Conditions: Type 2 Diabetes
Keywords: Long-acting insulin analog
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 180
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out if treatment with degludec insulin when compared to glargine U100 insulin will result in similar blood sugar control in patients with diabetes who are admitted to the hospital and then transition to home after discharge from the hospital.

Detailed description:
Degludec is a new generation basal insulin analog with a longer duration of action compared to insulin glargine. Several outpatient trials have reported that treatment with degludec results in comparable improvement in HbA1c levels and in lower rates of hypoglycemia compared to glargine U100 insulin. However, no previous studies have compared the safety and efficacy of the long-acting basal insulin degludec in the inpatient management of patients with diabetes. It is expected that a large number of patients with diabetes will be started on or transitioned to this new insulin formulation so acquiring knowledge on the safety and efficacy of degludec insulin is of great clinical interest. Accordingly, the proposed study will provide novel and clinically useful information on the efficacy (assessed as blood glucose control) and safety (assessed as hypoglycemia) of degludec in the inpatient setting and after hospital discharge in general medicine and surgery patients with Type 2 Diabetes (T2D).

Participants will be randomized to receive either a basal bolus with degludec or glargine U100 once daily during hospitalization. All participants will receive aspart insulin before meals. Participants with poorly controlled diabetes during the inpatient portion of the study will be invited to participate in the outpatient portion of the study. Participants in the outpatient portion of the study will be discharged on their preadmission oral antidiabetic medications plus degludec or glargine once daily, based on the study medication they were randomized to take during the inpatient portion of the study.

Arms:
arm 1: Study participants treated with insulin prior to admission will receive 80% or 100% of the total daily dose (TDD) given as a basal bolus regimen with degludec once daily plus rapid-acting aspart insulin before meals. arm 2: Study participants treated with insulin prior to admission will receive 80% or 100% of the total daily dose (TDD) given as basal bolus regimen with glargine once daily plus rapid-acting aspart insulin before meals.

Interventions: intervention 1: Degludec intervention 2: Glargine intervention 3: Aspart
Intervention descriptions: intervention 1: Degludec is a long-acting human insulin analog indicated to improve glycemic control in adults with diabetes mellitus. Patients will be treated with bolus regimen given half of total daily dose (TDD) as basal once daily and half as aspart divided in three equal doses before meals. Patients with poor oral intake or with medical instruction to withhold oral intake (NPO) will receive the basal dose, but prandial dose will be held. Insulin dose will be adjusted daily to maintain a fasting and pre-dinner blood glucose (BG) between 100 mg/dL and 180 mg/dL. intervention 2: Glargine is a long-acting human insulin analog indicated to improve glycemic control in adults with diabetes mellitus. Patients will be treated with bolus regimen given half of total daily dose (TDD) as basal once daily and half as aspart divided in three equal doses before meals. Patients with poor oral intake or with medical instruction to withhold oral intake (NPO) will receive the basal dose, but prandial dose will be held. Insulin dose will be adjusted daily to maintain a fasting and pre-dinner BG between 100 mg/dL and 180 mg/dL. intervention 3: Aspart insulin will be given in three equally divided doses before each meal. To prevent hypoglycemia, if a subject is not able to eat, aspart insulin dose will be held.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
A Randomized Controlled Trial Comparing the Safety and Efficacy of Liraglutide versus Glargine insulin 
for the Management of Patients with Type 2 Diabetes After Hospital Discharge  
NCT# NCT03336528 
Date: November 17, 2020 


