Conditions: Diabetes Mellitus, Type 1
Keywords: Insulin Degludec Insulin Glargine Air Travel Continuous Glucose Monitor
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 25
Healthy volunteers: no

Brief summary:
The purpose of the proposed study is to compare insulin Degludec \[TRESIBA® (insulin degludec injection)\] with insulin Glargine U100 \[Lantus® (insulin glargine injection)\] to determine the basal insulin of choice for adults with type 1 diabetes (T1D) who fly non-stop across multiple time zones. With the introduction of Degludec as basal insulin for T1D and the opportunity to vary time of injection between 8 and 40 hours, the use of Degludec as a basal insulin may make it easier for both people living with T1D and diabetologists to plan long-haul travel compared to the use of existing basal insulins when crossing multiple time zones.The study hypothesis is that once daily Degludec as the basal insulin will provide better glycemic control for people with type 1 diabetes on multiple daily injections who are traveling non-stop across multiple time zones than once daily Glargine U100.

Detailed description:
This study will be an open-label, single center, pilot study. Participants will be randomized to either Glargine U100 or Degludec as the basal insulin, then a 2 week break, and followed by a cross-over to the other insulin. Each study period will begin in Honolulu, Hawaii (HI) (airport code HNL) with a non-stop flight to Newark, New Jersey (NJ) (EWR) lasting approximately 10 hours with a 6 hour time difference between destinations. After up to 72 hours in EWR, participants will return to Honolulu and spend up to 72 hours at that destination. Investigators plan to recruit 25 adults with established T1D currently being treated with multiple daily injections of insulin (MDI).

Arms:
arm 1: Subjects with type 1 diabetes and on multiple daily injections will use basal insulin Degludec and the TRESIBA® FLEXTOUCH® pens during a long-haul flight and randomized to this arm first or second. arm 2: Subjects with type 1 diabetes and on multiple daily injections will use basal insulin Glargine U100 and the LANTUS® SOLOSTAR® INSULIN PEN during a long-haul flight and randomized to this arm first or second.

Interventions: intervention 1: Insulin Degludec intervention 2: Insulin Glargine intervention 3: TRESIBA® FLEXTOUCH® intervention 4: LANTUS® SOLOSTAR® INSULIN PEN
Intervention descriptions: intervention 1: Subjects will use Insulin Degludec (Tresiba) with TRESIBA® FLEXTOUCH® pens as their basal insulin during a 9-10 hour flight, at each destination, and then during a return flight. intervention 2: Subjects will use Insulin Glargine (Lantus) with LANTUS® SOLOSTAR® INSULIN PEN as their basal insulin during a 9-10 hour flight, at each destination, and then during a return flight. intervention 3: Subjects will use Tresiba FlexTouch pens when using Tresiba as their basal insulin during a 9-10 hour flight, at each destination, and then during a return flight. intervention 4: Subjects will use Lantus SoloStar insulin pens when using Lantus as their basal insulin during a 9-10 hour flight, at each destination, and then during a return flight.

Protocol document:
Prot_SAP_000.pdf: 
Version 2.0, January 18, 2019  
 
1 
 
`Comparison of Insulin Degludec U100 with Insulin Glargine U100 for 
1 
adults with type 1 diabetes travelling across multiple time zones. A pilot 
2 
study. 
3 
 
4 
 
5 
 
6 
INVESTIGATOR-SPONSORED STUDY PROPOSAL 
7 
UTN U1111-1210-7350 
8 
 
9 
 
10 
 
11 
 
12 
 
13 
Dr. David Kerr MD FRCPE 
14 
Sansum Diabetes Research Institute 
15 
Director of Research and Innovation 
16 
2219 Bath Street 
17 
Santa Barbara, CA 93105 
18 
1-805-682-7640 ext 241  
19 
Email: dkerr@sansum.org 
20 
 
21 
 
22 
 
23 
 
24 
 
25 
 
26 
 
27 
 
28 
 
 
29 


Version 2.0, January 18, 2019  
 
2 
 
BACKGROUND AND SIGNIFICANCE 
30 
 
31 
According to the latest estimates published by the International Diabetes Federation, 415 
32 
million adults were living with diabetes in 2015 and this number is expected to rise to 
33 
642 million (or 1 adult in 10) by 2040 (1). This makes it likely that a good proportion of 
34 
the 8 million people who board an aircraft each day (www.iata.org) are flying with an 
35 
established diagnosis of diabetes. In the United States and based on diabetes prevalence 
36 
data, approximately 17 million leisure and 5.6 million business travelers travel with 
37 
diabetes and at least a quarter will be using insulin on a daily basis (2).  
38 
 
39 
For insulin treated individuals planning long-haul travel (defined as a flight lasting more 
40 
than 6hours), consideration needs to be given to every stage of a journey from deciding 
41 
what to pack, choosing appropriate travel insurance, dealing with airport security, 
42 
anticipating consequences of late or delayed flights, preparing for the potential impact of 
43 
flying in a pressurized cabin on the performance of medical devices and choosing a meal 
44 
on board through to assessing the impact of crossing multiple times zones and jet lag on 
45 
insulin action and the perception of low blood glucose levels at altitude (3). Once a 
46 
traveler with diabetes arrives at their destination, it is advisable to plan in the event their 
47 
diabetes supplies are lost or stolen, as well as dealing with unfamiliar foods, 
48 
unaccustomed exercise, or even riding roller coasters (4). In one survey more than half of 
49 
travelers with diabetes reported difficulties in glucose management during their journey 
50 
compared to the month prior to leaving (5). In general, for insulin-treated individuals 
51 
around 10% of travelers on short as well as long-haul journeys experienced problems, 
52 
most commonly hypoglycemia during the journey or in the first 24 hours after arriving at 
53 
their destination (6). For long-haul travel in particular, there is evidence that most 
54 
physicians, including diabetes specialists, are uncertain about how to adjust insulin doses 
55 
for patients who travel across several time zones and some of the information provided is 
56 
described as “potentially harmful” (7). Furthermore, recent testimony from on-line 
57 
bloggers and patient forums continues to highlight specific problems related to diabetes 
58 
and travel (8). 
59 
 
60 
We sought to determine the real-life experiences of individuals traveling long distance 
61 
(across five or more time-zones) with type 1 diabetes (T1D). Members of the T1D 
62 
Exchange (n=503) online community (www.myglu.org) completed a 45-question survey 
63 
about their travel experiences flying long distance (9). The cohort was stratified by 
64 
duration of T1D and whether or not participants used continuous subcutaneous insulin 
65 
infusion (CSII) therapy and/or a continuous glucose monitor (CGM). In the last 5 years, 
66 
71% of participants had flown long distance. When asked about their perceived ‘‘fear of 
67 
flying,’’ CSII users (with and without a CGM) reported their primary anxiety was 
68 
‘‘losing supplies,’’ while non-CSII users described concerns over ‘‘unstable blood 
69 
glucose (highs and lows)’’ (P < 0.05). In addition, 74% of participants reported more 
70 
hypoglycemia and/or hyperglycemia while traveling overseas and 9% had avoided 
71 
international travel altogether because of problems related to diabetes management. 
72 
Furthermore, 22% of participants had run out of insulin at some point during a trip and 
73 
37% reported inadequate attention in current sources of information to the 
74 
unpredictability of self-management needs while traveling. Especially problematic for 
75 


Version 2.0, January 18, 2019  
 
3 
 
individuals traveling with T1D are a lack of resources adequately addressing: (a) 
76 
protocols for emergencies while abroad, (b) how to navigate airport security, and (c) 
77 
managing basal insulin rates when crossing time zones. A strong need exists for easily 
78 
accessible, free resources for traveling with T1D that is tailored to both device use and 
79 
duration of the disease  
80 
 
81 
Currently, there is a lack of patient-centered research evaluating the practical and 
82 
psychosocial aspects of travel and T1D. Few resources offer practical and easy to 
83 
understand travel guidance to individuals with T1D. Available sources of information 
84 
include publications targeting physicians and scientific researchers, online articles 
85 
providing generalized tips (transportation and storage of supplies, suggested 
86 
immunizations, diet regimens to follow, optimizing insulin dose modification across time 
87 
zones) and free electronic dosage calculators (10-14). For the most part these articles are 
88 
well written and offer sound counsel, but many guidelines are overly complicated with 
89 
medical jargon and complex tables describing insulin dosing adjustments. This poses a 
90 
problem for both patients and providers looking for simple travel advice (15). Diabetes 
91 
also contributes to medical emergencies that affect 1 in every 614 flights (16). 
92 
 
