Conditions: Diabetes Mellitus
Keywords: Type 2 Diabetes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 145
Healthy volunteers: no

Brief summary:
Basal-bolus insulin therapy is recommended for patients with poorly controlled type 2 diabetes (T2D) and HbA1c \>9%. However, basal-bolus insulin is labor intensive and associated with increased risk of hypoglycemia, glycemic variability, weight gain and poor compliance. Thus, there is a critical need for a simpler treatment regimen that could overcome these limitations. IDegLira, a fixed-ratio combination (FRC) therapy consisting of insulin degludec and liraglutide, is an attractive option for this population given its proven benefits on glycemic control, weight and compliance. This study aims to show that a simpler regimen using a novel FRC agent (IDegLira) can improve glycemic control, decrease hypoglycemia, reduce the burden of diabetes care, and improve satisfaction/adherence in patients with poorly controlled T2D with HbA1c between ≥ 9-12%. This open-label, treat-to- target, two-arm parallel, controlled trial will randomize participants with T2D and HbA1c ≥ 9%, treated with oral anti-diabetic agents and/or basal insulin therapy to lDegLira or basal-bolus insulin for 26 weeks.

Detailed description:
Extensive literature has shown that persistent hyperglycemia is associated with short- and long-term complications. Sustained hyperglycemia, also known as glucotoxicity, leads to progressive loss of beta-cell function and is considered a key pathophysiological process in the development of type 2 diabetes (T2D). Patients with severe hyperglycemia may respond poorly to oral anti-diabetic agents (OAD) alone initially and frequently require insulin to achieve glycemic targets. Current guidelines recommend to initiate therapy with basal insulin and progressively step up to basal-bolus insulin in patients with high HbA1c \>9%, particularly if symptomatic or with catabolic symptoms.

A basal-bolus insulin regimen increases the risk of hypoglycemia, weight gain and glycemic variability, which are limiting factors in achieving glycemic targets. A basal-bolus insulin regimen is also labor intensive and often requires multiple daily injections, further increasing the burden of diabetes care and decreasing patient adherence. In contrast, simplified treatment plans may improve adherence, leading to glycemic targets achievement. Thus, there is a critical need for simpler regimens that could overcome clinical inertia, improve patient adherence, and decrease glycemic variability in patients with poorly controlled type 2 diabetes. This prospective randomized control trial will compare IDegLira to basal-bolus insulin regimen in achieving glycemic control, while reducing hypoglycemia, glycemic variability, and weight gain in patients with uncontrolled T2D and HbA1c ≥9%.

Arms:
arm 1: Participants in this group will receive IDegLira (with metformin, unless contraindicated) for 26 weeks. arm 2: Participants in this group will receive basal-bolus insulin (with metformin, unless contraindicated) for 26 weeks. The basal-bolus insulin regimen includes Insulin Degludec (U-100) and Insulin Aspart.

Interventions: intervention 1: IDegLira intervention 2: Insulin Degludec (U-100) intervention 3: Insulin Aspart
Intervention descriptions: intervention 1: Participants in this study arm will discontinue all other diabetes medications, except for metformin which will be continued at prescribed dose (unless contraindicated). IDegLira will be given once daily, at the same time of the day with or without food for 26 weeks. IDegLira will be titrated until the maximum dose is reached, up to the target fasting blood glucose of 70 to 100 milligrams per deciliter (mg/dL). intervention 2: Participants in the basal-bolus insulin study arm will discontinue all other diabetes medications, except for metformin which will be continued at the prescribed dose (unless contraindicated). Insulin Degludec (U-100) will be given once daily at the same time for 26 weeks. The dose will be titrated up to the fasting blood glucose target of 70 to 100 mg/dL, with no maximum dose. intervention 3: Participants in the basal-bolus insulin study arm will discontinue all other diabetes medications, except for metformin which will be continued at the prescribed dose (unless contraindicated). Insulin aspart will be taken before meals with a titration schedule and dose adjustment protocol to target pre-meal blood glucose level of 70 to 100 mg/dL.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
A randomized controlled trial comparing the safety and efficacy of 
IDegLira versus basal 3 bolus in patients with poorly controlled type 2 
diabetes: IDegLira HIGH trial 
NCT03737240 
 
Date: October 10, 2021 
IRB00104726 


Version 3.2 10.12.21 Page. 1
1
2
Title: A randomized controlled trial comparing the safety and efficacy of IDegLira versus basal 
3
bolus in patients with poorly controlled type 2 diabetes: IDegLira HIGH trial
4
5
INVESTIGATOR-SPONSORED STUDY PROPOSAL
6
UNIVERSAL TRIAL NUMBER (UTN): U1111-1199-0366
7
8
9
Co-Principal Investigators:
10
Assistant Professor of Medicine
11
 
12
Professor of Medicine
13
14
Co- Investigators:
 
15
Assistant Professor of Medicine
16
 
17
Assistant Professor of Medicine
18
 
19
Assistant Professor of Medicine
20
21
Assistant Professor of Medicine
22
23
Correspondence to:
24
Assistant Professor of Medicine 
25
Emory University School of Medicine
26
Department of Medicine/Endocrinology
27
 
29
Email: 
30
Phone: 
31
32
33
34
35
36
37


Version 3.2 10.12.21 Page. 2
38
Abstract:
39
40
Basal-bolus insulin therapy is recommended for patients with poorly controlled type 2 
41
diabetes and HbA1c >9%. However, basal-bolus insulin is labor intensive and associated with 
42
increased risk of hypoglycemia, glycemic variability, weight gain and poor compliance. Thus, 
43
there is a critical need for a simpler treatment regimen that could overcome these limitations. 
44
IDegLira, a fixed-ratio combination (FRC) therapy consisting of insulin degludec and liraglutide, 
45
is an attractive option for this population given its proven benefits on glycemic control, weight 
46
and compliance. Accordingly, we propose a prospective randomized controlled trial comparing 
47
IDegLira and basal-bolus insulin therapy in achieving glycemic control (efficacy end-point), while 
48
preventing hypoglycemia and reducing glycemic variability and weight gain (safety end-point) in 
49
patients with uncontrolled T2D and HbA1c between ≥ 9-15%. This study aims to show that a 
50
simpler regimen using a novel FRC agent (IDegLira) can improve glycemic control, decrease 
51
hypoglycemia, reduce the burden of diabetes care, and improve satisfaction/adherence in 
52
patients with poorly controlled T2D with HbA1c between ≥ 9-15%. This open-label, treat-to- 
53
target, two-arm parallel, controlled trial will randomize (1:1 ratio) patients with T2D and HbA1c ≥ 
54
9%, treated with oral antidiabetic agents and/or basal insulin therapy (TDD ≤50 units), to 
55
lDegLira or basal-bolus insulin for 26 weeks. We will recruit a total of 150 patients from 
56
participating institutions. We anticipate recruiting 3-4 patients per week for a total recruitment 
57
period of approximately 12 months.
58


Version 3.2 10.12.21 Page. 3
59
BACKGROUND:
60
61
Extensive literature from landmark studies have shown that persistent hyperglycemia is 
62
associated with short- and long-term complications1,2. The UKPDS study, the largest study in 
63
patients with type 2 diabetes, showed that intensive glycemic control can reduce the risk of 
64
microvascular complications1-3. Sustained hyperglycemia, also known as glucotoxicity, leads to 
65
progressive loss of beta-cell function and is considered a key pathophysiological process in the 
66
development of T2D4. Patients with severe hyperglycemia may respond poorly to oral anti- 
67
diabetic agents (OAD) alone initially and frequently require insulin to achieve glycemic targets 
68
5,6. Current guidelines recommend to initiate therapy with basal insulin and progressively step- 
69
up to basal-bolus insulin in patients with high HbA1c >9%, particularly if symptomatic or with 
70
catabolic symptoms6-8.
71
Basal-bolus insulin regimen increases the risk of hypoglycemia, weight gain and  
72
glycemic variability9,10, which are limiting factors in achieving glycemic targets. Basal-bolus 
73
insulin regimen is also labor intensive and often requires multiple daily injections, further 
74
increasing the burden of diabetes care11-14 and decreasing patient adherence 12,13. In contrast, 
75
simplified treatment plans may improve adherence, leading to glycemic targets 
76
achievement12,13,15. Thus, there is a critical need for simpler regimens that could overcome 
77
clinical inertia, improve patient adherence, and decrease glycemic variability in patients with 
78
poorly controlled type 2 diabetes. With the advent of continuous glucose monitoring (CGM), we 
79
have recognized that hypoglycemia and glycemic variability are common events in many 
80
patients, even in patients with well-controlled T2D16-20. Despite large data supporting the efficacy 
81
and safety of combination therapy with basal insulin and GLP1-RA -including fixed-ratio 
82
combination (FRC) agents 21,22; no previous studies have compared the efficacy and safety of 
83
IDegLira in patients with very high HbA1c vs the standard-of-care with basal-bolus insulin 
84
regimen. Accordingly, this prospective randomized control trial will compare IDegLira to basal 
85
bolus insulin regimen in achieving glycemic control (efficacy end-point), while reducing 
86
hypoglycemia, glycemic variability and weight gain (safety end-point) in patients with 
87
uncontrolled T2D and HbA1c ≥9%.
88


Version 3.2 10.12.21 Page. 4
89
SPECIFIC AIMS:
90
Specific Aim 1:
91
1.
To determine whether treatment with IDegLira will result in similar improvement in 
92
glycemic control, as measured by change in HbA1c (non-inferiority limit of 0.4%), 
93
compared to treatment with basal-bolus insulin regimen in patients with poorly 
94
controlled T2D (HbA1c ≥9-15%).
95
-
Primary outcome: change in HbA1c from baseline after 26 weeks of treatment with 
96
IDegLira vs basal-bolus insulin (with metformin, unless contraindicated).
97
-
Hypothesis: After 26 weeks of treatment, IDegLira will result in similar improvement in 
98
glycemic control compared to basal-bolus insulin therapy.
99
Specific Aim 2:
100
2.
To determine whether treatment with IDegLira will result in lower rate of 
101
hypoglycemic events and less glycemic variability (superiority), as measured by 
102
continuous glucose monitoring (CGM), compared to basal-bolus insulin in patients 
103
with T2D and HbA1c >9-15%.
104
-
Patients with poorly controlled T2D randomized to IDegLira or basal-bolus (with 
105
metformin, unless contraindicated) will have a one-week blinded CGM study performed 
106
during follow-up visits at 1, 12, and 26 weeks as well as 8-point self-monitored blood 
107
glucose (SMBG). CGM will allow better detection of hypoglycemic events, particularly 
108
asymptomatic and nocturnal hypoglycemia. It will also provide critical information on 
109
time in glycemic range and glycemic variability.
110
-
Hypothesis: IDegLira will result in less hypoglycemia and glycemic variability 
111
compared to basal-bolus insulin regimen.
112
Specific Aim 3:
113
3.
To determine whether treatment with IDegLira will result in improved patient 
114
satisfaction compared to treatment with basal-bolus in patients with T2D and high 
115
HbA1c (>9-15%).
116
-
Patients with poorly controlled T2D randomized to IDegLira or Basal-Bolus will 
117
complete the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and Treatment-
118
related impact measures for diabetes (TRIM-D) survey during follow-up visits.
119
-
Hypothesis: Use of IDegLira is associated with higher patient satisfaction and 
120
adherence compared to a multiple-daily injection regimen with basal-bolus insulin.
121


