Clinical trial NCT02660242
Conditions: Diabetes Mellitus, Type 1
Keywords: T1D Type 1 Diabetes Mini-dose Glucagon Adults Exercise Hypoglycemia
Sponsor: Jaeb Center for Health Research
Start date: 2016-01-01; Completion date: 2017-02-15
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This project focuses on development of new strategy for the prevention of exercise-associated hypoglycemia using mini-dose glucagon.

Detailed description:
The primary objective of the protocol is to determine if the administration of mini-dose glucagon administered subcutaneously just before exercise produces better glucose stability than no adjustments for moderate intensity exercise in patients with Type 1 Diabetes (T1D). It will also be assessed whether mini-dose glucagon before exercise produces better glucose stability than basal insulin reductions or extra carbohydrate consumption.

This is a randomized, 4-way crossover trial. The trial will include 16 participants who complete the study.

Each participant will undergo four aerobic exercise sessions (in random order), with different strategies for glucose regulation:

* Control Trial: Fasted exercise, no basal insulin reduction
* Strategy 1: Fasted exercise, basal insulin reduction only (50% reduction in basal rate at 60 minutes before exercise, for the duration of the exercise)
* Strategy 2: Fasted exercise, no basal adjustment + pre-exercise glucose tabs (buccal route-40 grams in total )
* Strategy 3: Fasted exercise, no basal adjustment + pre-exercise mini-dose glucagon (sc)

In all 4 sessions, aerobic exercise will be performed in the fasted state (before a standardized meal) for 45 minuets at \~50-55% of the participant's per-determined aerobic capacity. The participant's pump will be blinded during the control trial, strategy 1, and strategy 3 and an injection of saline will be given during the control trial and strategy 1 so that participant is blinded to strategy.

The primary outcome for this study will be the glycemic response during exercise and early recovery.

Arms: arm 1: No basal insulin adjustment, no carbohydrate intake (until glucose drops \<70 mg/dL). arm 2: Basal insulin reduction to 50% five minutes before the start of exercise. arm 3: Dextrose tabs orally (20 grams) five minutes before the start of exercise and at 30 minutes of exercise (total 40 grams). arm 4: Glucagon (150 µg) five minutes before the start of exercise (SQ-abdomen).
Interventions: intervention 1: G-Pen Mini™ (glucagon injection) intervention 2: Glucose Tabs intervention 3: Basal Insulin Reduction
Intervention descriptions: intervention 1: Glucagon (150 µg) 5 minutes before the start of exercise (SQ-abdomen). intervention 2: Dextrose tabs orally (20 grams) 5 minutes before the start of exercise and at 30 minutes of exercise (total 40 grams). intervention 3: Basal insulin reduction to 50% 5 minutes before the start of exercise.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
The Use of Mini-dose Glucagon to 
Prevent Exercise-induced 
Hypoglycemia in Type 1 Diabetes 
 
 
 
 
 
 
 
 
PROTOCOL 
 
 
 
 
 
 
Version 3.0 
April 14, 2016 


TABLE OF CONTENTS 
1 
 
2 
 
3 
CHAPTER 1: INTRODUCTION ................................................................................................ 4 
4 
1.1 
Study Background and Rationale ..................................................................................... 4 
5 
1.2 
Synopsis of Study Protocol .............................................................................................. 5 
6 
1.2.1 
Objectives ................................................................................................................. 5 
7 
1.2.2 
Study Design ............................................................................................................. 5 
8 
1.2.3 
Major eligibility criteria ............................................................................................ 5 
9 
1.2.4 
Visit Schedule ........................................................................................................... 5 
10 
1.2.5 
Primary Outcome ...................................................................................................... 6 
11 
1.2.6 
Main Safety Outcomes .............................................................................................. 6 
12 
1.3 
General Considerations .................................................................................................... 6 
13 
1.4 
Flow Chart of Exercise Sessions ...................................................................................... 7 
14 
CHAPTER 2: PARTICIPANT ELIGIBILITY AND ENROLLMENT .................................. 8 
15 
2.1 
Study Population .............................................................................................................. 8 
16 
2.2 
Eligibility .......................................................................................................................... 8 
17 
2.2.1 
Inclusion Criteria ...................................................................................................... 8 
18 
2.2.2 
Exclusion Criteria ..................................................................................................... 8 
19 
2.3 
Screening Visit and Patient Enrollment ........................................................................... 9 
20 
2.3.1 
Laboratory Testing .................................................................................................... 9 
21 
2.3.2 
Historical Information and Physical Exam ............................................................... 9 
22 
2.3.3 
Informed Consent...................................................................................................... 9 
23 
2.3.4 
T1D Exchange Clinic Registry ............................................................................... 10 
24 
CHAPTER 3: STUDY PROTOCOL ........................................................................................ 11 
25 
3.1 
Procedures Prior to First Exercise Session ..................................................................... 11 
26 
3.2 
Exercise Sessions ........................................................................................................... 11 
27 
3.2.1 
Prior to Exercise Sessions ....................................................................................... 11 
28 
3.2.2 
During Exercise Sessions ........................................................................................ 11 
29 
3.2.3 
Following Exercise Sessions................................................................................... 12 
30 
3.2.4 
Sample collection .................................................................................................... 13 
31 
CHAPTER 4: ADVERSE EVENT REPORTING AND SAFETY MONITORING............ 14 
32 


 
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4.1 
Adverse Event Reporting and Monitoring ..................................................................... 14 
33 
4.1.1 
Definition ................................................................................................................ 14 
34 
4.1.2 
Recording of Adverse Events ................................................................................. 14 
35 
4.1.3 
Reporting Serious or Unexpected Adverse Events ................................................. 15 
36 
4.2 Risks .................................................................................................................................... 16 
37 
4.2.1 Potential Risks and Side Effects .................................................................................. 16 
38 
CHAPTER 5: MISCELLANEOUS CONSIDERATIONS ..................................................... 18 
39 
5.1 
Benefits........................................................................................................................... 18 
40 
5.2 
Participant Compensation .............................................................................................. 18 
41 
5.2.1 
Participant Reimbursement ..................................................................................... 18 
42 
5.2.2 
Study Costs ............................................................................................................. 18 
43 
5.3 
Participant Withdrawal ................................................................................................... 18 
44 
5.4 
Confidentiality ................................................................................................................ 18 
45 
5.5 
Discontinuation of Study ................................................................................................ 19 
46 
CHAPTER 6: STATISTICAL CONSIDERATIONS ............................................................. 20 
47 
6.1 
Sample Size .................................................................................................................... 20 
48 
6.2 
Analysis Plan .................................................................................................................. 20 
49 
6.2.1 Primary Outcome ......................................................................................................... 20 
50 
6.2.2 Primary Analysis .......................................................................................................... 20 
51 
6.2.3 Secondary Outcomes ................................................................................................... 20 
52 
6.3 
Safety Analyses .............................................................................................................. 21 
53 
CHAPTER 7: DATA COLLECTION AND MONITORING ................................................ 23 
54 
7.1 
Data Collection ............................................................................................................... 23 
55 
7.2 
Quality Assurance and Monitoring ................................................................................ 23 
56 
 
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CHAPTER 1: INTRODUCTION 
58 
 
59 
The study is being conducted by the T1D Exchange Clinic Network and is being coordinated by 
60 
the Jaeb Center for Health Research in Tampa, Florida.   
61 
 
62 
1.1 Study Background and Rationale 
63 
Exercise is at the cornerstone of type 1 diabetes (T1D) management (1). However, blood glucose 
64 
stability during exercise, and for up to 12-24 hours in recovery, remains a major challenge (2). A 
65 
fear of hypoglycemia deters many patients from engaging in aerobic exercise (3). For those who 
66 
choose to exercise on a regular basis, hypoglycemia is a common complaint that often requires 
67 
breaks in sports and competition, games and training (1). To reduce the incidence of 
68 
hypoglycemia during and immediately after exercise, patients are recommended to reduce their 
69 
bolus dose at the meal preceding exercise by 25-75% (1), however, this approach frequently 
70 
results in pre-exercise hyperglycemia, particularly if the exercise is performed 2 hours or more 
71 
after the meal (2,4,5).  Even exercise in the fasting state in patients on continuous subcutaneous 
72 
insulin infusion (CSII) promotes a drop in glycemia if basal insulin levels are unadjusted (6). 
73 
 