93 
On August 6th 2015 we launched www.DiabetesTravel.org, a free on-line resource 
94 
focusing exclusively on long-haul travel and diabetes. As well as providing information, 
95 
we have also offered a “travel calculator” to provide guidance on planning changes in the 
96 
timing and frequency of insulin therapy to aid discussions with diabetes teams caring for 
97 
individuals with T1D. Since launch almost 25,000 users have logged on with 52% 
98 
coming from the US (source Google Analytics, accessed 12/15/2017). We have also 
99 
received multiple, favorable comments on social media, and this has been achieved 
100 
without marketing the site or the use of search engine optimization techniques.  
101 
 
102 
 
103 
RATIONALE FOR THE STUDY 
104 
 
105 
The purpose of the proposed study is to compare insulin Degludec U100 with insulin 
106 
Glargine U100 to determine the basal insulin of choice for adults with type 1 diabetes 
107 
who fly non-stop across multiple time zones. With the introduction of Degludec as basal 
108 
insulin for T1D and the opportunity to vary time of injection between 8 and 40 hours, the 
109 
use of Degludec as a basal insulin may make it easier for both people living with T1D 
110 
and diabetologists to plan long-haul travel compared to the use of existing basal insulins 
111 
when crossing multiple time zones (insulin degludec injection) (Label – FDA 
112 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203314s003lbl.pdf.  
113 
Accessed March 6, 2018.) 
114 
 
115 
 
116 
SPECIFIC OBJECTIVES 
117 
 
118 
To compare glycemic control end points between Degludec U100 versus Glargine U100 
119 
as the basal insulin in a pilot study of adults with type 1 diabetes who are established on 
120 
multiple daily injections (MDI) of insulin and flying long-haul.  
 
121 


Version 2.0, January 18, 2019  
 
4 
 
RESEARCH DESIGN AND METHODS 
122 
Study Hypothesis: Once daily Degludec U100 as the basal insulin will provide better 
123 
glycemic control for people with type 1 diabetes on multiple daily injections who are 
124 
traveling non-stop across multiple time zones than once daily Glargine U100.   
125 
 
126 
Endpoints: 
127 
The Primary endpoint will be, using continuous interstitial glucose monitoring (CGM), 
128 
achieved glycemic control defined as time in range (70-140 mg/dl) during the initial 24 
129 
hours local time (starting within 2 hours after arriving) in Newark, NJ or JFK, NY after 
130 
flying 9-10 hours West to East (from Honolulu, HI) and after the return journey from 
131 
Newark to Honolulu (flying East to West) comparing Glargine U100 versus 
132 
DegludecU100 as the basal insulin.  
133 
 
134 
Participants will begin in Honolulu, HI (HNL), fly to Newark (EWR) or New York (JFK) 
135 
where they will stay for up to 72 hours followed by a return long-haul flight back to 
136 
Honolulu with up to 72 hours at this destination. This journey will be repeated after a 2 
137 
week period when subjects return to their original insulin treatment regimen and then 
138 
switch to the alternative basal insulin. When traveling east, the day gets shorter, so the 
139 
basal insulin dose given during travel needs to be adjusted (see below). 
140 
 
141 
Figure 1. Overview of protocol with Primary and Secondary endpoint timelines for 
142 
assessment. This journey will be undertaken twice - once using Glargine U100 and 
143 
once using Degludec as the basal insulin. 
144 
 
145 
 
146 
 
147 
Secondary CGM End-Points comparing Glargine U100 and Degludec as the basal 
148 
insulin are based on recent consensus related to reporting of trials for artificial pancreas 
149 
development (17): 
150 
• Time in range (70-180 mg/dl) within the first 24 hours after arriving in HNL and 
151 
EWR or JFK (starting within 2 hours after arrival). 
152 
• For the inflight period of time and for the 72 hours in each destination: 
153 
o Mean +SD CGM glucose (mg/dl)  
154 


Version 2.0, January 18, 2019  
 
5 
 
o % CGM time <50 mg/dl 
155 
o % CGM time <60 mg/dl 
156 
o % CGM time <70 mg/dl 
157 
o % CGM time 70–180 mg/dl 
158 
o % CGM time >180 mg/dl 
159 
o % CGM time >250 mg/dl 
160 
o % CGM time >300 mg/dl 
161 
o SD and coefficient of variation of CGM values  
162 
• Fasting BG at 0600 local time, using CGM 
163 
• Additionally, new CGM BG ranges will be included as consensus guidelines 
164 
emerge, including but not limited to those from the 2019 Advanced Technologies 
165 
and Treatments for Diabetes International Consensus on Time in Range (29): 
166 
o % CGM time 54–69 mg/dl 
167 
o % CGM time <54 mg/dl  
168 
 
169 
Secondary non-CGM derived endpoints will be (a) Fear of hypoglycemia (HFS II) (18) 
170 
and Hypoglycemic Confidence Scale (28), (b) Liverpool Jet-Lag Questionnaire (19), (c) 
171 
Salivary cortisol and melatonin and (d) Sleep duration and quality and (e) Activity 
172 
(ActiGraph, LLC, Florida)  (20). 
173 
 
174 
 
175 
STUDY DESIGN 
176 
 
177 
This study will be an open-label, single center, pilot study randomized to either Glargine 
178 
or Degludec as the basal insulin, and then a 2 week break, followed by a cross-over to the 
179 
other insulin. The study will begin in Honolulu (airport code HNL) with each non-stop 
180 
flight to Newark, NJ (EWR) or New York (JFK) lasting approximately 10 hours with a 
181 
5/6 hour time difference between destinations. After up to 72 hours in EWR or JFK, they 
182 
will return to Honolulu and spend up to 72 hours at that destination.  
183 
 
184 
Subjects will continue to use their regular meal-time fast-acting insulin. Based on our 
185 
experience with open and closed loop studies in T1D, subjects will have basal insulin 
186 
optimized using CGM profiles for up to 4 weeks prior to travel (21). One month of CGM 
187 
use for CGM naïve subjects is also a valid time for familiarity with this glucose 
188 
monitoring system. 
189 
 
190 
This is a single center pilot study based in the United States for which we are planning to 
191 
recruit adults with established T1D currently being treated with multiple daily injections 
192 
of insulin (MDI). Subjects for this trial will consist of individuals based on inclusion and 
193 
exclusion criteria (see below). The subjects must be willing to participate in the clinical 
194 
trial as per protocol and randomized to the use of Glargine or Degludec as their basal 
195 
insulin with a 2 week break period between insulins and flights.  
196 
 
197 
Potential subjects will be selected from the available subject database at the Sansum 
198 
Diabetes Research Institute (SDRI). Every effort will be made to establish eligibility of 
199 


Version 2.0, January 18, 2019  
 
6 
 
the participants prior to enrollment. Only participants who meet all eligibility criteria will 
200 
be enrolled in the study. 
201 
 
202 
We anticipate to screen up to 40 in order to obtain at least 22 evaluable subjects (see 
203 
below). If an enrolled subject must withdraw or fails to complete the study, the subject will 
204 
be replaced to ensure at least 25 evaluable subjects. Subjects who have been diagnosed 
205 
with T1D for at least 1 year and are under current treatment with any basal insulin 
206 
analogue will be considered for the trial. However, to minimize bias we plan to balance 
207 
the number of subjects using either Degludec or Glargine at enrollment. Subject 
208 
eligibility will be confirmed by study staff during a screening visit. Blood draws will be 
209 
collected as required to demonstrate study eligibility as noted below.  
210 
 