Version 3.2 10.12.21 Page. 5
122
CURRENT STATUS OF WORK IN THE FIELD
123
Epidemiology and treatment of patients with poorly controlled T2D and HbA1c >9%
124
125
126
Based on NHANES data from 2007-2010, up to 
127
12.6% of patients with diagnosed diabetes (18.8 millions) 
128
have an HbA1c >9%23. In the Emory Health Care system, 
129
the largest academic health system in Georgia, over 
130
64,000 patients have a diagnosis of diabetes, with ~16% 
131
having an HbA1c>9% (Figure 1). The evidence on the 
132
management of patients with T2D and very high HbA1c is 
133
very limited, with most studies excluding patients with 
134
HbA1c > 10%24-27. Figure 1. HbA1c Distribution in Patients 
135
with Diabetes: US and Emory Data
136
HbA1c Distribution
137
100%
138
90%
139
80%
140
70%
141
60%
142
50%
143
40%
144
30%
145
20%
146
10%
147
0%
148
US Data
Emory Data
149
<7%
7-8%
8-9%
>9
150
In a recent multi-national study of insulin-naïve patients with T2D, treated with or without 
151
oral agents, showed that only ~40% of patients with HbA1c > 9% were started on basal insulin. 
152
Moreover, the study showed that only 20.9% of such patients achieved HgA1c target (< 7%) at 3 
153
months after initiating basal insulin, indicating a need for coverage of prandial-related 
154
hyperglycemic excursions. Notably, failure to achieve HbA1c targets at 3 months was associated 
155
with an increased risk of not achieving HbA1c targets at 24 months, with < 30% of patients 
156
achieving glycemic targets28. This study suggests that providers delayed initiation of basal insulin 
157
as recommended by national guidelines, and frequently failed to intensify therapy to cover 
158
prandial-related hyperglycemic excursions. A recent study in ambulatory patients with T2D and 
159
high HbA1c (>10%) on metformin and sulfonylurea treatment, randomized patients to 
160
combination (COMB) therapy with exenatide plus pioglitazone vs basal-bolus insulin regimen. 
161
COMB provided greater HbA1c reduction at 6 months, with significantly less weight gain. 
162
However, the rates of hypoglycemia were unusually high, up to 56% and 83% in COMB and BB, 
163
respectively26. Our group recently validated the efficacy of a hospital discharge algorithm based 
164
on the admission HbA1c27. Among those patients with high admission HbA1c> 9% (n: 81), 54 
165
were discharged on basal-bolus insulin regimen. Mean admission HbA1c of 11.1% decreased to 
166
8.8% and to 8.0% after 4 and 12 weeks of hospital discharge (p<0.01), respectively. However, up 
167
to 44% of patients had hypoglycemia (BG < 70 mg/dl) during follow-up. Thus, there is a critical 
168
need for effective but safe and simpler anti-diabetic regimen for this high-risk population.
169
170
171
“Standards-of-Care” for Patients with Severe Hyperglycemia


Version 3.2 10.12.21 Page. 6
172
Based on expert consensus, the American Diabetes Association recommends “dual 
173
therapy” for patients with HbA1c >9% to achieve glycemic targets faster than with “sequential 
174
therapy” after 3 months of not achieving such targets. Based on historical availability and with 
175
no hierarchical preference by the ADA, dual therapy includes metformin and any of the following 
176
agents: sulfonylureas (SU), thiazolidinedione (TZD), glinides (GLN) dipeptidyl peptidase-4 
177
inhibitors (DPP-4), SGLT-2 inhibitors, GLP-1 agonists and basal insulin8. Similarly, the American 
178
Association of Clinical Endocrinologists (AACE) based on expert consensus recommends the 
179
addition of insulin in patients with HbA1c >9% if symptomatic, or on maximum doses of dual 
180
therapy6. Moreover, in patients with HbA1c >8% on dual therapy and/or long history of diabetes, 
181
AACE suggests that the addition of insulin will more likely achieve glycemic targets over adding 
182
a third agent6. It was also suggested that the addition of GLP-1 to dual oral therapy may 
183
similarly help achieving glycemic targets6, but still many patients will require insulin in this 
184
scenario29,30. In patients with HbA1c > 10%, or blood glucose > 300 mg/dl, and/or symptomatic 
185
hyperglycemia (polyuria or polydipsia) and catabolic symptoms (ketosis and weight loss), the 
186
ADA recommends “combination insulin injectable therapy”. This regimen includes: basal-bolus 
187
insulin or basal plus GLP1-RA or pre-mixed insulin8. Notably, recommendations from national 
188
guidelines in this area are mostly based on expert consensus and the notion that “dual injectable 
189
therapy” for patients with HbA1c >9% may achieve glycemic targets faster than with “sequential 
190
therapy” after re-evaluation every three months, rather than based on strong clinical trials 
191
evidence6,8. Unfortunately, the evidence is very limited in patients with T2D and v e r y  high 
192
HbA1c, with most studies excluding patients with HbA1c > 10%24-27.
193
194
In clinical practice, many patients with uncontrolled T2D and HbA1c > 9% are started on 
195
basal insulin, followed by dose up-titration and addition of prandial insulin (basal bolus)–in 
196
concordance with national guidelines6,8. Intensive insulin therapy, by either continuous 
197
subcutaneous insulin infusion (CSII) or multiple daily insulin injections (MDI), early in the 
198
disease course of patients with T2D results in rapid glycemic control within days, suggesting 
199
that avoiding the negative effects of long-term exposure to hyperglycemia may prevent further 
200
beta-cell failure31-33. However, the basal bolus regimen increases the risk of hypoglycemia and 
201
weight gain9,10, which are well-recognized limiting factors to achieve glycemic targets. More 
202
importantly, basal bolus regimen is labor intensive and increases the burden of diabetes care, 
203
number of injections per day 11-14, which may lead to poor patient adherence, increase re- 
204
admission rates, and increased risk of hypoglycemia 12,13. Studies comparing GLP1-RA therapy
205
vs thrice-daily bolus insulin added to basal insulin plus oral agents have found similar HbA1c 


Version 3.2 10.12.21 Page. 7
206
reduction30,34,35 accompanied by weight loss compared to weight gain in basal-bolus insulin 
207
regimen30,35. GLP1-RA therapy was also associated with better patient satisfaction and better 
208
quality of life34. Indeed, the combination of basal insulin and GLP1-RA is an attractive and 
209
simpler option for many patients with uncontrolled diabetes – ideally in a single daily injection 
210
from a fixed-ratio combination agent. Moreover, there is evidence suggesting that GLP-1 
211
agonist therapy may preserve beta-cell function36. Based on data from meta-analysis and 
212
randomized studies34,35,37, some authors favor this combination over basal-bolus insulin in 
213
patients with uncontrolled T2D on basal insulin38,39.
214
215
Combination of basal insulin and GLP-1 agonists – fixed-ratio combination agents
216
The combination of basal insulin and GLP1-RA therapy offers a complementary 
217
mechanism to target the main physiologic defects in T2D, by addressing fasting and prandial 
218
hyperglycemia 21,22. GLP1-RAs decrease post-prandial glycemic excursions and complement 
219
basal-insulin therapy by enhancing endogenous insulin responses in a glucose-dependent 
220
manner, inhibiting glucagon secretion, slowing gastric emptying and promoting satiety40. This 
221
combination has been shown to provide better glycemic control, less hypoglycemia, less weight 
222
gain, and reduce glycemic variability compared to basal bolus therapy or GLP1-RA 
223
alone21,22,41,42. IDegLira is a novel fixed-ratio combination of degludec 100 u/ml and liraglutide
224
3.6 mg in a pre-filled pen. IDegLira has been shown to improve glycemic control, with lower risk 
225
of hypoglycemia, less weight gain, and better patient satisfaction compared to basal-bolus or 
226
stepped-up basal therapy 43,44. Pharmacokinetics studies showed that IDegLira provided 
227
coverage over the 24-hours interval at steady levels43. In the recent DUAL V trial, IDegLira 
228
resulted in greater HbA1c reduction, weight loss and less hypoglycaemia, compared to up-
229
titration of insulin glargine in patients with T2D with HbA1c 7-10%45. More recently in the DUAL 
230
VII trial, patients with HgA1c 7-10% randomize to IDegLira had similar HbA1c reduction, but 
231
with an 89% reduction in the rate of severe or confirmed symptomatic hypoglycemia and weight 
232
loss compared to basal-bolus insulin46. Thus, IDegLira is an attractive and option for patients 
233
with severe hyperglycemia, due to potent HbA1c reduction, lower hypoglycemic risk, and 
234
flexibility of once-daily administration, compared to up to five injections per day in basal-bolus 
235
regimen. However, no previous studies have compared the efficacy and safety of IDegLira in 
236
patients with high HbA1c >9-15%.
237
238
239
SIGNIFICANCE AND INNOVATION:


Version 3.2 10.12.21 Page. 8
240
The proposed study will test three innovative questions in patients with poorly controlled 
241
T2D and HbA1c >9%: 1) whether IDegLira, a novel FRC of degludec and liraglutide, results in 
242
similar glycemic control, 2) less hypoglycemia, less glycemic variability and less weight gain 
243
compared to a basal-bolus, and 3) whether IDegLira results in better patient satisfaction and 
244
treatment adherence compared to a more complex multiple-daily insulin injection regimen. If 
245
successful, this study will show that a once-a-day simpler regimen using IDegLira can improve 
246
glycemic control, decrease hypoglycemia, improve satisfaction and decrease the burden of 
247
diabetes care, which in turn will improve patient adherence. Since improvements in HbA1c 
248
strongly correlate with a reduction in the risk of microvascular and macrovascular complication3, 
249
improved glycemic control with a simpler regimen like IDegLira have the potential to reduce the 
250
burden of complications associated with T2D. In addition, we will perform professional/blinded 
251
CGM at weeks -1, 12 and 26 of follow-up. By incorporating CGM, we will improve our ability to 
252
detect asymptomatic/unrecognized and/or nocturnal hypoglycemia and assess glycemic 
253
variability17,47 compare to SMBG (standard-of-care). Since IDegLira therapy is expected to result 
254
in less clinical significant hypoglycemia (defined as interstitial glucose < 54 mg/dl), less 
255
nocturnal hypoglycemia and less glycemic variability (as measured by MAGE, %CV or SD) 
256
compared to basal-bolus, this simpler regimen could become the standard-of-care for patients 
257
with uncontrolled T2D and HbA1c > 9%.
258
259
RESEARCH DESIGN and METHODS
260
261
262
ENDPOINTS:
263
The primary outcome of the study is to determine the difference in change in HbA1c at 26 
264
weeks of treatment to a non-inferiority limit of 0.4% between IDegLira and basal-bolus insulin 
265
therapy.
266
The secondary outcomes are to compare differences between IDegLira and basal-bolus 
267
insulin therapy in any of the following measures:
268

Mean fasting and mean daily blood glucose (per 8-point SMBG profile)
269

Percent of patients with HbA1c <7.0% at 26 weeks and hypoglycemia 
270

Percent of patients reaching A1c < 7% without weight gain and no hypoglycemia” 
271
(responder’s rate)
272

Percent of patients reaching A1c < 7.5% without weight gain and no hypoglycemia”
273

Percent of patients with A1c >10% and >11% that achieve A1c < 7.5% and < 8%


Version 3.2 10.12.21 Page. 9
274

Percent of patients with HbA1c <7.0% at 26 weeks and no weight gain
275

Percent of patients with HbA1c <7.0% at 12 weeks and no hypoglycemia
276

Incidence of documented symptomatic hypoglycaemia, defined as an event with typical 
277
symptoms of hypoglycaemia accompanied by SMBG or CGM (<70 mg/dL and < 54 
278
mg/dL) that occurs at any time of the day
279

Incidence of asymptomatic hypoglycaemia, defined as no typical symptoms reported by 
280
the subject but detected by SMBG or CGM (<70 mg/dL and < 54 mg/dL)
281

Incidence of severe hypoglycaemia, defined as severe cognitive impairment requiring 
282
assistance from another person
283

