Conditions: Diabetes Mellitus, Type 2 Diabetes
Keywords: Diabetes Mellitus, Type 2 Insulin Insulin, Long-Acting Insulin, Short Acting Detemir Liraglutide GLP-1 Glucagon Like Peptide Metformin Uncontrolled Diabetes Elevated A1c Incretins
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 157
Healthy volunteers: no

Brief summary:
The aim of this clinical trial is to assess and compare the effect of insulin detemir in combination with liraglutide and metformin versus insulin detemir in combination with insulin aspart and metformin in subjects with very uncontrolled Type 2 Diabetes (A1c \> 10%).

Detailed description:
The aim of this study is to compare a GLP-1 plus basal insulin and metformin treatment regimen to a basal-bolus plus metformin treatment regimen in patients with very uncontrolled (HbA1c\>10%) type 2 diabetes. The investigators will compare the two regimens with respect to efficacy in improving glycemic control, rate of hypoglycemia, change in weight, effect on patient quality of life, treatment burden, physician time, as well as healthcare related cost. The investigators hypothesize that at 26 weeks from randomization the two treatment regimens will have similar percentage of patients reaching A1c levels \<7.0%, while more patients on the GLP-1 plus basal insulin strategy will achieve the composite end point of A1c levels \<7.0% without severe hypoglycemia or significant weight gain.

Arms:
arm 1: Metformin titrated to max tolerated dose (at least 1000 mg/day); Insulin detemir titrated based on the study protocol; Insulin Aspart titrated by the physician arm 2: Metformin titrated to max tolerated dose (at least 1000mg/day); Insulin detemir titrated based on the study protocol"; Liraglutide titrated to max tolerated dose (at least 1.2 mg/day)

Interventions: intervention 1: Metformin intervention 2: Detemir intervention 3: Liraglutide intervention 4: Insulin Aspart
Intervention descriptions: intervention 1: Metformin will be started at 500 mg daily (or continued at current dose)and weekly titrated to 2000 mg or maximum tolerated dose (at least 1000 mg/day) intervention 2: Insulin detemir will be started in both groups at 0.3 units/kg or conversion 1:1 from dose of basal insulin prior to randomization. The titration will be primarily patient-driven, based on our study protocol table. Additional physician driven titration will be allowed in both groups if patient fails to intensify basal insulin dose as directed. intervention 3: Initial dose of 0.6 mg/day with weekly increments of 0.6 mg until dose of 1.8 mg/day or maximal tolerated dose (at least 1.2 mg/day)is reached intervention 4: Insulin aspart will be initiated at a dose of 0.3 units/kg/day divided among the number of meals taken daily and titrated based on physician clinical judgment with the goal of pre-prandial BG 70-130 mg/dL and post-prandial BG \<180

Protocol document:
Prot_SAP_000.pdf: 
 
Title: 
Study Protocol and Statistical Analysis Plan 
The Effect of Simple Basal Insulin Titration, 
Metformin Plus Liraglutide for Type 2 
Diabetes With Very Elevated HbA1c - The 
SIMPLE Study 
 
NCT Number: 
NCT01966978 
Date of the Document:  
05/06/2017 


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1 
SIMPLE STUDY: SIMPLE BASAL INSULIN 
2 
TITRATION, METFORMIN PLUS 
3 
LIRAGLUTIDE FOR TYPE 2 DIABETES WITH 
4 
VERY ELEVATED HBA1C 
5 
 
6 
(A RANDOMIZED TRIAL COMPARING THE EFFICACY, SAFETY, AND 
7 
HEALTHCARE RELATED COSTS OF TREATING PATIENTS WITH VERY 
8 
ELEVATED HBA1C LEVELS WITH BASAL-BOLUS INSULIN REGIMEN OR BASAL 
9 
INSULIN WITH A GLP-1 AGONIST) 
10 
 
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12 
 
13 
INVESTIGATOR-INITIATED STUDY PROPOSAL  
14 
FUNDING PROVIDED BY NOVONORDISK A/S 
15 
 
16 
 
17 
UNIVERSAL TRIAL NUMBER (UTN) 
18 
U1111-1145-7585 
19 
 
20 
 
21 
 
22 
 
23 
 
24 
Department of Internal Medicine – Division of Endocrinology and Diabetes  
25 
UT Southwestern Medical Center 
26 
5323 Harry Hines Blvd. Dallas, TX 75390-8857 
27 
 
28 
 
29 
Correspondence to:  
30 
Ildiko Lingvay, MD, MPH, MSCS 
31 
Associate Professor 
32 
UT Southwestern Medical Center, Division of Endocrinology 
33 
5323 Harry Hines Blvd 75390-8857 
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214-648-2779 
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Ildiko.Lingvay@UTSouthwestern.edu 
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38 
BACKGROUND AND SIGNIFICANCE: 
39 
1. Achieving glycemic goals in type 2 diabetes has multiple beneficial health 
40 
consequences. 
41 
There are over 25 million patients with diabetes in the US [1], a disease with tremendous 
42 
health, social, and economic implications. Studies like UKPDS [2, 3]  and Kumamoto [4, 
43 
5] have established an undeniable link between hyperglycemia and micro- and even 
44 
macrovascular complications. Such data serves as the background for the current 
45 
glycemic targets recommended by the American Diabetes Association. Despite 
46 
tremendous therapeutic advances and availability of numerous new classes of drugs in the 
47 
past decade, more than a third of the population with diabetes, particularly in minority 
48 
groups and those with lower level of education, still does not reach glycemic targets [6-
49 
8]. Given the large epidemic of obesity and type 2 diabetes, our efforts to curb diabetes 
50 
related morbidity and mortality have a whole new meaning and huge potential impact, 
51 
both on patient related outcomes as well as cost of healthcare – a very timely concern for 
52 
our healthcare system[9-11]. 
53 
 
54 
2. Treatment guidelines for type 2 diabetes advocate insulin treatment for patients with a 
55 
HbA1c>10%. 
56 
Treatment guidelines for diabetes have been published by ADA/EASD [12] and AACE 
57 
[13], with the purpose of providing guidance to healthcare providers caring for patients 
58 
with type 2 diabetes and ensure best possible outcomes. Currently metformin is well 
59 
accepted as the first line therapy for patients with type 2 diabetes in addition to lifestyle 
60 
changes [2, 12-14]. There is no general agreement as to what is the best way to advance 
61 
treatment in those who have not achieved target HbA1c levels with monotherapy [12, 
62 
13]. The current ADA and AACE guidelines both recommend an individualized approach 
63 
to treatment intensification which should take into consideration cost, patient’s 
64 
preference, and profile of available medications [12, 13] It is generally accepted that 
65 
patients with HbA1c level >10 % have a low probability of achieving ideal glycemic 
66 
target of <7.0% with any of the traditional oral hypoglycemic agents, or even after basal 
67 
insulin-only initiation. Therefore such patients will require prandial insulin, whether 
68 
administered as a mixed formulation or basal-bolus regimen in order to archive glycemic 
69 
goals [6, 12, 13, 15-26]. 
70 
 
71 
3. Insulin is a very effective glucose lowering agent, but it is associated with multiple 
72 
side effects and shortcomings. 
73 
Patients with a very elevated HbA1c (>10%) are traditionally thought to have more 
74 
advanced disease [2, 6] as well as glucotoxicity [27, 28],  which coupled with the need to 
75 
lower HbA1c by >3% to reach glycemic targets, make insulin an obvious treatment 
76 
choice [15, 29]. Insulin is considered the most effective hypoglycemic agent and 
77 
therefore capable of lowering HbA1c into target range regardless of baseline glycaemia 
78 
[15]. Yet an insulin based treatment regimen, when implemented correctly and 
79 
intensively, takes a significant toll on the patient’s lifestyle by requiring a higher 
80 
commitment to disease management in the form of more frequent self-monitoring, 
81 
multiple daily injections, requires more frequent dose adjustments, and a greater 
82 
investment in insulin-related diabetes education [30, 31]. Furthermore, insulin treatment 
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is commonly associated with two most undesirable side effects: weight gain and 
84 
hypoglycemia [30, 32]. 
85 
 
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4. Treatment-induced weight gain has a negative effect on the disease pathophysiology 
87 
and fuels its progression. 
88 
Most patients with diabetes are overweight and obese, development of which is often the 
89 
initial event in the pathophysiology of type 2 diabetes [1, 33, 34]. Using therapeutic 
90 
agents that focus primarily on blood glucose control but promote further weight gain 
91 
seems counterintuitive, as this further worsens insulin resistance, which in turns results in 
92 
an increase in insulin requirement, thus fueling a vicious cycle which promotes disease 
93 
progression [35]. A Swedish study confirmed the deleterious effects of weight gain after 
94 
diabetes diagnosis, as it demonstrated that patients with newly diagnosed diabetes who 
95 
gain, rather than lose or maintain weight, are at a significantly increased risk of 
96 
cardiovascular death [36]. 
97 
 
98 
5. Hypoglycemia is a common side effect of intensive insulin treatment and has far 
99 
reaching consequences. 
100 
Hypoglycemia has a greatly underestimated effect on patients’ life and beyond. Even 
101 
seemingly minor hypoglycemic events create treatment related anxiety, heighten social 
102 
anxiety, can limit or interfere with the patients’ professional and social life, and can lead 
103 
to treatment noncompliance. Hypoglycemia, especially severe hypoglycemia, has also 
104 
been associated with untoward medical consequences like dementia, cardiovascular risk, 
105 
seizures, and even death [30]. It also carries a great financial burden both in direct cost 
106 
related to the event, as well as indirect costs like lost wages and work absenteeism [31]. 
107 
The effects of hypoglycemia reach beyond the patient, affecting the psychological, social, 
108 
and financial well-being of the whole family [37]. 
109 
 
110 
6. We need treatment algorithms which are patient-centric and offer the best overall 
111 
benefit, rather than a glucose-centric approach. 
112 
With an ever increasing focus on personalized patient-centric treatment [12, 13], there is 
113 
a renewed focus on patient-related outcomes, including treatment burden and quality of 
114 
life. Insulin treatment requires an increased level of diabetes education, more intensive 
115 
glycemic monitoring, a heightened awareness for potential side effects, a larger daily 
116 
time commitment, all with potential negative effect on quality of life and treatment 
117 
satisfaction [31, 37, 38]. The increase in treatment acuity related to insulin translates into 
118 
higher healthcare related costs, a very timely concern for our economy [9-11, 31].  
119 
 