Degludec Hospital Trial
November 17, 2020
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Protocol Title 
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Degludec -Glargine Hospital Trial: A Randomized Controlled Trial Comparing Insulin 
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Degludec and Glargine U100 for the Inpatient Therapy and Post-Hospital Discharge 
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Management of Medicine and Surgery Patients with Type 2 Diabetes 
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INVESTIGATOR-SPONSORED STUDY PROPOSAL
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UNIVERSAL TRIAL NUMBER (UTN): U1111-1185-1178
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Emory University School of Medicine
16
Department of Medicine, Endocrinology
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Correspondence to:
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Guillermo E. Umpierrez, M.D.
21
Professor of Medicine 
22
Emory University School of Medicine
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Director, Diabetes and Endocrinology Section
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Grady Health System
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69 Jesse Hill Jr Dr.
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Atlanta, Georgia 30303
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USA
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Degludec Hospital Trial
November 17, 2020
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I.
BACKGROUND AND SIGNIFICANCE:
38
The association between hyperglycemia and poor clinical outcomes in hospitalized 
39
patients with and without diabetes is well established 1-5. Extensive data from observational and 
40
prospective randomized controlled trials (RCT) in hospitalized patients have reported a strong 
41
association between hyperglycemia and poor clinical outcome, such as increased mortality, 
42
morbidity, hospital length of stay (LOS), infections and overall complications 1,4,6-8.  Clinical 
43
trials in both critically ill and in non-ICU medicine and surgery patients have shown that 
44
improvement of glycemic control in patients with hyperglycemia reduces LOS, systemic 
45
infections 9-11 and short- and long-term mortality 6,11.  
46
Randomized multi-center trials have shown that basal bolus treatment with glargine U100 
47
improve glycemic control and reduce the rate of hospital complications compared to sliding scale 
48
regular insulin (SSI)12-14. In general surgery patients, the basal bolus approach results in 
49
significant reduction in a composite of hospital complications including postoperative wound 
50
infection, pneumonia, bacteremia, and acute renal and respiratory failure.15 The hypoglycemia 
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rate was reported in 3% in medicine 12 and 12% in surgery 13 patients treated with basal bolus 
52
regimen. Based on these results, clinical practice guidelines have recommended the use of basal 
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bolus approach as the preferred insulin regimen for the management of non-ICU patients with 
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diabetes 15-17. 
55
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The Food and Drug Administration and the European Commission recently approved 
57
insulin degludec for the treatment of patients with diabetes. Insulin degludec, a long-acting basal 
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insulin analog with a half-life of >25 hours and activity of >40 hours 18,19, results in comparable 
59
glycemic control to glargine 19-21, but with lower rates of hypoglycemia 19,20,22. The efficacy and 
60
safety of degludec is well documented in ambulatory patients; however, no studies have assessed 
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the safety and efficacy of these new formulations in the hospital setting. Although we can 
62
anticipate a reduced number of hypoglycemic events with insulin degludec, certain features 
63
needs to be investigated in the hospital including 1) prolonged duration of action, which may 
64
limit the ability to make day-to-day adjustments in insulin dosage; 2) a steady-state insulin 
65
concentration achieved after second or third day of therapy 21,23; and limited safety data in 
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acutely ill patients with altered nutritional status. Accordingly, the present pilot randomized trial 
67
will compare the efficacy and safety of a basal bolus regimen with degludec U100 and glargine 
68
U100 in medicine and surgery patients with type 2 diabetes (T2D).
69
70
Significance and Innovation. Degludec is a new generation basal insulin analog with a longer 
71
duration of action compared to insulin glargine 18,19. Several outpatient trials have reported that 
72
treatment with degludec results in comparable improvement in HbA1c levels and in lower rates 
73
of hypoglycemia compared to glargine U100 insulin. No previous studies; however, have 
74
compared the safety and efficacy of the long-acting basal insulin degludec in the inpatient 
75
management of patients with diabetes. It is expected that a large number of patients with diabetes 
76
will be started or transitioned to this new insulin formulation; so acquiring knowledge on their 
77
safety and efficacy is of great clinical interest. Accordingly, the proposed study will provide 
78
novel and clinically useful information on the efficacy (BG control) and safety (hypoglycemia) 
79
of degludec in the inpatient setting and after hospital discharge in general medicine and surgery 
80
patients with T2D.
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Degludec Hospital Trial
November 17, 2020
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II. SPECIFIC OBJECTIVES:
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Objective 1.  To determine differences in inpatient glycemic control, as measured by mean 
84
daily blood glucose concentration and the frequency of hypoglycemia in general medicine 
85
and surgery patients with T2D treated with basal bolus regimen with insulin degludec or 
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glargine once daily plus aspart insulin before meals.  We will analyze a total of 180 subjects 
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with T2D treated prior to admission with diet, oral hypoglycemic agents, short-acting GLP1-RA 
88
(except long-acting exenatide, dulaglutide and albiglutide), or insulin therapy (except degludec 
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and glargine U300) will be included in this prospective, randomized, open label trial to compare 
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the safety and efficacy of a basal bolus regimen with degludec and glargine in patients with T2D 
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admitted to general medicine and surgery services. Secondary end points include length of stay, 
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hospital complications, and hospital readmissions.
93
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Objective 2:  To determine differences in glycemic control after hospital discharge between 
95
treatment with degludec and glargine in medicine and surgery patients T2D.  Patients with 
96
poorly controlled diabetes (HbA1c ≥7.0%) enrolled in Aim 1 will be invited to participate in this 
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open label prospective outpatient study. At hospital discharge, patients will be treated following 
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an HbA1c based algorithm24 for a total duration of the outpatient follow-up of 3 months (see 
99
hospital discharge algorithm, page 7).  
100
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III. RESEARCH DESIGN AND METHODS
102
III.A Study Hypothesis (hypotheses):
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Hypothesis #1: Treatment with degludec and glargine will result in equivalent glycemic control 
104
in general medicine and surgery patients with T2D. Degludec will result in lower number of 
105
hypoglycemia compared to glargine.
106
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Hypothesis: treatment with degludec and glargine will result in a similar improvement in HbA1c 
108
levels after hospital discharge. Degludec will result in lower number of hypoglycemia compared 
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to glargine.
110
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III.B Endpoints:
112
The primary endpoint of the trial is non-inferiority in mean differences between treatment groups 
113
in their mean blood glucose concentrations during the first 10 days of therapy (non-inferiority 
114
will be determined at a difference <18 mg/dl). All participants who receive ≥ 2 doses of study 
115
drug will be included in the analysis.
116
117
Secondary outcomes include differences between treatment groups in any of the following 
118
measures: Endpoints 1-4 (glycemic control) will be analyzed during the first 10 days of therapy 
119
and endpoints 5, 7, 8, and 9 (length of stay and complications) will be analyzed during hospital 
120
stay. Endpoint 6 (readmissions) will be evaluated up to 12 weeks after hospital discharge.
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1. Proportion of BG readings between 70 mg/dl and 180 mg/dl before meals 
122
2. Number of hypoglycemia (< 70 mg/dl and 54 mg/dl) and severe hypoglycemia (< 40 mg/dl) 
123
episodes during the first 10 days of therapy in the inpatient setting.


Degludec Hospital Trial
November 17, 2020
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3. Number of episodes of severe hyperglycemia (BG > 240 mg/dl) after the first day of treatment 
125
until the tenth day of therapy 
126
4. Daily dose of basal insulin, daily dose of prandial insulin, and total daily dose
127
5. Length of hospital stay.
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6. Number of readmissions (hospitalization) and Emergency room visits.
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7. Cardiac complications are defined as myocardial infarction, cardiac arrhythmia requiring 
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medical treatment, or cardiac arrest.
131
8. Acute kidney injury defined as an increment in serum creatinine ≥ 0.3 mg/dL from baseline or  
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≥1.5 times baseline creatinine (KDIGO) 25.
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9. Hospital mortality. 
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135
III.C Study type:
136
This is a prospective, randomized, open label multicenter trial to compare the safety and efficacy 
137
of a basal bolus regimen with degludec and glargine in patients with T2D admitted to general 
138
medicine and surgery services.
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This study will include male or female subjects > 18 years. Due to the design of this hospital 
141
study, there will be no run-in period.  Upon arrival to the emergency department or medical or 
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general surgical wards, subjects will be screened. A total of 180 subjects will be analyzed. A 
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maximum of 108 (60%) surgical or medical patients will be randomized in the study to ensure a 
144
balanced proportion of each group is included. Patients with a known history of T2D treated with 
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diet alone, any combination of OADs, short acting GLP-1 RA (liraglutide or exenatide) and 
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insulin prior to admission will be considered potential candidates for this study. Patients treated 
147
with degludec, glargine U300 or with long-acting GLP1-RA (dulaglutide, albiglutide and weekly 
148
exenatide) prior to admission will be excluded. Patients admitted with acute or chronic medical 
149
illnesses, emergency or elective surgical procedures and trauma would be included in the study. 
150
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Insulin therapy will be aimed to maintain fasting and pre-meal blood glucose levels between 100 
152
mg/dl and 180 mg/dL while avoiding hypoglycemia. Blood glucose levels between 70 and 100 
153
mg/dL are still considered at goal, however BG values in this range will trigger insulin 
154
adjustment to minimize the risk of hypoglycemia as recommended by professional associations. 
155
Patients with T2D will be randomized to receive:
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Group 1.  Basal bolus with degludec once daily and aspart insulin before meals (n=90)
157
Group 2.  Basal bolus with glargine U100 once daily and aspart insulin before meals (n=90)
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Aim 1.  Inpatient (Hospital) Arm: Patients will be treated with a basal bolus insulin regimen as 
160
previously reported.12-14,16  In brief, subjects treated with insulin prior to admission will receive 
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80% of the total daily outpatient insulin dose given. Insulin naïve patients will discontinue oral 
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agents and will receive a starting total daily dose (TDD) of 0.4 U/kg/day for BG between 140 
163
mg/dl and 400 mg/dL. The starting TDD will be reduced to 0.3 U/kg/day in patients ≥ 70 years 
164
or with a GFR < 60 ml/min. Both groups will be treated with bolus regimen given half of TDD 
165
as basal (degludec or glargine) once daily and half as aspart divided in three equal doses before 
166
meals. Patients with poor oral intake or with medical instruction to withhold oral intake (NPO) 