211 
 
212 
INCLUSION CRITERIA 
213 
 
214 
1. Males or females ≥18 and ≤65 years of age. 
215 
2. Type 1 diabetes mellitus (diagnosed clinically) for ≥12 months. 
216 
3. HbA1c <10% within 30 days of being enrolled in the study 
217 
4. Current treatment with any basal insulin analogue as the once daily basal insulin 
218 
given in the evening (22) and no fewer than three injections with rapid acting 
219 
bolus insulin (e.g. insulin aspart, insulin lispro, or insulin glulisine) as mealtime 
220 
bolus insulin therapy. Must have been using this treatment for at least one month 
221 
prior to starting basal optimization. 
222 
5. No contraindication to long-haul travel. 
223 
6. No recurrent severe hypoglycemia (more than 1 severe hypoglycemic event 
224 
requiring hospitalization during the last 12 months), or hypoglycemia 
225 
unawareness as judged by a score of >4 on the Gold score (23), or hospitalization 
226 
for diabetic ketoacidosis during the previous 6 months. 
227 
7. Willing and able to use a continuous glucose monitoring (CGM) device (e.g. 
228 
Abbott Libre and/or Dexcom G4 or G6 system). 
229 
8. Ability to self-manage insulin therapy (verbal confirmation at screening visit) of a 
230 
changed bolus insulin dose the preceding 2 months prior to screening. 
231 
9. Ability and willingness to adhere to the protocol, including performance of self-
232 
monitored blood glucose (SMBG) readings and self-adjustment of insulin doses 
233 
according to protocol. 
234 
10. Subject must be willing to perform 8 BG Fingersticks during flights. 
235 
11. Subject must be able to read and understand English. 
236 
12. In the Investigator’s opinion, the subject must be able to follow the instructions 
237 
provided to him/her by the study staff and perform all study tasks as specified by 
238 
the protocol. 
239 
13. At the time of enrollment subject must be available and willing to travel on the 
240 
specified dates set up per protocol. 
241 
14. Subject must be willing and able to provide written signed and dated informed 
242 
consent.  
243 
 
244 
 
245 


Version 2.0, January 18, 2019  
 
7 
 
EXCLUSION CRITERIA 
246 
 
247 
1. Current use of an insulin pump. 
248 
2. Use within the last 3 months prior to enrollment visit 1 of any glucose-lowering 
249 
drug other than insulin. 
250 
3. Initiation or significant change of any systemic treatment which, in the 
251 
investigator’s opinion, could interfere with glucose metabolism, such as systemic 
252 
corticosteroids, beta-blockers or monoamine oxidase inhibitors (inhaled 
253 
corticosteroids allowed). 
254 
4. Proliferative retinopathy or maculopathy requiring treatment, according to the 
255 
investigator. 
256 
5. Pregnancy, breast-feeding, the intention of becoming pregnant or not using 
257 
adequate contraceptive measures. 
258 
6. Any clinically significant disease or disorder, which in the investigator’s opinion 
259 
could interfere with the results of the trial. 
260 
7. Mental incapacity, psychiatric disorder, unwillingness or language barriers 
261 
precluding adequate understanding or cooperation, including subjects not able to 
262 
read or write, and known or suspected abuse of alcohol, narcotics, or illicit drugs. 
263 
8. Known or suspected allergy to any of the trial products or related products. 
264 
9. Receipt of any investigational drug or participation in other trials within 1 month 
265 
prior to Visit 1. 
266 
10. Use of melatonin or sleeping aids for sleep during the travel portion of the study. 
267 
11. Subject is currently participating in another clinical trial. 
268 
12. Subject is unsuitable for participation due to any other cause as determined by the 
269 
Investigator. 
270 
 
271 
WITHDRAWAL CRITERIA 
272 
 
273 
Pregnancy or intention of becoming pregnant 
274 
Unable to participate in the flights 
275 
Unable to wear the continuous glucose monitoring device 
276 
New onset of serious inter-current illness as assessed by the investigator 
277 
Subjects will be replaced if they withdraw or become ineligible by the research staff from 
278 
the database of eligible participants.  
279 
 
280 
 
 
281 


Version 2.0, January 18, 2019  
 
8 
 
SUMMARY PROTOCOL 
282 
 
283 
 
284 
*East coast city can be EWR (Newark) or JFK (John F. Kennedy) 
285 
 
286 
Randomization will be to begin with either Glargine or Degludec. Subsequently 
287 
participants will switch basal insulin (i.e. from Glargine to Degludec or from Degludec 
288 
to Glargine). The direction of travel will be the same direction each time.
289 


Version 2.0, January 18, 2019  
 
9 
 
OVERVIEW OF VISIT PROCEDURES 
290 
 
291 
 
292 
*East coast city can be EWR (Newark) or JFK (John F. Kennedy) 
293 
 
294 
Screening Visit: Subjects that meet the eligibility criteria and have signed the informed 
295 
consent will continue to the screening visit which will be performed at SDRI 
296 
(www.sansum.org). The following screening assessments will be completed at baseline 
297 
(pre-randomization):  
298 
 
299 
• Signed and dated informed consent 
300 
• HbA1c assessment either via fingerstick and DCA2000 or equivalent NGSP-
301 
certified point-of-care method, or by local laboratory 
302 
• Inclusion and exclusion criteria 
303 
• Demographics (date of birth, gender, race and ethnicity) 
304 
• Medical history  
305 
• Substance use history (drinking, smoking, and drug habits) 
306 
• Concomitant medications 
307 
• Physical examination  
308 
• Weight and height 
309 
• Vital signs will be tested including oral temperature, blood pressure and pulse 
310 
• Urine pregnancy test for all premenopausal women who are not surgically sterile 
311 
• Blood draw for routine blood count, HbA1c, and chemistry panel (values within 3 
312 
months prior to enrollment acceptable). 
313 
• Hypoglycemia unawareness Gold score (23). 
314 
• Fear of hypoglycemia scale (HFS II) (18). 
315 
• Hypoglycemic Confidence Scale (28). 
316 
 
317 
Subject randomization - Visit #1. Subjects who meet all eligibility criteria, have signed 
318 
the informed consent and completed all screening assessments will continue to 
319 
randomization. Screening and Visit #1 may occur on the same day. A subject will be 
320 


Version 2.0, January 18, 2019  
 
10 
 
considered enrolled in the study after signing the informed consent.. After the study team 
321 
confirms enrollment, the subject will be assigned a unique subject identification number 
322 
which will be used to identify the subject throughout the study and will be used for all 
323 
source documents.,  At this visit travel plans will be also discussed and booked including 
324 
ground transportation, flights, hotels and meals.  
325 
 
326 
If for any reason a subject is determined to no longer be eligible for the study after 
327 
enrollment but prior to the start of the travel phase of the study, the subject will be 
328 
considered ineligible to continue and will be exited from the study. No additional study 
329 
assessments will be required to be completed. The reason for study exit will be clearly 
330 
documented on the corresponding (eCRF). If an enrolled subject must withdraw or fails 
331 
to complete the study, the subject will be replaced to ensure at least 25 evaluable 
332 
subjects. 
333 
 
334 
Randomization - Visit #1.  In Visit 1, subjects will be randomized to either starting 
335 
Degludec or Glargine insulin and begin using this insulin according to the label insert and 
336 
full prescribing information 
337 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/203314lbl.pdf and 
338 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021081s034lbl.pdf). For the 
339 
purpose of basal insulin optimization we will use CGM data. Subjects who do not 
340 
currently use CGM will be fitted with a blinded CGM system, the Abbott FreeStyle Libre 
341 
Pro (Abbott Laboratories, Abbott Park, IL).  Subjects who are current CGM users may 
342 
continue to use their personal CGM systems for the duration of the study. When 
343 
necessary, clinical study staff will train subjects on inserting and using the study CGM 
344 
devices.  The investigator will use clinical judgment to confirm that subjects are suitably 
345 
trained on the safe use of CGMs. Subjects will also be given a study glucometer and 
346 
strips.  Study staff will ensure that the study meters and strips pass quality control testing 
347 
and the subject is adequately trained on the use of the study meters as per the 
348 
manufacturer’s instructions.  
349 
 