Incidence of nocturnal symptomatic hypoglycaemia, defined as an event with typical 
284
symptoms of hypoglycaemia accompanied by SMBG or CGM <70 mg/dL and < 54 
285
mg/dL that occurs between 00:00 and 05:59 hrs
286

Incidence of nocturnal asymptomatic hypoglycaemia, defined as SMBG or CGM <70 
287
mg/dL and < 54 mg/dl between 00:00 and 05:59 hrs
288

Percentage of time below 70 mg/dL and <54 mg/dl as obtained by CGM
289
290

Percentage of time in range (BG 70-180) as measured by CGM
291

Glycemic variability, as measured by SD (standard deviation), %CV (coefficient of 
292
variance), Mean Amplitude Glucose Excursions (MAGE)
293

Patient satisfaction and quality of life, as measured by the DTSQ and 
294
T R I M - D  questionnaires
295

Number of emergency room visits and hospital readmissions
296

Change from baseline in total insulin dose (units/day)
297

Number of treatment emergent AE
298
299
300
STUDY DESIGN AND METHODS:
301
The study is a 26-week, open-label, treat-to-target, two-arm parallel, randomized, controlled trial 
302
investigating the efficacy and safety of lDegLira versus basal-bolus insulin in patients with T2D. 
303
Patients with HbA1c ≥ 9% treated with oral antidiabetic agents and/or basal insulin therapy 
304
(TDD ≤50 units) will be randomized in a 1:1 manner to receive IDegLira or basal-bolus insulin 
305
regimen (plus metformin unless contraindicated), as shown in Fig 2. Subjects will have contact 
306
with the study team via clinic visits or phone contacts for a total of 29-weeks, as shown in the 
307
figure below (Fig 2 and Table 1).
308
309
Figure 2. Study design


Version 3.2 10.12.21 Page. 10
310
T2D on OAD or 
basal insulin 
(n=140)
Basal-Bolus + metformin (70)
IDegLira     + metformin (70)  
Screening
-2
26
27
Week 
FUP
EOT
Randomization
Treatment period
0
311
Legend: OAD: Oral anti-diabetic agents, EOT: End-of-treatment, FUP: Follow-up safety visit
312
313
Visits will be distributed as follows: initial screening visit/CGM insertion (visit 1), 2 weeks of 
314
screening/run-in period, randomization visit (visit 2), 26-week treatment period (visits 4-18), and 
315
a follow-up safety visit after the end the 26-weeks treatment period (visit 19). Subjects will have 
316
contact with the study team via clinic visits or phone contacts for a total of 9 clinic visits and 9 
317
telephone contacts. This study will include patients with a known history of T2D, age 18-80, 
318
treated with oral antidiabetic agents including metformin, sulfonylurea, repaglinide/nateglinide, 
319
pioglitazone, DPP4 inhibitors, SGLT2 inhibitors, (monotherapy + basal insulin) or in combination 
320
therapy (2-3 agents), and/or on basal insulin at a total daily dose (TDD) of ≤50 units. 
321
Participants previously using basal insulin [neutral protamine hagedorn (NPH), mixed insulin, 
322
detemir or glargine insulin], will be switched to study-provided Degludec or IDegLira and/or 
323
Aspart pens. Metformin will be continued at same dose during the study, unless contraindicated. 
324
Patients previously treated ambulatory with basal-bolus insulin therapy and/or GLP1-RA will be 
325
excluded. Patients transiently treated with  basal-bolus insulin (standard-of-care treatment) 
326
during hospital admission can be included. Recommendations on insulin adjustment will be 
327
provided at each visit or phone encounter by a study physician.
328
329
Rationale for study design
330
Based on the DUAL trial program, a total of 26 weeks of treatment is sufficient to reach 
331
stable HbA1c levels, with a minimum of 12 weeks in the maintenance period. This timeline has 
332
been previously shown to be sufficient to collect data for efficacy and safety. A parallel design 
333
will allow for assessment of efficacy and safety in the shortest time in each group, compared to 
334
a cross-over design. An open label design allows us to use a simpler regimen with a single 
335
injection of IDegLira, as blinding the subjects will require a double dummy design with three 
336
extra subcutaneous injections per day, thus imposing a high burden on subjects, thereby
337
increasing the non-compliance and withdrawal rates. Patients in both arms will 
338
receive the same degree of self-monitoring and follow-up. Patients will have 


Version 3.2 10.12.21 Page. 11
339
blinded CGM to avoid the bias of glycemic improvement by using real-time glucose 
340
data from CGM. The primary endpoint will use HgA1c changes, a standard 
341
laboratory test shown to correlate with risk of diabetes complication, thus limiting 
342
the assessment bias. Secondary endpoints will include rates of asymptomatic 
343
hypoglycemia or nocturnal hypoglycemia as detected by CGM, which will typically 
344
not be detected by the standard-of-care SMBG.
345


Version 3.2 10.12.21 Page. 12
346
Table 1- Schedule of events during the study period
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
383
384
385
386
387
388
389
390
391
*+/- 3 days. **+/- 7 days. Labs: ^ pregnancy test, ketones, lipid panel^* and GAD65 (If concern for Type 1 diabetes, GAD65 and ketones 
392
will be ordered during screening, per PI discretion). Pregnancy test for WOCP as deemed by investigator &fasting defined as at least 8 
393
hours without food or drinks or diabetes medications, except water and other prescribed medications. 1 +/- 7 days, but before 
394
randomization visit. Fasting glucose could be obtained from a chemistry sample obtained during the visit or POC BG. Body 
395
measurement includes: weight, height and waist and hip circumference. @ During “randomization” and “vital signs” visits, subjects will 
396
receive training on device use.
Visit # (V) 
Phone visit (P)
V1*
V2*
P3*
P4*
P5*
V6*
P7*
P8*
P9*
V10**
P11**
V12**
V13**
P14**
V15**
P16**
V17**
V18**
Time-wks
-2
0
1
2
3
4
5
6
7
8
10
12
14
16
20
24
26
27
Inf. Consent
X
Inc/exclusion
X
X
Rando@
X
Withdrawal cx
X
X
X
X
X
X
X
X
X
X
X
X
x
X
X
x
x
Drug compl
X
X
X
X
x
x
X
x
Dose adjust
X
X
X
X
X
X
X
X
X
X
X
x
X
X
X
x
Efficacy
Vital signs@
X
X
X
X
X
x
x
X
x
Phys exam
x
Pregnancy test*
X
X
X
X
X
X
Body 
Measurements
X
X
X
X
X
X
x
X
BMI
X
X
X
X
X
x
x
Hba1c
x
X
X
CMP
X&
X
X
Fasting glucose&
X
X
X
X
X
x
Instruct 8-p 
SMBG
x
X
X
X
Collect 8-pt 
SMBG
X
X
X
X
Labs
X^
X^*
7d-CGM  insert
X1
X
X
7d- CGM collect
x
x
x
DTSQ&TRIM-D
X
X
X
Safety
Adverse events
X
X
X
X
X
X
X
X
X
X
X
x
X
X
X
X
Hypoglycemia
X
X
X
X
X
X
X
X
X
X
X
x
X
X
X
X
Trial material
Drug dispensing
X
X
X
X
Drug account
X
X
X
X
x
End-of-Trial
x


Version 3.2 10.12.21 Page. 13
397
Treatment of subjects: 
398
Group 1) IDegLira Group
399

Discontinue OADs (SU, DPPIVi, glinides, and pioglitazone), except metformin 
400
(unless contraindicated) and SGLT2i. 
401

Start IDegLira at 16 dose steps (degludec 16 units/liraglutide 0.6 mg), per U.S 
402
labeling indications and/or provider discretion.
403

IDegLira will be given once daily, at the same time of the day with or without food.
404

IDegLira will be titrated until the maximum dose (50 steps) is reached, up to target fasting 
405
BG between 70 and 100 mg/dl (Treat-To-Target Trial protocol), see algorithm below.
406

Titration will occur twice a week: 1) self-titration by patients once a week and 2) phone call/ 
407
contact by research team once a week, for the initial 8 weeks. After that, patients will self-
408
titrate study medications per dosing algorithm. 
409

IDegLira will be titrated by 2-step-dose increment (2 IU of degludec and 0.072 of liraglutide), 
410
to a maximum of 8 steps per week. 
411

The maximum allowed dose of IDegLira 50 dose steps provide 50 U of degludec and 1.8mg 
412
of liraglutide.
413

Titration will be performed twice weekly (every 3 to 4 days) based on the previous self-
414
monitored fasting (pre-breakfast) BG measurement (mean of 3 consecutive days). Patients 
415
will be provided with self-titration algorithms for insulin adjustments.
416

Subjects not at goal (fasting or mean SMBG from 3 consecutive days > 300 mg/dl) requiring
417
> 50 dose steps of IDegLira, will be considered “treatment failures”. Degludec will be added 
418
to IDegLira as “rescue” basal insulin therapy. The dose of IDegLira will remain unchanged.
419

The dose of “rescue” Degludec will be recorded and titrated twice weekly to target FPG of 
420
70-100 mg/dl, per provider discretion, as shown below. 


Version 3.2 10.12.21 Page. 14
Titration algorithm for IDegLira and Degludec pens 
Insulin dosage IU/d)*
>181
8
141-180
6
121-140
4
101-120
2
71-100
no adjustments
<70
-2
If dose > 45 U/d, decrease by 10%
<56
-4
If dose > 45 U/d, decrease by 10%
421
* Maximum titration dose per week: 8 units
422
423
Group 2: Basal-Bolus Insulin Group (Begin BB trial48)
424
425

Discontinue OADs (SU, DPPIVi, glinides, and pioglitazone), except metformin (unless 
426
contraindicated) and SGLT2i. 
427

Insulin naïve participants will start at a daily dose of 10 units of degludec U-100 (or 
428
0.2 u/kg/d per investigator discretion). 
429

Participants previously using basal insulin [neutral protamine hagedorn (NPH), mixed 
430
insulin, detemir or glargine U100] will be switched to study-provided degludec pens. 
431

For participants taking basal insulin prior to randomization, the conversion dose is 
432
1:1 unit. The total daily basal dose could be the same or reduced by 20% at the 
433
investigator’s discretion. 
434

Titration will be performed twice weekly based on the previous self-monitored fasting (pre-
435
breakfast) BG measurement (mean of 3 consecutive days). Titration will occur as follows: 1) 
436
self-titration by patients once a week and 2) phone call/ contact by research team once a 
437
week, for the initial 8 weeks. After that, patients will self-titrate study medications per dosing 
438
algorithm. 
439
Degludec will be given once daily at the same time, and titrate up to fasting 
440
blood glucose 70-100 mg, with no maximum dose. 
441
Basal insulin should be adjusted before adjusting pre-meal aspart, as shown 
442
below. 
443
444
445
446
447


Version 3.2 10.12.21 Page. 15
448
Degludec U100 Insulin adjustment
449
Mean fasting BG from preceding 3 days 
(mg/dl)
Insulin dosage IU/d)
>181
8
141-180
6
121-140
4
101-120
2
71-100
no adjustments
<70
-2
If dose > 45 U/d, decrease by 5%
<56
-4
If dose > 45 U/d, decrease by 10%
450
451
452
Aspart Insulin dosage:
453
Aspart will be given before meals, to target pre-meal BG < 70-100 mg/dl.
454

At the start of the trial, participants will be prescribed 4 U insulin aspart before the 
455
largest/main meal or; before each main meal (3 typical large meals per day: 
456
breakfast, lunch, and dinner, <4 times per day) per investigator discretion. 
457

For insulin naïve participants or per investigator discretion, total aspart dose will 
458
calculated at 0.2 u/kg/d, and equally divided in three doses to be started before the 
459
main/largest meal or before each meal (3 typical large meals per day: breakfast, 
460
lunch, and dinner, <4 times per day), per investigator discretion. 
461