Degludec Hospital Trial
November 17, 2020
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will receive the basal dose, but prandial dose will be held.14 Insulin dose will be adjusted daily to 
168
maintain a fasting and pre-dinner BG between 100 mg/dl and 180 mg/dl.
169
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Initiation and Dosing of Basal insulin
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Patients treated with insulin prior to admission will receive 80% of their total home daily insulin 
172
dose.  Half of the total daily dose will be given as basal degludec/glargine) and half as prandial 
173
(aspart) insulin.  The basal insulin will be given at the same time every day.  The prandial 
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(aspart) insulin will be held in patients with poor oral intake or NPO, but they will receive the 
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usual basal insulin dose.
176
Insulin naïve patients will receive a starting insulin dose of 0.4 U/kg/day. Half of the total daily 
177
dose will be given as basal degludec/glargine) and half as prandial (aspart) insulin.  The basal 
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insulin will be given at the same time every day.  The prandial (aspart) insulin will be held in 
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patients with poor oral intake or NPO, but they will receive the usual basal insulin dose.
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Adjustment/Titration of daily insulin dose:
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The basal insulin dose will be adjusted daily per fasting blood glucose concentration. The target 
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BG concentration during insulin treatment is 100-180 mg/dl.  The daily basal (degludec/glargine) 
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dose will be increased by 10% if the fasting BG is between 180 and 240 mg/dl or by 20% if 
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fasting BG concentration is >240 mg/dL  The total daily insulin dose (basal and prandial insulin) 
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will be increased by 20% in patients with mean BG > 240 mg/dl.  In addition, the basal insulin 
186
dose will be reduced by 10% if any BG is between 70-100 mg/dl, and by 20% in patients with 
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any BG < 70 mg/dl.  The total daily dose will be reduced 30-40% in the event of severe 
188
hypoglycemia (BG < 40 mg/dl).
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Several clamp studies in patients with type 1 and type 2 diabetes and observations from clinical 
190
practice showed that insulin degludec quickly reaches steady state after the 2nd or 3rd day of 
191
therapy, a similar period reported with other basal insulin analogs 26,27. Based on its steady-state 
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condition, clinical pharmacology studies show that insulin degludec has a flatter, less variable 
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and more consistent glycemic effect. 
194
 Treatment randomization.  Patients will be randomized using a computer-generated 
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randomization table. Treatment randomization/assignment will be coordinated by the research 
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pharmacy. A research pharmacist at each institution will follow a computer-generated block 
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randomization table based on glucose levels (BG≤200 or BG>200) at randomization.
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TREATMENT PROTOCOL - Basal Bolus Insulin Regimen with Degludec or Glargine 
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Once Daily plus Aspart before Meals
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Patients Treated with Insulin Prior to Admission
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
Discontinue oral antidiabetic drugs on admission.
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Subjects treated with insulin prior to admission will receive 80% or 100 % of the total daily 
205
dose (TDD) given as basal bolus regimen.  
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Starting Insulin Doses:
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-
BG < 200 mg/dl give 80% of TDD*
209
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BG ≥ 200 mg/dl give 100% of TDD*
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Degludec Hospital Trial
November 17, 2020
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
Half of TDD will be given as degludec or glargine and half as rapid-acting insulin.  
213

Degludec and glargine will be given once daily at the same time of the day
214

Patients will receive the full-dose of degludec or glargine (even if NPO) the day of 
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surgery or diagnostic procedure(s).    
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
Aspart insulin will be given in three equally divided doses before each meal.  To prevent 
217
hypoglycemia, if a subject is not able to eat, aspart insulin dose will be held.
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* If patient was on basal only therapy consider adding prandial dose as calculated above.
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Insulin Naïve Patients Treated with Oral Agents or GLP1-RAs
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
Discontinue oral antidiabetic drugs on admission.
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
Starting total daily insulin dose: 
223

0.4 U/Kg/day when randomization BG between 140-400 mg/dL
224

Reduce TDD to 0.3 units per kg in patients ≥ 70 years of age and/or with an eGFR < 
225
60 ml/min.
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
Half of TDD will be given as glargine or degludec and half as aspart.  
227

Degludec or glargine will be given once daily, at the same time of the day.  
228

Patients will receive the full-dose of degludec or glargine insulin (even if NPO) the day 
229
of surgery or diagnostic procedure(s).    
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
Aspart insulin will be given in three equally divided doses before meals. To prevent 
231
hypoglycemia, if a subject is not able to eat, the dose of aspart insulin will be held. 
232
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Supplemental insulin. Aspart insulin will be administered following the “supplemental or 
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correction insulin scale” protocol (Appendix 1, page 21). Supplemental doses will be given for 
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BG > 140 mg/dl before meals.  At bedtime, supplemental insulin will be reserved for patients 
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with BG > 250 mg/dl. 
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If a patient is able and expected to eat most of his/her meals, supplemental insulin will be 
238
administered before meals and at bedtime following the “usual” dose of the insulin scale 
239
protocol.
240