350 
Visits for Basal Optimization – Visits #2 and #3. Once the randomization phase has 
351 
been initiated, the subject will be sent home and CGM data collection will be ongoing for 
352 
the purpose of basal and meal-time insulin optimization. Over the next (up to 4) weeks 
353 
clinical staff will review the dose of basal insulin and make necessary adjustments based 
354 
on the CGM values at least once a week. Subjects will perform up to 4 fingerstick (FS) 
355 
blood glucose (BG) measurements with the study meter. The investigator will use clinical 
356 
judgment to adjust the basal rate, insulin to carbohydrate ratio, and correction factor to 
357 
ensure subject safety prior to continuing the study. The next visits for basal optimization 
358 
visits may be conducted remotely via telephone at the subject’s preference and 
359 
investigator’s discretion. If any visits are planned to be conducted via telephone, the 
360 
subject will need to be able to upload their CGM data for the investigator to review 
361 
remotely. At each visit the investigator will re-assess glycemic control. If the investigator 
362 
determines that it is unsafe for the subject to continue into the travel phase of the study, 
363 
the subject will not be allowed to continue in the study, and the reason for study exit will 
364 
be documented on the corresponding source document.  
365 
 
366 


Version 2.0, January 18, 2019  
 
11 
 
Travel to Newark (EWR) or New York (JFK) from Honolulu (HNL) (Visit #4), up 
367 
to 72 hours in Newark or New York (Visit #5), return flight from EWR (or JFK) to 
368 
HNL (visit #6) and 48 hours in Honolulu (visit #7). Subjects originating in Santa 
369 
Barbara will travel to Honolulu and spend up to 2 days adjusting. At this point subjects 
370 
will begin their trip to the New York area. Subjects will base their travel plans at this 
371 
stage according to routine advice from their clinicians and from 
372 
www.diabetestravel.org .  During travel U100 Glargine and Degludec and rapid acting 
373 
insulin will be maintained in cool storage (36°F – 46°F [2°C – 8°C]) until first use using 
374 
a proprietary travel storage pack (e.g. Frio Cooling Pack). Once open for use insulins can 
375 
be used for up to 28 days. During this time they can be safely kept at room temperature 
376 
up to 86°F (30°C). The sponsor-investigator will ensure the availability of proper storage 
377 
conditions. During each flight, blood glucose meters and strips and continuous glucose 
378 
monitoring devices will be taken in hand luggage. All doses of insulin (basal and rapid 
379 
acting) and time of insulin injections will be recorded in the subject’s travel diary as well 
380 
as sleep and meals. Subjects will perform at least 8 FS BGs during the flight. Subjects 
381 
who regularly use CGMs may continue their personal CGM systems. 
382 
 
383 
For each flight the relevant basal insulin will be adjusted as described below. The 
384 
following secondary end-point measurements will be taken starting immediately before a 
385 
flight, during the flight, immediately after the flight, and after 48 hours at the destination 
386 
and immediately before the beginning of each flight: 
387 
 
388 
Salivary cortisol and melatonin  
389 
Liverpool Jet-Lag Questionnaire. 
390 
Sleep and Activity (ActiGraph wGT3X-BT activity monitor) (ActiGraph, Pensacola, FL)  
391 
Interstitial glucose (CGM) Abbott FreeStyle Libre Pro.   
392 
Fingerstick blood sugar readings, approximately 8 times a day 
393 
 
394 
Crossover. The return to home will be followed by a 2 week period where the subject 
395 
will return to their original insulin regimen and recover from long-haul travel.  Study 
396 
insulin will not be provided during this time. 
397 
 
398 
Visits #8 to #14. After 2 weeks, subjects will start the alternative basal insulin (Glargine 
399 
U100 to Degludec or Degludec to Glargine U100) and the protocol outlined above 
400 
repeated with the same direction of travel on the new basal insulin (Figure 3). The above 
401 
measurements will be repeated as before.  
402 
 
403 
Visit #15 will be a final visit to return equipment and complete documentation. At time 
404 
of study completion, the corresponding source document will be completed with the date 
405 
of study exit. Any new or ongoing adverse events will also be documented. A summary 
406 
letter will be provided for each subject to inform their usual health care provider.  
407 
 
408 
 
409 
BASAL INSULIN ADJUSTMENTS FOR TRAVEL 
410 
 
411 


Version 2.0, January 18, 2019  
 
12 
 
For subjects taking long acting basal insulin by injection, travel requires a 4% adjustment 
412 
to the insulin dose for each time zone traversed (1 hour is 4% of the 24 hour day) (24). To 
413 
avoid any confounding from the direction of travel, both journeys will be identical for 
414 
each basal insulin, i.e. beginning in Honolulu. With Degludec as the basal insulin, 
415 
subjects will take this the next day after arriving at their destination taking into 
416 
consideration the change in time at the destination. As shown in clinical trials in T1 and 
417 
T2 diabetes, Degludec allows for flexibility in the timing of dose administration provided 
418 
a minimum of 8 h and maximum of 40 hours between injections is ensured 
419 
(www.ncbi.nlm.nih.gov/pubmed/23393185). 
420 
 
421 
With Glargine as the basal insulin, subjects will adjust their basal insulin based on 
422 
discussion with their specialist diabetes team and with information provided at 
423 
www.DiabetesTravel.org.  
424 
 
425 
Westward travel from Newark (EWR)/or New York (JFK) to Honolulu (HNL) 
426 
 
427 
This example uses a current dose of Glargine 20 units at 8 PM. The flight departs at 
428 
10 AM Eastern Standard Time (EST) and arrives at 3 PM the same day local (Honolulu 
429 
time -HST). Total travel time is 11 hours. 
430 
 
431 
Using the Westward Travel Algorithm (Appendix 1), information on the starting time at 
432 
departure is recorded along with the last time Glargine should be given - 20 units at 
433 
8 PM the prior evening. As a rule, if Glargine is due during a flight, only half the usual 
434 
dose (10 units) should be taken. 
435 
 
436 
The subject’s watch/clock should still be on departure time (EST) and the half of the 
437 
normal dose (10 units) is given at 8 PM EST. Immediately after this, the watch/clock 
438 
should be reset to the destination time. Upon landing in Honolulu, the day is now ‘longer’ 
439 
despite 11 hours having passed, as it is 3 PM HST. Since only half the basal insulin was 
440 
given earlier in the day, the subject should give the remaining 50% dose (10 units) at 
441 
8 PM HST after landing in Hawaii. The next night, the normal insulin dose (20 units) is 
442 
given at 8PM HST at the new location. By giving half the dose at 2 different times, the 
443 
Glargine dose is extended out to cover the longer day to prevent hypoglycemia. Use of a 
444 
time zone map (http://www.worldtimezone.com/wtz-pacific24.php) can help to determine 
445 
how many time zones are traversed. 
446 
 
447 
Eastward travel from Honolulu (HNL) to Newark (EWR)/or New York (JFK) 
448 
 
449 
This example uses a current dose of Glargine 20 units at 8 PM. The flight departs at 3 
450 
PM HST from Honolulu and arrives at 7 AM EST in Newark the next day. Total travel 
451 
time is 10 hours. When traveling east, the day gets shorter, so the basal insulin dose given 
452 
during travel can be adjusted one time using the formula (25) (Appendix 2): 
453 
 
454 


Version 2.0, January 18, 2019  
 
13 
 
For this journey only a single dosage reduction is needed. After the reduced travel dose is 
455 
given, the subject should resume their normal dosing. For other journeys the number of 
456 
time zones to be crossed can be found at http://www.timeanddate.com/time/map/.  
457 
 
458 
Here the normal dose (20 units) of Glargine is given at 8 PM local time the evening 
459 
before departure. During the flight at 8 PM HST, 13 units of Glargine are given per the 
460 
formula. After this dose is given, the subject needs to change his/her watch to EST. The 
461 
next full dose of Glargine is due 8 PM EST after arrival, which turns out to be 18 hours 
462 
after the last dose. This reduced time between doses is why less Glargine is given on the 
463 
flight. 
464 
 
465 
During each flight subjects will be provided with prepared food containing 15g snacks to 
466 
be eaten every 3 hours until the appropriate time for a main meal at the destination. These 
467 
snacks and all meals at each destination will be logged. Larger meals will be covered 
468 
using the subject’s usual insulin: carbohydrate ratio and correction factor relevant to the 
469 
carbohydrate content of the meal. If the subject’s glucose falls outside of the required 
470 
ranges during this time period, the CGM sensor will alert and prompt the subject to 
471 
perform a confirmatory finger stick. If the BG value is confirmed to be outside of the 
472 
acceptable range, the subject will self-treat according to usual practice, printed 
473 
information and with the help of study staff traveling with them.  
474 
 