120 
7. GLP-1 agonist have pleiotropic effects which target the core pathophysiologic 
121 
abnormalities in type 2 diabetes. 
122 
GLP-1 agonists have been a relatively recent addition to our diabetes treatment 
123 
armamentarium. They exert many beneficiary actions, counteracting many of the basic 
124 
pathophysiologic determinants of diabetes: enhance glucose stimulated insulin secretion, 
125 
suppress glucagon production, promotes satiety, decreases food intake, improves insulin 
126 
sensitivity, lower ectopic fat deposition (i.e. liver steatosis, visceral fat), etc. GLP-1 
127 
agonists lower HbA1c by 1.5-2%, have a very low risk of hypoglycemia, and promote 
128 
weight loss – all very desirable effects in patients with type 2 diabetes [35]. While this 
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treatment does require an injection, it is very easy to use, does not require continuous 
130 
treatment titration, and greatly reduces the need for frequent glucose self-monitoring. All 
131 
these attributes make it quite an appealing treatment alternative for patients with type 2 
132 
diabetes. In the current diabetes treatment guidelines it is recommended as a second or 
133 
third line agent after metformin failure. 
134 
 
135 
8. The combination of basal insulin and GLP-1 agonists has been proven to be safe and 
136 
very effective. 
137 
A meta-analysis of pooled data from across the LEAD program demonstrated that in 
138 
patients with baseline HbA1c of > 9%  liraglutide was better than glargine as an add on to 
139 
oral hypoglycemic medications with average reduction in HbA1c of 1.9% [39]. Several 
140 
other studies support equal or superior HbA1c reduction when a GLP-1 agonist is added 
141 
to  background therapy and compared to basal insulin, with the additional benefit of 
142 
weight loss and minimal hypoglycemia [40-43]. GLP-1 agonist has also demonstrated 
143 
superiority when added to maximized basal insulin therapy and metformin, when 
144 
compared to prandial insulin alone [40, 44-48]. Furthermore, treatment with GLP-1 
145 
agonist in combination with basal insulin was shown to have a synergistic effect on 
146 
glycemic control, with GLP-1 agonists exerting an insulin sparing effect, as well as 
147 
ameliorating or eliminating the undesirable weigh gain associated with insulin therapy. 
148 
 
149 
The current evidence suggests the combination of metformin, GLP-1 agonist, and basal 
150 
insulin to be the most effective and simple strategy to achieve near normal glycemia in 
151 
patients with a baseline HbA1c < 10%, while avoiding the side effects of weight gain, 
152 
complexity of care, and  hypoglycemia associated with insulin alone, or post-prandial 
153 
hyperglycemia, weight gain, and hypoglycemia from the association of basal insulin to 
154 
orals agents [40, 41, 43-48]. It is still not known whether these favorable effects extent to 
155 
the more challenging group of patients with type 2 diabetes who have a baseline HbA1c 
156 
>10%. Liraglutide reduces blood glucose by several mechanisms independent of insulin 
157 
secretion and its superior effect on HbA1c and weight loss was found to be largely 
158 
independent of diabetes duration and baseline HbA1c [39]. Treatment with GLP-1 
159 
agonists has also been associated with low secondary failure rates, durable and sustained 
160 
long term blood glucose control, and durability of the initial weight loss [39, 42, 49].  
161 
 
162 
Given all these distinct properties of GLP-1 agonists and simplicity of use, we 
163 
propose they could represent a viable alternative to intensive insulinization in 
164 
patients with very uncontrolled (HbA1c >10%) type 2 diabetes. 
165 
 
166 
The aim of this study is to compare a GLP-1 plus basal insulin treatment regimen to a 
167 
basal-bolus treatment regimen in patients with very uncontrolled (HbA1c>10%) type 2 
168 
diabetes. We will compare the two regimens with respect to efficacy in improving 
169 
glycemic control, rate of hypoglycemia, change in weight, effect on patient quality of 
170 
life, treatment burden, physician time, as well as healthcare related cost. We hypothesize 
171 
that the two treatment regimens will have equal effectiveness, while the GLP-1 based 
172 
regimen will be superior with respect to all other variables.  
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We chose to focus on a specific patient population which is generally considered to be 
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most challenging to manage, use up greater heathcare resources, have higher potential for 
176 
morbidity, and have traditionally been excluded from most clinical trials. Therefore this 
177 
study will fill in an existing knowledge gap and provide high level evidence for future 
178 
diabetes treatment guidelines pertaining to this patient population. We will obtain 
179 
information not only in regards to the effectiveness of the treatment, but also safety and 
180 
impact on healthcare cost beyond the cost of the drug.  
181 
 
182 
Our findings will have great impact on the way we treat this – unfortunately – significant 
183 
segment of the diabetic population, with huge potential benefits beyond just glycemic 
184 
control, including quality of life, other metabolic co-morbidities, healthcare cost, etc. 
185 
Additionally, if our proposed alternative regimen proves to be superior, this would 
186 
represent a simple treatment alternative that primary care physicians can easily initiate 
187 
and manage in their office, mitigating the need for referral to the specialist – representing 
188 
a further healthcare cost control in addition to that observed in our study and a small step 
189 
in alleviating the huge shortage of endocrinologists nationwide. 
190 
 
191 
We are uniquely positioned to perform this study for multiple reasons: (1) we serve 
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the largest county hospital in the US where this specific study population is greatly 
193 
overrepresented; (2) our county hospital is a closed healthcare system, where all 
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actual health-care related costs incurred by these patients can be readily captured; 
195 
(3) the PI (and sub-I) have extensive clinical experience with this study population; 
196 
(4) the PI has extensive clinical research experience, with proven track record of 
197 
successfully designing clinically relevant studies and caring out to final completion 
198 
even the most challenging research protocols. 
199 
 
200 
 
201 
SPECIFIC OBJECTIVES: 
202 
We plan to evaluate a new GLP-1 based treatment strategy for patients with very 
203 
uncontrolled (HbA1c>10%) type 2 diabetes and compare it to a standard basal-bolus 
204 
insulin regimen. 
205 
 
206 
Primary Specific Aim: To determine the non-inferiority of the basal insulin-GLP-1 
207 
agonist combination therapy to full basal-bolus insulin combination therapy in patients 
208 
with very uncontrolled (HbA1c>10%) type 2 diabetes. 
209 
 
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Specific aims: 
211 
1. Compare the two treatment regimens with respect to a disease and patient-
212 
relevant composite outcome of effectiveness (HbA1c <7%) and safety (no 
213 
hypoglycemia and no weight gain); 
214 
2. Compare the two treatment regimens with respect to treatment burden (number of 
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daily shots, amount of glucose self-monitoring, need for treatment titration); 
216 
3. Compare the two treatment regimens with respect to quality of life [as measured 
217 
by a disease specific (DQOL) questionnaire and general heath (SF-36) 
218 
questionnaire]; 
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4. Compare the two treatment regimens with respect to all healthcare related costs: 
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actual cost of the pharmacologic agents, glucose monitoring supplies, all other 
221 
pharmacologic (non-study related) and non-pharmacologic healthcare related 
222 
costs (outpatient and inpatient, diabetes related and non-diabetes related). We will 
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also compare actual physician time spent during office visits and non-visit related 
224 
care of these patients. While no actual dollar amount can be attached to this 
225 
(phone visits and longer office visits required by the need for extra patient 
226 
education are not customarily reimbursable) time commitment is of great 
227 
relevance to our physicians who care for these very complex patients. 
228 
 
229 
Primary outcome:  
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Change in HbA1c from randomization to 26 weeks of therapy. 
231 
 
232 
Secondary outcomes: 
233 
1. The main secondary outcome is a less traditional but very patient-centric and 
234 
clinically meaningful composite outcome of HbA1c <7% AND no documented 
235 
hypoglycemia (capillary glucose level <56 mg/dl) AND no significant weight 
236 
gain (<3% body weight) during the 6-mo study follow-up; 
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2. % reaching target HbA1c of <7% at end of study; 
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3. 7-point glucose profile results; 
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4. % patients reaching pre-specified “treatment failure” outcome; 
240 
5. Change in weight from baseline (both absolute weight lost and percent of body 
241 
weight); 
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6. % patients with weight loss >5% of body weight; 
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7. Number of hypoglycemic episodes defined as mild (symptoms of hypoglycemia 
244 
confirmed by a CBG reading of <70 mg/dl), moderate (any CBG reading <56 
245 
mg/dl), severe (need for help to recover regardless of CBG reading); 
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8. Number of patients experiencing any hypoglycemic episodes; 
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9. DQOL questionnaire score; 
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10. SF-36 questionnaire score; 
249 
11.  Number of daily injections; 
250 
12. Total daily dose of insulin; 
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13.  Health care cost, total; 
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14.  Health care cost, diabetes-related; 
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15.  Total number of CBG checks/study; 
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16.  Number of CBG checks/month; 
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17.  Number of titration events by healthcare professional; 
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18.  Number of titration events by patient; 
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19.  Healthcare provider time during scheduled  office (minutes/visit); 
258 
20.  Healthcare provider time, unscheduled (total minutes); 
259 
21.  Compliance with pharmacologic therapy; 
260 
22. Change in LDL cholesterol from baseline; 
261 
23. Change in Triglycerides from baseline; 
262 
24. Tolerability - defined as percentage of patients with side effects (other than 
263 
hypoglycemia) related to the study medications; 
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25. Tolerability - defined by percentage of patients dropping out of the study due to 
265 
side effects related to the study medications. 
266 
 
267 
 
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RESEARCH DESIGN AND METHODS 
269 
Study type: 
270 
 Single Center (UT Southwestern Medical Center at Dallas, TX) 
271 
 Randomized 
272 
 Single blind (evaluator) 
273 
 Two treatment arms (treatment and control) 
274 
 Length of intervention: 6 months 
275 
 Efficacy & safety trial 
276 
 Non-inferiority trial for primary outcome 
277 
 
278 
Study Design:  
279 
We will conduct a prospective, randomized, single blind, two-arm, parallel trial 
280 
comparing two treatment regimens (liraglutide, detemir, and metformin versus aspart, 
281 
detemir, and metformin) in patients with very uncontrolled (HbA1c>10%) type 2 
282 
diabetes. The investigator performing the study related measurements will be blinded to 
283 
the patients’ treatment assignment. 
284 
 
285 
 
286 
Figure 1: Study design showing the run-in period, followed by the randomization visit 
287 
and the 6-mo intervention period. 
288 
 
289 
The University of Texas Southwestern Medical Center Institutional Review Board will 
290 
review the study and approve all relevant documents. Furthermore, study approval will be 
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obtained from Parkland Health and Hospital System (PHHS), which represents the study 
292 
site. 
293 
 
294 
Rationale for study Design 
295 
 The randomized design, with stratification for pertinent variables, will allow us to 
296 
fully compare the effects of the two treatment algorithms in this hard to treat 
297 
patient population. 
298 
 A 3-7 day run-in period was introduced in order to ensure patient compliance with 
299 
study procedures prior to randomization. 
300 
 The patient-guided titration schedule for basal insulin is well validated in the 
301 
literature and should help to lower fasting glucose level within a shorter period of 
302 
time. 
303 
 A 6-month intervention period was chosen as nadir HbA1c after initiation of a 
304 
treatment regimen is achieved by this time, therefore allowing us to evaluate the 
305 
full effectiveness of these interventions.  
306 
 