If a patient is not able to eat, supplemental insulin will be administered every 6 hours 
241
(Appendix 1) following the “sensitive” dose of the supplemental insulin scale protocol.
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243
Basal Insulin adjustment.  
244

Daily basal insulin dose will be adjusted as follow: 
245

If the fasting and/or pre-dinner BG is between 100 - 140 mg/dl in the absence of 
246
hypoglycemia the previous day: no change 
247

If the fasting and/or pre-dinner BG is between 141 - 180 mg/dl in the absence of 
248
hypoglycemia: increase basal insulin by 10% every day*
249

If the fasting and/or pre-dinner BG is 181 – 299 mg/dl in the absence of 
250
hypoglycemia the previous day: increase basal insulin (degludec or glargine) dose by 
251
20% every day* 
252

If the fasting and/or pre-dinner BG is ≥ 300 mg/dl in the absence of hypoglycemia the 
253
previous day: increase basal insulin (glargine) dose by 30% every day*
254

If the fasting and pre-dinner BG is between 70 - 99 mg/dl in the absence of 
255
hypoglycemia: decrease TDD (basal and prandial) insulin dose by 10% every day


Degludec Hospital Trial
November 17, 2020
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256

If a patient develops hypoglycemia (BG <70 mg/dL), the insulin TDD (basal and 
257
prandial) should be decreased by 20%.  
258

If a patient develops severe hypoglycemia (BG <40 mg/dL), the insulin TDD (basal 
259
and prandial) should be decreased by 30-40%.  
260
*Consider adjusting prandial dose according to medical discretion
261
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Aim 2:  Outpatient (Post-Discharge) Arm: To determine differences in glycemic control 
263
after hospital discharge between treatment with degludec and glargine in medicine and 
264
surgery patients T2D.  We will compare the efficacy and safety of degludec and glargine after 
265
hospital discharge.  Several outpatient insulin trials have shown that treatment with degludec 
266
results in similar improvement in glycemic control 19,20,28, but in significant reduction in 
267
hypoglycemia. We expect that degludec treatment will be a safer alternative to current use of 
268
glargine U100 formulation.
269
 
270
 Insulin Discharge algorithm: 
271
Patients with poorly controlled diabetes (HbA1c ≥7.0 %) enrolled in Aim 1 will be invited to 
272
participate in this open label prospective outpatient study. The total duration of the study is 3 
273
months. Patients with an HbA1c between 7.0% and 10% will be discharged on preadmission oral 
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antidiabetic agents plus degludec or glargine once daily. Patients with an admission A1C ≥ 10% 
275
will be discharged on basal bolus regimen with degludec or glargine and aspart insulin before 
276
meals.  Participants will be trained in using each devices including how to differentiate these 
277
from each other (rapid acting from long acting insulin).
278
                                                                         **
279
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**If previous basal bolus only therapy and/or contraindications to previous oral therapy, 
281
discharge on basal bolus at 100% of daily hospital dose.
282
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Follow-up Care:
284

Provide degludec or glargine 1 or 2months supply at each clinic visit. 


Degludec Hospital Trial
November 17, 2020
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
A member of the diabetes research team will contact patients via telephone call every 2 
286
weeks for a total of 3 months.  
287

Patients will be asked to attend outpatient visits at 4 and 12 weeks after hospital 
288
discharge.  
289

Recommendation on insulin adjustment to be provided after each telephone contact 
290
and/or clinic visit by research staff under supervision of research licensed healthcare 
291
professional.
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
Research staff will follow the algorithm for outpatient insulin dose adjustment according 
293
to fasting blood glucose levels (FBG) and/or random blood glucose levels (RBG) 
294
described below (algorithm for primary care physician).
295
296
During follow up we will collect the following information:  
297
1. Glycemic control:
298
a.
Mean daily fasting and premeal blood glucose levels
299
b. HBA1C at 1 and 3 months after hospital discharge
300
c.
Hypoglycemic events
301
i. A glucose alert value of <70mg/dl. 
302
ii. Clinically important hypoglycemia (BG < 54 mg/dl) 
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iii. Severe hypoglycemia, as defined by the ADA, which denotes severe 
304
cognitive impairment requiring external assistance for recovery
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d. Hyperglycemic events (BG > 240 mg/dl)
306
307
2. Diabetes treatment:
308
a.
Number of patients receiving insulin 
309
b. Insulin dosage (unit/day)
310
c.
Use of oral agents
311
d. Protocol adherence 
312
3. Clinical Outcome:
313
a.
Hospital readmissions
314
b. Emergency room visits
315
c.
Postoperative complications
316
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4. Management after end of study 
318
a.
Post treatment telephone call (telephone contact 2 weeks after last clinic visit) to 
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confirm appropriate number of refills and follow up with primary care physician 
320
b. Collect information on adverse events post treatment  
321
 
322
Primary care physicians will be provided with the following algorithm for outpatient 
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insulin dose adjustment according to fasting blood glucose levels (FBG) or random blood 
324
glucose levels (RBG)
Basal Insulin (degludec and glargine)
If mean FBG > 180 mg/dL for the last 
3 consecutive days and no hypoglycemia or no 
random BG (RBG) <70 mg/dL
Increase daily dose by 4 IU
If mean FBG > 140 mg/dL for the last 
3 consecutive days and no hypoglycemia < or 
Increase daily dose by 2 IU