475 
 
476 
Assessments for Safety: As both Degludec and Glargine are approved for use for type 1 
477 
diabetes in the United States no additional safety requirements are required beyond usual 
478 
clinical care. All subjects will be provided with oral glucose for the prevention of 
479 
hypoglycaemia. In addition, subjects may have an experienced staff person with them 
480 
during travel and will be in contact with SDRI physicians for any advice or problems that 
481 
may arise. 
482 
 
483 
 
484 
STATISTICAL CONSIDERATIONS 
485 
 
486 
Sample Size Calculation and statistical analyses 
487 
The study will have an open label, randomised cross-over design. Randomisation will be 
488 
for basal insulin alone. This is a pilot study as no previous studies have been performed 
489 
comparing basal insulins during long-haul travel. Given the novelty and practical 
490 
relevance of the study and our recent information about the challenges face by 
491 
individuals with T1D undertaking travel (see above) we believe that this project will have 
492 
a very high chance of publication in a high impact peer-reviewed journal. 
493 
 
494 
The aim is to compare the impact of long-haul travel on glycemic control (CGM derived 
495 
data for time in range (70-140 mg/dl) as the primary end point with the assessment 
496 
during the initial 24 hours after arriving at EWR or JFK and HNL (starting within 2 
497 
hours after arrival) comparing Glargine U100 versus Degludec U100 as the basal 
498 
insulin.  
499 
 
500 


Version 2.0, January 18, 2019  
 
14 
 
Primary Endpoint: time in 70 to 140 mg/dl after a long-haul flight from HNL to EWR 
501 
or JFK and from EWR or JFK to HNL during the initial 24 hours after arriving at EWR 
502 
or JFK and HNL (starting within 2 hours after arrival). 
503 
 
504 
Secondary CGM End-Points comparing Glargine and Degludec as the basal insulin): 
505 
• Time in range (70-180 mg/dl) within the first 24 hours after arriving in HNL and 
506 
EWR or JFK (starting within 2 hours after arrival). 
507 
• Mean +SD CGM glucose (mg/dl)  
508 
• % CGM time <50 mg/dl 
509 
• % CGM time <60 mg/dl 
510 
• % CGM time <70 mg/dl 
511 
• % CGM time 70–180 mg/dl 
512 
• % CGM time >180 mg/dl 
513 
• % CGM time >250 mg/dl 
514 
• % CGM time >300 mg/dl 
515 
• SD and coefficient of variation of CGM values  
516 
• Fasting BG at 0600 local time, using CGM 
517 
• Additionally, new CGM BG ranges will be included as consensus guidelines 
518 
emerge, including but not limited to those from the 2019 Advanced Technologies 
519 
and Treatments for Diabetes International Consensus on Time in Range (29): 
520 
o % CGM time 54–69 mg/dl 
521 
o % CGM time <54 mg/dl  
522 
 
523 
Comparisons will be made for 
524 
• Total travel  
525 
• Total East to West travel and West to East travel 
526 
• 24 hours prior to each flight 
527 
• During each flight (total time, from take-off to meal and from meal to landing) 
528 
• 24, 48 and 72 hours at the destination 
529 
 
530 
In addition the secondary end–points will be compared for Glargine and Degludec for 
531 
specific time blocks to assess the contribution from each basal insulin: 
532 
A. Between 2200 and 0700 hours the night before each flight 
533 
B. Between 2200 and 0700 hours for Days 2 and 3 at each destination 
534 
For the purpose of our primary outcome data CGM data will primarily be obtained from 
535 
the Abbott FreeStyle Libre Pro system, but in the case of missing data, we will also 
536 
evaluate any secondary personal CGM data. 
537 
 
538 
Sample size for this pilot study is based on recent data indicating that individuals with 
539 
type 1 diabetes spend approximately 669+208 minutes between 70-180 mg/dl (26). With 
540 
the criterion for significance set at 0.05, and using a paired t-test analysis, a sample size 
541 
of 22 subjects will achieve a power of at least 80% to detect a difference of 10% between 
542 
basal insulins assuming the standard deviation of the difference is <106 minutes (Table 
543 
1). Although Battelino et al (26) reported the standard deviation of the target 
544 
measurement, it did not report the standard deviation of the difference in the 
545 


Version 2.0, January 18, 2019  
 
15 
 
measurements.  Since this is unknown, yet needed for the power calculation, an estimate 
546 
was derived using the two treatment groups reported by the Battelino et al (26) using 
547 
Altman (27). This derivation yielded a value of 25.7.  It is acknowledged that the two 
548 
treatment groups reported by Battelino et al (26) are different than those investigated in 
549 
this protocol (and the groups were independent rather than paired), but since similarities 
550 
exist the derived estimate is sufficient for preliminary power calculations.  Table 1 
551 
reports that when the standard deviation of the difference is 25, this investigation will 
552 
have over 99% power to detect a difference between the two insulin groups.  Since 25 is a 
553 
low estimate, Table 1 also reports standard deviation estimates up to 110, and reports that 
554 
>80% power is achieved up to 106 but <80% when the standard deviation of the 
555 
difference is >106. Assuming that the standard deviation of the difference in this 
556 
investigation will be <106 minutes is justified given that the value of this standard 
557 
deviation in a previous study (26) is 25.7 which is well below the 106 threshold. In 
558 
anticipation of potential drop-outs 25 subjects will be recruited. 
559 
 
560 
Table 1: Power obtained under a range of various assumptions for the Standard 
561 
Deviation of the Difference  
562 
 
563 
Alpha 
0.05 
0.05 
0.05 
0.05 
0.05 
0.05 
0.05 
Sample Size 
22 
 
22 
 
22 
 
22 
 
22 
 
22 
 
22 
 
Effect Size 
2.680 
0.893 
0.670 
0.638 
0.632 
0.626 
0.609 
Mean Difference 
67 
67 
67 
67 
67 
67 
67 
SD of Difference 
25 
75 
100 
105 
106 
107 
110 
Power 
>99% 
97.89 
84.99 
81.42 
80.69 
79.96 
77.76 
 
564 
Comparisons will be made using Student’s paired t-tests (two-sided) for normative and 
565 
log-transformed data, Wilcoxon signed rank testing for non-parametric data, and N1 chi-
566 
square tests for proportions (30). Data will be expressed wherever possible as mean 
567 
difference with 95% confidence limits for the difference or as mean + standard error or 
568 
deviation for the difference. For non-parametric data, these will be presented as median 
569 
differences with inter-quartile ranges. All data will be analysed on an intention to treat 
570 
basis. No interim analysis is anticipated.  Furthermore, to gain as much information as 
571 
possible from this pilot study, all hypotheses will be tested at 0.05 and no adjustments for 
572 
multiplicity will be made. 
573 
 
574 
DATA HANDLING AND RECORD KEEPING 
575 
 
576 
All records and data will be held by staff employed by SDRI which has a long and 
577 
established track record of exemplary recruitment and execution of clinical research 
578 
studies with varying degrees of complexity. Staff are experienced and trained in HIPAA 
579 
regulations and ICH GCP guidelines. All staff have signed agreements related to all 
580 
appropriate regulatory and legal requirements and oversight is provided by a dedicated 
581 
Objectivity and Integrity in Science Committee consisting of staff and independent 
582 
members.  
583 
 
584 


Version 2.0, January 18, 2019  
 
16 
 
This trial will utilize Source documents to collect subject data.. The research team will be 
585 
responsible for the accuracy and completeness of data reported. The investigator also 
586 
agrees to maintain accurate source documentation as part of the subject’s medical 
587 
records. These source documents may include chart notes, laboratory reports, images, etc. 
588 
 