74 
Post-exercise nocturnal hypoglycemia is also very common in T1D, with roughly 50% of young 
75 
patients developing the condition about 7-11 hours after the end of vigorous afternoon exercise 
76 
(7). If insulin administration occurs to correct post-exercise meal-related hyperglycemia (often 
77 
called rebound hyperglycemia), severe post-exercise hypoglycemia can occur which may even 
78 
result in death (8). Patients can reduce the dose of rapid-acting insulin administered with the 
79 
dinner meal after late day exercise to reduce nocturnal hypoglycemia risk (9) or lower basal 
80 
insulin delivery for 6 hours at bedtime (10) to help mitigate risk, but these strategies often result 
81 
in hyperglycemia (9, 10). Although extra carbohydrate ingestion not covered by insulin 
82 
administration can help prevent hypoglycemia during and after exercise (11), excessive intake 
83 
defeats the ability of the patient to have a negative caloric balance, thereby limiting the capacity 
84 
for patients to maintain or lose body weight. 
85 
 
86 
Patients on insulin pump therapy have the flexibility to reduce basal insulin delivery in 
87 
anticipation of exercise and in recovery to help guard against hypoglycemia. The International 
88 
Society for Pediatric and Adolescent Diabetes guidelines recommend that basal insulin 
89 
reductions should be done 60-90 minutes before the start of exercise so that circulating insulin 
90 
levels are lowered by the start of the activity (12). This is a somewhat cumbersome and 
91 
unpredictable task that is usually not performed correctly, even by the most educated and 
92 
motivated patients. Since glucose production by the liver during moderate intensity exercise is 
93 
primarily facilitated by a rise in the glucagon to insulin ratio (13) and patients with T1D have a 
94 
reduction in this ratio during exercise because of a relative peripheral hyperinsulinemia (13) and 
95 
impaired glucagon secretion (14), it may be better to attempt to change this ratio by the 
96 
administration of glucagon at the onset of exercise. The recent development of a more stable 
97 
form of soluble glucagon (e.g. G-Pen MiniTM glucagon from Xeris Pharmaceuticals, Inc.  
98 
(Xeris)) has given researchers and clinicians the possibility of using this product as a 
99 
preventative strategy to combat exercise-associated hypoglycemia. However, to date, studies 
100 
have not been done that examine the efficacy of mini-dose glucagon administration for exercise.  
101 
 
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1.2  Synopsis of Study Protocol 
103 
This project focuses on the development of a new strategy for the prevention of exercise-
104 
associated hypoglycemia using mini-dose glucagon.  
105 
 
106 
1.2.1 Objectives 
107 
The primary objective of the protocol is to determine if the administration of mini-dose glucagon 
108 
administered subcutaneously just before exercise produces better glucose stability than no 
109 
adjustments for moderate intensity exercise in patients with T1D.  It will also be assessed 
110 
whether mini-dose glucagon before exercise produces better glucose stability than basal insulin 
111 
reductions or extra carbohydrate consumption.  In addition, the impact of mini-dose glucagon 
112 
administration before exercise on nocturnal glycemia after exercise will be evaluated. 
113 
 
114 
1.2.2 Study Design 
115 
This is a randomized, 4-way crossover trial. 
116 
 
117 
1.2.3 Major eligibility criteria 
118 
 Clinical diagnosis of presumed autoimmune type 1 diabetes, receiving daily insulin  
119 
 Age 18-<65 years 
120 
 Duration of type 1 diabetes ≥2 years 
121 
 Random C-peptide < 0.6 ng/ml 
122 
 Using CSII (e.g., insulin pump) for at least 6 months 
123 
 Exercises regularly: i.e. ≥30 minutes moderate or more vigorous aerobic activity ≥3 
124 
times/week  
125 
 
126 
See section 2.2 for a complete listing of inclusion and exclusion criteria. 
127 
 
128 
1.2.4 Visit Schedule 
129 
1. Screening/Baseline Visit  
130 
o Sign informed consent form and assessment of eligibility 
131 
o Assessment of VO2max for fitness evaluation and for the determination of 
132 
exercise intensity for the experimental trials.  
133 
 
134 
2. Randomized Crossover Trial  
135 
Each participant will undergo four aerobic exercise sessions (in random order) in the 
136 
CRC, with different strategies for glucose regulation: 
137 
 Control Trial: Fasted exercise, no basal insulin reduction  
138 
 Strategy 1: Fasted exercise, basal insulin reduction only (50% reduction in basal rate 
139 
five minutes before exercise, for the duration of the exercise)  
140 
 Strategy 2: Fasted exercise, no basal adjustment + pre-exercise glucose tabs (buccal 
141 
route-40 grams in total )  
142 
 Strategy 3: Fasted exercise, no basal adjustment + pre-exercise mini-dose glucagon  
143 
(sc)  
144 
 
145 
In all 4 sessions, aerobic exercise will be performed in the fasted state (before a 
146 
standardized meal) for 45 minutes at ~50-55% of the participant’s pre-determined aerobic 
147 


 
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capacity (see flow chart in section 1.4). The strategies for select sessions will be blinded as 
148 
described in section 3.2.2. 
149 
 
150 
1.2.5 Primary Outcome 
151 
The primary outcome for this study will be the glycemic response during exercise and 
152 
early recovery. 
153 
 
154 
1.2.6 Main Safety Outcomes 
155 
 Hypoglycemic events 
156 
 Hyperglycemic events 
157 
 Dizziness, pallor and other symptoms of poor perfusion and/or exercise 
158 
intolerance 
159 
 
160 
1.3 General Considerations 
161 
The study is being conducted in compliance with the policies described in the study policies 
162 
document, with the ethical principles that have their origin in the Declaration of Helsinki, with 
163 
the protocol described herein, and with the standards of Good Clinical Practice. 
164 
 
165 
A risk-based monitoring approach will be followed, consistent with the FDA “Guidance for 
166 
Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring” (August 
167 
2013). 
168 
 
169 
The mini-dose glucagon preparation (G-Pen Mini™) is not FDA approved.  Therefore, an IND 
170 
(#119733) has been received from the FDA by Xeris in order to conduct the study. The Daily 
171 
Dose™ syringes used to inject the mini-dose glucagon are also not FDA approved in the U.S.  
172 
While use of the syringes will be considered investigational, the study investigators believe they 
173 
do not meet significant risk device criteria per 21 CFR 812.3(m) and thus an IDE from the FDA 
174 
is not needed. 
175 
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177 
 
178 
1.4 Flow Chart of Exercise Sessions 
179 
 
180 
 
181 
 
182 
 
183 
 
184 
 
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CHAPTER 2: PARTICIPANT ELIGIBILITY AND ENROLLMENT 
186 
 
187 
2.1 Study Population 
188 
The crossover trial will include 16 participants who complete the study.  Participants may be 
189 
replaced if a participant does not complete the entire protocol.  Each site is expected to have 8 
190 
participants completing the crossover trial, but this could be increased at a given site if necessary 
191 
to meet the recruitment goal. 
192 
 
193 
2.2 Eligibility 
194 
To be eligible for the study, a participant must meet the following inclusion criteria and none of 
195 
the exclusion criteria: 
196 
 
197 
2.2.1 Inclusion Criteria 
198 
1) Clinical diagnosis of presumed autoimmune type 1 diabetes, receiving daily insulin  
199 
2) Age 18-<65 years 
200 
3) Duration of T1D ≥ 2 years 
201 
4) Random C-peptide < 0.6 ng/ml 
202 
5) Using CSII (e.g., insulin pump) for at least 6 months, with no plans to discontinue pump 
203 
use during the study 
204 
6) Exercises regularly, i.e. ≥30 minutes moderate or more vigorous aerobic activity X ≥3 
205 
times/week  
206 
7) Body mass index (BMI) <30 kg/m2 
207 
8) Females must meet one of the following criteria: 
208 
a. Of childbearing potential and not currently pregnant or lactating, and agrees to 
209 
use an accepted contraceptive regimen as described in the study procedure manual 
210 
throughout the entire duration of the study; or 
211 
b. Of non-childbearing potential, defined as a female who has had a hysterectomy or 
212 
tubal ligation, is clinically considered infertile or is in a menopausal state (at least 
213 
1 year without menses) 
214 
9) In good general health with no conditions that could influence the outcome of the trial, 
215 
and in the judgment of the investigator is a good candidate for the study based on review 
216 
of available medical history, physical examination and clinical laboratory evaluations 
217 
10) Willing to adhere to the protocol requirements for the duration of the study 
218 
11) Must be enrolled in the T1D Exchange clinic registry or willing to join the registry 
219 
 