If patients are started on only one dose for the largest meal, a second and third dose 
462
may be added, as detailed above. Subjects will be provided with titration algorithms. 
463

The dose adjustment of insulin aspart will be based on the pre-prandial BG of the 
464
subsequent meal or bedtime BG (i.e. the pre-dinner value will be based on the 
465
bedtime BG), per provider discretion, as shown below:
466
467
468
469
470
471
472
473
474
475
476
Pre-prandial and bedtime BG (mean BG from 
preceding 3 days), mg/dl
 Aspart dosage IU/d)
>181
+4
141-180
+3
101-140
+2
71-100
no adjustments
<70
-2
<56
-4 


Version 3.2 10.12.21 Page. 16
477
Study population:
478
A total of 150 subjects (75 subjects in each arm) will be included in the study (screening 
479
about 300), randomized in a 1:1 manner, and started on study medications (as show in Fig 2). 
480
Based on an anticipated screening failure rate of 40% and an attrition rate of 20%, total of 300 
481
patients will be screened. The study will be conducted at Emory University Hospital Midtown 
482
and Grady Hospital in Atlanta, Ga and second site TBA
483
484
Inclusion Criteria
485
1.  Males or females between the ages of 18 to 80 years
486
2.  Type 2 diabetes, diagnosed for ≥ 6 months
487
3.  HBA1c ≥ 9% - 15%
488
4.  Previously treated with oral antidiabetic agents, including metformin, sulfonylurea, 
489
repaglinide/nateglinide, pioglitazone, DPP4 inhibitors, SGLT2 inhibitors, (monotherapy + 
490
basal insulin) or in combination therapy (2-3 agents), and/or on basal insulin (neutral 
491
protamine hagedorn (NPH), mixed insulin, detemir or glargine U100) at a total daily dose 
492
(TDD) ≤50 units (stable doses of basal insulin for at least 90 days, defined as up to ±10% 
493
variability)
494
5.  BMI ≤ 45 Kg/m2
495
496
497
Exclusion Criteria
498
1.
Age < 18 or > 80 years
499
2.
Subjects with type 1 diabetes or LADA: positive GAD-65 antibody and/or ketones 
500
3.
Subjects with a BG > 400 mg/dL during the screening visit and laboratory evidence of diabetic 
501
ketoacidosis
502
4.
Previous treatment with GLP-1 agonists (during prior 3 months) 
503
5.
Previous treatment with basal-bolus insulin (within prior 3 months, except transient treatment 
504
with during hospital admission)
505
6.
Recurrent severe hypoglycemia or known hypoglycemia unawareness.
506
7.
Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2
507
8.
Patients with acute or chronic pancreatitis, pancreatic cancer 
508
9.
Patients with clinically significant hepatic disease (cirrhosis, jaundice, end-stage liver 
509
disease) or significantly impaired renal function (GFR < 30 ml/min).
510
10. Treatment with oral or injectable corticosteroid (equivalent or higher than prednisone 5 
511
mg/day), parenteral nutrition and immunosuppressive treatment.
512
11. Mental condition rendering the subject unable to understand the nature, scope, and possible 


Version 3.2 10.12.21 Page. 17
513
consequences of the study
514
12. Hypersensitivity to study drugs
515
13. Participating in another investigational drug trial 
516
14. The receipt of any investigational drug (within 3 months) prior to this trial.
517
14. Previously randomized in this trial
518
15. Heart Failure NYHA class 4 or uncontrolled hypertension (blood pressure > 180/110 
519
mmHg)
520
16. Female subjects who are pregnant or breast-feeding at time of enrollment into the study
521
17. Females of childbearing potential who are not using adequate contraceptive methods (as 
522
required by local law or practice)
523
18. Known or suspected allergy to trial medications (degludec, liraglutide, aspart), excipients, or 
524
related products.
525
19. Subjects could be excluded based on PI’s discretion
526
20. Unable to comply with trial protocol, and/or at investigator discretion
527
21. Patients receiving treatment for active diabetic retinopathy or with proliferative retinopathy
528
529
Withdrawal Criteria
530
-
The subject may withdraw at will at any time during the trial.
531
-
Pregnancy or intention of becoming pregnant.
532
-
The subject may be withdrawn at the discretion of the investigator due to non- 
533
compliance or due to a safety concern
534
-
The subject will be withdrawn if starting any drugs that interfere with glucose metabolism 
535
(steroids doses equivalent to prednisone > 5 mg/day)
536
-
The subject may be withdrawn if diagnosed with acute pancreatitis (defined as meeting 2 
537
of the following 3 rules: typical abdominal pain, amylase/lipase > 3x UNL and/or 
538
characteristic US, CT or MRI findings)
539
-
If the fasting or mean SMBG during 3 consecutive days is > 300 mg/dl, the investigator 
540
will schedule an unplanned visit as soon as possible, to obtain confirmatory fasting BG 
541
and investigate the cause. If no apparent or intercurrent cause is detected, the patient 
542
may be withdrawn.
543
-
Unable to comply with trial protocol, at investigator discretion.
544
545
Subject Replacement
546
There will be no replacement of subjects withdrawn after randomization in this trial.
547
548


Version 3.2 10.12.21 Page. 18
549
550
551
Rationale for Study Population
552
The target population will include subjects with uncontrolled T2D with HbA1c ≥9%-15%, 
553
treated with oral anti-diabetic agents and low dose basal insulin (TDD ≤50 units/d), in whose 
554
treatment intensification is recommended. Subjects should have been on oral anti-diabetic 
555
agents or basal insulin for at least 90 days (with stable doses of insulin, 10% of dose 
556
fluctuations are acceptable). These subjects need intensification of therapy, and should start 
557
basal insulin and progressively step-up to basal-bolus insulin per national guidelines. However, 
558
these patients may benefit more from a simpler regimen consisting of a single daily injection, 
559
with lower risk of hypoglycaemia and less weight gain, which could improve treatment 
560
adherence. IDegLira is an attractive therapeutic option for these patients for its potency, 
561
flexibility, and potential lower risk of hypoglycaemia and weight gain.
562
563
Visit Procedures
564
Figure 2 and Table 1 provides a description of procedures to be performed at each visit 
565
during the study period. Visits will be distributed as follows: initial/screening visit/CGM baseline 
566
insertion, (visit 1), 2 weeks of screening/run-in period, randomization visit (visit 2), 26-week 
567
treatment period (visits 4-18), and a follow-up safety visit after the end the 26- weeks treatment 
568
period (visit 19). Subjects will have contact with the study team via clinic visits or phone 
569
contacts for a total of 9 clinic visits and 9 telephone contacts. If subjects cannot participate in a 
570
scheduled visit (+/- 3 days), the investigators will arrange for an urgent (as soon as possible) 
571
visit. During follow-up, we will collect the following data (as described in Table 1): glycemic 
572
data, hypoglycemia events, drug compliance, protocol adherence, body measurements, and 
573
adverse events.
574
575
Definitions:
576

CGM Hypoglycemia: CGM glucose levels < 70, < 54, < 40 mg/dl, with a duration at least 
577
15 minutes by CGM. The end of the event will be when glucose is > 70 mg/dl for 15 
578
minutes. A prolonged hypoglycemic event will be defined as CGM levels < 54 mg/dl for 
579
120 minutes or more”.52 
580

We will only analyze CGM data collected after the first 24 hours from insertion. Patients 
581
should have worn the CGM for at least > 4 days. 
582

Documented symptomatic hypoglycemia, defined as an event with typical symptoms of 


Version 3.2 10.12.21 Page. 19
583
hypoglycemia confirmed by SMBG or CGM (< 70 mg/dL and < 54 mg/dL) that occurs at 
584
any time of the day
585

Incidence of asymptomatic hypoglycemia, defined as no typical symptoms reported by 
586
the subject but detected by SMBG or CGM (<70 mg/dL and < 54 mg/dL)
587

Incidence of severe hypoglycemia, defined as severe cognitive impairment requiring 
588
assistance from another person
589

Incidence of nocturnal symptomatic hypoglycemia, defined as an event with typical 
590
symptoms of hypoglycemia confirmed by SMBG or CGM < 70 mg/dL and < 54 mg/dL 
591
that occurs between 00:00 and 05:59 hrs
592

Incidence of nocturnal asymptomatic hypoglycemia, defined as no typical symptoms 
593
reported by the subject but detected by SMBG or CGM (<70 mg/dL and < 54 mg/dL) 
594
between 00:00 and 05:59 hrs
595

Confirmed hypoglycaemia includes: severe hypoglycemia and episodes with or without 
596
symptoms with biochemical confirmation of glucose < 54 mg/dL.
597

Relative hypoglycemia includes: typical symptoms but with glucose > 70 mg/dL
598
599
600
Body measurements (Visits V1, V2, V6, V10, V12, V13, V15, V17)
601
602
Body weight: Body weight should be measured in kilogram or pound, without shoes and only 
603
wearing light clothing.
604
Height: Height (without shoes) should be measured in centimeters or inches and recorded 
605
without decimals.
606
Waist and hip circumference: The waist circumference is defined as the minimal abdominal 
607
circumference located midway between the lower rib margin and the iliac crest. The hip 
608
circumference is defined as the widest circumference around the buttocks.  Three consecutive 
609
measurements of waist and hip circumference should be taken and recorded.  Mean values will 
610
be used for result analysis. The waist and hip circumferences will be measured to the nearest
611
1.5 cm (0.2 inches) using a non-stretchable measuring tape.
612
The subject should be measured in a standing position with an empty bladder and wearing light 
613
clothing with accessible waist and hip. The tape should touch skin, but not compress soft tissue 
614
and twist in tape should be avoided. The subject should be asked to breathe normally and the 
615
measurement should be taken when the subject is breathing out gently.
616
Body Mass Index (BMI): BMI will be calculated by the formula Body weight 
617
(Kg)/m2.Screening Visit: (visit 1, week -2)
618
Approximately 2 weeks prior to starting study medications, all potential study subjects will be 


Version 3.2 10.12.21 Page. 20
619
screened to check their eligibility. After providing the subjects with detailed information about the 
620
trial, subjects will sign the informed consent form and will be assigned a patient identification 
621
number.
622
During this visit, investigators will perform a comprehensive assessment, including: 
623
present and past medical history (concomitant illness), diabetes history (onset, prior 
624
complications, current and prior anti-diabetes medication’s duration, allergies, or intolerances), 
625
physical examination, height, weight, vital signs, laboratory assessment (HbA1c, chemistry, 
626
pregnancy test for women of child-bearing potential (WOCBP), documentation of current 
627
medications, and prior intolerances or allergies. Investigators will notify the primary care 
628
physician that the subjects have consented to participate in the study. In WOCBP, the 
629
contraceptive methods will be documented. 
630
631
After review of all inclusion and exclusion criteria, including laboratory results, patients 
632
who do not meet all the inclusion criteria at Visit 1 will be considered screen failures and will not 
633
be randomized to participate in the study. 
634
635
During this visit, the investigator will insert the CGM to obtain baseline information 
636
(before drug exposure). During this visit, patients will receive training on CGM use and reinforce 
637
SMBG diary collection. Trained personnel will proceed with sensor insertion. After that, the 
638
sensor will be activated, the CGM session will be started. 
639
640
Eligible patients will be trained on the use of the glucose meter to monitor their BG levels 
641
(i.e. 8-point SMBG). Patients will be given diabetes diaries and associated training to record all 
642
glucose levels, insulin doses, and episodes of hypoglycemia. Subcutaneous injections 
643
administration technique will be reviewed prior to randomization to ensure good technique. 
644
Reinforcement will be provided as needed during the follow-up visits. 
645
646
Patients will be instructed in performing glucose testing at home before meals, with a 
647
minimum of 2 out of the 4 pre-meal and/or bedtime glucose measurements per day. In addition, 
648
patients must perform an 8-point SMBG for at least 1 day prior to week 0, 12, 26, as follows:
649
650
651
Time-points for 8-point SMBG profile:
652
653
The blood glucose levels should be measured and recorded in the diary (including date, 
654
actual clock time and blood glucose value) at the following time points, always starting with 