589 
Subject Identifiers 
590 
All data used in the analysis and reporting of the study will be without identifiable 
591 
reference to the subject. Only the unique subject number will be used to identify subject 
592 
data submitted to the sponsor, and only the investigating site will be able to link the 
593 
unique subject ID to the subject’s name. All records and data will be held by staff 
594 
employed by the Institute. SDRI has a long and established track record of exemplary 
595 
recruitment and execution of clinical research studies with varying degrees of 
596 
complexity. Staff are experienced and trained in HIPPA regulations and ICH GCP 
597 
guidelines. All staff have signed agreements related to all appropriate regulatory and 
598 
legal requirements and oversight is provided by a dedicated Objectivity and Integrity in 
599 
Science Committee consisting of staff and independent members.  
600 
 
601 
Study Record Retention 
602 
Investigators will maintain all study-related documentation for a period of fourteen (14) 
603 
years following completion of the study, or as per the local regulatory authority’s 
604 
guidelines and practices, whichever is longer. 
605 
 
606 
ETHICS 
607 
 
608 
Ethical Conduct of the Study 
609 
The investigator agrees that the study will be conducted according to the applicable FDA 
610 
regulations (21CFR 812, 56, 54, 50), ISO 14155: 2011 and the principles of the World 
611 
Medical Association Declaration of Helsinki 2008. The investigator will conduct all 
612 
aspects of this study in accordance with all national, state, and local laws or regulations. 
613 
As the investigator of this clinical trial, the Institute has the overall responsibility for the 
614 
conduct of the study, including assurance that the study meets the requirements of the 
615 
appropriate regulatory bodies. In this study, the investigator will have certain direct 
616 
responsibilities and may delegate certain study tasks to the clinical study staff.  
617 
 
618 
Institutional Review Board (IRB) 
619 
Federal regulations, ISO 14155 and 21 CFR 812 require that approval be obtained from 
620 
an IRB prior to participation of subjects in research studies. This study will require 
621 
approval by the QuorumIRB and will be undertaken in accordance with the Declaration 
622 
of Helsinki. Prior to subject enrolment, a signed copy of the IRB approval letter will be 
623 
submitted to the sponsor. In addition, the protocol, informed consent, advertisements to 
624 
be used for subject recruitment, and any other written information regarding this study to 
625 
be provided to the subject will be approved by the IRB. Documentation of all IRB 
626 
approvals will be maintained by the Institute and will be available for review by the 
627 
Sponsor or its designee. All IRB approvals will be signed by the IRB chairperson or 
628 
designee and we will identify the IRB by name and address, the clinical protocol by title 
629 
and/or protocol number, and the date approval was granted. 
630 


Version 2.0, January 18, 2019  
 
17 
 
The Investigator will be responsible for submitting and obtaining initial and continuing 
631 
review of the trial at intervals not exceeding 1 year or as otherwise directed by the IRB. 
632 
Sansum Diabetes Research Institute will supply Novo Nordisk or its designee written 
633 
documentation of continued review of the study. 
634 
 
635 
Informed consent 
636 
Subjects that appear to meet the eligibility criteria will be consented for participation in 
637 
the trial. The subject will be asked to sign an informed consent form (ICF) prior to 
638 
performance of any study-specific procedures. The ICF will have prior approval from the 
639 
Quorum IRB. 
640 
 
641 
 
642 
 
643 
STUDY DRUGS AND MATERIALS 
644 
 
645 
U100 Insulin Glargine is manufactured by Sanofi and approved for use for type 1 
646 
diabetes by the United States Food and Drug Administration Packaging, Storage and 
647 
Prescribing information is available at http://products.sanofi.us/lantus/lantus.html.  
648 
 
649 
Degludec U100 is manufactured by Novo Nordisk and prescribing information is 
650 
available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/203314lbl.pdf  
651 
 
652 
Abbott FreeStyle Libre Pro is a blinded CGM system manufactured by Abbott 
653 
Laboratories, Abbott Park, IL. Information is available at: 
654 
https://provider.myfreestyle.com/freestyle-libre-pro-product.html 
655 
 
656 
 
657 
Storage and Drug Accountability of Study Medication(s) 
658 
During travel Glargine and Degludec will be maintained in cool storage (36°F – 46°F 
659 
[2°C – 8°C]) until first use using a proprietary travel storage pack (e.g. Frio Cooling 
660 
Pack). Once open for use both insulins can be used for up to 28 days. During this time 
661 
they can be safely kept at room temperature up to 86°F (30°C). The sponsor-investigator 
662 
will ensure the availability of proper storage conditions. Also and during each flight, 
663 
blood glucose meters and strips and continuous glucose monitoring devices will be taken 
664 
in hand luggage. The investigator/study team will ensure the availability of proper 
665 
storage conditions 
666 
 
667 
Auxiliary Supply 
668 
All supplies will be purchased by the Institute. These include 
669 
• Blood glucose meters and strips for the duration of the study 
670 
• Insulin, pens and/or syringes based on participant preference 
671 
• Dexcom G4 or G6 and Abbott FreeStyle Libre CGM systems for the duration of 
672 
the study 
673 
• Snacks for travel 
674 
• Flight, accommodation and meal expenses – these will be arranged by research 
675 
staff 
676 


Version 2.0, January 18, 2019  
 
18 
 
 
677 
 
678 
RANDOMIZATION AND BLINDING 
679 
 
680 
The study is open label so no blinding is required.  At randomisation the subjects will be 
681 
randomised to Degludec or Glargine as their basal insulin with the direction of travel 
682 
identical for both basal insulin periods.  Randomization will be performed using a 
683 
computer generated sequence system. There will be a 2 week wash-out period between 
684 
each set of trips.   
685 
 
686 
 
687 
CONCOMITANT ILLNESSES AND MEDICATIONS 
688 
 
689 
Definitions: 
690 
Concomitant illness is defined as any illness that is present at the start of the trial (i.e. at 
691 
the first visit). Concomitant medication are any medications (including over-the-counter) 
692 
other than Degludec or Glargine that are taken during the trial. At the screening visit the 
693 
research team will base inclusion or exclusion of each subject according the criteria listed 
694 
above. Details of all concomitant illnesses and medication will be recorded at trial entry 
695 
(i.e. at the first visit). Any changes in concomitant medication will be recorded at each 
696 
visit.  The information collected for each concomitant medication includes, at a 
697 
minimum, start date, stop date or continuing, and indication. For each concomitant 
698 
illness, date of onset, date of resolution or continuing, at a minimum, will be recorded. 
699 
 
700 
 
701 
ADVERSE EVENTS 
702 
 
703 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
704 
clinical investigation subject administered/using a Product that affect the risk/benefit ratio 
705 
of the study; the rights, safety, or welfare of the participants or others; or the integrity of 
706 
data of the study. An Adverse Event can therefore be any unfavourable and unintended 
707 
sign (including an abnormal laboratory finding), symptom, or disease temporally 
708 
associated with the use of a Product, whether or not considered related to the Product. 
709 
This includes events reported from the first trial related activity after the subject has 
710 
signed the informed consent and until post treatment follow-up period as defined in the 
711 
protocol. The following should not be recorded as AEs, if recorded as medical 
712 
history/concomitant illness on the CRF at screening: 
713 
• Pre-planned procedure, unless the condition for which the procedure was planned has    
714 
worsened from the first trial related activity after the subject has signed the informed 
715 
consent 
716 
• Pre-existing conditions found as a result of screening procedures 
717 
  
718 
Serious Adverse Drug Reaction (SADR):  
719 
An adverse drug reaction (ADR) is an adverse event (AE) for which a causal relationship 
720 
to the trial product is at least possible i.e. causal relationship is conceivable and cannot be 
721 


Version 2.0, January 18, 2019  
 
19 
 
dismissed. Serious adverse reaction (SAR): Adverse event which fulfils both the criteria 
722 
for a Serious Adverse Event and the criteria for an Adverse Reaction. 
723 
 
724 
Serious Adverse Events 
725 
A serious adverse event (SAE) is defined as any event that results in the following: 
726 
• Death 
727 
• A life-threatening* experience 
728 
• In-patient hospitalisation or prolongation of existing hospitalization 
729 
• A persistent or significant disability/incapacity 
730 
• A congenital anomaly/birth defect 
731 
• Important medical events that may not result in death, be life-threatening*, or require 
732 
  hospitalization may be considered an SAE when, based upon appropriate medical 
733 
judgement, they may jeopardise the subject and may require medical or surgical 
734 
intervention to prevent one of the outcomes listed in this definition 
735 
• Suspicion of transmission of infectious agents  
736 
*The term life-threatening in the definition of SAE refers to an event in which the subject 
737 
was at risk of death at the time of the event. It does not refer to an event which 
738 
hypothetically might have caused death if it was more severe. 
739 
 