220 
 
221 
2.2.2 Exclusion Criteria 
222 
1) One or more severe hypoglycemic episodes in the past 12 months (as defined by an 
223 
episode that required third party assistance for treatment)  
224 
2) Active diabetic retinopathy (PDR or VH in past 6 months) that could potentially be 
225 
worsened by exercise protocol 
226 
3) Peripheral neuropathy with insensate feet 
227 
4) Cardiovascular autonomic neuropathy with inappropriate heart rate response to exercise 
228 
(could be diagnosed with screening EKG: rule out tachycardia with fixed RR interval) 
229 
5) Use of non-insulin anti-diabetic medications 
230 
6) Use of beta-blockers 
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7) Use of agents that affect hepatic glucose production such as beta adrenergic agonists, 
232 
xanthine derivatives 
233 
8) Use of Pramlintide 
234 
9) Currently following a very low calorie or other weight-loss diet 
235 
10) Participation in other studies involving administration of an investigational drug or 
236 
device within 30 days or 5 half-lives, whichever is longer, before screening for the 
237 
current study or  planning to participate in another such study during participation in the 
238 
current study  
239 
 
240 
2.3 Screening Visit and Patient Enrollment 
241 
Potential participants will have a screening visit to assess eligibility through the elicitation of a 
242 
medical history and performance of a physical examination by a study investigator. Screening labs 
243 
will be collected as outlined in section 2.3.1. A urine pregnancy test will be done for females with 
244 
child-bearing potential. Clinical sites will keep a record of the reason why screened participants 
245 
are not enrolled. 
246 
 
247 
2.3.1 Laboratory Testing 
248 
The following laboratory testing results, typically obtained as part of routine care, will be 
249 
assessed by the investigator as part of the general assessment for eligibility. Time periods prior to 
250 
enrollment for which each test should have been performed are given in parenthesis. 
251 
 Basic Metabolic Panel (within 3 months) 
252 
 Complete Blood Count (within 3 months) 
253 
 Liver Function Panel (within 6 months) 
254 
 Random C-peptide (since diagnosis, subjects must be < 0.6 ng/ml) 
255 
 Lipids (within 6 months) 
256 
 Thyroid-Stimulating Hormone (within 12 months) 
257 
 HbA1c will be measured using point-of-care device or local lab if not available within the 
258 
3 months prior to enrollment.  
259 
 Urine pregnancy test if indicated (see inclusion criteria) 
260 
 
261 
2.3.2 Historical Information and Physical Exam 
262 
A history will be elicited from the participant and extracted from available medical records with 
263 
regard to the participant’s diabetes history, current diabetes management, other past and current 
264 
medical problems, past and current medications, drug allergies, and family history.  A standard 
265 
physical exam (including vital signs and height and weight measurements) will be performed by 
266 
the study investigator or his or her designee (an endocrinologist, endocrine fellow, endocrine 
267 
nurse practitioner or a physician assistant).     
268 
 
269 
2.3.3 Informed Consent 
270 
The study will be discussed with potential participants.  A copy of the consent form will be 
271 
provided to the participant and another copy will be added to the participant’s clinic chart. 
272 
 
273 
Written informed consent will be obtained prior to performing any study-specific procedures that 
274 
are not part of the participant’s routine care. 
275 
 
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2.3.3.1 Authorization Procedures 
277 
As part of the informed consent process, each participant will be asked to sign an authorization 
278 
for release of personal information.  The investigator, or his or her designee, will review what 
279 
study specific information will be collected and to whom that information will be disclosed.  
280 
After speaking with the participant, questions will be answered about the details regarding 
281 
authorization. 
282 
 
283 
2.3.4 T1D Exchange Clinic Registry 
284 
If a participant is not already enrolled in the T1D Exchange clinic registry, he/she will become 
285 
part of the registry when joining this study.  Registry participants’ information from their 
286 
medical record may be entered into the registry database at least once a year and they will have 
287 
an opportunity to provide their email address to be contacted in the future about other studies for 
288 
which they may be eligible.  Participants also may be asked to complete a questionnaire(s) either 
289 
on a computer, paper, or via telephone.  Participants may be given the option to have 
290 
questionnaires emailed to them and may decide whether or not to complete a questionnaire each 
291 
time they are asked.  
292 
 
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CHAPTER 3: STUDY PROTOCOL 
294 
 
295 
3.1 Procedures Prior to First Exercise Session 
296 
 Assessment of VO2max following the Bruce protocol  
297 
 Optimization of basal insulin dose as per investigator’s usual routine 
298 
 
299 
3.2 Exercise Sessions 
300 
Each participant will be assigned to a sequence of control trial, strategy 1, strategy 2, and 
301 
strategy 3 through a randomization process as outlined in section 3.2.2.  Each exercise session 
302 
will be separated by at least 3 days and participants will be expected to complete all sessions 
303 
within 12 weeks from the time of the baseline/screening visit.  Participants will be advised to 
304 
avoid any vigorous exercise within 24 hours before or after the laboratory-based exercise tests. 
305 
Subjects will be asked about activity to monitor adherence to these recommendations. 
306 
 
307 
3.2.1 Prior to Exercise Sessions 
308 
The day before each exercise session participants will: 
309 
 Insert new insulin infusion set into abdomen or upper buttock (ensure not in exercising 
310 
limb). 
311 
 For CGM users, insert a new CGM sensor 
312 
 For non-CGM users, come into clinic to have a CGM sensor inserted to use with a 
313 
blinded receiver  
314 
 
315 
The participant will be contacted by the research staff on the evening before and the morning of 
316 
each exercise session to review glucose levels and help mitigate pre-exercise hyperglycemia or 
317 
hypoglycemia.  
318 
 If at the time of the morning call, the glucose concentration is below target (<100 
319 
mg/dL), then supplemental fast-acting carbohydrate will be taken. If above target (>140 
320 
mg/dL), then a conservative correction bolus will be recommended (based on insulin 
321 
sensitivity factor).   
322 
 
323 
The participant will arrive at the CRC in a fasted state (minimum of 8 hour fast) by 9 a.m., but 
324 
exercise sessions can begin as early as 8 a.m.   
325 
 Blood glucose concentration will be checked upon arrival to the clinic. Oral glucose or 
326 
IV glucose may be given to bring participant into range before exercise. 
327 
 Females will have a urine pregnancy test performed prior to each exercise session (if 
328 
applicable). 
329 
 
330 
 Before an exercise session can begin:  
331 
1. Participant glucose must be: 100- 140 mg/dL (venous, plasma) 
332 
2. Last insulin bolus (mealtime or correction) should be ≥3 hours previously 
333 
  
334 
3.2.2 During Exercise Sessions 
335 
At each visit, participants will complete one of the following four exercise sessions (sequence of 
336 
sessions determined by randomization): 
337 
 
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Control Trial:  No basal insulin adjustment, no carbohydrate intake until glucose drops <70 
339 
mg/dL.  Then 20 grams of dextrose will be given orally. 
340 
Strategy 1:  
Basal insulin reduction to 50% five minutes before the start of exercise. Basal 
341 
insulin rate will be returned to usual rate 45 minutes after the start of exercise.   
342 
Strategy 2: 
Dextrose tabs taken orally (20 grams) five minutes before the start of exercise and 
343 
at 30 minutes of exercise (total 40 grams). 
344 
Strategy 3*:  Glucagon (150 µg) five minutes before the start of exercise (SQ-abdomen). 
345 
 
346 
*The dose for strategy 3 will likely be 150 µg, but may be modified to be lower or higher, with a 
347 
possible range of 75-300 µg. One or more pilot phases of up to 6 participants will be conducted 
348 
prior to study initiation to determine the most appropriate dose.  
349 
 
350 
The participant’s pump will be blinded during the control trial, strategy 1, and strategy 3 and an 
351 
injection of saline will be given during the control trial and strategy 1 so that participant is 
352 
blinded to strategy.  
353 
 
354 
Exercise will consist of moderate intensity aerobic activity (treadmill jogging/brisk walking) 
355 
performed at 50-55% of predetermined VO2max for 45 minutes. Continuous heart rate 
356 
measurements will be conducted along with intermittent ratings of perceived exertion (Borg 6-20 
357 
scale). 
358 
 