Degludec Hospital Trial
November 17, 2020
9
no RBG <70 mg/dL
If mean FBG between 100 – 140 mg/dL and 
no hypoglycemia or no RBG <70 mg/dL
No Change
If any FBG between 70 – 99 mg/dl
Decrease by 4 IU or 10% of total daily dose
If any FBG or RBG 40- 69 mg/dl
Decrease by 8 IU or 20% of total daily dose
If any FBG or RBG < 40 mg/dl
Decrease total daily dose by 30 – 40%
325
326
For patients discharged on basal bolus, prandial insulin will be adjusted according to 
327
postprandial blood glucose levels (PPG) measured 2 hours after the start of the meal. 
328
Prandial Insulin (rapid acting insulin)
PPG   < 180
No change 
PPG  180-240 mg/dl
Increase dose by 2 IU
PPG  >240 mg/dl
Increase dose by 4 IU
329
330
Rationale for study Design
331
332
Aim 1, Hospital:  Several studies have shown improved clinical outcome with improved 
333
glycemic control in hospitalized patients with T2D 4,5,9,11,29-31. RCTs in medicine and surgical 
334
patients with T2D have shown that basal bolus regimen with glargine results in a lower mean 
335
daily BG concentration compared to the sole use of SSI and in lower rate of hospital 
336
complications (see preliminary results section). Insulin degludec results in similar improvement 
337
but in lower rate of hypoglycemia than treatment with glargine 19,20,28. No previous studies; 
338
however, have compared the efficacy and safety of degludec and glargine in the management of 
339
hyperglycemia and diabetes in hospital setting.  Determining the safety and efficacy of new 
340
insulin formulations in the hospital, an environment associated with reduced insulin sensitivity 
341
and altered nutritional intake, is an exceedingly important clinical question. 
342
343
Aim 2, Outpatient (post-discharge):  Few studies have addressed the efficacy of insulin alone 
344
or in combination with oral agents after hospital discharge. In a recent study (see preliminary 
345
results section), patients were discharged on a combination of OADs and glargine U100 insulin 
346
or on a basal bolus regimen according to HbA1c levels and achieved a marked reduction in 
347
HbA1c from 8.75% on admission to 7.9% and 7.35% after 4 and 12 weeks of hospital discharge. 
348
However, the use of glargine U100 alone or in combination to oral agents or as basal bolus 
349
insulin resulted in 30% and close to 40% incidence of hypoglycemia, respectively. In this study, 
350
we will compare the efficacy and safety of degludec and glargine after hospital discharge.  
351
Several outpatient insulin trials have shown that treatment with degludec results in similar 
352
improvement in glycemic control 19,20,28, but in significant reduction in hypoglycemia. Thus we 
353
expect that degludec treatment will be a safer alternative to current use of glargine U100 
354
formulation.
355
356
IV.
Study population:
357
358
Number of subjects to be studied: 180
359
Planned number of subjects to be screened/consented: 220-250 
360
Planned number of subjects to be treated in run-in period: No run-in period as patient will be 
361
admitted to the hospital with an acute medical/surgical illness.
362
Planned number of subjects to be randomized/started on study medication(s): 180


Degludec Hospital Trial
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10
363
Anticipated number of trial sites: 3 sites (Emory University Hospitals/Grady Hospital in 
364
Atlanta, GA; additional Sites: Mount Sinai, NY-PI: Dr. David Lam and Providence Medical 
365
Research Centre PI: Dr. Radica Alicic)
366
Anticipated number of subjects to be randomised/started on trial medication(s) at each 
367
trial site: 60.
368
Country planned to participate: United States. 
369
370
Inclusion Criteria
371
1.
Males or females between > 18 years admitted to a general medicine or surgical service.  
372
2.
A known history of T2D treated either with oral monotherapy, any combination of oral 
373
antidiabetic agents, short-acting GLP1-RA (exenatide, liraglutide) or insulin therapy 
374
except for degludec and glargine U300. 
375
3.
Subjects with diet alone and HbA1c>7.0%
376
4.
Medical and surgical patients expected to be admitted (LOS) longer than 2 days
377
5.
Subjects must have a randomization BG > 140 mg and < 400 mg/dL without laboratory 
378
evidence of diabetic ketoacidosis (bicarbonate < 18 mEq/L, pH < 7.30, or positive serum 
379
or urinary ketones).
380
6.
Signed, informed consent and HIPAA documentation prior to any study procedures
381
382
Exclusion Criteria
383
1.
Subjects with increased BG concentration, but without a known history of diabetes (stress 
384
hyperglycemia).
385
2.
Subjects treated with diet alone (no antidiabetic agents) and admission HbA1c <7%. 
386
3.
Admission or pre-randomization BG≥400 mg/dl
387
4.
Subjects with a history of diabetic ketoacidosis and hyperosmolar hyperglycemic state, or 
388
ketonuria 32. 
389
5.
Patients treated with degludec or glargine U300, or with long-acting weekly GLP1-RA 
390
(weekly exenatide, dulaglutide or albiglutide). 
391
6.
Patients with acute critical or surgical illness admitted to the ICU, except for observation 
392
(<24 hours and did not require vasopressors and/or mechanical ventilation). 
393
7.
Patients with history of clinically relevant hepatic disease (diagnosed liver cirrhosis and 
394
portal hypertension), ongoing corticosteroid therapy (equal to a prednisone dose ≥5 
395
mg/day), or impaired renal function (eGFR< 30 ml/min), or congestive heart failure 
396
(NYHA- IV).
397
8.
Mental condition rendering the subject unable to understand the nature, scope, and 
398
possible consequences of the study.
399
9.
Female subjects who are pregnant or breast-feeding at time of enrollment into the study.
400
10.
Known or suspected allergy to trial medication(s), excipients, or related products.
401
11.
Previous participation in this trial. 
402
403
Withdrawal Criteria
404
1. The subject may withdraw at will at any time.
405
2. The subject may be withdrawn from the trial at the discretion of the investigator due to a 
406
safety concern or if judged non-compliant with trial procedures or included in contravention 
407
to the inclusion and/or exclusion criteria.