307 
Study Population:  
308 
Inclusion Criteria: 
309 
1. Informed consent obtained before any trial-related activities;  
310 
2. Both genders and all ethnicities; 
311 
3. Currently receiving medical care at Parkland Health and Hospital System (PHHS), 
312 
Dallas, TX; 
313 
3. Age > 18 years; 
314 
4. Diagnosis of Type-2 Diabetes, regardless of time since diagnosis; 
315 
5. Confirmed HbA1c >10%. 
316 
 
317 
 
318 
Exclusion criteria: 
319 
1. Age <18 as the feasibility and safety of this treatment regimen should be first 
320 
established in the adult population; if successful, a subsequent pediatric study will 
321 
be proposed; 
322 
2. Current use (within the past 30 days) of prandial-insulin; 
323 
3. Current use (within the past 30 days) of GLP-1 analogues or DPP-4 inhibitors; 
324 
4. Type 1 diabetes as purposefully withholding meal-time insulin is contraindicated; 
325 
5. Clinical state requiring inpatient admission/treatment; 
326 
6. Contraindication or strong cautions to any of the study medications: 
327 
a. eGFR <30 ml/min if already on metformin, or eGFR<45 ml/min is not 
328 
currently on metformin (per metformin label) 
329 
b. History of lactic acidosis (per metformin label) 
330 
c. Advanced hepatic or cardiac disease (per metformin label) 
331 
d. Age >80 years (per metformin label) 
332 
e. Chronic alcohol use (>14 drinks/week) 
333 
f. History of pancreatitis (per liraglutide label) 
334 
g. Personal or family history of medullary thyroid cancer or MEN syndrome 
335 
(per liraglutide label) 
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h. Pregnancy, intention of becoming pregnant, or lactation (per liraglutide 
337 
label)  
338 
i. Female of reproductive age not using adequate contraceptive methods (per 
339 
liraglutide label). Adequate contraceptive measures include sterilization, 
340 
intrauterine devices, oral contraceptives, approved hormonal implant, 
341 
diaphragm with spermicide or condom with spermicide; 
342 
7. Any serious or unstable medical condition as it would interfere with treatment 
343 
assignment as well as outcome measurement; 
344 
8. Any scheduled elective procedures/surgeries; 
345 
9. Active infections, including osteomyelitis; 
346 
10. Not willing to participate, unable to keep projected appointments, unwillingness 
347 
to receive injectable treatment; 
348 
11. Known or suspected allergy to any of the trial products or related products; 
349 
12. Prior participation in this or another trial, or receipt of any investigational drugs 
350 
within 3 months prior to screening; 
351 
13. Non-English speaking patients are excluded for safety reasons.  
352 
 
353 
Rationale for Study Population 
354 
Patients who have a very elevated HbA1c (>10%) are thought to have significant glucose 
355 
and lipotoxicity and the current guidelines recommend initiation of a full insulin regimen. 
356 
This is a difficult to treat population, as they generally have more advanced disease, less 
357 
beta-cell reserve, and, often time, poor compliance. Finding a simpler, safer, and effective 
358 
treatment algorithm for these patients would have a great impact on the rate of 
359 
comorbidities, as well as healthcare cost. This is also a population traditionally excluded 
360 
from all regulatory studies, therefore little information is available on how to best 
361 
approach their treatment. 
362 
 
363 
Rationale for Study Location 
364 
Only patients from the PHHS system will be recruited. PHHS is a county hospital that 
365 
provides comprehensive care (primary, specialty, inpatient and outpatient) to the indigent 
366 
population of Dallas County. EPIC is the electronic medical record that is deployed at all 
367 
sites and covers all aspects of care, including financial data. Therefore PHHS is the ideal 
368 
location to conduct this study, as all patient-related information is captured and can be 
369 
queried at multiple levels, including cost. 
370 
 
371 
Randomization Criteria 
372 
1. Patient returned a fully completed 7-point glucose profile – suggesting likely 
373 
compliance with proposed study procedures. 
374 
 
375 
Withdrawal Criteria 
376 
1. The subject may withdraw consent at any time. 
377 
2. Severe drug-related side effects including (but not limited to) acute pancreatitis, 
378 
severe nausea and/or vomiting, renal failure, diagnosis of medullary thyroid 
379 
cancer, or hypersensitive to any study drug.   
380 
3. Pregnancy or intention of becoming pregnant. 
381 
4. Subject’s diabetes control remains unchanged or becomes worse. 
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5. Subject participation in the research is no longer safe 
383 
6. The researchers believe that other treatment may be more helpful. 
384 
7. The sponsor or the FDA stops the research for the safety of the participants. 
385 
8. The sponsor cancels the research. 
386 
9. Subject is unable to keep appointments or to follow the researcher’s instructions. 
387 
 
388 
Subject Replacement 
389 
Subjects who withdraw or become ineligible will not be replaced. A drop-out rate of 12% 
390 
is estimated and already calculated in the recruitment plan. 
391 
 
392 
Study Schedule 
393 
Recruitment: 
394 
We will recruit patients from the following locations within the PHHS: emergency room 
395 
(only if discharged home after the evaluation), primary care clinics, any specialty clinic 
396 
(including diabetes clinic). Eligible patients will be informed about the trial by their 
397 
treating physician. If agreeable, they will be contacted by the study staff and a screening 
398 
appointment scheduled as soon as feasible (within days).  
399 
 
400 
Screening Visit (visit 1): 
401 
During the screening visit patients will complete the informed consent process and will 
402 
undergo a complete assessment for all inclusion and exclusion criteria. A complete 
403 
medical history and comprehensive physical examination will be performed. Blood will 
404 
be drawn (if not done within the past 7 days) to assess for all eligibility criteria (HbA1c, 
405 
creatinine, liver function tests and pregnancy test, if applicable). Patients will receive an 
406 
identification card with information about participation in the study. Patients will be 
407 
asked to complete a 7-point glucose profile on the day prior to their next visit. 
408 
 
409 
Randomization (visit 2):  
410 
Randomization will occur at the second visit (3-7 days from visit 1-screening). The study 
411 
statistician will generate a blocked randomization scheme (1:1) stratified by “any insulin 
412 
treatment at time of screening” (yes/no) and BMI (cutoff 37 kg/m2 – the average BMI of 
413 
this study population in our PHHS Diabetes Clinic). 
414 
 
415 
At this visit we will obtain a full baseline evaluation of all outcome parameters. All 
416 
patients will meet with the dietician to received education regarding recommended 
417 
lifestyle modifications. Patient will undergo diabetes education as well as teaching 
418 
regarding insulin injection and titration. 
419 
 
420 
Phone follow-up/ Drug titration visit: 
421 
At 2-wk from randomization (visit 3) a phone visit will take place to assess for safety 
422 
parameters (particularly hypoglycemia) and perform protocol-driven treatment titration. 
423 
 
424 
Follow-up visits:  
425 
At 1-, 3-, and 6-months (visits 4, 5, 6) patients will be followed-up in person for interim 
426 
(and end of study, respectively) evaluations of all outcome parameters, as well as 
427 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
11
protocol-driven treatment titration. A 7-point glucose profile will be repeated prior to the 
428 
last visit in the study. 
429 
 
430 
Interventions: 
431 
Both groups will either continue or initiate treatment with metformin. To minimize 
432 
gastrointestinal side effects metformin will be initiated at 500 mg daily (or continued at 
433 
current dose) and titrated weekly in 500 mg increments to the final dose of 1000 mg 
434 
twice daily (or maximum tolerated dose which should be at least 500 mg BID). 
435 
 
436 
Both groups will be initiated on basal insulin detemir. If new to insulin, this will be 
437 
started at 0.3 units/kg once daily at bedtime and self-titrated based on the study protocol 
438 
(see detemir patient self-titration table). If already on basal insulin, will take the total 
439 
daily dose of basal insulin and perform a 1:1 dose conversion  to insulin detemir, which 
440 
will be administered once daily at bedtime, followed by the same titration. Additionally, 
441 
physician-directed titration will occur, if needed, during the scheduled phone and/or 
442 
office visits, as well as any unscheduled patient-initiated visits (phone/in person, if 
443 
applicable). All patients new to insulin will be seen by the diabetes educator to receive 
444 
instruction in insulin injection techniques. 
445 
 
446 
Detemir patient self-titration table: 
447 
 Fasting Blood glucose 
 Change in your insulin dose  
<45 
Decrease by 5 units 
<70 mg/dL 
Decrease by 3 units 
71- 100 mg/dL 
No change in your insulin dose  
101-120 mg/dL 
Increase by 1 units 
 
448 
Patients randomized to liraglutide will stop any insulin products besides detemir (if 
449 
applicable), initiate liraglutide at 0.6 mg/day, and  dose escalate weekly to 1.2 mg/dl and 
450 
final dose of 1.8 mg/dl. Patients who develop significant and persistent gastrointestinal 
451 
side effects  are allowed to down-titrate  the dose of liraglutide to 1.2 mg/dl  for 1 week 
452 
or until the side effect resolve.   
453 
 
454 
Patients randomized to meal-time insulin will initiate insulin aspart before each meal. 
455 
Aspart insulin will be initiated at a dose of 0.3 units/kg/day divided among the number of 
456 
meals taken daily. Meal-time insulin titration, if needed, can be either patient driven (see 
457 
table below) or physician-directed during the scheduled follow-up visits (phone or in 
458 
person), as well as any unscheduled patient-initiated visits (if applicable). 
459 
 
460 
Novolog patient self-titration table: 
461 
Glucose 
prior to 
lunch 
Change in 
breakfast 
insulin dose 
Glucose 
prior to 
dinner 
Change in 
lunch insulin 
dose 
Glucose 
prior to 
bedtime 
Change in 
dinner 
insulin dose 
<54 
-2 units 
<54 
-2 units 
<54 
-2 units 
55-69 
-1 unit 
55-69 
-1 unit 
55-69 
-1 unit 
70-120 
No change 
70-120 
No change 
70-130 
No change 
121-160 
+1 unit 
121-160 
+1 unit 
131-180 
+1 unit 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
12
>160 
+2 units 
>160 
+2 units 
>180 
+2 units 
 
462 
Rescue therapy: 
463 
Should any patients randomized to liraglutide treatment experience persistent 
464 
hyperglycemia (defined as a confirmed Hb1c>10%) at the 3-mo visit (visit 5), meal-time 
465 
insulin aspart will be initiated per the same protocol as above. This is a pre-specified 
466 
“treatment failure” end-point. Following initiation of rescue therapy patients will 
467 
continue all scheduled visits and procedures through the end of the trial. 
468 
 
469 
Should any patients randomized to the “standard of care” group experience persistent 
470 
hyperglycemia (defined as a confirmed HbA1c >10%) at the 3-mo visit (visit 5), 
471 
treatment and insulin titration will continue as scheduled. This is also a pre-specified 
472 
“treatment failure” end-point. 
473 
 
