 
941 
Appendix 1: Glucose and Insulin Dose Diary  
942 
 
943 
 
944 
 
945 
 
946 
 
947 
 
948 
 
949 
 
950 
 
951 


Version  08-31-2020_R 
 
   Page 44 of 44 
 
Table: Summary of protocol changes and rationale.  
952 
Revisions 
Rationale 
Email address change (page 1) 
Due to domain change at CU Anschutz, email 
address of the protocol PI was changed 
Exclusion criteria 4. (page 10) 
Tandem Control IQ is a HCL system that is 
approved by the US FDA for T1D in December 
2019. Therefore, it is added in the exclusion 
criteria.   
Section 5.5 (page 12). Total number of 
patients required for screening are increased 
from 34 to 40.  
Due to covid related institutional closure and 
restrictions, we lost data for 1 patient, 1 patient 
withdrew from study and 4 screen failed, we 
increased screening sample size to have 30 
patients complete the entire study to have adequate 
power.  
Insulin degludec dose conversion guidance 
(page 18).  
A line is added to have clarification that if total 
insulin dose in last 3 day is rounded for calculation 
of insulin degludec. E.g. is patient’s total daily 
dose is 32.4, it is rounded to 32.0 and if 32.7, it is 
rounded to 33.0 units per day.  
Sample size calculation (Page 24 and 25) 
Typographical errors were corrected on page 24 
and 25.  
Statistical Methods (Page 26) 
Sensitivity analysis of CGM metrics in the first 72 
hours vs entire 1 week is added. This is because 
we expect the differences in hyperglycemia to be 
more pronounced in the first 72 hours.  
Secondary endpoint 4: there was a 
typographic mistake (page 7)  
 
As stated on page 19, we intended to collect 
correction boluses information during first 72 
hours only. 
 
953