359 
Exercise will be terminated if: 
360 
 Glucose is <70 mg/dL; participants will be treated for hypoglycemia (initially 20 grams 
361 
of oral dextrose tabs or IV dextrose or IM glucagon depending on the severity of the 
362 
hypoglycemia). 
363 
 Participants experience dizziness, pallor and other symptoms of poor perfusion and or 
364 
exercise intolerance 
365 
 
366 
Any treatment given will be recorded. 
367 
 
368 
Participants who are not able to complete an exercise session due to termination will still 
369 
complete remaining study procedures as outlined in sections 3.2.3 and 3.2.4. 
370 
 
371 
3.2.3 Following Exercise Sessions 
372 
Following each exercise session, the participant will rest for 30 minutes and then consume a 
373 
standardized meal containing 44-50 grams of carbohydrate that constitute ~55% of calories, 
374 
together with ~20% calories from protein and ~25% calories from fat. The amount of bolus 
375 
insulin given will be based on the carbohydrate content of the meal and the patient’s own 
376 
individualized insulin to carbohydrate ratio. Insulin will be administered five minutes before the 
377 
standardized meal. In the first phase of the experiments, insulin “corrections” will not be given 
378 
unless subjects have post exercise/ pre meal hyperglycemia ≥270 mg/dl. If hypoglycemia occurs 
379 
prior to the meal, subjects will be treated with 20 grams of fast acting carbohydrate prior to meal 
380 
consumption.  
381 
 
382 
The participant will be monitored for at least 2 hours after the meal prior to discharge. 
383 
 
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Participants will be given a meal log and another standardized meal to take with them at 
385 
discharge. Participants will be instructed to eat the standardized meal for their next meal and log 
386 
the time it was eaten. They will also be asked to log any meals they consume through noon the 
387 
following day. 
388 
 
389 
For participants using the blinded CGM, the sensor will be removed at 12PM the next day at 
390 
home (~ 24 hours after the end of exercise).  The participant will bring the device to the next 
391 
visit or mail it back to the clinic.   
392 
 
393 
Participants will receive a phone call the day after each exercise session to elicit any adverse 
394 
events. 
395 
 
396 
For CGM users, the CGM data will be downloaded at each visit and arrangements made to 
397 
transmit the data following the last exercise session. 
398 
 
399 
The participant’s insulin pump will be downloaded at each visit and arrangements made to 
400 
transmit the data following the last exercise session. 
401 
 
402 
3.2.4 Sample collection 
403 
Blood samples collected through a venous catheter with plasma glucose measured by an YSI 
404 
analyzer. Blood samples will be collected at:  
405 
 Baseline (at -30, -15, -5,  0 min)  
406 
 During exercise (at 5, 10, 15, 25, 35, 45 min) 
407 
 In recovery post exercise (at 50, 55, 60, 75 min) 
408 
 Regularly following a standardized mixed meal for 90 minutes (at 90, 105, 120, 135, and 
409 
165 min) 
410 
 
411 
Plasma from the collected blood samples will be used to measure the following hormones, 
412 
proinflammatory markers and metabolites at baseline, during exercise, in recovery post exercise, 
413 
and regularly following the standardized mixed meal: 
414 
 Insulin 
415 
 Glucagon  
416 
 Cortisol 
417 
 Growth hormone 
418 
 Catecholamines (epinephrine and norepinephrine)  
419 
 Interleukin-6, tumor necrosis factor-α 
420 
 Nonesterified fatty acids  
421 
 β-hydroxybutyrate 
422 
 Lactate 
423 
 
424 


 
 
mini-dose glucagon exercise protocol v3.0_04-14-16 clean      
Page 14 of 25 
 
CHAPTER 4: ADVERSE EVENT REPORTING AND SAFETY MONITORING 
425 
 
426 
4.1 Adverse Event Reporting and Monitoring 
427 
4.1.1 Definition 
428 
A reportable adverse event is any untoward medical occurrence in a study participant, irrespective 
429 
of whether or not the event is considered treatment-related, that occurs 12 hours prior, during, or the 
430 
day after each exercise session, except for hypoglycemia, hyperglycemia, injection-related, and 
431 
exercise-induced events which are only reported as adverse events when the criteria described 
432 
below are met. 
433 
 
434 
Hypoglycemic events are recorded as Adverse Events if the event required IV dextrose or IM 
435 
glucagon to treat.  
436 
 
437 
Hyperglycemic events are recorded as Adverse Events if evaluation or treatment was obtained from 
438 
a health care provider or if the event involved DKA, as defined by the Diabetes Control and 
439 
Complications Trial (DCCT) and described below, or in the absence of DKA if evaluation or 
440 
treatment was obtained from a health care provider or an acute event involving hyperglycemia or 
441 
ketosis. 
442 
 
443 
Hyperglycemic events are classified as DKA if all of the following are present:  
444 
 Symptoms such as polyuria, polydipsia, nausea, or vomiting  
445 
 Serum ketones >1.5 mmol/L or large/moderate urine ketones 
446 
 Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15  
447 
 Treatment provided in a health care facility  
448 
 
449 
Injection-related events are recorded as Adverse Events if sufficiently severe that treatment was 
450 
given. 
451 
 
452 
Exercise-induced events are recorded as Adverse Events if the subject falls during the exercise 
453 
protocol or develops signs or symptoms of a myocardial infarction, poor perfusion (pallor, 
454 
cyanosis), angina, pathologic arrhythmia, or another medical condition not expected to occur during 
455 
or following the exercise.     
456 
 
457 
4.1.2 Recording of Adverse Events 
458 
Throughout the course of the study, all efforts will be made to remain alert to possible adverse 
459 
events or untoward findings.   
460 
 
461 
All adverse events whether volunteered by the participant, discovered by study personnel during 
462 
questioning, or detected through physical examination, laboratory test, or other means will be 
463 
reported on a web-based case report form specifically for adverse event reporting. 
464 
 
465 
The study investigator will assess the relationship of each adverse event to be related or unrelated to 
466 
study drug by determining if there is a reasonable possibility that the adverse event may have been 
467 
caused by the treatment.  Reasonable possibility is not the same as “any possibility.”   The 
468 
following should be considered when evaluating the relationship: 
469 
• 
Timing of event 
470 
• 
Patient’s history 
471 


 
 
mini-dose glucagon exercise protocol v3.0_04-14-16 clean      
Page 15 of 25 
 
• 
Prevalence of finding in population at risk 
472 
• 
Other possible causes - diseases, exposures, therapies, etc 
473 
• 
Known pharmacology of study drug (and control) or side effect of drug 
474 
 
475 
The intensity of adverse events will be rated on a three-point scale: (1) mild, (2) moderate, or (3) 
476 
severe.  It is emphasized that the term severe is a measure of intensity: thus, a severe adverse event 
477 
is not necessarily serious. For example, itching for several days may be rated as severe, but may not 
478 
be clinically serious. 
479 
Adverse events that continue after the study participant’s discontinuation or completion of the study 
480 
will be followed until their medical outcome is determined or until no further change in the 
481 
condition is expected.   
482 
Each reported adverse event is reviewed by the Medical Monitor to verify the coding and the 
483 
reporting that is required.  Adverse events will be coded using the MedDRA dictionary.  
484 
 
485 
4.1.3 Reporting Serious or Unexpected Adverse Events 
486 
A serious adverse event is any untoward occurrence that: 
487 
 Results in death 
488 
 Is life-threatening (a non-life-threatening event which, had it been more severe, might have 
489 
become life-threatening, is not necessarily considered a serious adverse event) 
490 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
491 
 Results in significant disability/incapacity  
492 
 Is a congenital anomaly/birth defect 
493 
 Could have resulted in death, be life-threatening, or require hospitalization without medical 
494 
or surgical intervention to prevent any of these events 
495 
 
496 
Serious or unexpected adverse events must be reported to the Coordinating Center immediately via 
497 
completion of the online serious adverse event form.   
498 
 
499 
The Medical Monitor responsible for reviewing serious or unexpected adverse events is: 
500 
 
501 
Roy W. Beck, M.D., Ph.D. 
502 
Jaeb Center for Health Research 
503 
15310 Amberly Drive, Suite 350 
504 
Tampa, FL  33647 
505 
Phone:  (813) 975-8690 
506 
Fax: (888) 795-2859 
507 
Email: rbeck@jaeb.org 
508 
 