474 
A graphical review of the visit procedures and timing is presented below:  
475 
Visit 
1 
2 
3 
4 
5 
6 
Time 
3-7 
days 
0 
2 weeks 
1 
month 
3 
months 
6 
months 
Type 
Office 
Office 
Phone 
Office 
Office 
Office 
Consent 
x 
  
  
  
  
  
I&E criteria 
x 
  
  
  
  
  
Randomization criteria 
  
x 
  
  
  
  
Randomization 
  
x 
  
  
  
  
Physical exam 
x 
  
  
x 
x 
x 
Height 
x 
  
  
  
  
  
Vitals (weight, BP, pulse) 
x 
x 
  
x 
x 
x 
Dietary counseling 
x 
x 
x 
x 
x 
x 
Lifestyle counseling 
x 
x 
x 
x 
x 
x 
7-point glucose 
  
x 
  
  
  
x 
Labs (HbA1c, lipids, CMP, Hb) 
x 
  
  
  
x 
x 
Dispense trial drug 
  
x 
  
x 
x 
  
Hypoglycemia assessment 
X  
X  
X  
x 
x 
x 
Frequency of glucose monitoring 
  
  
  
x 
x 
x 
Titrate insulin 
  
x 
x 
x 
x 
  
Liraglutide titration (if applicable) 
  
  
x 
  
  
  
Insulin dose assessment 
  
x 
x 
x 
x 
x 
Compliance assessment 
  
  
  
x 
x 
x 
# daily injections 
  
  
  
x 
x 
x 
QoL questionnaires (DQOL and 
SF36) 
  
x 
  
  
  
x 
AE and SAE assessment 
  
x 
x 
x 
x 
x 
Pregnancy test (if needed) 
x 
x 
  
x 
x 
x 
Physician time assessment 
  
x 
x 
x 
x 
x 
Healthcare cost data extraction 
  
  
  
  
  
x 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
13
 
476 
Dietary Modifications: 
477 
Counseling regarding the type and amount of food consumed with strong encouragement 
478 
to count carbohydrates and/or calories will be performed for all patients by the dietitian at 
479 
visit 2 and investigator at visits 3-5. 
480 
 
481 
Lifestyle Modifications: 
482 
All patients will receive recommendations regarding type/amount/intensity of physical 
483 
activity and be provided future goals at visit 1. Reinforcement of these objectives will 
484 
take place at visits 2-5.  
485 
 
486 
Assessments for Efficacy 
487 
1. HbA1c – measured at screening, visit 5 (3-months) and end of study (6 months). 
488 
Samples are processed immediately and stored at 0-5°C. It will be analysed within 24 
489 
hrs at the UT Southwestern Medical Centre Diabetes laboratory using an HPLC 
490 
technique. The laboratory is accredited by the National Glycohemoglobin 
491 
Standardization Program. HbA1c interassay coefficient of variability is ≤2%, and the 
492 
intra-assay variability is ≤0.3%.  
493 
2. Weight - will be measured at each office visit using the same calibrated digital scale, 
494 
while patients wearing no shoes and only light clothing. 
495 
3. Total daily insulin dose – will be calculated in units/kg at each visit by summing all 
496 
insulin shots of all types over a 24 hrs period. The average of the 3 most recent 24 hrs 
497 
prior to each visit will be used. 
498 
4. Number of daily injections – will be counted at each visit, by adding all shots 
499 
regardless of the type of insulin. The average of the 3 most recent 24 hrs prior to each 
500 
visit will be used. 
501 
5. Systolic and diastolic blood pressure - will be measured in sitting position using an 
502 
Omron digital manometer, on the right arm, after 5 minutes of rest. 
503 
6. Lipid profile, liver function test, haemoglobin - will be collected at screening, 3-
504 
months, and end of study in fasting state. The blood will be processed and analysed 
505 
immediately by PHHS Clinical Laboratory. 
506 
7. 7-point glucose measurement – will be performed by the patient on the day prior to 
507 
the randomization visit and prior to the end-of-study visit. 
508 
8. Frequency of glucose monitoring – will be assessed by downloading the glucose 
509 
monitor. Average number of readings/day will be recorded at each visit. 
510 
 
 
511 
Assessments for Safety 
512 
All safety assessments are performed at each visit, in person or by phone. Any 
513 
unanticipated or serious adverse events will be reported to the local IRB and  FDA in 
514 
accordance with local guidelines. 
515 
 
516 
1. Hypoglycemia – All plasma glucose values ≤ 70 mg/dL, as well as values >70 
517 
mg/dL when hypoglycemic symptoms have occurred, should be recorded by the 
518 
subjects in the blood glucose diaries provided at each visit. The recording should 
519 
include: 
520 
• 
date of hypoglycemic episode 
521 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
14
• 
time of hypoglycemic episode 
522 
• 
time of last main meal prior to episode 
523 
• 
whether the episode was symptomatic 
524 
• 
whether the episode was in relation to exercise 
525 
• 
whether seizure or coma developed 
526 
• 
 whether the subject was able to treat him/herself 
527 
• 
the plasma glucose level before treating the episode 
528 
 
529 
The following definitions for hypoglycemia will be used: 
530 
• 
Mild- Symptomatic or asymptomatic hypoglycemia with blood glucose 56-69 
531 
mg/dl and subject was able to treat him/herself 
532 
• 
Moderate- Symptomatic or asymptomatic hypoglycemia with blood glucose <56 
533 
mg/dl and subject was able to treat him/herself  
534 
• 
Severe- Blood sugar <70 mg/dl or symptoms highly suggestive of hypoglycemia 
535 
and the subject needed assistance to be treated with carbohydrates, glucagon, or 
536 
other resuscitative actions 
537 
• 
Nocturnal hypoglycaemia- blood glucose <70 with a time of onset between 00:01 
538 
and 05:59 (both included) 
539 
• 
Relative Hypoglycemia- Blood glucose >69 mg/dl with symptoms highly 
540 
suggestive of hypoglycemia 
541 
• 
Probable symptomatic hypoglycemia- Symptoms highly suggestive of 
542 
hypoglycemia but subject did not measure blood glucose.  
543 
 
544 
2. Other treatment specific side effects 
545 
• Nausea, vomiting, diarrhea, and headache; 
546 
• Abdominal pain suspicious for pancreatitis would prompt immediate physician 
547 
evaluation and laboratory testing for amylase and lipase measurement which 
548 
would be processed immediately and analysed by PHHS Clinical Laboratory.  
549 
3. Pregnancy Test- females of childbearing potential will have urine pregnancy test 
550 
(human chorionic gonadotropin, hCG) performed if clinically indicated in the 
551 
assessment of the investigator. Urine-stick pregnancy test will be performed for 
552 
females of childbearing potential at any time during the trial, if a menstrual period is 
553 
missed or if the participant voices concern. 
554 
 
555 
Other Assessments 
556 
Treatment satisfaction and quality of life will be assessed at the randomization visit (Visit 
557 
2) and end of study (Visit 6) using a modified DQoL and SF-36 questionnaires.  Total 
558 
score as well as individual domain scores will be analysed and reported. 
559 
 
560 
Subject Compliance: Participants will bring all study medication to each appointment for 
561 
review and study drug will be distributed at each appointment (visit 1, 2, 3, 4, and 5). 
562 
Percent compliance will be calculated and recorded at each visit. 
563 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
15
 
564 
Healthcare Cost Assessment: At the conclusion of the study, the EPIC integrated medical 
565 
record system will be queried for the data regarding all healthcare related expenditures. 
566 
From this information a data subset of diabetes-related expenditure will also be reported.  
567 
 
568 
Physician Time Assessment: Each physician interaction (office visit or phone visit) will 
569 
be timed to compare the two treatment regimens with respect to burden on healthcare 
570 
provider’s time. 
571 
 
572 
 
573 
RISKS ASSOCIATED WITH THE PARTICIPATION IN THE STUDY: 
574 
Risks of Liraglutide: 
575 
  
576 
Very common (reported by more than 10 percent  of the patients): 
577 
 -  Gastrointestinal adverse events are the most common side effect of liraglutide 
578 
and reported in up to 41% of patients. Nausea is seen in approximately 13% of 
579 
patients treated with liraglutide and is usually developed in the first 2 weeks. It 
580 
tends to be mild, dose-related and decline over time. In some patients the nausea 
581 
can be more severe and be associated with vomiting which is usually transient 
582 
and self-resolving. 
583 
 
584 
Common (reported by 5-10 percent of the patients) 
585 
 Low blood sugar (hypoglycemia) - - The risk of having hypoglycemia with 
586 
liraglutide is higher if taking it with another medicine that can cause 
587 
hypoglycemia, such as a sulfonylurea or insulin. In some people, the blood 
588 
glucose may get so low that they need another person to help them. The dose of 
589 
your sulfonylurea medicine or insulin may need to be lowered while using 
590 
liraglutide.  
591 
 Headache and upper respiratory tract infections have been reported in 7-9% of 
592 
patients treated with liraglutide. A similar percentage of patients developed 
593 
headaches with placebo or comparator drug.  
594 
 
595 
Uncommon side effects (reported by 1-5 percent of the patients):  
596 
 Injection site reactions (e.g., injection site rash, erythema) were reported in 
597 
approximately 2% of liraglutide treated patients in the five clinical trials of at 
598 
least 26 weeks duration. Less than 0.2% of liraglutide-treated patients 
599 
discontinued due to injection site reactions. 
600 
 
601 
Very rare  side effects (affects less than 1 percent of patients)  
602 
 Acute pancreatitis (inflammation of the pancreas) - there have been few reported 
603 
event of acute pancreatitis presenting with persistent severe abdominal pain 
604 
(usually accompanied by vomiting). Patients  experiencing the above symptoms 
605 
should contact the  study doctor who will decide on whether they should 
606 
discontinue the trial medication and /or require additional diagnostic procedures. 
607 
 Rarely, a severe form of allergic reaction (anaphylactic reaction) with additional 
608 
symptoms such as breathing problems, swelling of throat and face, fast heart beat 
609 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
16
etc. has been reported with marketed use of Liraglutide. Patients experiencing 
610 
these symptoms  should seek immediate medical help and inform the  trial doctor 
611 
as soon as possible.  
612 
 Kidney failure – Liraglutide may cause nausea, vomiting or diarrhea, leading to 
613 
loss of fluids (dehydration). Dehydration may cause kidney failure which can 
614 
lead to the need for dialysis. This can happen in people who have never had 
615 
kidney problems before. Drinking plenty of fluids may reduce the risk of 
616 
dehydration.  
617 
 