Degludec Hospital Trial
November 17, 2020
11
408
3. Subject admitted to the ICU who required continuous intravenous insulin infusion to maintain 
409
glycemic control.
410
4. Pregnancy or intention to become pregnant.
411
5. Treatment with oral or injectable corticosteroid (equivalent or higher than prednisone 
412
5mg/day), parenteral nutrition and immunosuppressive treatment after randomization.
413
Treatment Failure Criteria
414
Subjects with persistent hyperglycemia (≥ 2 glucose readings ≥ 400 mg/dL, ≥ 3 consecutive 
415
glucose readings > 280 mg/dL, or with a mean daily blood glucose concentration ≥ 280 mg/dL) 
416
and no treatable intercurrent cause for the hyperglycemia has been identified, will be considered 
417
as treatment failure and discontinued from the study.  Subjects will be started on continuous 
418
insulin infusion if needed.  
419
420
Subject Replacement
421
There will be no replacement of subjects in this trial.
422
423
V. Visit Procedures
424
Upon arrival to the emergency department or medical or general surgical wards, subjects will be 
425
screened.  Patients with a known history of T2D treated with diet alone, any combination of 
426
OADs, and insulin prior to admission will be considered potential candidates for this study. 
427
Patients admitted with acute or chronic medical illnesses, emergency or elective surgical 
428
procedures and trauma would be included in the study. 
429
Patients will be treated with a basal bolus insulin regimen as previously reported.  In brief, 
430
subjects treated with insulin prior to admission will receive 80% of the total daily outpatient 
431
insulin dose given. Insulin naïve patients will discontinue oral agents and will receive a starting 
432
total daily dose (TDD) of 0.4 U/kg/day for BG between 140 mg/dl and 400 mg/dL. The starting 
433
TDD will be reduced to 0.3 U/kg/day in patients ≥ 70 years or with a GFR < 60 ml/min. Both 
434
groups will be treated with bolus regimen given half of TDD as basal (degludec or glargine) once 
435
daily and half as aspart divided in three equal doses before meals. Patients with poor oral intake 
436
or to be kept NPO will receive the basal dose, but prandial dose will be held.14 Insulin dose will 
437
be adjusted daily to maintain a fasting and pre-dinner BG between 80 mg/dl and 180 mg/dl.
438
439
Aim 1.  Inpatient Arm – Flow Chart
440
Visit Type
Hosp-
Day 1
Hosp-
Day 2
Hosp-
Day 3
Hosp-
Day 4
Hosp-
Day 5
Hosp-
Day 6
Hosp-
Day 7
Hosp-
Day 8
Hosp-
Day 9
Hosp-
Day 10
Visit #
1
2
3
4
5
6
7
8
9
10
Time-days
1
2
3
4
5
6
7
8
9
10
Inf. consent 
x
Inclusion/excl criteria
x
Randomization
x
Withdrawal criteria
x
x
x
x
x
x
x
x
x
x
Dose adjustment
x
x
x
x
x
x
x
x
x
Efficacy
Vital signs
x
x
Phys Exam
x
x
Body weight
x
x


Degludec Hospital Trial
November 17, 2020
12
BMI
x
HbA1c1
x
Fasting BG
x
x
x
x
x
x
x
x
x
Pre-meal BG
x
x
x
x
x
x
x
x
x
x
Safety
Adv events
x
x
x
x
x
x
x
x
x
x
Hypoglycemia
x
x
x
x
x
x
x
x
x
x
Urine pregnancy test
x
Trial material
Drug dispense2
x
441
1 From medical records if < 3months, order it otherwise after subject has provided consent for study 
442
participation.
443
2 As needed
444
Aim 2.  Outpatient Arm – Flow Chart
445
Visit Type
Discharge 
Day 1
TC
Clinic 
visit
TC
TC
TC
Clinic 
visit
post 
treatment 
follow-up
Visit #
1
2
3
4
5
6
7
8 
Time-wks1
0
2
4
6
8
10
12
14
Inf. consent 
x
Incl/excl criteria
x
Random
x
Withdrawal criteria
x
x
x
x
x
x
Drug Compliance
x
x
x
x
x
x
Dose adjustment
x
x
x
x
x
x
Efficacy
Vital signs
x
x
x
Phys Exam
x
x
x
Body wgt
x
x
x
BMI
x
x
x
HbA1c
x
x
Fasting BG
x
x
x
Safety
Adv events
x
x
x
x
x
x
x
x
Hypoglycemia
x
x
x
x
x
x
x
x
Urine pregnancy test
x
Chem, GFR
x
x
x
Trial material
Drug dispense
x
x
Drug account
x
x
x
446
1Telephone calls (TC) and outpatient visits can be completed ±7 days
447
448
449
450
Assessments for Efficacy
451
Laboratory measurements will be conducted per standard hospital practices. Samples will be 
452
collected and labelled at the clinical research center at each individual institution. Samples will 
453
not be stored. Clinical research coordinators and research nurses will obtain data and blood 
454
samples to be sent to the central lab at each institution for standard measurements (HbA1c, 
455
chemistry)  
456


Degludec Hospital Trial
November 17, 2020
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457
Assessments for Safety
458
459
Potential Risks to the Subject:
460
461
Protection against risks:
462
We will follow safeguards to minimize the risk to our subjects: a) we will carefully monitor 
463
capillary BG at the bedside using a hand-held glucose meter, b) only experienced nurses/or 
464
phlebotomist will draw blood samples, and c) women of reproductive age who are sexually 
465
active will undergo a urine pregnancy tests prior to participation in the study.  To prevent 
466
significant clinical events, no patients with history of significant liver (diagnosed liver cirrhosis 
467
and portal hypertension), renal impairment (eGFR<30ml/min/1.73m2) or severe cardiac failure 
468
will be recruited in this study.   
469
Hypoglycemia:  It is possible that following the proposed protocol, patients receiving 
470
insulin degludec or glargine may develop hypoglycemia. The risk of hypoglycemia (BG < 70 
471
mg/dl) in non-ICU patients treated with subcutaneous insulin is between 5–30% 13,33-35. The 
472
number of hypoglycemia (< 70, < 54 and < 40 mg/dl) will be analyzed statistically. For the 
473
purpose of this analysis, hypoglycemia is defined as follows: 1) BG < 70mg/dL is a glucose alert 
474
value, 2) BG < 54 mg/dL will be considered as clinically important hypoglycemia, and 3) Severe 
475
hypoglycemia, will be defined as a BG < 40 mg/dl.16,36 We expect that approximately 10% in the 
476
inpatient setting and ~20% in the outpatient (post-discharge) arm will experience one or more 
477
episodes of hypoglycemia.  To minimize the risk of hypoglycemia, the starting dose will be 
478
reduced in the basal bolus insulin regimen (TDD: 0.4 units per kg of body weight), in addition, in 
479
patients ≥ 70 years of age and/or eGFR < 60 ml/min the TTD will be further reduce to 0.3 
480
units/kg.  To avoid hypoglycemia, the total daily dose of insulin will be decreased by 10% for 
481
BG between 70-99 mg/dl and by 20% after each episode of hypoglycemia (BG < 70 mg/dl).  In 
482
addition, in patients treated with insulin at home, the TDD of insulin will be reduced by 20% on 
483
admission and the attending physician may further reduce insulin dose in the presence of severe 
484
hypoglycemia.
485
486
Hypoglycemia will be treated with dextrose infusion.  Dextrose 50% solution will be given for 
487
glucose values < 70 mg/dl.  If the patient is awake, 25 ml (1/2 amp) will be given IV or oral 
488
juice/snack (crackers) as per protocol.  If the patient is not awake:  50ml (1 amp) will be given 
489
STAT.  Blood glucose levels will be repeated in 15 minutes and dextrose administration will be 
490
repeated as needed for values < 70 mg/dl.  
491
492
Subject Compliance
493
Aim 1.  Inpatient (hospital) trial.  We will use electronic medical records and nursing records to 
494
document day and time of insulin administration of study drug (degludec and glargine) given 
495
once daily and prandial- rapid-acting insulin (aspart) given before meals. We will also record 
496
dose and number of units given as supplement (correction) to correct hyperglycemia.
497
498
Aim 2.  Patients will be contacted every 2 weeks after discharge by a study coordinator to assess 
499
insulin administration, glycemic control, hypoglycemia and medication adherence.  Patients are 
500
to bring all used and unused insulin pens (study drug).  Patients will keep daily record of time 
501
and dose of insulin administered every day during the study period.
502
503
VI. STATISTICAL CONSIDERATIONS:


Degludec Hospital Trial
November 17, 2020
14
504
VI.A Aim 1.  To determine differences in inpatient glycemic control in patients treated with 
505
degludec or glargine in patients with T2D. 
506
Sample Size and Power Calculations: 
507
The primary endpoint in this study is glycemic control measured by mean daily BG 
508
concentration.  To show the non-inferiority of degludec and glargine in terms of glycemic 
509
control, we set the equivalence margin as 18 mg/dl (1 mosm/l), from a view that a difference <18 
510
mg/dl is usually not considered as clinically significant 12-14,37. Based on the results of the Rabbit 
511
medicine and surgery trials, it is reasonable to assume the standard deviation of mean daily BG is 
512
bounded above by 45 mg/dl. Assuming the true BG difference between the treatment groups is 
513
zero, and using one-sided, two-sample t-tests, we require 78 subjects for each treatment group to 
514
achieve 80% power with alpha=0.05. Accounting for 10-14% attrition rate, we would need 90 
515
patients per treatment group, which means 180 subjects in total, to achieve >80% power in Aim 
516
1. 
517
518
Analysis of Primary Endpoint:
519
The primary endpoint for Aim 1 is non-inferiority in mean differences between treatment groups 
520
in their mean blood glucose concentrations during the first 10 days of therapy (non-inferiority 
521
will be determined at a difference <18 mg/dl). Blood glucose will be measured before each meal 
522
and at bedtime. Average mean daily BG between the two study groups will also be compared 
523
based on the nonparametric Wilcoxon tests. We will also perform cross-sectional analysis of 
524
mean daily BG recorded on different days based on Wilcoxon tests or linear regression that 
525
accounts for potential confounders. In addition, we will conduct repeated measures ANOVA or 
526
repeated measures linear regression to estimate and test the difference in mean daily BG between 
527
the two treatment groups while simultaneously examining mean daily BG across multiple days 
528
during treatment. Transformations will be applied if normality violation is detected. Stepwise, 
529
backward, or forward model selection strategy will be adopted to determine the variables to be 
530
included in the final model. Standard diagnostic and model checking procedures will be applied 
531
to examine the fit of the developed models.
532
Analysis of Secondary Endpoints:
533
Secondary endpoints for Aim 1 in this study include incidence of hypoglycemia, number of 
534
hypoglycemic events, number of severe hyperglycemia, mean daily fasting BG, daily insulin 
535
dose, length of hospital stay, acute renal failure and hospital mortality. Blood glucose will be 
536
measured before each meal and at bedtime.  For discrete outcomes (such as hypoglycemia 
537
outcomes), we will first conduct nonparametric comparisons based on a two-sided Chi-square 
538
test (or Fisher’s exact test), followed by the Cochran-Mantel-Haenszel test, which adjusts for the 
539
potential center effect. We will further conduct logistic regression (for binary outcomes) and 
540
Poisson or Negative Binomial regression (for count outcomes) to assess and estimate the 
541
treatment effect while adjusting for potential confounders. We will analyze continuous secondary 
542
outcomes by following the plan proposed for the primary outcome. 
543
544
545
VI.B Aim 2: Sample Size and Power Calculations:  The primary endpoint in Aim 2 is 
546
difference in glycemic control (mean daily BG) after hospital discharge. Under the same 
547
assumptions for equivalence margin and BG variability as in Aim 1, we have the same sample 
548
size requirement (i.e. 78 subjects per group after 10% attrition). Accounting for 10-14% attrition 
549
rate, we would need 90 patients per treatment group, which means 180 subjects in total, to 
550
achieve >80% power. 


Degludec Hospital Trial
November 17, 2020
15
551
552
Analysis of Primary Endpoint:  The primary endpoint in this study is glycemic control 
553
measured by mean daily BG concentration after hospital discharge. Secondary outcomes include 
554
rate of hypoglycemia during follow-up, change in HbA1c, body weight, number of episodes of 
555
severe hyperglycemia, complications and emergency room visits or hospital readmissions at 12 
556
weeks post-discharge. To analyze these outcomes, we will follow the same analytic strategy 
557
proposed for the secondary endpoints of Aim 1. We will first compare the primary outcome 
558
using two-sample t-tests (or Wilcoxon tests) or one-way ANOVA, followed by multivariate 
559
linear regression to estimate and test the difference between the two treatment groups while 
560
simultaneously accounting for other potential confounders. Transformations will be applied if 
561
normality violation is detected. Stepwise, backward, or forward model selection strategy will be 
562
adopted to determine the variables to be included in the final model. Standard diagnostic and 
563
model checking procedures will be applied to examine the fit of the developed models.
564
565
VII.
DATA HANDLING AND RECORD KEEPING:
566
Data collection records with personal identifiers will be stored in locked file cabinets.  Blood 
567
samples drawn in conjunction with this study will not be labeled with information that could 
568
directly identify study subjects.  Blood samples will be not be stored. Presentation of the study 
569
results at regional or scientific meetings or in publications will not identify subjects.  Access to 
570
research and confidential records will be limited to clinical investigators, research coordinators, 
571
and the IRB at Emory University. 
572
573
VIII.
ETHICS:
574
Informed Consent.
575
After identification of eligible patients these individuals will be provided basic information 
576
regarding the study and, if interested, a member of the research staff using inclusion/exclusion 
577
criteria delineated elsewhere in the protocol will then screen patients.  Informed consent will be 
578
obtained before any trial related procedures including screening procedures. The consent form, 
579
potential risks and benefits, and the rights of research participants will be explained to the 
580
participant by the investigators or research coordinator.  Individuals will be asked if they have 
581
questions, and a member of the research staff will answer questions.  The principal investigator 
582
(PI) will also be available at all times to answer questions that participants may have during the 
583
consent procedure or during the time a participant is enrolled in the study.  The consent form will 
584
be completed only by trained research personnel familiar with the study protocol procedures, 
585
informed consent process, who have undergone CITI training in accordance with the IRB 
586
guidelines of Emory University.  A signed copy of the consent form will be provided to the 
587
participant and a copy will be placed in the file that is maintained for each participant in the 
588
study office.  
589
The study will be conducted in accordance with the Declaration of Helsinki and will be 
590
conducted in accordance with the ICH GCP guidelines. The sponsor-investigator will comply 
591
with all applicable regulatory and legal requirements, ICH GCP guidelines and the Declaration 
592
of Helsinki in obtaining and documenting the informed consent.
593
594
Recruitment Procedure. 
595
We screen all patients with hyperglycemia admitted to the hospital every day. Patients with 
596
diabetes and hyperglycemia will be identified electronically following inclusion/exclusion 
597
criteria. Once a potential candidate is identified, we will approach the primary team as well as 