509 
The Coordinating Center will notify all participating investigators of any adverse event that is 
510 
serious, related to the study drug or procedures, and unexpected.  Notification will be made within 
511 
10 days after the Coordinating Center becomes aware of the event. The Coordinating Center also 
512 
will notify Xeris of any such events, who will be responsible for fulfilling reporting requirements to 
513 
the Food and Drug Administration (FDA). 
514 


 
 
mini-dose glucagon exercise protocol v3.0_04-14-16 clean      
Page 16 of 25 
 
Each principal investigator is responsible for informing his/her IRB of serious, related, and 
515 
unexpected adverse events and abiding by any other reporting requirements specific to his/her IRB.  
516 
 
517 
4.2 Risks 
518 
4.2.1 Potential Risks and Side Effects 
519 
Glucagon has a long history of medical use in the U.S., and is currently marketed by Eli Lilly & Co. 
520 
as Glucagon for Injection [rDNA origin], and Novo Nordisk as GlucaGen® HypoKit®, both 
521 
reference listed drugs for treatment of severe hypoglycemia. Glucagon has a rapid onset of action 
522 
and an extremely short half-life, and its safety, efficacy and clinical pharmacology have been well 
523 
established.  
524 
 
525 
In a Phase 2 study, Protocol No. XSGP-201, healthy, fasted adult volunteers were administered 
526 
rescue doses of Xeris G-Pen™ (glucagon injection) (0.5 mg and 1.0 mg) and Lilly Glucagon for 
527 
Injection [rDNA origin] (1.0 mg) in a randomized, crossover fashion.  Overall, all Xeris and Lilly 
528 
treatments were well tolerated.  There were no SAEs during the study, and all AEs observed were 
529 
transient and generally expected with rescue injections of glucagon.  The most commonly reported 
530 
AE was injection site pain, and the incidence of this AE was significantly higher in the Xeris 0.5 mg 
531 
and Xeris 1 mg groups compared with the Lilly 1 mg group; however, edema and erythema at the 
532 
injection site occurred infrequently and did not vary significantly with treatment.  Within the Lilly 1 
533 
mg group, the most commonly reported AE was nausea, the incidence of which was significantly 
534 
higher compared with the Xeris 0.5 mg and 1 mg groups.  The incidences of all remaining AEs 
535 
were low and not notably different across treatment groups. 
536 
 
537 
However, as reported by Haymond (15), when subcutaneous glucagon in dosages of 20–150 μg was 
538 
given to children to manage impending hypoglycemia due to gastroenteritis or poor oral intake of 
539 
carbohydrates, it did not result in a perceived worsening of the patient’s nausea, nor did it result in 
540 
emesis immediately after glucagon administration, as is commonly observed with the recommended 
541 
single large 500–1,000 μg rescue dose.   
542 
 
543 
In Xeris’ completed Phase 2a safety/PK/PD study, Protocol No. XSMP-201, which tested 75–300 
544 
μg G-Pen Mini™ doses in adult T1D patients, neither nausea nor vomiting were observed with 
545 
doses of 75-150 μg. Nausea, but not vomiting was reported by 4/12 subjects given the 300 μg dose 
546 
(3 mild, 1 moderate).  Since doses of subcutaneous G-Pen Mini™ (glucagon injection) given to 
547 
adults per this protocol will range from 75–300 μg, some nausea is possible, but the incidence is 
548 
expected to be relatively low and severe nausea is not expected. 
549 
Although available data from prior studies indicate that mini-dose glucagon is likely to successfully 
550 
treat mild to moderate hypoglycemia, this is not definitively proven. Therefore, there is a risk that 
551 
mini-dose glucagon will not work as well as glucose tablets or other oral carbohydrates and if this is 
552 
the case, severe hypoglycemia could result.    
553 
Endurance exercise, as will be performed in this study, may be associated with generalized fatigue 
554 
and mild to moderate hypoglycemia. In rare situations, exercise can promote myocardial infarction, 
555 
sudden cardiac death or arrhythmias. In persons who have proliferative retinopathy, exercise that 
556 
increases blood pressure significantly (>180 mmHg) can promote retinal bleeding (PMID: 
557 
21800941). Since all participants will be screened prior to the exercise test for diabetes-related 
558 
complications and glucose monitoring will be performed throughout the experiments, the risk of a 
559 
serious exercise-associated adverse event will be extremely remote.    
560 
 
561 


 
 
mini-dose glucagon exercise protocol v3.0_04-14-16 clean      
Page 17 of 25 
 
The blood draws and IV placement could result in discomfort or bruising, or rarely, an infection or a 
562 
blood clot.  Fainting may also occur. The exact blood volumes collected may vary according to 
563 
local IRB regulations.  The maximum blood volume collected from adults >18 years will not exceed 
564 
250 ml at each visit. 
565 
 
566 
 
 
567 


 
 
mini-dose glucagon exercise protocol v3.0_04-14-16 clean      
Page 18 of 25 
 
CHAPTER 5: MISCELLANEOUS CONSIDERATIONS 
568 
 
569 
5.1 Benefits 
570 
Participants may benefit by gaining a better understanding of how to prevent exercise-associated 
571 
hypoglycemia. 
572 
 
573 
5.2  Participant Compensation 
574 
5.2.1 Participant Reimbursement 
575 
The participant will receive $100 for the screening visit/VO2 max testing and $225 for each exercise 
576 
session. Participants will receive compensation for transportation to and from each exercise session. 
577 
Participants who participate in the pilot phase will receive $100 for the screening visit/ VO2 max 
578 
testing and $100 for each exercise session that is part of the pilot.  Participant compensation will be 
579 
paid by check, merchandise gift card or money card. 
580 
 
581 
Additional travel expenses may be paid in select cases for participants with higher expenses. 
582 
 
583 
5.2.2 Study Costs 
584 
All study costs will be covered by the study.  The participant will use his/her own pump, blood 
585 
glucose meter, and CGM (if used).  The participant will be asked to insert a new infusion set on the 
586 
day prior to each exercise session and if CGM is used, a new CGM sensor.  The participant will also 
587 
be asked to perform additional blood glucose meter checks.  Participants will be permitted to 
588 
request reimbursement through their site for any CGM sensors, infusion sets, or blood glucose 
589 
meter strips required specifically for the purpose of the study. 
590 
 
591 
5.3 Participant Withdrawal 
592 
Participation in the study is voluntary, and a participant may withdraw at any time.  The investigator 
593 
may withdraw a participant who is not complying with the protocol. For participants who withdraw 
594 
or are withdrawn, their data will be used up until the time of withdrawal. 
595 
 
596 
Participants will not be withdrawn from the study if the study drug is discontinued due to adverse 
597 
events. 
598 
 
599 
5.4 Confidentiality 
600 
For security and confidentiality purposes, participants will be assigned an identifier that will be used 
601 
instead of their name.  Protected health information gathered for this study will be shared with the 
602 
Coordinating Center, the Jaeb Center for Health Research in Tampa, FL.  Information also may be 
603 
provided to Xeris, Inc which is providing the glucagon for the study, and Unitio, Inc., which is a 
604 
T1D Exchange collaborating organization. 
605 
 
606 
Some of the study data will be entered on the Coordinating Center’s secure website through an SSL 
607 
encrypted connection. The Coordinating Center websites are maintained on Unix and Linux servers 
608 
running Apache web server software and on a Windows server running IIS, all with strong 
609 
encryption. The study website is password-protected and restricted to users who have been 
610 
authorized by the Coordinating Center to gain access. No identifiable health information of an 
611 
enrolled participant will be released by the Coordinating Center. 
612 
 
613 


 
 
mini-dose glucagon exercise protocol v3.0_04-14-16 clean      
Page 19 of 25 
 
5.5 Discontinuation of Study 
614 
Participation of a participant can be discontinued at any time at discretion of the investigator, 
615 
particularly if the investigator believes that there is a safety concern with continued participation. 
616 
 
617 
The study can be stopped by the Steering Committee if events occur that warrant discontinuation of 
618 
the study.  
619 
 
620 


 
 
mini-dose glucagon exercise protocol v3.0_04-14-16 clean      
Page 20 of 25 
 
CHAPTER 6: STATISTICAL CONSIDERATIONS 
621 
 
622 
The approach to sample size and statistical analyses are summarized below.  A detailed statistical 
623 
analysis plan will be written and finalized prior to the completion of the study. 
624 
 