618 
Other potential risks related to liraglutide: 
619 
 Hyperglycemia  (too high blood glucose) can occur, especially if there is 
620 
insufficient treatment. . The symptoms of hyperglycemia include increased 
621 
urination, feeling thirsty, losing appetite, feeling sick (nausea or vomiting), 
622 
feeling drowsy or tired, flushed, dry skin, dry mouth and a fruity (acetone) smell 
623 
of the breath. If not treated, these symptoms may develop into a serious condition 
624 
called diabetic ketoacidosis which may even lead to death.  
625 
 Thyroid tumors, including cancer -During the drug testing process, the medicine 
626 
in Victoza caused rats and mice to develop tumors of the thyroid gland. Some of 
627 
these tumors were cancers. It is not known if Victoza will cause thyroid tumors 
628 
or a type of thyroid cancer called medullary thyroid cancer in people. If 
629 
medullary thyroid cancer occurs, it may lead to death if not detected and treated 
630 
early. If you develop tumors or cancer of the thyroid, your thyroid may have to 
631 
be surgically removed. Fibrosarcomas (cancer underneath the skin) were seen at 
632 
the point of injection (skin) in male mice that underwent a 2 year study of 
633 
liraglutide. These fibrosarcomas were attributed to the high local concentration 
634 
of drug near the injection site. The liraglutide concentration in the preparation 
635 
used for humans is 10 times higher than the concentration used in mice. It is not 
636 
known if liraglutide will cause fibrosarcomas in people. 
637 
 
638 
Risk of insulin detemir and aspart:  
639 
 
640 
Very common (1-10 in 100 patients): 
641 
 Hypoglycemia (low blood sugar) is the most common adverse reaction of insulin 
642 
therapy and may be life- threatening if severe and not treated appropriately. 
643 
 Mild-moderate weight gain is expected with any insulin therapy 
644 
 
645 
Less common (less than 1 in 100 patients): 
646 
 Severe, life-threatening, generalized allergy, including anaphylaxis, can occur 
647 
with any insulin products, including detemir insulin or aspart insulin. 
648 
 Other adverse reactions associated with detemir insulin and/or aspart insulin 
649 
include injection site reactions, lipohypertrophy, rash, itching. 
650 
 Needles and insulin pens should never be shared. 
651 
 
652 
Risk of Metformin:  
653 
 
654 
Very common (1-10 in 100 patients): 
655 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
17
• 
Abdominal or stomach discomfort 
656 
• 
Decreased appetite 
657 
• 
Diarrhea 
658 
• 
Bloating 
659 
• 
Low serum Vitamin B12 levels without clinical manifestations 
660 
 
661 
Precautions:  
662 
 Lactic Acidosis: Lactic acidosis is a very rare, but serious, metabolic complication 
663 
that can occur due to Metformin accumulation during treatment with Metformin 
664 
HCl; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis 
665 
may also occur in association with a number of pathophysiologic conditions, 
666 
including diabetes mellitus.  Metformin should be discontinued immediately and 
667 
health care provider should be promptly notifed if unexplained increase in 
668 
breathing rate, muscle aches, fatigue and unusual somnolence occur. 
669 
 Patients with Renal disease or renal dysfunction (e.g., as suggested by eGRF <30 
670 
ml/min) should not use metformin 
671 
 Metformin should be temporarily discontinued 48h prior to radiologic studies 
672 
involving intravascular administration of iodinated contrast materials 48h prior to 
673 
procedure to avoid increased risk of development of lactic acidosis and restarted 
674 
24h after the procedure. 
675 
 Excessive alcohol intake, either acute or chronic should be avoided while 
676 
receiving Metformin. 
677 
 
678 
SAFEGUARDS AND PRECAUTIONS TO MINIMIZE RISKS/HARMS: 
679 
 Hypoglycaemia episodes will very closely monitored trough the study using self-
680 
glucose monitoring. Review of blood glucose diary and hypoglycaemic events 
681 
will be discussed during office, phone visits and as needed. Patient will be 
682 
instructed during randomization visit on how to proper handle mild, moderate and 
683 
severe hypoglycemic episodes and how to reduce their basal insulin doses 
684 
according to study protocol. Those instructions will be reinforced as needed 
685 
during the study.  
686 
 
687 
 Should any patients randomized to liraglutide treatment experience persistent 
688 
hyperglycemia (defined as Hb1c>10%) at the 3-mo visit (visit 5), meal-time 
689 
insulin aspart will be initiated per the same protocol as the standard group 
690 
 
691 
 Should any patients randomized to the “standard of care” group  experience 
692 
persistent hyperglycemia (defined as HbA1c>10%) at the 3-mo visit (visit 5), 
693 
treatment and insulin titration will continue as scheduled.    
694 
 
695 
 Patients will be monitored closely for any drug-related side effects. They will be 
696 
provided with instruction on when to call the PI and a direct phone line, so they 
697 
can immediately report any problems or concerns. Instructions will be given on 
698 
possible side effects and how to avert/minimize them. 
699 
 
700 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
18
 Only qualified personnel will perform blood draws to minimize the risk of 
701 
complications. 
702 
 
703 
 Patients are allowed to skip questions on the questionnaire should they feel that 
704 
the question might pose a psychological burden.      
705 
 
706 
 
707 
STATISTICAL CONSIDERATIONS: 
708 
Sample Size Calculation 
709 
We propose to test a non-inferiority hypothesis comparing the 6-month change from 
710 
baseline in HbA1c between the two treatment groups, with a non-inferiority margin of 
711 
0.4%. We conservatively estimate the standard deviation of the difference at 0.5% based 
712 
on results from reported studies with similar design[44, 45, 47]. Using a one-sided alpha 
713 
of 0.025, we determine that 44 subjects per group completing 6 months will provide 
714 
power 0.96 to test this non-inferiority hypothesis, shown below amongst with other 
715 
scenarios (Hintze, J. (2011). PASS 11. NCSS, LLC. Kaysville, Utah, USA. 
716 
www.ncss.com). We will need to randomize 100 patients to test this hypothesis assuming 
717 
a 12% drop-out rate (estimated drop-out rate based on our extensive prior experience 
718 
with similar population and length of study). We plan to screen 120 patients to account 
719 
for approximately 20% anticipated screen failures. 
720 
 
721 
Power and sample size estimation for Non-Inferiority Test (H0: Diff >= NIM; 
H1: Diff < NIM) 
Higher Means are Worse 
Test Statistic: T-Test 
Non-
Inferiority 
Actual 
Significance
Standard 
Margin 
Difference
Level 
Deviation1
Power
N1/N2
(NIM) 
(D) 
(Alpha) 
Beta 
(SD1) 
1.000 
44/44 
0.4 
0 
0.025 
0.000
0.3 
1.000 
48/48 
0.4 
0 
0.025 
0.000
0.3 
1.000 
50/50 
0.4 
0 
0.025 
0.000
0.3 
0.960 
44/44 
0.4 
0 
0.025 
0.040
0.5 
0.973 
48/48 
0.4 
0 
0.025 
0.028
0.5 
0.977 
50/50 
0.4 
0 
0.025 
0.023
0.5 
0.755 
44/44 
0.4 
0 
0.025 
0.245
0.7 
0.791 
48/48 
0.4 
0 
0.025 
0.209
0.7 
0.808 
50/50 
0.4 
0 
0.025 
0.192
0.7 
 
722 
Further, this sample size will yield at least 80% power at two-sided alpha=0.05, 
723 
superiority hypothesis, for the secondary composite outcome endpoint of HbA1c<7% 
724 
with no hypoglycemia and no significant weight gain, expecting that 25% and 5% reach 
725 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
19
this endpoint with liraglutide treatment and standard basal-bolus insulin treatment, 
726 
respectively. 
727 
 
728 
Randomization  
729 
Treatment assignment will occur at the second visit. The study statistician will generate a 
730 
blocked randomization scheme (1:1) stratified by “any insulin treatment at time of 
731 
screening” (yes/no) and BMI (cutoff 37 kg/m2 – the average BMI of this study 
732 
population in our PHHS Diabetes Clinic), programmed using SAS Proc Plan. 
733 
 
734 
Statistical Analysis Plan 
735 
All statistical analyses will be performed by the study statistician (Beverley Huet), who 
736 
has extensive experience in clinical trials analysis.  
737 
Primary analysis: The primary analysis will be intention-to-treat (ITT) which will include 
738 
all randomized participants who receive at least one dose of a study medication.  The 
739 
non-inferiority of liraglutide treatment strategy compared to standard basal-bolus insulin 
740 
regimen will be assessed using a 95% confidence interval for the between treatment 
741 
group net difference (month 6 minus month 0) in HbA1c at 6 months. This 95% 
742 
confidence interval will be derived from the differences of least square means estimated 
743 
from a mixed model repeated measures analysis. Non-inferiority of liraglutide treatment 
744 
will be concluded if the upper limit of the 95% confidence interval is less than the non-
745 
inferiority margin of 0.4%.    
746 
 
747 
Secondary analyses:  We will also perform a per-protocol analysis comparing HbA1c 
748 
response because, in non-inferiority hypothesis testing, the ITT analysis may be biased 
749 
toward the null hypothesis. The per-protocol population is defined as the population who 
750 
continued the assigned intervention as randomized for the duration of the study period. 
751 
Secondary outcomes include the composite endpoint of HbA1c<7% with no 
752 
hypoglycemia and no significant weight gain, a binary variable, which will be compared 
753 
between the randomized study groups with a logistic regression model. The odds ratio 
754 
and corresponding 95% confidence intervals will be reported.  From healthcare related 
755 
cost data, cost-effectiveness ratios will be summarized as point estimates with 95% 
756 
confidence intervals, accounting for the skewness in the distribution of the ratio[50]. 
757 
Sensitivity cost analyses will be performed to further assess variables such as treatment 
758 
failure and quality of life weights. Multiple logistic regression models will be constructed 
759 
to evaluate any association of baseline covariates on treatment efficacy.   Binary 
760 
secondary endpoints will also be assessed with logistic regression models. Group 
761 
comparisons and changes from baseline over time (study visits) of continuous secondary 
762 
outcome variables will be analysed with mixed model repeated analysis. The logrank test 
763 
will be used to compare the pre-specified “treatment failure” end-point between groups.  
764 
Safety endpoints and hypoglycemic and other adverse events will summarize in detail 
765 
with descriptive statistics. The analysis of safety data will be performed for the ITT 
766 
population. 
767 
Model assumptions regarding normality and covariance structure will be carefully 
768 
assessed. Nonparametric tests or data transformations will be used if necessary to meet 
769 
assumptions. Statistical analysis will be performed with SAS software (SAS Institute, 
770 
Cary NC), particularly Proc Mixed for linear models with both fixed and random effects. 
771 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
20
A two-sided alpha <5% will be considered significant for all analyses. 
772 
 
773 
Interim Analysis 
774 
No interim analysis is planned. 
775 
 
776 
DATA HANDLING AND RECORD KEEPING: 
777 
All data will be collected in strict compliance with the University’s HIPPA rules. 
778 
Research records (source documents) will be kept in a double-locked filing system in a 
779 
secure locked room.  Collected data will be stored in an electronic study database will be 
780 
encrypted and password protected and saved on the University’s secure network.  Only 
781 
study personnel will have access to these records. 
782 
 