Version 3.2 10.12.21 Page. 21
655
measurement before breakfast. Subjects will be instructed to collect the SMBG on a day where 
656
the subject does not anticipate unusual strenuous exercise.
657
Before breakfast
658
90 min after the start of breakfast
659
Before lunch
660
90 min after the start of lunch
661
Before dinner
662
90 min after the start of dinner
663
At bedtime
664
In the middle of the night at 3 or 4 am
665
Subject will also be instructed to check and record BG when hypoglycemia is suspected. Values
666
< 70 mg/dl should trigger an intervention, as described below (safety section).
667
668
Instructions for Run-In Period (2 weeks):
669
The main purpose of this period is to ensure that patients can comply with 8-point SMBG, pen 
670
instructions and trial recommendations.
671

Oral antidiabetic agents will be continued at same dose until randomization visit. 
672
Metformin dose will be titrated up to 1000mg twice daily or to the maximum tolerated 
673
dose, unless contraindicated, per investigator’s discretion. 
674

Basal Insulin therapy [NPH, mixed insulin, or basal insulin (glargine U100, detemir)] at 
675
TDD ≤50 units will continue at same insulin dosage until randomization. Insulin can be 
676
initiated, or dose could be increased during run-in period in those subjects with severe 
677
hyperglycemia (BG>300 mg/dL) and/or glucotoxicity per investigator’s discretion, for 
678
subject’s safety reasons. 
679

Patients will be instructed in performing glucose testing at home before meals, with a 
680
minimum of 2 out of the 4 pre-meal and/or bedtime glucose measurements per day.
681

Patient not randomized in the trial will be considered screening failures, and no data will 
682
be collected since these patients will not receive study medication.
683
684
685
686
Preparation for Visit 2 (Randomization visit)
687

Patient will be instructed to complete the 8-point SMBG, and to titrate up metformin, 
688
unless contraindicated.
689

All patients will be instructed to provide daily glucose records. In addition, they will 


Version 3.2 10.12.21 Page. 22
690
perform an 8-point SMBG done prior to Visit 3 (as described above).
691

Patients who complied with the 8-point glucose testing (up to 6 points) and fulfill the 
692
eligibility criteria at Visit 2 will be randomized to participate in the study.
693

Reminder to bring CGM sensor for collect and download.
694
695
696
Randomization (Visit 2, Week 0)
697

Patients will be randomized to each treatment group
698

Continue metformin therapy at same dose, unless contraindicated or for safety issues
699

Discontinue other OADs and insulin formulation
700

If BG > 400 mg/dl, patients will not be randomized, and considered screening failures. 
701

If BG > 300 mg/dl, investigator may order a confirmatory glucose test (at a different time) 
702
before considering the subject screen failure. 
703

Subjects will receive detailed instruction on the use of the IDegLira pen or IDeg and 
704
Aspart Pens and the titration algorithm.
705

Patient will receive study medications. Subjects randomized to IDegLira will be 
706
instructed to not exceed 50 dose steps and to notify investigators if needed.
707

Dose of insulin will be adjusted as needed.
708
709

Patients will be instructed in performing glucose testing at home before meals, with a 
710
minimum of 2 out of the 4 pre-meal and bedtime glucose measurements per day.
711

Patients will complete the DTSQ and TRIM-D questionnaires
712

Investigator will collect CGM sensors 
713
714
715
Telephone Visits (weeks 1, 2, 3, 5, 6, 7, 10, 16, and 24)
716

Between each office visit, subjects will have a telephone visit with study personnel
717

The purpose of these visits will be to monitor compliance with SMBG, CGM use, and 
718
study medication. Also hypoglycaemia and hyperglycemia data, as well as AEs, will be 
719
collected.
720

Study diaries will be collected and reviewed for BG levels, episodes of hypoglycemia, 
721
SQ injections self-administration.
722
723
Follow-up Visits (visit 6-18)
724
The following activities will occur during interim visits:
725

Subjects will receive detailed instruction on the use of the insulin or IDegLira pens
726

Study diaries will be collected and reviewed for BG levels, episodes of hypoglycemia, 


Version 3.2 10.12.21 Page. 23
727
insulin self-administration
728

Dose of IDeglira or insulin will be adjusted as needed. Study medication will be 
729
dispensed
730
731

Subjects will be instructed in performing glucose testing at home before meals, with a 
732
minimum of 2 out of the 4 pre-meal and bedtime glucose measurements per day.
733

Drug compliance will be reviewed (see below “subject compliance” section)
734

AE and hypoglycemia data will be collected, as well as concomitant medications.
735

Laboratory blood work as indicated on page 12 (schedule of events during study 
736
period)
737
738
Visit 12 (12 weeks follow up)
739
The following activities will occur during interim visits:
740

Study diaries (8p-SMBG) will be collected and reviewed for BG levels, episodes of 
741
hypoglycemia, insulin self-administration
742

Dose compliance will be reviewed 
743

Dose of IDeglira or insulin will be adjusted as needed. Dispensing study medication.
744
745

Body measurements, vital signs, BMI will be collected
746

HbA1c, Fasting Glucose/CMP and pregnancy test (WOCP per PI discretion) will be 
747
obtained
748

CMG will be inserted
749

Patients will complete the DTSQ and TRIM-D questionnaires
750

AE and hypoglycemia data will be collected, as well as concomitant medications.
751

Drug dispensing 
752
753
754
CGM visits (insertion on weeks -2, 12, 26 and collection on week 0, 14, 27)
755
All enrolled participants will have a blinded/professional CGM study performed during 
756
week -2, 12, and 26 weeks of follow-up.
757
During this visit, participants will receive training on CGM use and reinforce SMBG diary 
758
collection. Trained personnel will proceed with sensor insertion, transmitter placement and 
759
hook-up. After that, the transmitter will be activated, the CGM session will be started.
760
After 7 days, subjects will remove the sensor and return to the scheduled visit. Transmitter 
761
will be connected to the computer for data downloading. CGM summary will be reviewed to 
762
determine the quality.
763
Sensor will be stored following standard precautions. Onsite visits will be allowed for upload of 
764
the study devices and face-to-face discussion about hypoglycemia and hyperglycemia 


Version 3.2 10.12.21 Page. 24
765
episodes, insulin doses, AE/SAE evaluation, and replacement of study medication, if required. 
766
Trained personnel will input required clinical and demographic data into the sensor database 
767
software. Subjects will complete an 8-point SMBG for 1 day (as shown in Table 1) prior to clinic 
768
visit. Subjects will bring their glucose meter, CGM sensor (if applicable), BG diary, to each 
769
onsite visit.
770
Visit 17 (Week 26, end-of-study)
771

Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) and TRIM-D survey
772

Blood sampling as indicated on page 12- schedule of events during the study period, 
773
including HbA1c assessment to determine efficacy of treatment
774

Study diaries collected and reviewed for BG levels, episodes of hypoglycemia, insulin 
775
self-administration
776
777
Visit 18 (week 27, case sign-off)
778

This visit should occur at least one week after the last treatment visit
779

Since degludec has a prolonged duration of action, this visit will serve to monitor for 
780
adverse events.
781

Sensor removal (after 7 days).
782
During each visit, participants will have their insulin dose titrated to achieve a fasting 
783
glucose 70-100 mg/dL as detailed in the insulin titration algorithm. Once the fasting glucose 3- 
784
day average is <100 mg/dL, insulin doses will be kept constant, unless the participant 
785
experiences recurrent or severe hyperglycemia.
786
787
788
789
790
Assessments for Efficacy
791
The primary outcome of efficacy will be determined by change of HbA1c from baseline 
792
a f t e r  2 6  w e e k s  o f  t r e a t m e n t . HbA1c will be measured by the clinical laboratory of 
793
Grady Memorial Hospital and Emory University, a NGSP-certified laboratory. Subjects will 
794
complete an 8-point SMBG for at least 1 day before the CGM visits. We will also compare the 
795
time in target range (70-180) as detected by CGM, allowing us to assess glycemic control for > 7 
796
days with frequent testing (CGM and POC BG). We will compare the rate of “responders”, 
797
defined as patients HbA1c
798
<7.0% and no hypoglycemia at week 26.
799
800
Assessments for Safety
801
The safety endpoint of the study will be incidence of hypoglycaemia, as measured by the 


Version 3.2 10.12.21 Page. 25
802
current standard-of-care of POC monitoring. Subjects will complete an 8-point POC BG log 
803
before weeks -1, 12, 26. In addition, we will perform blinded/professional CGM studies for 7 
804
days, during week -1, 12, and 26. CGM will allow better detection of hypoglycemic events, 
805
particularly asymptomatic and nocturnal hypoglycemia, usually not detected by POC monitoring. 
806
It will also provide critical information on time in glycemic range and glycemic variability. We will 
807
also compare differences in glycemic variability, by SD, %CV and MAGE. GV will be calculated 
808
by mean daily standard deviation (SD) of glucose values in absolute terms, and as a percentage 
809
of variance from the overall mean (%CV). These are measures of dispersion of glucose values 
810
around a measure of central tendency, which represents the overall glucose excursion during 
811
the study. We will also analyze GV by mean amplitude of glycemic excursion (MAGE), which 
812
represents the average of all BG excursions (up or down), with a magnitude of > 1 standard 
813
deviation of all BG measures47.
814
815
Potential Risks to the Subjects:
816
Hypoglycemia. It is possible that following the proposed protocol, subjects receiving IDegLira 
817
or Basal-bolus may develop hypoglycemia, as defined above.
818
Gastrointestinal side effects, including nausea and vomiting are more common in patients 
819
treated with liraglutide compared to placebo. The frequency of nausea and vomiting is reported 
820
in up to 5-15% patients receiving IDegLira. The number of adverse events will be collected at 
821
each telephone contact or clinic visit. There have been few reported events of acute 
822
pancreatitis. Subjects should be informed of the characteristic symptoms of acute pancreatitis: 
823
persistent, severe abdominal pain. If pancreatitis is suspected, Degludec-liraglutide should be 
824
discontinued. If the investigator suspects acute pancreatitis, all suspected drugs should be 
825
discontinued until confirmatory test have been conducted and appropriate treatment should be 
826
initiated. Subjects diagnosed with acute pancreatitis (as a minimum 2 of 3: characteristic 
827
abdominal pain, amylase and/or lipase >3xUNR or characteristic findings on CT scan/ MRI 
828
should be withdrawn from the study. In a cardiovascular outcomes trial (LEADER trial) 3.1% of 
829
patients treated with liraglutide, versus 1.9% of placebo treated patients reported an acute 
830
event of gallbladder disease, such as cholelithiasis or cholecystitis. The majority of events 
831
required hospitalization or cholecystectomy. If cholelithiasis is suspected, gallbladder studies 
832
and appropriate clinical follow-up will be indicated.
833
834
Protection against Risks:
835
We will follow safeguards to minimize the risk to our subjects: a) we will carefully monitor 
836
response to medical treatment every 1-2 weeks by telephone contact and every 1-2 months 