625 
6.1 Sample Size 
626 
A target of 16 subjects, with replacement of any participants who do not complete the study, was 
627 
selected as a reasonable sample size for this feasibility study. Considering the primary outcome of 
628 
glucose, power was approximated using a t-test.  The table below provides power estimates based 
629 
on a paired t-test comparing glucose during the mini-dose glucagon treatment and glucose during 
630 
the control treatment.  
631 
 
632 
Power Estimates* 
633 
Mean 
difference 
(mg/dL) 
Correlation 
 
0.2 
0.3 
0.4 
0.5 
0.6 
0.7 
0.8 
20 
32% 
35% 
40% 
47% 
55% 
68% 
84% 
25 
46% 
51% 
57% 
65% 
74% 
85% 
96% 
30 
60% 
66% 
73% 
80% 
88% 
95% 
99% 
35 
74% 
79% 
85% 
91% 
96% 
99% 
>99% 
*Power was calculated for a sample size of 16 participants with a two-sided alpha of 0.05 and assuming a standard 
634 
deviation of 40 mg/dL for each treatment. (A previous DirectNet exercise study was considered when estimating 
635 
standard deviation [16].) 
636 
 
637 
6.2 Analysis Plan 
638 
 
 
639 
6.2.1 Primary Outcome 
640 
The primary outcome for this study will be glucose, as measured by YSI analysis, during exercise 
641 
and early recovery.  
642 
 
643 
6.2.2 Primary Analysis 
644 
The primary analysis for this study will be a descriptive comparison of glycemic response during 
645 
exercise and early recovery between the mini-dose glucagon group (strategy 3) and the control 
646 
group. Summary statistics will be calculated. In the event that exercise is terminated early due to 
647 
glucose <70 mg/dL and the participant is treated for hypoglycemia, the nadir glucose value will be 
648 
carried forward through early recovery.  
649 
 
650 
To obtain a test of significance, a treatment comparison of glucose during exercise and early 
651 
recovery will be completed using a linear mixed model with repeated measures that accounts for the 
652 
correlation due to the cross-over design and the correlation due to multiple measures, adjusting for 
653 
baseline glucose level and period.  Regression diagnostics will be performed and if the distribution 
654 
of residuals is skewed, non-parametric methods and transformations will be considered. 
655 
 
656 
6.2.3 Secondary Outcomes 
 
657 
The following outcome measures will also be analyzed.  
658 
 Occurrence of hypoglycemia (<70 mg/dL) as measured by YSI analysis during exercise or 
659 
early recovery 
660 


 
 
mini-dose glucagon exercise protocol v3.0_04-14-16 clean      
Page 21 of 25 
 
 Occurrence of hyperglycemia (≥270 mg/dL) as measured by YSI analysis in the following 
661 
time periods: during exercise, after exercise in early recovery/prior to meal ingestion and for 
662 
90 minutes after the meal (2 hours after the end of exercise)  
663 
 Glucose levels during exercise and early recovery (venous plasma) 
664 
 Glucose levels after a standardized meal (glucose area under the curve analysis, venous 
665 
plasma) 
666 
 Glucose levels in late recovery (afternoon and overnight following the exercise protocols-
667 
CGM analysis) 
668 
o Mean 
669 
o Nadir 
670 
o Area above and below curve threshold (i.e. area above or below 70-180 mg/dL) 
671 
o % of time in range (70-180 mg/dL) 
672 
o % of time below 70 mg/dL 
673 
o Occurrence of hypoglycemia (<70 mg/dL) overnight 
674 
 Carbohydrate intake (before, during and for 30 min post exercise) 
675 
 HR and ratings of perceived exertion 
676 
 Insulin and glucose counterregulatory hormones (glucagon, GH, catecholamines, cortisol) 
677 
 Inflammatory cytokines (TNFα, IL-6) 
678 
 Metabolites (nonesterified fatty acids, β-hydroxybuterate, lactate) 
679 
 
680 
 
681 
6.2.4 Secondary Analyses 
 
682 
The primary and secondary outcomes will largely be examined in a descriptive manner. Summary 
683 
statistics will be calculated by treatment strategy. For binary variables, percentage of participants 
684 
developing the outcome, with 95% confidence interval, will be calculated by strategy. Each of the 
685 
three strategies will be compared to the control in secondary analyses.  
686 
 
687 
Tests of significance will also be obtained using a 2-sided alpha of 0.05. For binary variables, a 
688 
generalized linear mixed model with a logistic link function for a binary outcome will be fit to 
689 
assess differences between strategy 3 and each of the other strategies.  The model will be adjusted 
690 
for baseline glucose and period. For continuous variables, repeated measures linear regression 
691 
models will be fit adjusting for period and where applicable the baseline value. Regression 
692 
diagnostics will be performed and if the distribution of residuals is skewed, non-parametric methods 
693 
and transformations will be considered.  No formal correction will be made for multiple 
694 
comparisons. 
695 
 
696 
6.3 Safety Analyses 
697 
Adverse events will be tabulated by strategy:    
698 
 Proportion reporting at least one adverse event 
699 
 Proportion with an adverse event thought by investigator to be related to strategy 
700 
 Proportion who stopped study treatment in response to an adverse event 
701 
 Total number of adverse events reported 
702 
 Number of serious adverse events reported 
703 
 Number of non-serious adverse events reported 
704 
 
705 


 
 
mini-dose glucagon exercise protocol v3.0_04-14-16 clean      
Page 22 of 25 
 
Adverse events will be tabulated by MedDRA categories with frequencies compared between 
706 
strategies.  Similar models and diagnostics will be performed as described for the efficacy outcomes 
707 
above. 
708 
 
709 
 
710 


 
 
mini-dose glucagon exercise protocol v3.0_04-14-16 clean      
Page 23 of 25 
 
CHAPTER 7: DATA COLLECTION AND MONITORING 
711 
 
712 
7.1 Data Collection 
713 
Data will be collected directly on electronic case report forms and will be considered source 
714 
documents when data are directly entered.  Other data will be collected from participant logs, 
715 
downloads of devices and from laboratories processing the samples. 
716 
 
717 
7.2 Quality Assurance and Monitoring 
718 
Designated personnel from the Coordinating Center will be responsible for maintaining quality 
719 
assurance (QA) and quality control (QC) systems to ensure that the trial is conducted and data 
720 
are generated, documented and reported in compliance with the protocol, GCP and the applicable 
721 
regulatory requirements.  
722 
 
723 
A risk-based monitoring (RBM) plan will be developed and revised as needed during the course 
724 
of the study.  The RBM plan will focus mainly on data related to eligibility, adverse events and 
725 
the primary efficacy analysis.  As much as possible, remote monitoring will be performed in 
726 
real-time, with on-site monitoring performed to evaluate the verity and completeness of the key 
727 
site data. 
728 
 
729 
Xeris, the Jaeb Center for Health Research, or their representatives may visit the study facilities 
730 
at any time in order to maintain current and personal knowledge of the study through review of 
731 
the records, comparison with source documents, observation and discussion of the conduct and 
732 
progress of the study.  
733 
 
734 
735 


 
 
mini-dose glucagon exercise protocol v3.0_04-14-16 clean      
Page 24 of 25 
 
CHAPTER 8: REFERENCES 
736 
 
737 
1) Chu L, Hamilton J, Riddell MC (2011) Clinical management of the physically active patient 
738 
with type 1 diabetes. Physiol Sports Med 39: 64–77. 
739 
 
740 
2) West DJ, Morton RD, Bain SC, Stephens JW, Bracken RM (2010) Blood glucose responses 
741 
to reductions in pre-exercise rapid-acting insulin for 24 h after running in individuals with 
742 
type 1 diabetes. J Sports Sci 28: 781–788. 
743 
 
744 
3) Brazeau AS, Rabasa-Lhoret R, Strychar I, Mircescu H. Barriers to physical activity among 
745 
patients with type 1 diabetes. Diabetes Care. 2008 Nov;31(11):2108-9. 
746 
 
747 
4) Rabasa-Lhoret R, Bourque J, Ducros F, Chiasson JL (2001) Guidelines for premeal insulin 
748 
dose reduction for postprandial exercise of different intensities and durations in type 1 
749 
diabetic subjects treated intensively with a basal-bolus insulin regimen (ultralente-lispro). 
750 
Diabetes Care 24: 625–630. 
751 
 
752 
5) Campbell MD, Walker M, Trenell MI, Jakovljevic DG, Stevenson EJ, et al. (2013) Large 
753 
Pre-and Postexercise Rapid-Acting Insulin Reductions Preserves Glycemia and Prevents 
754 
Early-but Not Late-Onset Hypoglycemia in Patients With Type 1 Diabetes. Diabetes Care 
755 
36: 2217–2224. 
756 
 