783 
The institutional review board (IRB) governing this study may inspect the medical 
784 
records of any patient involved in this study at any time. 
785 
 
786 
Laboratory specimens will be collected under standard of care protocol at Parkland 
787 
hospital laboratory and handled in accordance with the hospital policy.  
788 
 
789 
The study blind will be maintained by the designated statistician and only broken by 
790 
request from a treating physician in case of a medical emergency. 
791 
 
792 
ETHICS: 
793 
Ethical Considerations: 
794 
1. Exclusion of non-English speakers- while translators are available during working 
795 
hours, the investigators are worried that no translator will be available to assure 
796 
safety measures at all times. 
797 
2. Compliance with Insulin Regimen- At times patients are not compliant with 
798 
complicated insulin regimens and providers often continue to uptitrate insulin 
799 
dosage when patients remain above HbA1c goal.  If patient compliance improves 
800 
once enrolled in the study, there is a higher risk of hypoglycemia.  Every effort 
801 
will be made at all visits to determine exactly what amount of insulin the patient 
802 
is taking and the overall compliance. 
803 
 
804 
Informed Consent: 
805 
Informed consent will be obtained during the first face-to-face contact.  Once a 
806 
prospective subject is identified, we will explain the study details and preliminary 
807 
eligibility is accessed either through phone or face-to-face interview.  If the prospective 
808 
volunteer remains interested in the study and fulfils preliminary eligibility criteria, 
809 
baseline studies are scheduled.  Only study personnel listed on the consent will be 
810 
permitted to obtain consent.  The subject will be provided informed consent and it will be 
811 
signed and witnessed.  The consent form will discuss the procedures to be performed at 
812 
each visit, the number of visits, and what is expected of the patient, along with all 
813 
possible side effects.  A copy will be given to the subject and the original will be kept on 
814 
file.  Potential subjects may be screened for eligibility using a study-specific HIPAA 
815 
waiver.  Volunteers who call to inquire about the study will have their demographic and 
816 
contact information collected over the phone, and the study will be described to them.  
817 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
21
Once the subject has agreed to participate and appears in person, a study specific HIPAA 
818 
Authorization will be signed, along with the consent form document. 
819 
 
820 
Confidentiality/HIPAA: 
821 
Every effort will be made to keep all information about the patient confidential. Consent 
822 
forms will be placed in the patient charts.  Research records will be kept in a double-
823 
locked filing system in a secure locked room.  The electronic study database will be 
824 
encrypted and password protected and saved on the University’s secure network.  Only 
825 
study personnel will have access to these records. 
826 
 
827 
The institutional review board (IRB) governing this study may inspect the medical 
828 
records of any patient involved in this study. 
829 
 
830 
IRB Approval: 
831 
The study is approved by the UT Southwestern IRB.   
832 
 
833 
FDA Approval: 
834 
An IND/NDA exception was granted by the FDA for possible use of rescue therapy with 
835 
prandial insulin add-on to detemir-liraglutide combination should patients in the 
836 
liraglutide arm reach the pre-defined failure end-point. 
837 
 
838 
Declarations: 
839 
This study will be conducted in accordance with the Declaration of Helsinki. 
840 
This study will be conducted in accordance with the ICH GCP guidelines. 
841 
The sponsor-investigator will comply with all applicable regulatory and legal 
842 
requirements, ICH GCP guidelines, and the Declaration of Helsinki in obtaining and 
843 
documenting informed consent. 
844 
 
845 
Study schedule: 
846 
IRB approval: December 2013 
847 
Start of Study: as soon as funding received (estimate March 2014) 
848 
Recruitment period: March 2014 – February 2015 
849 
First Patient First Visit: March 2014 
850 
Last Patient First Visit: February 2015 
851 
Last Patient Last Visit: August 2015 
852 
Final Report: October 2015 
853 
Final Manuscripts: December 2015 
854 
 
855 
STUDY DRUGS AND MATERIALS: 
856 
Study medication 
857 
Liraglutide 6 mg/ml solution for subcutaneous injection delivered in a 3 ml prefilled 
858 
disposable pen 
859 
Detemir insulin 300 units/prefilled disposable pen 
860 
Aspart insulin 300 units/prefilled disposable pen 
861 
 
862 
Provided and manufactured by NovoNordisk A/S. 
863 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
22
 
864 
NovoFine Pen needles – provided by NovoNordisk US. 
865 
 
866 
Storage and Drug Accountability of Study Medication(s) 
867 
Patients will be instructed as follows: 
868 
-Store unused pens in a refrigerator at a temperature between +2°C and + 8°C 
869 
(36°F to 46°F). Keep away from the cooling element. Do not freeze and do not 
870 
use if it has been frozen. 
871 
-Store pens in use for 30 days at room temperature (15°C to 30°C; 59°F to 86°F) 
872 
or in a refrigerator (2°C-8°C; 36°F to 46°F). 
873 
-Do not freeze and do not use if it has been frozen. 
874 
-The pen must be protected from all sources of light, and the pen cap should be 
875 
kept on when the pen is not in use. 
876 
-Product should not be used if it does not appear clear and colorless. 
877 
Investigator will ensure availability of proper storage conditions and record and evaluate 
878 
the temperature. While at the site, drug will be stored in a temperature-monitored 
879 
refrigerator at 4°C. 
880 
There will be no trial medication dispensed to any person not enrolled in the study. 
881 
Unused medication will be stored separately from used trial medication(s). 
882 
Procedures for Drug Accountability: 
883 
-At study site all trial products will be kept in locked refrigerator and counted at 
884 
regular intervals 
885 
-At study site only enough medication will be dispensed to reach next 
886 
appointment.  All medication will be counted at visits and discussed at phone 
887 
encounters. 
888 
Procedure for return of used/unused trial products: 
889 
-Unused product will be properly destroyed at the site or returned to sponsor if 
890 
requested. 
891 
 
892 
Auxiliary Supply 
893 
Subjects will use their own glucose monitors, lancet devices, and lancets. They will be 
894 
provided with log books.  
895 
Randomization 
896 
Treatment assignment will be made using stratified blocked randomization at visit 2. The 
897 
stratification variables will be prior insulin use and BMI (cut off 37 kg/m2).   The 
898 
randomization code will be generated by the study statistician using SAS software, and 
899 
consecutively numbered envelopes will be created. The investigator opens the next 
900 
envelope at the randomization visit to determine the group assignment of the patient. 
901 
 
902 
Blinding 
903 
This study is only blinded to the investigator performing the study assessments. The 
904 
study is not blinded to the patient, nor the study doctor who will be providing diabetes 
905 
care to the patient and aid in insulin titration. 
906 
 
907 
CONCOMITANT ILLNESSES AND MEDICATIONS: 
908 
Definitions: 
909 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
23
Concomitant illness: any illness that is present at the start of the trial (i.e. at the first 
910 
visit). 
911 
Concomitant medication: any medication other than the trial product(s) that is taken 
912 
during the trial, including the screening and run-in periods. 
913 
Details of all concomitant illnesses and medication will be recorded at trial entry (i.e. at 
914 
the first visit). Any changes in concomitant medication will be recorded at each visit. If 
915 
the change influences the subject’s eligibility to continue in the trial, the Sponsor will be 
916 
informed. 
917 
The information collected for each concomitant medication will include, at a minimum, 
918 
start date, stop date or continuing, and indication. 
919 
For each concomitant illness, date of onset, date of resolution or continuing, at a 
920 
minimum, will be recorded. 
921 
 
922 
ADVERSE EVENTS AND PREGNANCY: 
923 
During each contact (phone or face-to-face) the subject will be asked about adverse 
924 
events.  All serious adverse events (SAE), suspected unexpected serious adverse 
925 
reactions (SUSAR), and serious adverse drug reactions (SADR) will be evaluated by the 
926 
investigator and recorded in the patients record.  Other adverse events (AE) will be 
927 
evaluated and documented according to standard clinical practice 
928 
The sponsor-investigator will collect the following information at minimum for each of 
929 
these events: 
930 
1. Study name 
931 
2. Patient identification (e.g. initials, sex, age) 
932 
3. Event (preferably a diagnosis) 
933 
4. Drug  
934 
5. Reporter identification (e.g. Name, or initials) 
935 
6. Causality 
936 
7. Outcome. 
937 
 
938 
Definitions 
939 
 
940 
Adverse Event (AE): 
941 
An AE is any undesirable medical event occurring to a subject in a clinical trial, whether 
942 
or not related to the trial product(s). This includes events reported from the first trial 
943 
related activity after the subject has signed the informed consent and until post treatment 
944 
follow-up period as defined in the protocol. The following should not be recorded as 
945 
AEs, if recorded as medical history/concomitant illness on the CRF at screening: 
946 
• Pre-planned procedure, unless the condition for which the procedure was planned has    
947 
worsened from the first trial related activity after the subject has signed the informed 
948 
consent 
949 
• Pre-existing conditions found as a result of screening procedures 
950 
 
951 
Clinical Laboratory Adverse Event: 
952 
A clinical laboratory AE is any clinical laboratory abnormality regarded as clinically 
953 
significant i.e. an abnormality that suggests a disease and/or organ toxicity and is of a 
954 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
24
severity, which requires active management, (i.e. change of dose, discontinuation of trial 
955 
product, more frequent follow-up or diagnostic investigation). 
956 
 
957 
Serious Adverse Event (SAE): 
958 
A serious AE is an experience that at any dose results in any of the following: 
959 
• Death 
960 
• A life-threatening* experience 
961 
• In-patient hospitalisation or prolongation of existing hospitalization 
962 
• A persistent or significant disability/incapacity 
963 
• 
• A congenital anomaly/birth defectSuspicion of transmission of infectious agents via 
964 
the product.  
965 
• Important medical events that may not result in death, be life-threatening*, or require 
966 
hospitalization may be considered an SAE when, based upon appropriate medical 
967 
judgement, they may jeopardise the subject and may require medical or surgical 
968 
intervention to prevent one of the outcomes listed in this definition  
969 
*The term life-threatening in the definition of SAE refers to an event in which the subject was at risk of 
970 
death at the time of the event. It does not refer to an event which hypothetically might have caused death if 
971 
it was more severe. 
972 
 
973 
Serious Adverse Drug Reaction (SADR):  
974 
An adverse drug reaction (ADR) is an adverse event for which a causal relationship 
975 
(Possible/Probable relation) between the study drug and the occurrence of the event is 
976 
suspected. The ADR should be classified as serious if it meets one or more of the 
977 
seriousness criteria. Clinical judgement following thorough review of any event will be 
978 
used to determine the relatedness of the event to the study drug. . 
979 
 