Version 3.2 10.12.21 Page. 26
837
during clinic visits, b) women of reproductive age who are sexually active will undergo a urine 
838
pregnancy tests prior to participation in the study and in-person visits as deemed by the 
839
investigator, c) female subjects who are pregnant, breast-feeding, or not willing to use 
840
appropriate contraception at time of enrollment will not be included in the study, d) patients with 
841
significant comorbidities such as chronic kidney disease greater than stage III, liver cirrhosis, 
842
gastroparesis, and pancreatic disorders will be excluded from the study. Hypoglycemia: Patients 
843
will receive diabetes education and will be instructed on hypoglycemia sign/symptoms and 
844
treatment. Patients will be asked to call the diabetes center and/or PCP in the event of 
845
hypoglycemia. If a patient develops hypoglycemia, the dose of basal insulin will be reduced (see 
846
treatment algorithm). Gastrointestinal side effects including nausea and vomiting may be 
847
expected, more commonly in patients treated with liraglutide. In subjects with suspected acute 
848
pancreatitis liraglutide and other potentially suspect medicinal products should be discontinued 
849
until confirmatory tests have been conducted and appropriate treatment initiated.
850
851
Other Assessments
852
We will assess patient satisfaction by using the DTSQs at baseline and the DTSQc at the end- 
853
of-study, as recommended by Health Psychology Research.
854
For treatment satisfaction, subjects’ responses to questions 1, 7 and 8 of the DTSQc will be 
855
used. A comparison of the score on the DTSQs from week 0 to week 24, as well as using the 
856
score on the other questions of the DTSQc, which would overcome the ceiling limitation of using 
857
the DTSQs by itself49. The Diabetes Treatment Satisfaction Questionnaire Status (DTSQs) form 
858
will be administered at weeks 0, 12 and the DTSQc will be administered at week 26. The 
859
amplitude of the score on the DTSQc gives the degree of change in satisfaction, while the 
860
direction (positive or negative) will provide guidance on the preference of one treatment regimen 
861
over the other one.
862
For quality of life, we will use the “Treatment-related impact measures for diabetes” (TRIM-D)” 
863
in order to determine the impact of the type of therapy on this outcome.  Subjects will be given 
864
the questionnaire at baseline, and weeks 12 and 26 to assess their quality of life and any 
865
potential impact of the treatment regimen 50.
866
Subject Compliance
867
Subject compliance will be assessed by monitoring of drug accountability. Subjects will be 
868
encouraged at every visit to adhere to the study medications and follow-up schedule. Unused 
869
trial medications will be compared with dispensed amount at each corresponding visit. If 
870
discrepancies are noted, the subject will be asked.


Version 3.2 10.12.21 Page. 27
871
872
STATISTICAL CONSIDERATIONS:
873
Sample Size Calculation
874
The primary outcome is the change in HbA1c from baseline after 26-weeks of treatment.
875
The primary hypothesis is that HbA1c change is similar between the IDegLira group and the 
876
basal-bolus group. Given the data reported for the DUAL V study, we assume the HbA1c 
877
change from baseline has a standard deviation bounded above by 0.85 (%). We assume the 
878
margin of equivalence is 0.4 (%) and the true mean difference in the primary outcome is 0 (%). 
879
Given 57 subjects per study group, based on a one-sided, two-sample t-tests, we would achieve 
880
80% power to detect non-inferiority, with alpha (type-1 error) set as 0.05. Accounting for 20% 
881
attrition rate of 20%, we need to recruit 75 subjects per group (150 in total).
882
883
Statistical Methods
884
This is a randomized, open-label study. We will first compare the primary outcome (i. e. 
885
change in HbA1c from baseline to after 26 weeks of treatment) between the two study groups 
886
using nonparametric and parametric two-sample tests, such as Wilcoxon tests and t-tests. A 
887
logarithm transformation may be employed to make the data better conform to the normality 
888
assumption. We will apply standard variable selection and model checking procedures to decide 
889
the final model.
890
Secondary outcomes include various measurements (related to glycemic control, qualify 
891
of life, adverse effects, and etc.) collected at a single or multiple time points. For continuous 
892
outcomes measured a single time point (i.e. non-longitudinal outcome), we shall analyze them 
893
following the same strategy designed for the primary outcome. For discrete non-longitudinal 
894
outcome, we will use Chi-square (or Fisher’s Exact) tests to compare them between the two 
895
study groups. This will be followed by logistic regression or Poisson (or Negative Binomial) 
896
regression to assess other potential confounders.  We will perform appropriate model selection 
897
and diagnostic procedures to ensure adequate fit to the data. For outcomes measured at 
898
multiple time points (i.e. longitudinal outcome), we will first conduct cross-sectional analyses as 
899
planned for the non-longitudinal outcomes. Next we will perform repeated measures analyses 
900
that account for with-subject correlations in the longitudinal outcomes. We will analyze 
901
longitudinal continuous outcomes based on repeated measures ANOVA followed by repeated 
902
measures linear regression, and we will analyze longitudinal discrete outcomes by using
903
repeated measures generalized linear model (GLM). If the assumption of missing completely at 
904
random (MCAR) is reasonable, we shall handle missing data by excluding them from the cross- 


Version 3.2 10.12.21 Page. 28
905
sectional and the longitudinal data analyses. When MCAR assumption is questionable, we will 
906
assume missing values are missing at random and deal with them by the standard multiple 
907
imputation methods. We plan to conduct statistical analyses using SAS 9.4.
908
909
Interim Analysis
910
911
We plan to perform interim analysis on the primary safety endpoint every 6 months. The 
912
trial will be stopped if there is evidence beyond a reasonable doubt of a difference in the rate of 
913
death (two-sided alpha level, <0.01) between the treatment groups. In addition, the trial will be 
914
stopped if the rate of severe hypoglycemic events (BG <40 mg/dl) in either group is > 40%.
915
Explorative Statistical Analysis for Pharmacogenetics and Biomarkers
916
N/A
917
DATA HANDLING AND RECORD KEEPING:
918
Data collection records with personal identifiers will be stored in locked file cabinets.
919
Sponsor site expects data to be entered in REDCap within 10 days of phone call or outpatient 
920
visit. The study coordinators will enter data from each visit into data collection paper forms and 
921
into an electronic database (REDCap) that meets HIPPA and confidentiality regulations, 
922
provided by the Emory Research Information Technology Department. Baseline data will include 
923
demographics/history form (subject’s gender, date of birth, ethnicity, history of diabetes, and 
924
treatment of diabetes and comorbid conditions, body weight, BMI. During follow-up visits, data 
925
from SMBG, laboratory and/or CGM will be also collected. Data on adverse events will also be 
926
collected and enter into the database. Presentation of the study results at regional or scientific 
927
meetings or in publications will not identify subjects.  Access to research and confidential  
928
records will be limited to clinical investigators, research coordinators, and the IRB at Emory 
929
University.
930
931
ETHICS:
932
Informed Consent.
933
After identification of eligible patients these individuals will be provided basic information 
934
regarding the study and, if interested, a member of the research staff using inclusion/exclusion 
935
criteria delineated elsewhere in the protocol will enroll patients.  Informed consent will be 
936
obtained before any trial related procedures including screening procedures. The consent form,
937
potential risks and benefits, and the rights of research participants will be explained to the 
938
participant by the investigators or research coordinator. Individuals will be asked if they have 
939
questions, and a member of the research staff will answer questions.  The principal investigator 


Version 3.2 10.12.21 Page. 29
940
will also be available at all times to answer questions that participants may have during the 
941
consent procedure or during the time a participant is enrolled in the study.  The consent form 
942
will be completed in accordance with the IRB guidelines of Emory University.  A signed copy of 
943
the consent form will be provided to the participant and a copy will be placed in the file that is 
944
maintained for each participant in the study office.
945
Informed consent will follow the procedure of Emory University Institutional Review 
946
Board.  Every potential participant will be informed in writing and verbally with the important and 
947
key points of the study.   One of the investigators or research coordinators will obtain an 
948
informed consent prior to inclusion of a patient into the study.
949
The study will be conducted in accordance with the Declaration of Helsinki and will be 
950
conducted in accordance with the ICH GCP guidelines. The sponsor-investigator will comply 
951
with all applicable regulatory and legal requirements, ICH GCP guidelines and the Declaration 
952
of Helsinki in obtaining and documenting the informed consent.
953
954
STUDY SCHEDULE:
955
The study will be conducted at two sites: at 1) Emory University Hospital Midtown and 
956
Grady Memorial Hospital in Atlanta, GA; and at 2) TBA. An additional site will be considered if 
957
funds are available.
958
Based on our prior trials experience, we anticipate 3-4 potential candidates per week, 
959
including the collaborating institutions, for a total recruitment period of approximately 12 
960
months. Since the study requires a 6-month follow up period, we anticipate a study length of 
961
18-24 months. 
First subject in
2019 January
Screening
~300
Randomized
150
Last subject recruited
2020 June/July
Last subject in (completed)
2021 Nov/Dec
Data analysis
2021 DEC
Submission to congress or journal
ADA 2021, Major journal and/or Diabetes Care 2021
962
963
Study DRUGS and materials:
964
Study medication(s) / devices(s)
965

Group 1: IDegLira pens will be supplied by the sponsor and given free of charge to the study 
966
subjects. IDegLira is a FRC agent, including basal insulin degludec and GLP-1 agonist 


Version 3.2 10.12.21 Page. 30
967
liraglutide. The starting dose of IDegLira is at 16 dose steps (degludec 16 units/liraglutide
968
0.6 mg). The maximum allowed dose of IDegLira 50 dose steps provide 50 U of     
969
degludec and 1.8mg of liraglutide.
970

Group 2: Degludec U-100 and Aspart U-100 insulin pens will be supplied by the 
971
sponsor and given free of charge to the study subjects.
972

We will use a professional CGM device. The investigator will keep the sensor readers, and 
973
will store the transmitters after the completion of each sensor study for up to 5 years- as 
974
part of the study information.
975
976
Packaging and Labelling of Study Medication(s)
977
Trial products will be packed and labelled by Emory and Grady Investigational Drug Service. 
978
Labelling will be in accordance with local law and study requirements.
979
980
Storage and Drug Accountability of Study Medication(s)
981
Emory and Grady Investigational Drug Service, is a full-service research pharmacy with 
982
all required conditions for proper storage and dispensing of study medications. The investigator 
983
will ensure the availability of proper storage conditions and record and evaluate the temperature. 
984
There will be no trial medication(s) dispensed to any person not enrolled in the study. Any 
985
unused medication(s) will be stored separately from used trial medication(s). Subject 
986
compliance will be assessed by asking subjects to return all unused, partly used and unused 
987
cartridges and vials of liraglutide and degludec insulin at each visit. Subjects will be instructed to 
988
return all used, partially used or unused study products before each dispensing visit. Subjects 
989
will be encouraged at every visit to adhere to the study medications and follow-up schedule. Any 
990
partially used or unused study medications will be destroyed accordingly to local procedures.
991
After study completion, any surplus of study medications or supplies will be disposed as per local 
992
regulations.
993
994
Auxiliary Supply
995
Investigator will provide the following supplies:
996

Needles for insulin pens, IDegLira, Degludec and Aspart pens
997
Randomization and Blinding
998
This is an open label randomized controlled trial.  Patients will be randomized 
999
consecutively using a computer-generated randomization table provided by Dr. Limin Peng, 
1000
Professor of Statistics at the Emory School of Public Health. Patient will be randomized based 
1001
on HbA1c (HbA1c <10 or >10). The randomization table will be mailed to each institution where 