757 
6) Stenerson M, Cameron F, Payne SR, Payne SL, Ly TT, Wilson DM, Buckingham BA. The 
758 
Impact of Accelerometer Use in Exercise-Associated Hypoglycemia Prevention in Type 1 
759 
Diabetes. J Diabetes Sci Technol. 2014 Sep 17. pii: 1932296814551045.[Epub ahead of 
760 
print] PubMed PMID: 25231116. 
761 
 
762 
7) Tsalikian E, Mauras N, Beck RW, Tamborlane WV, Janz KF, Chase HP, Wysocki T, 
763 
Weinzimer SA, Buckingham BA, Kollman C, Xing D, Ruedy KJ; Diabetes Research In 
764 
Children Network Direcnet Study Group. Impact of exercise on overnight glycemic control 
765 
in children with type 1 diabetes mellitus. J Pediatr. 2005 Oct;147(4):528-34. 
766 
 
767 
8) Tanenberg RJ, Newton CA, Drake AJ. Confirmation of hypoglycemia in the "dead-in-bed" 
768 
syndrome, as captured by a retrospective continuous glucose monitoring system. Endocr 
769 
Pract. 2010 Mar-Apr;16(2):244-8. 
770 
 
771 
9) Campbell MD, Walker M, Trenell MI, Luzio S, Dunseath G, Tuner D, Bracken RM, Bain 
772 
SC, Russell M, Stevenson EJ, West DJ. Metabolic implications when employing heavy pre- 
773 


 
 
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Page 25 of 25 
 
and post-exercise rapid-acting insulin reductions to prevent hypoglycaemia in type 1 
774 
diabetes patients: a randomised clinical trial. PLoS One. 2014 May 23;9(5):e97143. 
775 
 
776 
10) Taplin CE, Cobry E, Messer L, McFann K, Chase HP, Fiallo-Scharer R. Preventing post-
777 
exercise nocturnal hypoglycemia in children with type 1 diabetes. J Pediatr.2010 
778 
Nov;157(5):784-8 .e1. doi: 10.1016/j.jpeds.2010.06.004. 
779 
 
780 
11) Riddell MC, Bar-Or O, Ayub BV, Calvert RE, Heigenhauser GJ. Glucose ingestion matched 
781 
with total carbohydrate utilization attenuates hypoglycemia during exercise in adolescents 
782 
with IDDM. Int J Sport Nutr. 1999 Mar;9(1):24-34.  
783 
 
784 
12) Robertson K, Riddell MC, Guinhouya BC, Adolfsson P, Hanas R. Exercise in children and 
785 
adolescents with diabetes. Pediatr Diabetes. 2014 Sep;15 Suppl 20:203-23. doi: 
786 
10.1111/pedi.12176. 
787 
 
788 
13) Camacho RC, Galassetti P, Davis SN, Wasserman DH. Glucoregulation during and after 
789 
exercise in health and insulin-dependent diabetes. Exerc Sport Sci Rev. 2005 Jan;33(1):17-
790 
23. 
791 
 
792 
14) Oskarsson PR, Lins PE, Wallberg Henriksson H, Adamson UC. Metabolic and hormonal 
793 
responses to exercise in type 1 diabetic patients during continuous subcutaneous, as 
794 
compared to continuous intraperitoneal, insulin infusion. Diabetes Metab. 1999 
795 
Dec;25(6):491-7. 
796 
 
797 
15) Haymond MW, Schreiner B. Mini-dose glucagon rescue for hypoglycemia in children with 
798 
type 1 diabetes. Diabetes Care. 2001;24:643-5. 
799 
 
800 
16)  Tsalikian E, Kollman C, Tamborlane WB, Beck RW, Fiallo-Scharer R, Fox L, et al; 
801 
Diabetes Research In Children Network Direcnet Study Group. Prevention of hypoglycemia 
802 
during exercise in children with type 1 diabetes by suspending basal insulin. Diabetes Care. 
803 
2006; 29:2200-4. 
804 

SAP_001.pdf: 
 
 
 
Page 1 of 7 
MDG Exercise Study Primary SAP V1.0 2-24-17 
 
 
              
 
 
1 
 
2 
THE USE OF MINI-DOSE GLUCAGON TO 
PREVENT EXERCISE-INDUCED 
HYPOGLYCEMIA IN TYPE 1 DIABETES  
 
 
 
 
 
Statistical Analysis Plan v. 1.0 
Protocol v. 3.0 
 
 
 
 
February 24, 2017 
 
 
3 


 
 
 
Page 2 of 7 
MDG Exercise Study Primary SAP V1.0 2-24-17 
Version History 
 
Version 
Number 
Author 
Approver 
Effective 
Date 
Study Stage 
Revision Description   
1.0 
Stephanie 
DuBose 
Craig 
Kollman 
February 
24, 2017 
Data collection 
in progress; no 
analyses 
performed 
Original version 
 
4 
 
 
5 


 
 
 
Page 3 of 7 
MDG Exercise Study Primary SAP V1.0 2-24-17 
1.0 Study Overview 
6 
This project focuses on the development of a new strategy for the prevention of exercise-
7 
associated hypoglycemia using mini-dose glucagon.  
8 
 
9 
The primary objective of the protocol is to determine if the administration of mini-dose glucagon 
10 
administered subcutaneously just before exercise produces better glucose stability than no 
11 
adjustments for moderate intensity exercise in patients with T1D.  It will also be assessed 
12 
whether mini-dose glucagon before exercise produces better glucose stability than basal insulin 
13 
reductions or extra carbohydrate consumption.   
14 
 
15 
Subjects 18 to <65 years old with type 1 diabetes (T1D) for at least 2 years and receiving daily 
16 
insulin who exercise regularly will be enrolled into the multi-center study.  The study is a 
17 
randomized, 4-way crossover trial.  
18 
 
19 
Each participant will undergo four aerobic exercise sessions (in random order) in the 
20 
CRC, with different strategies for glucose regulation: 
21 
 Control Trial: Fasted exercise, no basal insulin reduction  
22 
 Strategy 1: Fasted exercise, basal insulin reduction only (50% reduction in basal rate 
23 
five minutes before exercise, for the duration of the exercise)  
24 
 Strategy 2: Fasted exercise, no basal adjustment + pre-exercise glucose tabs (buccal 
25 
route-40 grams in total )  
26 
 Strategy 3: Fasted exercise, no basal adjustment + pre-exercise mini-dose glucagon  
27 
(sc)  
28 
 
29 
In all 4 sessions, aerobic exercise will be performed in the fasted state (before a 
30 
standardized meal) for 45 minutes at ~50-55% of the participant’s pre-determined aerobic 
31 
capacity (determined by VO2 max test at screening visit). 
32 
 
33 
2.0 Sample Size 
34 
A target of 16 subjects, with replacement of any participants who do not complete the study, was 
35 
selected as a reasonable sample size for this feasibility study. Considering the primary outcome 
36 
of glucose, power was approximated using a t-test.  The table below provides power estimates 
37 
based on a paired t-test comparing glucose during the mini-dose glucagon treatment and glucose 
38 
during the control treatment.  
39 
 
40 
Power Estimates* 
41 
Mean 
difference 
(mg/dL) 
Correlation 
 
0.2 
0.3 
0.4 
0.5 
0.6 
0.7 
0.8 
20 
32% 
35% 
40% 
47% 
55% 
68% 
84% 
25 
46% 
51% 
57% 
65% 
74% 
85% 
96% 
30 
60% 
66% 
73% 
80% 
88% 
95% 
99% 
35 
74% 
79% 
85% 
91% 
96% 
99% 
>99% 


 
 
 
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MDG Exercise Study Primary SAP V1.0 2-24-17 
*Power was calculated for a sample size of 16 participants with a two-sided alpha of 0.05 and assuming a standard 
42 
deviation of 40 mg/dL for each treatment. (A previous DirectNet exercise study was considered when estimating 
43 
standard deviation [Tsalikian 2006]. 
44 
 
45 
3.0 Analysis Plan  
46 
 
47 
3.1 Sample collection 
48 
Blood samples collected through a venous catheter with plasma glucose measured by an YSI 
49 
analyzer. Blood samples will be collected at:  
50 
 Baseline (at -30, -15, -5,  0 min)  
51 
 During exercise (at 5, 10, 15, 25, 35, 45 min) 
52 
 In recovery post exercise (at 50, 55, 60, 75 min) 
53 
 Regularly following a standardized mixed meal for 90 minutes (at 90, 105, 120, 135, and 
54 
165 min) 
55 
 