980 
 
981 
Non-Serious Adverse Event: 
982 
A non-serious AE is any AE which does not fulfil the definition of an SAE. 
983 
 
984 
Severity Assessment Definitions: 
985 
• Mild: Transient symptoms, no interference with the subject’s daily activities 
986 
• Moderate: Marked symptoms, moderate interference with the subject’s daily activities 
987 
• Severe: Considerable interference with the subject’s daily activities, unacceptable 
988 
 
989 
Relationship to study medication Assessment Definitions: 
990 
• Probable: Good reasons and sufficient documentation to assume a causal relationship 
991 
• Possible: A causal relationship is conceivable and cannot be dismissed 
992 
• Unlikely: The event is most likely related to an etiology other than the trial product 
993 
 
994 
Outcome Categories and Definitions: 
995 
• Recovered: Fully recovered or by medical or surgical treatment the condition has 
996 
returned to the level observed at the first trial related activity after the subject signed the 
997 
informed consent 
998 
• Recovering: The condition is improving and the subject is expected to recover from the 
999 
event. This term should only be used when the subject has completed the trial 
1000 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
25
• Recovered with sequelae: As a result of the AE, the subject suffered persistent and     
1001 
significant disability/incapacity (e.g. became blind, deaf, paralysed). Any AE recovered 
1002 
with sequelae should be rated as an SAE 
1003 
• Not recovered 
1004 
• Fatal 
1005 
• Unknown 
1006 
 
1007 
Collection, Recording and Reporting of Adverse Events 
1008 
All events meeting the definition of an adverse event will be collected and reported from 
1009 
the first trial related activity after the subject has signed the informed consent and until 
1010 
the end of the study. This will be monitored by an independent committee (see below).  
1011 
All serious and unexpected adverse events will be reported using FDA form 3500.  All 
1012 
reports of SAEs/SAR/SUSARs or any events reported to the local health authorities must 
1013 
be sent to Novo Nordisk A/Swithin the same timeline used for reporting to regulatory 
1014 
authorities (see below). Further information about safety related events will be provided 
1015 
to Novo Nordisk A/S if specific requests are received. 
1016 
 
1017 
Data Safety Monitoring Board (DSMB) 
1018 
An independent DSMB will be set up for the trial to oversee safety and perform ongoing 
1019 
safety surveillance.  The DSMB will be composed of 3 members who cover the relevant 
1020 
specialty as well as an independent statistician: 
1021 
 Maria Ramos, MD (Endocrinology) 
1022 
 Sumitha Hathiramani, MD (Endocrinology) 
1023 
 Naim Maalouf, MD (Endocrinology) 
1024 
 Song Zhang, PhD (Statistician) 
1025 
The first meeting will occur after the enrolment of 15 subjects or three months after the 
1026 
first patient is enrolled, whichever comes first.  The meetings will then occur on a 
1027 
quarterly basis, although the board may request more frequent meetings as needed.  A 
1028 
formal report approved by all DSMB members will be sent to the PI and study 
1029 
coordinator within 3 weeks of the meeting and then forwarded to the IRB. 
1030 
 
1031 
All AEs will be presented at each meeting and will be available for informal review by 
1032 
the DSMB at any time after study initiation.  All SAE and unanticipated but related AE 
1033 
will be promptly reported to the IRB (within 2 working days of PI’s awareness for SAEs 
1034 
and within 10 working days for other reportable AEs).  We intend to comply with all 
1035 
local legal, regulatory, and IRB requirements. We will also report to Novo Nordisk all 
1036 
SAEs, SUSARs, and SADRs at the same time such events are reported to regulatory 
1037 
authorities or within 15 working days from the sponsor-investigator becoming aware of 
1038 
such adverse events, whichever comes first. 
1039 
 
1040 
Follow-up of Adverse Events 
1041 
During and following a subject’s participation in a clinical trial, the sponsor-investigator 
1042 
and institution will provide adequate medical care to the study subject for any study-
1043 
related adverse events, including clinically significant laboratory values related to the 
1044 
study.  This medical care for study subjects will be provided regardless of their insurance 
1045 
status.  
1046 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
26
All adverse events classified as serious or severe or possibly/probably related to the trial 
1047 
product must be followed until the subject has recovered and all queries have been 
1048 
resolved. For cases of chronic conditions follow-up until the outcome category is 
1049 
“recovered” is not required, as these cases can be closed with an outcome of “recovering” 
1050 
or “not recovered”. 
1051 
All other adverse events must be followed until the outcome of the event is “recovering” 
1052 
(for chronic conditions), or “recovered” or until the end of study, whichever comes first, 
1053 
and until all queries related to these AEs have been resolved. 
1054 
 
1055 
Pregnancy 
1056 
Study subjects will be instructed to notify the sponsor-investigator immediately if they 
1057 
become pregnant. If using liraglutide this medication will be discontinued immediately. 
1058 
 
1059 
The sponsor-investigator will report to Novo Nordisk any pregnancy occurring during the 
1060 
trial period. Reporting of pregnancy by sponsor-investigator should occur within the 
1061 
same timelines described above for reporting of Adverse Events.  
1062 
  
1063 
Pregnancy complications will be recorded as adverse event(s). If the infant has a 
1064 
congenital anomaly/birth defect this must be reported and followed up as a serious 
1065 
adverse event. 
1066 
 
1067 
Precautions/Over-dosage 
1068 
The following precautions and procedures will be observed in the event of overdose by 
1069 
any trial product provided during the study: if asymptomatic, the patient is instructed to 
1070 
call the study doctor immediately after discovering the overdosage and obtain case-
1071 
specific instructions; if symptomatic, the patient is instructed to call the EMS for 
1072 
immediate treatment. 
1073 
 
1074 
LIABILITY AND SUBJECT INSURANCE: 
1075 
During and following a subject’s participation in trial, the sponsor-investigator and 
1076 
his/her institution will provide adequate medical care to the study subject for any study-
1077 
related adverse events, including clinically significant laboratory values related to the 
1078 
study. This medical care for study subjects will be provided regardless of their insurance 
1079 
status. 
1080 
 
1081 
The sponsor-investigator will be responsible for the conduct of the study and that the 
1082 
sponsor-investigator agrees to defend, indemnify, and hold harmless Novo Nordisk, any 
1083 
of its parent companies, affiliates, or subsidiaries, and their respective officers, directors, 
1084 
employees, agents, representatives, distributors, salespersons, customers, licensees, and 
1085 
end-users from and against any claim, suit, demand, loss, damage, expense or liability 
1086 
imposed by any third party arising from or related to: (a) any breach of sponsor-
1087 
investigator's obligations; or (b) sponsor-investigator’s negligent or grossly negligent use 
1088 
or willful misuse of the study drug, the results, or services derived therefrom.  This 
1089 
indemnification shall not apply in the event and to the extent that a court of competent 
1090 
jurisdiction or a duly appointed arbiter determines that such losses or liability arose as a 
1091 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
27
result of Novo Nordisk’s gross negligence, intentional misconduct, or material breach of 
1092 
its responsibilities.  
1093 
 
1094 
EVALUABILITY OF SUBJECTS: 
1095 
All patients and collected data will be included in the intention to treat analysis. 
1096 
A secondary confirmatory analysis will be performed using only completers data, where 
1097 
all data from patients with an overall compliance rate during the study period of <50% 
1098 
will be excluded. The subjects and observations to be excluded, and the reasons for their 
1099 
exclusion will be documented and signed by those responsible prior to database release. 
1100 
The documentation must be stored together with the remaining trial documentation. 
1101 
 
1102 
PREMATURE TERMINATION OF STUDY: 
1103 
Study can be discontinued if funding is withdrawn or by the Data Safety Monitoring 
1104 
Board (DSMB) if there is evidence of futility or excess harm. The study statistician will 
1105 
monitor the data quarterly and discuss any observed trends with the other members of the 
1106 
DSMB who will make such decision following pre-established guidelines. 
1107 
 
1108 
PUBLICATION PLAN: 
1109 
We plan to publish the data from this clinical trial in peer reviewed scientific journals 
1110 
(i.e. Diabetes Care).  We anticipate at least two manuscripts to results from this work 
1111 
(possibly one on clinical efficacy and safety, one on healthcare utilization and cost 
1112 
data).We expect the final manuscripts to be completed around December 1st, 2016. All 
1113 
manuscripts will be submitted to Novo Nordisk for review and commenting 1 month 
1114 
before external submission. We also plan to present the data at the American Diabetes 
1115 
Association and/or The Endocrine Society scientific meetings as poster or oral 
1116 
presentations. 
1117 
We have registered the study with clinicaltrials.gov. 
1118 
1119 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
28
REFERENCES: 
1120 
 