740 
 
741 
Adverse Event Reporting 
742 
The sponsor-investigator will collect the following information at minimum for each of 
743 
these events: 
744 
1. Study name 
745 
2. Patient identification (e.g. initials, sex, age) 
746 
3. Event (preferably a diagnosis) 
747 
4. Trial Drug  
748 
5. Reporter identification (e.g. Name, or initials) 
749 
6. Causality  
750 
7. Outcome  
751 
All adverse events will be reported by the investigator and reviewed by Novo Nordisk in 
752 
compliance with applicable regulations. Adverse events may be volunteered by subjects, 
753 
elicited by the investigator or designee, or collected via observation by the investigator. 
754 
 
755 
All AEs will be assessed by the investigator who will determine whether or not the event 
756 
is related to the study procedures or related to the study device, and whether or not the 
757 
event meets serious criteria.  If it is determined that an AE has occurred, the investigator 
758 
will be responsible for reporting of all adverse events, including serious adverse events 
759 
(SAE) and serious adverse drug reactions (SADRs), to the competent authority and 
760 
independent ethics committee/institutional review boards based upon federal regulations 
761 
and local/IRB policies.  
762 
 
763 
Adverse events will be assessed on an ongoing basis throughout the study. Adverse event 
764 
reporting will begin at the start time of the study (i.e., insertion of the CGM sensor during 
765 
Visit #1) and continue through until subject participation has ended (i.e., either time of 
766 
the post-discharge telephone follow- up, or time of study exit if the subject was 
767 


Version 2.0, January 18, 2019  
 
20 
 
discontinued early from the study). All adverse events will be followed until resolution, 
768 
or until the AE has stabilized, or until the study has been completed. 
769 
 
770 
Pre-existing medical conditions or symptoms observed prior to the start time of the study 
771 
will not be recorded as an AE and will be collected in the subject’s medical history. In the 
772 
event there is a change (i.e., worsening) in the pre-existing medical condition or 
773 
symptoms after the start of the open loop phase, then an AE will be reported.  Typical 
774 
events such as a mild cold, stomach flu, headache, etc, that are self-limiting and do not 
775 
meet any aforementioned reporting requirements, will not be reported to the IRB. 
776 
 
777 
Serious Adverse Event Reporting 
778 
All SAEs and SADRs will be reported to Novo Nordisk at the same time such events are 
779 
reported to regulatory authorities or within 15 days from the sponsor-investigator 
780 
becoming aware of such adverse events, whichever comes first.. All events will be 
781 
documented on the corresponding eCRF. SDRI will also be responsible for submitting 
782 
relevant source documentation for the SAE. If the subject is hospitalized because of or 
783 
during the course of an SAE, then a copy of the hospital discharge summary will also be 
784 
included with the SAE source documentation. In case of death, the investigator will make 
785 
every effort to obtain a copy of the death certificate to submit to Novo Nordisk. When 
786 
submitting copies of source documentation, all subject identifying information will be 
787 
redacted and only the unique subject number will be used to label the forms for 
788 
identification purposes. 
789 
 
790 
Withdrawal from the study and all therapeutic measures will be at the discretion of the 
791 
investigator. All SAEs will be followed until satisfactory resolution or until the 
792 
investigator deems the event to be chronic or the subject to be stable. 
793 
 
794 
For any event where there is suspicion that the study device is involved, the investigator 
795 
will return the device to Novo Nordisk for evaluation. The investigator will provide 
796 
procedures for cleaning and preparation of contaminated product as well as shipping 
797 
materials for the return of used and potentially biohazardous materials. 
798 
  
799 
 
800 
MANAGEMENT OF HYPOGLYCEMIA 
801 
 
802 
Fast acting oral carbohydrates will be used to treat hypoglycaemia. Staff will have 
803 
Glucagon available as needed for the treatment of severe hypoglycemia. All treatment for 
804 
hypoglycemia will be recorded on study forms. 
805 
 
806 
A SMBG with the glucose meter should be tested anytime there is: 
807 
• A low threshold alert (set at 70 mg/dL) on the CGM 
808 
• Anytime the participant has symptoms of hypoglycemia 
809 
• Anytime staff has concern about the potential for hypoglycemia 
810 
• Following treatment for hypoglycemia as indicated 
811 
 
812 
Hypoglycemia/Hyperglycemia Event Reporting 
813 


Version 2.0, January 18, 2019  
 
21 
 
For the purpose of this protocol, mild symptoms of hypoglycemia and hyperglycemia 
814 
(i.e., clinically non-significant) or blood glucose values out of the normal range (whether 
815 
or not they resulted in delayed meals or correction boluses) will not be reported as SAEs 
816 
unless determined to meet the criteria below for SAE reporting. 
817 
 
818 
Hypoglycemic events are recorded as SAEs if the event required assistance of another 
819 
person due to altered consciousness and required another person to actively administer 
820 
carbohydrate, glucagon, or other resuscitative actions. This means that the subject was 
821 
impaired cognitively to the point that they were unable to treat themselves, they were 
822 
unable to verbalize their needs, they were incoherent, disoriented, and/or combative, or 
823 
they experienced seizure or coma. These episodes may be associated with sufficient 
824 
neuroglycopenia to induce seizure or coma. If plasma glucose measurements are not 
825 
available during such an event, neurological recovery attributable to the restoration of 
826 
plasma glucose to normal is considered sufficient evidence that the event was induced by 
827 
a low plasma glucose concentration. 
828 
 
829 
Adverse Event Relatedness 
830 
The investigator will be responsible for making a determination on the causal relationship 
831 
of the AE. Specifically, the investigator will report whether the AE was related to the 
832 
study procedure, study drug, and/or related to the study device (malfunction of any 
833 
component of the Dexcom System). 
834 
 
835 
The causal relationship to the study procedure and the study device for each adverse 
836 
event will be rated as follows: 
837 
• Unrelated: The event is not related to the study drug. 
838 
• Possibly Related: The temporal sequence is such that the relationship is not 
839 
unlikely or there is no contradicting evidence that can reasonably explain the 
840 
subject’s condition. There is a possibility of any relation between the event and 
841 
the study drug. 
842 
• Related: The event is related or most likely associated with the study drug. 
843 
Full prescribing information can be found at http://www.novo-pi.com/tresiba.pdf  
844 
For Patient Counseling and FDA approved labelling see Tresiba [package insert]. 
845 
Plainsboro, NJ: Novo Nordisk Inc; March 2018.  
846 
 
847 
Adverse Event Severity 
848 
The severity of the AE will be rated based upon the following grades: 
849 
• Mild – asymptomatic or mild symptoms; usually transient, requires no special 
850 
treatments, and does not interfere with the subject’s daily activities 
851 
• Moderate – minimal, local or non-invasive intervention indicated; usually causes 
852 
a low level of inconvenience or concern to the subject and may interfere with 
853 
daily activities, but is usually ameliorated by simple therapeutic measures 
854 
• Severe – medically significant, life-threatening; hospitalization or prolongation of 
855 
hospitalization indicated; interrupts a subject’s usual daily activities and generally 
856 
requires system drug therapy or other treatment. 
857 
 
858 
Pregnancy: 
859 


Version 2.0, January 18, 2019  
 
22 
 
The study subjects will be instructed to notify the sponsor-investigator immediately if 
860 
they become pregnant.  
861 
The sponsor-investigator will report to Novo Nordisk any pregnancy occurring during the 
862 
trial period. Reporting of the pregnancy by the sponsor-investigator will occur within the 
863 
same timelines described above for reporting of Adverse Events.  
864 
Pregnancy complications will be recorded as adverse event(s). If the infant has a 
865 
congenital anomaly/birth defect this must be reported and followed up as a serious 
866 
adverse event. 
867 
 