56 
3.2 Definitions of Time Periods 
57 
 Exercise—45 minutes of scheduled exercise, even if participant terminated exercise early 
58 
 Early recovery—all time points through 30 minutes post exercise session 
59 
 Late recovery—all CGM data through noon the day after each exercise session will be 
60 
included. Periods of interest during late recovery include the below. Timing of meals 
61 
indicated on participant log; if log is missing or incomplete, meal timing will be 
62 
estimated. 
63 
o Standard meal during study (30 minutes post exercise) to standard box lunch 
64 
provided at discharge 
65 
o Box lunch provided at discharge to dinner (of participant’s choice) 
66 
o Dinner to 10:00 PM 
67 
o 10:00 PM to 8:00 AM the day following exercise 
68 
o 8:00 AM to noon the day following exercise   
69 
 
70 
3.3 Primary Outcome 
71 
The primary outcome for this study will be glucose, as measured by YSI analysis, during 
72 
exercise and early recovery.  
73 
 
74 
3.3.1 Primary Analysis 
75 
The primary analysis for this study will be a descriptive comparison of glycemic response during 
76 
exercise and early recovery between the mini-dose glucagon group (strategy 3) and the control 
77 
group. Summary statistics will be calculated. In the event that exercise is terminated early due to 
78 
glucose <70 mg/dL and the participant is treated for hypoglycemia (or if participant is treated for 
79 
hypoglycemia during early recovery [prior to the meal]), the nadir glucose value will be carried 
80 
forward through the end of early recovery.  
81 
 
82 
Analysis will follow the intent-to-treat principle with each visit allocated to one of the above 
83 
strategies (Section 1.0) according to the randomization assignment. Analysis will include 
84 
subjects who completed both the mini-dose glucagon and the control exercise session visits with 
85 
baseline glucose and at least three YSI glucose measurements during exercise and at least two 
86 
YSI glucose measurements during early recovery available from each visit.   
87 
 
88 


 
 
 
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MDG Exercise Study Primary SAP V1.0 2-24-17 
To obtain a test of significance, a treatment comparison of glucose during exercise and early 
89 
recovery will be completed using a linear mixed model with repeated measures that accounts for 
90 
the correlation due to the cross-over design and the correlation due to multiple measures, 
91 
adjusting for baseline glucose level and any period effect.  Regression diagnostics will be 
92 
performed and if the distribution of residuals is skewed, non-parametric methods and 
93 
transformations will be considered. 
94 
 
95 
3.4 Secondary Outcomes 
 
96 
The following outcome measures will also be analyzed.  
97 
 Occurrence of hypoglycemia (<70 mg/dL) as measured by YSI analysis during exercise 
98 
or early recovery, at the visit level 
99 
 Occurrence of hyperglycemia (≥250 mg/dL) as measured by YSI analysis in the 
100 
following time periods: during exercise, after exercise in early recovery/prior to meal 
101 
ingestion and for 90 minutes after the meal (2 total hours after the end of exercise), at the 
102 
visit level  
103 
 Glucose levels after a standardized meal (glucose area under the curve analysis) 
104 
 Glucose levels in late recovery (afternoon and overnight following the exercise protocols-
105 
CGM analysis) 
106 
o Mean 
107 
o Nadir 
108 
o Area above and below curve threshold (i.e. area above or below 70-180 mg/dL) 
109 
o % of time in range (70-180 mg/dL) 
110 
o % of time below 70 mg/dL 
111 
o Occurrence of hypoglycemia (<70 mg/dL) overnight 
112 
 
113 
For sensor data after an exercise session to be included in the analysis, a subject must have at 
114 
least 12 hours (i.e., 144 CGM readings) from the window after the exercise session through noon 
115 
the following day.  
116 
 
117 
3.4.1 Secondary Analyses 
 
118 
The secondary outcomes will largely be examined in a descriptive manner. Summary statistics 
119 
will be calculated by treatment strategy. For binary variables, percentage of participants 
120 
developing the outcome, with 95% confidence interval, will be calculated by strategy. Strategy 3 
121 
will be compared with each of the other strategies in secondary analyses.  
122 
 
123 
Tests of significance will also be obtained using a 2-sided alpha of 0.05. For binary variables, a 
124 
generalized linear mixed model with a logistic link function for a binary outcome will be fit to 
125 
assess differences between strategy 3 and each of the other strategies.  The model will be 
126 
adjusted for baseline glucose and any period effect. For continuous variables, a repeated 
127 
measures linear regression model will be fit adjusting for period and where applicable the 
128 
baseline value. One model will be run per outcome measure, with multiple pairwise comparisons 
129 
from the same model. Regression diagnostics will be performed and if the distribution of 
130 
residuals is skewed, non-parametric methods and transformations will be considered.  No formal 
131 
correction will be made for multiple comparisons. 
132 
 
133 
 
 
134 


 
 
 
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MDG Exercise Study Primary SAP V1.0 2-24-17 
3.5 Exploratory Analyses 
135 
The following outcome measures may be explored: 
136 
 Carbohydrate intake (before, during and for 30 min post exercise) 
137 
 HR and ratings of perceived exertion 
138 
 Insulin and glucose counterregulatory hormones (glucagon, GH, catecholamines, 
139 
cortisol) 
140 
 Inflammatory cytokines (TNFα, IL-6) 
141 
 Metabolites (nonesterified fatty acids, β-hydroxybuterate, lactate) 
142 
 
143 
3.6 Additional Tabulations 
144 
 Baseline characteristics 
145 
 Number of subjects who did not complete the study and reasons for discontinuation 
146 
 
147 
4.1 Safety  
148 
Information from all subjects throughout the study will be used to assess safety. 
149 
 
150 
4.1.1 Adverse Event Definitions 
151 
A reportable adverse event is any untoward medical occurrence in a study participant, 
152 
irrespective of whether or not the event is considered treatment-related, that occurs 12 hours 
153 
prior, during, or the day after each exercise session, except for hypoglycemia, hyperglycemia, 
154 
injection-related, and exercise-induced events which are only reported as adverse events when 
155 
the criteria described below are met. 
156 
 
157 
Hypoglycemic events are recorded as Adverse Events if the event required IV dextrose or IM 
158 
glucagon to treat.  
159 
 
160 
Hyperglycemic events are recorded as Adverse Events if evaluation or treatment was obtained 
161 
from a health care provider or if the event involved DKA, as defined by the Diabetes Control and 
162 
Complications Trial (DCCT) and described below, or in the absence of DKA if evaluation or 
163 
treatment was obtained from a health care provider or an acute event involving hyperglycemia or 
164 
ketosis. 
165 
 
166 
Hyperglycemic events are classified as DKA if all of the following are present:  
167 
 Symptoms such as polyuria, polydipsia, nausea, or vomiting  
168 
 Serum ketones >1.5 mmol/L or large/moderate urine ketones 
169 
 Either arterial blood pH <7.30 or venous pH <7.24 or serum bicarbonate <15  
170 
 Treatment provided in a health care facility  
171 
 
172 
Injection-related events are recorded as Adverse Events if sufficiently severe that treatment was 
173 
given. 
174 
 
175 
Exercise-induced events are recorded as Adverse Events if the subject falls during the exercise 
176 
protocol or develops signs or symptoms of a myocardial infarction, poor perfusion (pallor, 
177 
cyanosis), angina, pathologic arrhythmia, or another medical condition not expected to occur 
178 
during or following the exercise.     
179 
 
180 


 
 
 
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MDG Exercise Study Primary SAP V1.0 2-24-17 
4.1.2 Safety Analysis 
181 
Adverse events will be tabulated by strategy. 
182 
 Proportion reporting at least one adverse event 
183 
 Proportion with an adverse event thought by investigator to be related to study treatment 
184 
 Proportion who stopped study treatment in response to an adverse event 
185 
 Total number of adverse events reported 
186 
 Number of serious adverse events reported 
187 
 Number of non-serious adverse events reported 
188 
 
189 
Adverse events will be tabulated by MedDRA categories with frequencies compared between 
190 
strategies.  Similar diagnostics and models will be performed as described for the efficacy 
191 
outcomes above. 
192 
 
193 
 
194