1121 
1. 
CDC. National Diabetes Fact Sheet 2011. 2013  [cited 2013 07/05/2013]; 
1122 
Available from: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. 
1123 
2. 
Intensive blood-glucose control with sulphonylureas or insulin compared with 
1124 
conventional treatment and risk of complications in patients with type 2 diabetes 
1125 
(UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet, 1998. 
1126 
352(9131): p. 837-53. 
1127 
3. 
Holman, R.R., et al., 10-year follow-up of intensive glucose control in type 2 
1128 
diabetes. N Engl J Med, 2008. 359(15): p. 1577-89. 
1129 
4. 
Ohkubo, Y., et al., Intensive insulin therapy prevents the progression of diabetic 
1130 
microvascular complications in Japanese patients with non-insulin-dependent 
1131 
diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin 
1132 
Pract, 1995. 28(2): p. 103-17. 
1133 
5. 
Shichiri, M., et al., Long-term results of the Kumamoto Study on optimal diabetes 
1134 
control in type 2 diabetic patients. Diabetes Care, 2000. 23 Suppl 2: p. B21-9. 
1135 
6. 
Stark Casagrande, S., et al., The Prevalence of Meeting A1C, Blood Pressure, and 
1136 
LDL Goals Among People With Diabetes, 1988-2010. Diabetes Care, 2013. 
1137 
7. 
McWilliams, J.M., et al., Differences in control of cardiovascular disease and 
1138 
diabetes by race, ethnicity, and education: U.S. trends from 1999 to 2006 and 
1139 
effects of medicare coverage. Ann Intern Med, 2009. 150(8): p. 505-15. 
1140 
8. 
Saydah, S.H., J. Fradkin, and C.C. Cowie, Poor control of risk factors for 
1141 
vascular disease among adults with previously diagnosed diabetes. JAMA, 2004. 
1142 
291(3): p. 335-42. 
1143 
9. 
American Diabetes, A., Economic costs of diabetes in the U.S. In 2007. Diabetes 
1144 
Care, 2008. 31(3): p. 596-615. 
1145 
10. 
Herman, W.H., The economic costs of diabetes: is it time for a new treatment 
1146 
paradigm? Diabetes Care, 2013. 36(4): p. 775-6. 
1147 
11. 
Li, R., et al., Medical costs associated with type 2 diabetes complications and 
1148 
comorbidities. Am J Manag Care, 2013. 19(5): p. 421-30. 
1149 
12. 
Inzucchi, S.E., et al., Management of hyperglycaemia in type 2 diabetes: a 
1150 
patient-centered approach. Position statement of the American Diabetes 
1151 
Association (ADA) and the European Association for the Study of Diabetes 
1152 
(EASD). Diabetologia, 2012. 55(6): p. 1577-1596. 
1153 
13. 
Garber, A.J., Methods to enhance delivery of prandial insulin and basal-prandial 
1154 
insulin. Diabetes Obes Metab, 2013. 15 Suppl 1: p. 11-7. 
1155 
14. 
Lamanna, C., et al., Effect of metformin on cardiovascular events and mortality: a 
1156 
meta-analysis of randomized clinical trials. Diabetes Obes Metab, 2011. 13(3): p. 
1157 
221-8. 
1158 
15. 
Simonson GD, C.R., Reader D, Bergenstal RM, International Diabetes Center 
1159 
treatment of type 2 diabetes glucose 
1160 
algorithm. Diabetes Management, 2011. 1: p. 175–189. 
1161 
16. 
Bergenstal, R.M., et al., Adjust to target in type 2 diabetes: comparison of a 
1162 
simple algorithm with carbohydrate counting for adjustment of mealtime insulin 
1163 
glulisine. Diabetes Care, 2008. 31(7): p. 1305-10. 
1164 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
29
17. 
Blonde, L., et al., Patient-directed titration for achieving glycaemic goals using a 
1165 
once-daily basal insulin analogue: an assessment of two different fasting plasma 
1166 
glucose targets - the TITRATE study. Diabetes Obes Metab, 2009. 11(6): p. 623-
1167 
31. 
1168 
18. 
Davidson, M.B., et al., A stepwise approach to insulin therapy in patients with 
1169 
type 2 diabetes mellitus and basal insulin treatment failure. Endocr Pract, 2011. 
1170 
17(3): p. 395-403. 
1171 
19. 
Garber, A.J., Treat-to-target trials: uses, interpretation and review of concepts. 
1172 
Diabetes Obes Metab, 2013. 
1173 
20. 
Hermansen, K., et al., A 26-week, randomized, parallel, treat-to-target trial 
1174 
comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-
1175 
lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care, 2006. 
1176 
29(6): p. 1269-74. 
1177 
21. 
Holman, R.R., et al., Three-year efficacy of complex insulin regimens in type 2 
1178 
diabetes. N Engl J Med, 2009. 361(18): p. 1736-47. 
1179 
22. 
Jabbour, S., Primary care physicians and insulin initiation: multiple barriers, lack 
1180 
of knowledge or both? Int J Clin Pract, 2008. 62(6): p. 845-7. 
1181 
23. 
Lankisch, M.R., et al., Introducing a simplified approach to insulin therapy in 
1182 
type 2 diabetes: a comparison of two single-dose regimens of insulin glulisine 
1183 
plus insulin glargine and oral antidiabetic drugs. Diabetes Obes Metab, 2008. 
1184 
10(12): p. 1178-85. 
1185 
24. 
Meneghini, L., et al., Comparison of 2 intensification regimens with rapid-acting 
1186 
insulin aspart in type 2 diabetes mellitus inadequately controlled by once-daily 
1187 
insulin detemir and oral antidiabetes drugs: the step-wise randomized study. 
1188 
Endocr Pract, 2011. 17(5): p. 727-36. 
1189 
25. 
Rosenstock, J., et al., Advancing insulin therapy in type 2 diabetes previously 
1190 
treated with glargine plus oral agents: prandial premixed (insulin lispro 
1191 
protamine suspension/lispro) versus basal/bolus (glargine/lispro) therapy. 
1192 
Diabetes Care, 2008. 31(1): p. 20-5. 
1193 
26. 
Umpierrez, G.E., et al., Randomized Study Comparing a Basal Bolus With a Basal 
1194 
Plus Correction Insulin Regimen for the Hospital Management of Medical and 
1195 
Surgical patients With Type 2 Diabetes: Basal Plus Trial. Diabetes Care, 2013. 
1196 
27. 
Rossetti, L., et al., Effect of chronic hyperglycemia on in vivo insulin secretion in 
1197 
partially pancreatectomized rats. J Clin Invest, 1987. 80(4): p. 1037-44. 
1198 
28. 
Del Prato, S., Role of glucotoxicity and lipotoxicity in the pathophysiology of Type 
1199 
2 diabetes mellitus and emerging treatment strategies. Diabet Med, 2009. 26(12): 
1200 
p. 1185-92. 
1201 
29. 
Henry, R.R., et al., Intensive conventional insulin therapy for type II diabetes. 
1202 
Metabolic effects during a 6-mo outpatient trial. Diabetes Care, 1993. 16(1): p. 
1203 
21-31. 
1204 
30. 
Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 
1205 
Diabetes. New England Journal of Medicine, 2008. 358(24): p. 2560-2572. 
1206 
31. 
Charbonnel, B., et al., Insulin therapy for diabetes mellitus: treatment regimens 
1207 
and associated costs. Diabetes Metab, 2012. 38(2): p. 156-63. 
1208 
32. 
Effects of Intensive Glucose Lowering in Type 2 Diabetes. New England Journal 
1209 
of Medicine, 2008. 358(24): p. 2545-2559. 
1210 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
30
33. 
Pi-Sunyer, F.X., Weight loss and mortality in type 2 diabetes. Diabetes Care, 
1211 
2000. 23(10): p. 1451-2. 
1212 
34. 
Williamson, D.F., et al., Intentional weight loss and mortality among overweight 
1213 
individuals with diabetes. Diabetes Care, 2000. 23(10): p. 1499-504. 
1214 
35. 
Defronzo, R.A., Banting Lecture. From the triumvirate to the ominous octet: a 
1215 
new paradigm for the treatment of type 2 diabetes mellitus. Diabetes, 2009. 58(4): 
1216 
p. 773-95. 
1217 
36. 
J., B., et al. Weight gain within the first year after new onset diabetes is 
1218 
associated with risk of cardiovascular mortality: A cohort of 8326 primary care 
1219 
patients. in European Association for the Study of Diabetes 2012 Meeting. 2012. 
1220 
Berlin, Germany. 
1221 
37. 
Anderson, R.T., et al., Effect of intensive glycemic lowering on health-related 
1222 
quality of life in type 2 diabetes: ACCORD trial. Diabetes Care, 2011. 34(4): p. 
1223 
807-12. 
1224 
38. 
Giordano, C., Insulin therapy: unmet needs and new perspectives. Minerva 
1225 
Endocrinol, 2013. 38(1): p. 95-102. 
1226 
39. 
Henry, R.R., et al., Efficacy of antihyperglycemic therapies and the influence of 
1227 
baseline hemoglobin A(1C): a meta-analysis of the liraglutide development 
1228 
program. Endocr Pract, 2011. 17(6): p. 906-13. 
1229 
40. 
Avramidis, I., et al., Optimizing Glycemic Control in T2DM Patients Previously 
1230 
Treated with Intensive Insulin Therapy and Switched to Exenatide-Insulin 
1231 
Glargine Combination. Diabetes, 2013. 62(Supplement 1): p. A217-A364. 
1232 
41. 
Blase, E.B., S; Li, Y; Grimm, M, Add-On Treatment with Exenatide Once Weekly 
1233 
vs. Daily Basal Insulin in Patients with A1C ≥8.5%. Diabetes, 2013. 
1234 
62(Supplement 1): p. A217-A364. 
1235 
42. 
Trautmann, M.V.g., L., Guerci, B.; Stranks, S.; Han, J.;  Malloy, J.; Boadman, M.; 
1236 
Diaman, M. , Exenatide Once Weekly: Sustained Glycemic and Weight Control 
1237 
Through 3 Years Compared with Insulin Glargine. Diabetes, 2013. 
1238 
62(Supplement 1): p. A1-A98. 
1239 
43. 
Riddle, M.S., Y, Cariou, B.; Huelgas, R.G.; Roy-Duval, C; Hecquet, C.; Digenio, 
1240 
A.; Rosenstock,J, Once-daily lixisenatide as add-on to basal insulin ± OADs in 
1241 
patients with Type 2 diabetes selectively reduces postprandial hyperglycemic 
1242 
daytime exposure. Diabetes, 2013. 62(Supplement 1): p. A217-A364. 
1243 
44. 
Rosenstock, J., et al., Expanding the Basal-Plus Regimen: Basal Insulin + 
1244 
Lixisenatide is More Likely to Achieve the Composite Outcome of Hba1c<7%, No 
1245 
Documented Symptomatic Hypoglycemia and No Weight Gain Compared with 
1246 
Basal + Prandial Insulin. Diabetes, 2013. 62(Supplement 1): p. A217-A364. 
1247 
45. 
Diamant, M.N., M.; Shaginian, R.; Malone, J.; Cleall, S.; De Vries, D.; Hoogwerf, 
1248 
B; Macconell, L; Wolffenbuttel, B. , Exenatide BID vs. Insulin Lispro TIDM 
1249 
Added to Titrated Insulin Glargine QD in Metformin-Treated T2DM Patients 
1250 
Resulted in Similar Glycemic Control but Weight Loss and Less Hypoglycemia: 
1251 
The 4B Study. Diabetes, 2013. 62(Supplement 1): p. A1-A98. 
1252 
46. 
Balena, R., et al., Combination therapy with GLP-1 receptor agonists and basal 
1253 
insulin: a systematic review of the literature. Diabetes, Obesity and Metabolism, 
1254 
2013. 15(6): p. 485-502. 
1255 


U1111-1145-7585      PROTOCOL VERSION 3.1       05/06/2014 
 
31
47. 
Mathiel, C.R., H; Cariou, B, Handelsman, Y; Philis-Tsimikas, A; Francisco, A; 
1256 
Rana, A; Zinman, B, Comparison of Addition of Liraglutide to Insulin Degludec 
1257 
Plus Metformin vs. Addition of a Single Dose of Rapid-Acting Insulin Analog to 
1258 
Largest Meal in Type-2 Diabetes. Diabetes, 2013. 62(Supplement 1): p. A217-
1259 
A364. 
1260 
48. 
DeVries, J.H., et al., Sequential intensification of metformin treatment in type 2 
1261 
diabetes with liraglutide followed by randomized addition of basal insulin 
1262 
prompted by A1C targets. Diabetes Care, 2012. 35(7): p. 1446-54. 
1263 
49. 
Macconell, L., et al., Exenatide once weekly: sustained improvement in glycemic 
1264 
control and cardiometabolic measures through 3 years. Diabetes Metab Syndr 
1265 
Obes, 2013. 6: p. 31-41. 
1266 
50. 
Chaudhary, M.A. and S.C. Stearns, Estimating confidence intervals for cost-
1267 
effectiveness ratios: an example from a randomized trial. Stat Med, 1996. 15(13): 
1268 
p. 1447-58. 
1269 
 
1270 
 
1271