868 
Liability and subject insurance: 
869 
For this study, the Sansum Diabetes Research Institute will provide adequate medical 
870 
care to the study subject for any study-related adverse events, including clinically 
871 
significant laboratory values related to the study. Medical care for study subjects will be 
872 
provided regardless of their insurance status. Sansum Diabetes Research Institute agrees 
873 
to indemnify Novo Nordisk in accordance with the written contract executed between the 
874 
parties for this study.  
875 
 
876 
Publication plan: 
877 
It is the expectation that data from this study will be presented at meeting(s) of learned 
878 
societies and submitted for publication in appropriate and high impact journals within the 
879 
timelines outlined above. It is our intent to register the study with a publicly assessable 
880 
database such as clinicaltrials.gov.  
881 
 
882 
REFERENCES 
883 
 
884 
1. World Tourism Organization UNWTO. Over 1.1 billion tourists travel abroad in 2014, 
885 
http://media.unwto.org/press-release/2015-01-27/over-11-billion-tourists-travelled-abroad-
886 
2014. 
887 
2. International Diabetes Federation. IDF Diabetes Atlas, 7 ed. Brussels, Belgium: International 
888 
Diabetes Federation, 2015. 
889 
3. Neithercott T. 35 top tips for travel with diabetes. Diabetes Forecast June 2013. 
890 
4. Tovar K, Pinsker J and Kerr D Diabetes and the happiest place on earth: safely attending an 
891 
amusement park and riding roller coasters. Practical Diabetes 2015; 32: 329-31. 
892 
5. Driessen S, Cobelens F and Ligthelm R. Travel-related morbidity in travelers with insulin 
893 
dependent diabetes mellitus. J Travel Med 1991; 6: 12-15. 
894 
6. Burnett J. Long and short-haul travel by air. Issues for people with diabetes on insulin. J 
895 
Travel Medicine 2006; 13: 255-60. 
896 
7. Gill G and Redmond S. Insulin treatment, time-zones and air travel: a survey of current 
897 
advice from British Diabetic Clinics. Diabetic Med 1993; 10: 764-7. 
898 
8. http://www.diabetesmine.com/2011/12/navigating-the-friendly-skies-with-diabetes.html 
899 
9. Schoenberg B, Gianferante D, Martinez J, Runion A, Kraus A, Pinsker J and Kerr. 
900 
Turbulence of travel with type 1 diabetes. Diabetes Technology &Therapeutics 2017; 19: 
901 
744-8. 
902 


Version 2.0, January 18, 2019  
 
23 
 
10. American Diabetes Association. Air travel and diabetes, http://www.diabetes.org/living-with-
903 
diabetes/know-your-rights/discrimination/public-accommodations/air-travel-and-
904 
diabetes/?referrer=https://www.google.com/; 2013 [accessed 14.03.2016]. 
905 
11. Boerner H. Tips to trip by. The art and science of traveling with diabetes. Diabetes Forecast 
906 
2008, 61:42–45. 
907 
12. Kidson W. The problems of travel in diabetes. Med J Aust 1979, 1:125–126. 
908 
13. Chandran M and Edelman SV: Have insulin, will fly: diabetes management during Air travel 
909 
and time zone adjustment strategies. Clin Diabetes 2003, 21:82–85. 
910 
14. Living with diabetes: when you travel. http://www.diabetes.org/living-
911 
withdiabetes/treatment-and-care/medication/when-you-travel.html. 
912 
15. Nassar AA, Cook CB and Edelman S: Diabetes management during travel. Diabetes 
913 
Management 2012, 2:205–212. 
914 
16. Nable J, Tupe C, Gehle B and Brady W. In-flight medical emergencies during commercial 
915 
travel. New Eng J Med 2015; 373: 939-45. 
916 
17. Maahs D, Buckingham B, Castle J, Cinar A, Damiano E, Dassau E, DeVries J, Doyle F, 
917 
Griffen S, Haidar A, Heinemann L, Hovorka R, Jones T, Kollman C, Kovatchev B, Levy B, 
918 
Nimri R, O'Neal D, Philip M, Renard E, Russell S, Weinzimer S, Zisser H, and Lum J. 
919 
Outcome measures for artificial pancreas trials: a consensus report. Diabetes Care 2016; 39: 
920 
1175-9. 
921 
18. Gonder-Frederick L, Schmidt K, Vajda K, Greear M, Singh H, Shepard J and Cox D. 
922 
Psychometric Properties of the Hypoglycemia Fear Survey-II for Adults with Type 1 
923 
Diabetes. Diabetes Care 2011; 34: 801-6. 
924 
19. Waterhouse J, Edwards B, Nevill A, Carvalho S, Atkinson G, Buckley P, Reilly T, Godfrey R 
925 
and Ramsay R. Identifying some determinants of “jet lag” and its symptoms: a study of 
926 
athletes and other travelers. Br J Sports Med 2002; 36: 54-60. 
927 
20. Colberg S, Bevier W, Pinsker J, Lee J-B, Ehrlich B, Dassau E, Doyle F, Chen K and Kerr D. 
928 
Short and Long Term Glycemic Impact of Sprinting in Type 1 Diabetes. J Diabetes Sci and 
929 
Technol 2015 ePub ahead of print December 30th. 
930 
21. Pinsker JE, Lee JB, Dassau E, Seborg DE, Bradley PK, Gondhalekar R, Bevier WC, Huyett 
931 
L, Zisser HC, Doyle FJ, 3rd. Randomized Crossover Comparison of Personalized MPC and 
932 
PID Control Algorithms for the Artificial Pancreas. Diabetes Care 2016; 39: 1135-42.  
933 
22. Pocellati F, Lucidi P, Cioli P, Candeloro P, Andreoli A, Marzotti S, Ambrogi M, Bolli G and 
934 
Fabelli C. Pharacokinetics and pharmacodynamics of insulin Glargine U100 given in the 
935 
evening as compared with in the morning in type 2 diabetes. Diabetes Care 2015; 38: 503-
936 
512. 
937 
23. Gold A, Macleod K and Frier B. Frequency of severe hypoglycemia in patients with type 1 
938 
diabetes with impaired awareness of hypoglycemia. Diabetes Care 1994; 17: 697-03. 
939 
24. Pinsker J, Becker E, Mahnke C, Ching M Larson and Roy D. Extensive clinical experience: a 
940 
simple guide to basal insulin adjustments for long distance travel. J Diabetes Metab Disorders 
941 
2013; 12: 59. 
942 


Version 2.0, January 18, 2019  
 
24 
 
25. Saskatchewan advanced insulin dose adjustment 
943 
module. http://www.health.gov.sk.ca/adx/aspx/adxGetMedia.aspx?DocID=97064501-e3e6–
944 
4220-be0c-94586997530f&MediaID=4670&Filename=sask-advanced-insulin-dose-
945 
adjustment-module-nov-2010.pdf&l=English  
946 
26. Battelino T, Conget I, Olsen B, Schutz-Fuhrmann I, Hommel E, Hoogma R, Schierloh U, 
947 
Sulli N, Bollinder J for the SWITCH study group. The use and efficacy of continuous glucose 
948 
monitoring in type 1 diabetes treated with insulin pump therapy: a randomized controlled trial. 
949 
Diabetologia 2012; 55: 3155-62. 
950 
27. Altman, D.G. Practical statistics for medical research.  1991. Chapman & Hall, London. 
951 
28. Polonsky, W. H., Fisher, L. Hessler, D., Edelman, S. V. Investigating Hypoglycemic 
952 
Confidence in Type 1 and Type 2 Diabetes. Diabetes Technol Ther. 2017; 19 (2):131-136. 
953 
29. Battelino, T., Danne T., Bergenstal R. M., et al. Clinical targets for continuous glucose 
954 
monitoring data interpretation: Recommendations from the International Consensus on Time 
955 
in Range. Diabetes Care 2019; dci190028. 
956 
30. Richardson, J. T. E. The analysis of 2x2 contingency tables – yet again. Statistics in Medicine 
957 
2011; 30:890. 
958 


Version 2.0, January 18, 2019  
 
25 
 
  
959 


Version 2.0, January 18, 2019  
 
26 
 
 
960 
 
961