Version 3.2 10.12.21 Page. 31
1002
a member of the research team will be in charge of the randomization process and group 
1003
assignment.
1004
Breaking of Blinded Codes
1005
N/A
1006
1007
1008
CONCOMITANT ILLNESSES AND MEDICATIONS:
1009
Definitions:
1010
Concomitant illness: any illness that is present at the start of the trial (i.e. at the first visit).  
1011
Concomitant medication: any medication other than the trial product(s) that is taken during the 
1012
trial, including the screening and run-in periods.
1013
Details of all concomitant illnesses and medication must be recorded at trial entry (i.e. at the first 
1014
visit). Any changes in concomitant medication must be recorded at each visit. If the change 
1015
influences the subject’s eligibility to continue in the trial, the sponsor must be informed.
1016
The information collected for each concomitant medication includes, at a minimum, start date, 
1017
stop date or continuing, and indication.
1018
For each concomitant illness, date of onset, date of resolution or continuing, at a minimum, 
1019
should be recorded.
1020
1021
ADVERSE EVENTS:
1022
The investigator will be responsible for reporting of all adverse events including serious 
1023
adverse events (SAE), serious adverse drug reactions (SADRs) to the competent authority and 
1024
independent IRB boards based upon federal regulations and local/IRB policies. The investigator 
1025
will report to the sponsor all S A R D s  at the same time it’s reported to the IRB or within 15 
1026
days of the investigator becoming aware.
1027
The investigators will collect the following information at minimum for each of these events:
1028
1029
1. Study name
1030
2. Patient identification (e.g. initials, sex, age)
1031
3. Diagnosis
1032
4. Drug
1033
5. Reporter identification (e.g. Name, or initials)
1034
1035
Also 6) Causality, and 7) Outcome might be reported, but this is not mandatory.
1036
1037
1038
1039


Version 3.2 10.12.21 Page. 32
1040
Definitions
1041
Adverse Event (AE):
1042
An AE is any undesirable medical event occurring to a subject in a clinical trial, whether 
1043
or not related to the trial product(s). This includes events reported from the first trial related 
1044
activity after the subject has signed the informed consent and until post treatment follow-up 
1045
period as defined in the protocol. 
1046
Adverse Reaction (AR)
1047
An AR is an adverse event for which the causal relationship between the product and the 
1048
adverse event is suspected. 
1049
The following should not be recorded as AEs, if recorded as medical history/concomitant illness 
1050
on the CRF at screening:
1051
• Pre-planned procedure, unless the condition for which the procedure was planned has 
1052
worsened from the first trial related activity after the subject has signed the informed consent
1053
• Pre-existing conditions found as a result of screening procedures
1054
1055
1056
Clinical Laboratory Adverse Event:
1057
A clinical laboratory AE is any clinical laboratory abnormality regarded as clinically 
1058
significant i.e. an abnormality that suggests a disease and/or organ toxicity and is of a severity, 
1059
which requires active management, (i.e. change of dose, discontinuation of trial product, more 
1060
frequent follow-up or diagnostic investigation).
1061
1062
Serious Adverse Event (SAE):
1063
A serious AE is an experience that at any dose results in any of the following:
1064
• Death
1065
• A life-threatening* experience
1066
• In-patient hospitalization or prolongation of existing hospitalization
1067
• A persistent or significant disability/incapacity
1068
• A congenital anomaly/birth defect
1069
• Important medical events that may not result in death, be life-threatening*, or require 
1070
hospitalization may be considered an SAE when, based upon appropriate medical judgement, 
1071
they may jeopardize the subject and may require medical or surgical intervention to prevent one 
1072
of the outcomes listed in this definition
1073
• Suspicion of transmission of infectious agents


Version 3.2 10.12.21 Page. 33
1074
*The term life-threatening in the definition of SAE refers to an event in which the subject was at 
1075
risk of death at the time of the event. It does not refer to an event which hypothetically might 
1076
have caused death if it was more severe.
1077
1078
Serious Adverse Drug Reaction (SADR):
1079
An adverse drug reaction is an adverse event (AE) for which a causal relationship to the 
1080
trial product is at least possible i.e. causal relationship is conceivable and cannot be dismissed. 
1081
Serious adverse reaction (SAR): Adverse event which fulfils both the criteria for a Serious 
1082
Adverse Event and the criteria for an Adverse Reaction.
1083
1084
1085
1086
Suspected Unexpected Serious Adverse Reaction (SUSAR):
1087
An SAE which is unexpected and regarded as possibly or probably related to the 
1088
trial/study product by the investigator.
1089
1090
Medical Events of Special Interest (MESI): A MESI is (1) a medication error (e.g. wrong drug 
1091
administration or wrong route of administration) or (2) a suspected transmission of an infectious 
1092
agent via the product
1093
1094
Non-Serious Adverse Event:
1095
A non-serious AE is any AE which does not fulfil the definition of an SAE.
1096
1097
1098
Severity Assessment Definitions:
1099
• Mild: Transient symptoms, no interference with the subject’s daily activities
1100
• Moderate: Marked symptoms, moderate interference with the subject’s daily activities
1101
• Severe: Considerable interference with the subject’s daily activities, unacceptable
1102
1103
1104
Relationship to study medication Assessment Definitions:
1105
• Probable: Good reasons and sufficient documentation to assume a causal relationship
1106
• Possible: A causal relationship is conceivable and cannot be dismissed
1107
• Unlikely: The event is most likely related to an ethology other than the trial product
1108
1109
1110
The US PI, will be used to evaluate all unexpected events and adverse reactions.
1111
1112


Version 3.2 10.12.21 Page. 34
1113
Outcome Categories and Definitions:
1114
• Recovered: Fully recovered or by medical or surgical treatment the condition has returned to 
1115
the level observed at the first trial related activity after the subject signed the informed consent
1116
• Recovering: The condition is improving and the subject is expected to recover from the event. 
1117
This term should only be used when the subject has completed the trial
1118
• Recovered with sequelae: As a result of the AE, the subject suffered persistent and 
1119
significant disability/incapacity (e.g. became blind, deaf, paralyzed). Any AE recovered with 
1120
sequelae should be rated as an SAE
1121
• Not recovered
1122
• Fatal
1123
• Unknown
1124
1125
Collection, Recording and Reporting of Adverse Events
1126
All events meeting the definition of an adverse event must be collected and reported 
1127
from the first trial related activity after the subject has signed the informed consent and until the 
1128
end of the posttreatment follow-up period as stated in the protocol.
1129
1130
Follow-up of Adverse Events
1131
During and following a subject’s participation in a clinical trial, the investigator will provide 
1132
adequate medical care to the study subject for any study-related adverse events, including 
1133
clinically significant laboratory values related to the study, regardless of their insurance status.
1134
All adverse events classified as serious or severe or possibly/probably related to the trial 
1135
product must be followed until the subject has recovered and all queries have been resolved.
1136
For cases of chronic conditions follow-up until the outcome category is “recovered” is not 
1137
required, as these cases can be closed with an outcome of “recovering” or “not recovered”.
1138
All other adverse events must be followed until the outcome of the event is “recovering” (for 
1139
chronic conditions), or “recovered” or until the end of the post-treatment follow-up stated in the 
1140
protocol, whichever comes first, and until all queries related to these AEs have been resolved.
1141
1142
Pregnancy
1143
Subjects will be instructed to notify the sponsor-investigator immediately if they become 
1144
pregnant.
1145
The investigator will report to Novo Nordisk any pregnancy occurring during the trial 
1146
period. Reporting of pregnancy by investigator should occur within the same timelines described 


Version 3.2 10.12.21 Page. 35
1147
above for reporting of Adverse Events.
1148
Pregnancy complications should be recorded as adverse event(s). If the infant has a 
1149
congenital anomaly/birth defect this must be reported and followed up as a serious adverse 
1150
event.
1151
1152
Precautions/Over-dosage
1153
We will follow safeguards to minimize the risk to our subjects: a) we will carefully monitor 
1154
capillary blood glucose and reported symptoms. To minimize significant clinical events, we will 
1155
exclude patients with history of significant liver, renal or cardiac failure in this study.
1156
1157
Hypoglycemia can occur during the treatment with insulin. Hypoglycemia will be treated 
1158
accordingly to the best local practices, and insulin will be adjusted as per a predefined 
1159
algorithm. Subjects will be instructed to not exceed the maximum dose of IDegLira of 50 
1160
steps. Subjects will be instructed to maintain good hydration, and to report the presence of 
1161
severe nausea, vomiting, or diarrhea. Insulin doses will be adjusted for hypoglycemic values.
1162
1163
1164
LIABILITY AND SUBJECT INSURANCE:
1165
No additional cost to patients or to the institution will be incurred for research purposes.
1166
Patients will not be billed for the laboratory work or any test that is being done only for study 
1167
purposes. Novo Nordisk will provide IDegLira, Degludec and Aspart at no cost to 
1168
participants. Patients will be responsible for the cost of their usual ongoing medical care, 
1169
including procedures (glucose meter supplies) and/or non-study medications that your 
1170
doctor requires as part of your usual medical care.
1171
During and following a subject’s participation in a clinical trial, the investigator and 
1172
institution will provide adequate medical care to the study subject for any study-related adverse 
1173
events, including clinically significant laboratory values related to the study at patient own cost, 
1174
regardless of their insurance status. Financial compensation for such things as lost wages, 
1175
disability or discomfort due to an injury related to the study is not available.
1176
The sponsor-investigator will be responsible for the conduct of the study and that the 
1177
sponsor-investigator agrees to defend, indemnify, and hold harmless Novo Nordisk, any of its 
1178
parent companies, affiliates, or subsidiaries, and their respective officers, directors, employees, 
1179
agents, representatives, distributors, salespersons, customers, licensees, and end-users from
1180
and against any claim, suit, demand, loss, damage, expense or liability imposed by any third 
1181
party arising from or related to: (a) any breach of sponsor-investigator's obligations or 


Version 3.2 10.12.21 Page. 36
1182
representations; or (b) sponsor-investigator’s negligent or grossly negligent use or willful misuse 
1183
of the study drug, the results, or services derived therefrom. This indemnification shall not apply 
1184
in the event and to the extent that a court of competent jurisdiction or a duly appointed arbiter 
1185
determines that such losses or liability arose as a result of Novo Nordisk’s gross negligence, 
1186
intentional misconduct, or material breach of its responsibilities.
1187
1188
PREMATURE TERMINATION OF STUDY:
1189
The investigator may decide to stop prematurely the trial. In this case, the investigator 
1190
will notify the subjects promptly and ensure appropriate follow up. The investigator will also 
1191
notify the IRB and local regulatory authorities.
1192
1193
PUBLICATION PLAN:
1194
We anticipate completion of the study in Dec 2019.  Data will be analyzed between 
1195
October and December 2019. One abstract will be submitted to the 2020 American Diabetes 
1196
Association meeting and manuscript(s) will be submitted during the first six months of 2020. 
1197
The investigator will register the study with a publicly assessable database, such as 
1198
clinicaltrials.gov.
1199
1200
1201
1202
1203
1204
1205
1206
1207
1208
1209
1210
1211
1212
1213
1214


Version 3.2 10.12.21 Page. 37
1215
REFERENCES:
1216
1217
1218
1.
Intensive blood-glucose control with sulphonylureas or insulin compared with 
1219
conventional treatment and risk of complications in patients with type 2 diabetes 
1220
(UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 
1221
1998;352(9131):837-853.
1222
2.
Effect of intensive blood-glucose control with metformin on complications in 
1223
overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes 
1224
Study (UKPDS) Group. Lancet. 1998;352(9131):854-865.
1225
3.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of 
1226
intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577- 
1227
1589.
1228
4.
Kahn SE. Clinical review 135: The importance of beta-cell failure in the 
1229
development and progression of type 2 diabetes. J Clin Endocrinol Metab. 
1230
2001;86(9):4047-4058.
1231
5.
Ferrannini E. The stunned beta cell: a brief history. Cell Metab. 2010;11(5):349- 
1232
352.
1233
6.
Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus Statement by the 
1234
American Association of Clinical Endocrinologists and American College of 
1235
Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 
1236
2017 Executive Summary. Endocr Pract. 2017;23(2):207-238.
1237
7.
Umpierrez GE, Hellman R, Korytkowski MT, et al. Management of hyperglycemia 
1238
in hospitalized patients in non-critical care setting: an endocrine society clinical 
1239
practice guideline. J Clin Endocrinol Metab. 2012;97(1):16-38.
1240
8.
American Diabetes A. 8. Pharmacologic Approaches to Glycemic Treatment.
1241
Diabetes Care. 2017;40(Suppl 1):S64-S74.
1242
9.
Garber AJ. Insulin intensification strategies in type 2 diabetes: when one injection 
1243
is no longer sufficient. Diabetes Obes Metab. 2009;11 Suppl 5:14-18.
1244
10.
Garber AJ. The importance of titrating starting insulin regimens in patients with 
1245
type 2 diabetes. Diabetes Obes Metab. 2009;11 Suppl 5:10-13.
1246
11.
Peyrot M, Barnett AH, Meneghini LF, Schumm-Draeger PM. Insulin adherence 
1247
behaviours and barriers in the multinational Global Attitudes of Patients and 
1248
Physicians in Insulin Therapy study. Diabet Med. 2012;29(5):682-689.
1249
12.
Peyrot M, Rubin RR, Khunti K. Addressing barriers to initiation of insulin in 
1250
patients with type 2 diabetes. Prim Care Diabetes. 2010;4 Suppl 1:S11-18.
1251
13.
Rubin RR, Peyrot M, Kruger DF, Travis LB. Barriers to insulin injection therapy: 
1252
patient and health care provider perspectives. Diabetes Educ. 2009;35(6):1014- 
1253
1022.
1254
14.
Vijan S, Hayward RA, Ronis DL, Hofer TP. Brief report: the burden of diabetes 
1255
therapy: implications for the design of effective patient-centered treatment 
1256
regimens. J Gen Intern Med. 2005;20(5):479-482.
1257
15.
Josse RG, Woo V. Flexibly timed once-daily dosing with degludec: a new ultra- 
1258
long-acting basal insulin. Diabetes Obes Metab. 2013;15(12):1077-1084.
1259
16.
Chico A, Vidal-Rios P, Subira M, Novials A. The continuous glucose monitoring 
1260
system is useful for detecting unrecognized hypoglycemias in patients with type 1 
1261
and type 2 diabetes but is not better than frequent capillary glucose


Version 3.2 10.12.21 Page. 38
1262
measurements for improving metabolic control. Diabetes Care. 2003;26(4):1153- 
1263
1157.
1264
17.
Vigersky R, Shrivastav M. Role of continuous glucose monitoring for type 2 in 
1265
diabetes management and research. J Diabetes Complications. 2017;31(1):280- 
1266
287.
1267
18.
Munshi MN, Segal AR, Suhl E, et al. Frequent hypoglycemia among elderly 
1268
patients with poor glycemic control. Arch Intern Med. 2011;171(4):362-364.
1269
19.
Leinung M, Nardacci E, Patel N, Bettadahalli S, Paika K, Thompson S. Benefits 
1270
of short-term professional continuous glucose monitoring in clinical practice. 
1271
Diabetes Technol Ther. 2013;15(9):744-747.
1272
20.
Gehlaut RR, Dogbey GY, Schwartz FL, Marling CR, Shubrook JH. Hypoglycemia 
1273
in Type 2 Diabetes--More Common Than You Think: A Continuous Glucose 
1274
Monitoring Study. J Diabetes Sci Technol. 2015;9(5):999-1005.
1275
21.
Tibaldi J. Achieving glycemic goals with addition of incretin-based therapies to 
1276
insulin in patients with type 2 diabetes mellitus. Am J Med Sci. 2014;347(6):491- 
1277
501.
1278
22.
Vora J, Bain SC, Damci T, et al. Incretin-based therapy in combination with basal 
1279
insulin: a promising tactic for the treatment of type 2 diabetes. Diabetes Metab. 
1280
2013;39(1):6-15.
1281
23.
Ali MK, Bullard KM, Gregg EW. Achievement of goals in U.S. Diabetes Care, 
1282
1999-2010. N Engl J Med. 2013;369(3):287-288.
1283
24.
Palermo NE, Modzelewski KL, Farwell AP, et al. Open Access to Diabetes 
1284
Center from the Emergency Department Reduces Hospitalizations in the 
1285
Susequent Year. Endocr Pract. 2016;22(10):1161-1169.
1286
25.
Magee MF, Nassar CM, Mete M, White K, Youssef GA, Dubin JS. The Synergy 
1287
to Enable Glycemic Control Following Emergency Department Discharge 
1288
Program for Adults with Type 2 Diabetes: Step-Diabetes. Endocr Pract. 
1289
2015;21(11):1227-1239.
1290
26.
Abdul-Ghani M, Mujahid O, Mujahid A, DeFronzo RA, Zirie M, Jayyousi A. 
1291
Efficacy of Exenatide Plus Pioglitazone Versus Basal/Bolus Insulin in T2DM 
1292
Patients With Very High HbA1c. J Clin Endocrinol Metab. 2017.
1293
27.
Umpierrez GE, Reyes D, Smiley D, et al. Hospital discharge algorithm based on 
1294
admission HbA1c for the management of patients with type 2 diabetes. Diabetes 
1295
Care. 2014;37(11):2934-2939.
1296
28.
Mauricio D, Meneghini L, Seufert J, et al. Glycaemic control and hypoglycaemia 
1297
burden in patients with type 2 diabetes initiating basal insulin in Europe and the 
1298
USA. Diabetes Obes Metab. 2017.
1299
29.
DeVries JH, Bain SC, Rodbard HW, et al. Sequential intensification of metformin 
1300
treatment in type 2 diabetes with liraglutide followed by randomized addition of 
1301
basal insulin prompted by A1C targets. Diabetes Care. 2012;35(7):1446-1454.
1302
30.
Rosenstock J, Fonseca VA, Gross JL, et al. Advancing basal insulin replacement 
1303
in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a 
1304
comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice- 
1305
daily prandial insulin lispro. Diabetes Care. 2014;37(8):2317-2325.
1306
31.
Ilkova H, Glaser B, Tunckale A, Bagriacik N, Cerasi E. Induction of long-term 
1307
glycemic control in newly diagnosed type 2 diabetic patients by transient 
1308
intensive insulin treatment. Diabetes Care. 1997;20(9):1353-1356.


Version 3.2 10.12.21 Page. 39
1309
32.
Ryan EA, Imes S, Wallace C. Short-term intensive insulin therapy in newly 
1310
diagnosed type 2 diabetes. Diabetes Care. 2004;27(5):1028-1032.
1311
33.
Weng J, Li Y, Xu W, et al. Effect of intensive insulin therapy on beta-cell function 
1312
and glycaemic control in patients with newly diagnosed type 2 diabetes: a 
1313
multicentre randomised parallel-group trial. Lancet. 2008;371(9626):1753-1760.
1314
34.
Diamant M, Nauck MA, Shaginian R, et al. Glucagon-like peptide 1 receptor 
1315
agonist or bolus insulin with optimized basal insulin in type 2 diabetes. Diabetes 
1316
Care. 2014;37(10):2763-2773.
1317
35.
Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor 
1318
agonist and basal insulin combination treatment for the management of type 2 
1319
diabetes: a systematic review and meta-analysis. Lancet. 2014;384(9961):2228- 
1320
2234.
1321
36.
Retnakaran R, Kramer CK, Choi H, Swaminathan B, Zinman B. Liraglutide and 
1322
the preservation of pancreatic beta-cell function in early type 2 diabetes: the 
1323
LIBRA trial. Diabetes Care. 2014;37(12):3270-3278.
1324
37.
Buse JB, Han J, Miller S, MacConell L, Pencek R, Wintle M. Addition of 
1325
exenatide BID to insulin glargine: a post-hoc analysis of the effect on glycemia 
1326
and weight across a range of insulin titration. Curr Med Res Opin. 
1327
2014;30(7):1209-1218.
1328
38.
Wilding JP, Rajeev SP, DeFronzo RA. Positioning SGLT2 Inhibitors/Incretin- 
1329
Based Therapies in the Treatment Algorithm. Diabetes Care. 2016;39 Suppl 
1330
2:S154-164.
1331
39.
Owens DR, Monnier L, Barnett AH. Future challenges and therapeutic 
1332
opportunities in type 2 diabetes: Changing the paradigm of current therapy. 
1333
Diabetes Obes Metab. 2017.
1334
40.
Owens DR, Monnier L, Bolli GB. Differential effects of GLP-1 receptor agonists 
1335
on components of dysglycaemia in individuals with type 2 diabetes mellitus. 
1336
Diabetes Metab. 2013;39(6):485-496.
1337
41.
Investigators F-ST. Glucose Variability in a 26-Week Randomized Comparison of 
1338
Mealtime Treatment With Rapid-Acting Insulin Versus GLP-1 Agonist in 
1339
Participants With Type 2 Diabetes at High Cardiovascular Risk. Diabetes Care. 
1340
2016;39(6):973-981.
1341
42.
Mathieu C, Rodbard HW, Cariou B, et al. A comparison of adding liraglutide 
1342
versus a single daily dose of insulin aspart to insulin degludec in subjects with 
1343
type 2 diabetes (BEGIN: VICTOZA ADD-ON). Diabetes Obes Metab. 
1344
2014;16(7):636-644.
1345
43.
Freemantle N, Mamdani M, Vilsboll T, Kongso JH, Kvist K, Bain SC. IDegLira 
1346
Versus Alternative Intensification Strategies in Patients with Type 2 Diabetes 
1347
Inadequately Controlled on Basal Insulin Therapy. Diabetes Ther. 2015;6(4):573- 
1348
591.
1349
44.
Hughes E. IDegLira: Redefining insulin optimisation using a single injection in 
1350
patients with type 2 diabetes. Prim Care Diabetes. 2016;10(3):202-209.
1351
45.
Lingvay I, Perez Manghi F, Garcia-Hernandez P, et al. Effect of Insulin Glargine 
1352
Up-titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in 
1353
Patients With Uncontrolled Type 2 Diabetes: The DUAL V Randomized Clinical 
1354
Trial. JAMA. 2016;315(9):898-907.
1355
46.
A/S NN. Xultophy® demonstrates similar glucose control with reduced risk of 


Version 3.2 10.12.21 Page. 40
1356
hypoglycaemia and a superior weight profile compared to basal-bolus therapy.
1357
47.
Bergenstal RM. Glycemic Variability and Diabetes Complications: Does It 
1358
Matter? Simply Put, There Are Better Glycemic Markers! Diabetes Care. 
1359
2015;38(8):1615-1621.
1360
48.
Garber AJ, King AB, Del Prato S, et al. Insulin degludec, an ultra-longacting 
1361
basal insulin, versus insulin glargine in basal-bolus treatment with mealtime 
1362
insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, 
1363
randomised, open-label, treat-to-target non-inferiority trial. Lancet. 
1364
2012;379(9825):1498-1507.
1365
49.
Bradley C. Diabetes treatment satisfaction questionnaire. Change version for use 
1366
alongside status version provides appropriate solution where ceiling effects 
1367
occur. Diabetes Care. 1999;22(3):530-532.
1368
50.
Brod M, Christensen T, Hammer M, Busk AK, Bushnell DM. Examining the 
1369
ability to detect change using the TRIM-Diabetes and TRIM-Diabetes Device 
1370
measures. Quality of Life Research. 2011;20(9):1513-1518. 
1371
doi:10.1007/s11136-011-9886-7
1372
51.
Philis-Tsimikas A, Brod M, Niemeyer M, et al. Insulin Degludec Once-Daily in Type 2 
1373
Diabetes: Simple or Step-Wise Titration (BEGIN: Once Simple Use). Advances in 
1374
Therapy. 2013;30(6):607-622.
1375
52.
Danne T, Nimri R, Battelino T, et al. International Consensus on Use of Continous 
1376
Glucose Monitoring. Diabetes Care. 2017; Dec; 40 (12): 1631-1640