Degludec Hospital Trial
November 17, 2020
16
598
the patient and family for consent. We estimate that we will screen approximately 220-250 
599
patients to analyze a total of 180 subjects, and expect to recruit about 2-4 patients per week”    
600
601
602
IX.STUDY SCHEDULE:
FIRST PATIENT IN
DEC 2017
SCREENING
~220-250
ANALYZED
180
LAST PATIENT RECRUITED
MARCH 2020
LAST PATIENT IN
JUNE 2020
DATA ANALYSIS
AIM 1: 09/2020 ; AIM: 2: 12/2020
SUBMISSION TO CONGRESS OR JOURNAL
1/ 2021 (ADA);  4/2021:  EASD
603
604
X. STUDY DRUGS AND MATERIALS:
605
Study medication(s) / devices(s)
606
Degludec insulin (U-100): 100 units/mL (U-100): 10 mL multiple-dose vial (1 vial per subject 
607
during hospital admission): Inpatient arm: 90 patients. Total number of vials: 90
608
Degludec insulin 100 Units/mL, provided in 3 mL pen cartridges (outpatient arm).  
609
Outpatient arm: 90 patients, average insulin dose: 30-45 U/day. Total number of cartridges: 100
610
611
Glargine insulin (U-100):  100 units/mL (U-100): 10 mL multiple-dose vial (1 vial per subject 
612
during hospital admission): Inpatient arm: 90 patients. Total number of vials: 90
613
Glargine (U-100) insulin 100 Units/mL, provided in 3 mL pen cartridges.
614
Outpatient arm: 90 patients, average insulin dose: 30-45 U/day. Total number of cartridges: 100
615
616
Aspart insulin (U-100): 100 units/mL (U-100): 10 mL multiple-dose vial (1 vial per subject 
617
during hospital admission): Inpatient arm: 180 patients. Total number of vials: 180
618
Aspart (U-100) insulin 100 Units/mL, provided in 3 mL pen cartridges
619
Outpatient arm: 180 patients, average insulin dose: 20-30 U/day. Total number of cartridges: 180
620
BG-Meters are considered standard of care and will not be provided. 
621
622
623
Packaging and Labelling of Study Medication(s)
624
Degludec, aspart, and glargine will be stored and dispensed by the research pharmacy at each 
625
institution. During the hospital stay (Aim 1) insulin will be kept at nursing stations and dosing 
626
will be administered by nursing staff as per hospital protocol. Once dispensed and in use (after 
627
first opening), insulin glargine can be stored for one month at room temperature (+15°C to 
628
+30°C)/(59°F to 86°F) or in a refrigerator (+2°C to +8°C)/(+36°F to +46°F).  
629
During the outpatient trial, all insulin prefilled pens \ will be stored in a refrigerator at a 
630
temperature between +2°C and +8°C (+36°F and +46°F). Once dispensed and in use (after first 
631
opening), insulin glargine can be stored for one month at room temperature (+15°C to 
632
+30°C)/(59°F to 86°F) or in a refrigerator (+2°C to +8°C)/(+36°F to +46°F
633


Degludec Hospital Trial
November 17, 2020
17
634
Drug accountability:  The trial product will be dispensed to each subject as required according 
635
to treatment group. The research/clinical staff will perform drug accountability by asking 
636
patients to return all unused, partly used and unused cartridges and vials of degludec and glargine 
637
insulin at each visit.  
638
639
Randomization and Blinding
640
This is an open label randomized multicenter controlled trial.  Patients will be randomized 
641
consecutively using a computer-generated randomization table provided by Dr. Limin Peng at 
642
the Emory School of Public Health.  The randomization table will be mailed to the research 
643
pharmacist at each institution who will be in charge of the randomization and group assignment. 
644
645
XI. CONCOMITANT ILLNESSES AND MEDICATIONS:
646
Definitions:
647
During the hospital arm (Aim 1), all oral agents and insulin formulations will be discontinued at 
648
randomization and patients will be treated as per study protocol with degludec/glargine as basal 
649
bolus regimen with aspart as prandial insulin.  
650
After discharge, patients will be treated with glargine or degludec insulin alone or in 
651
combination with oral agents according to HbA1c levels. 
652
653
XII.
ADVERSE EVENTS:
654
Definition:  An adverse event (AE) is any untoward medical occurrence in a subject 
655
administered a product, and which does not necessarily have a causal relationship with this 
656
treatment. An AE is an unfavorable and unintended sign (including abnormal laboratory 
657
findings), symptom or disease temporally associated with the use of a product, whether or not 
658
considered related to the product.
659
This includes events from the first trial related activity after the subject has signed the informed 
660
consent and until post treatment follow-up period (telephone contact 2 weeks after last study 
661
visit).
662
AEs include a clinically significant worsening of a concomitant illness and clinical laboratory 
663
adverse event (CLAE).  An AE is either a serious AE (SAE) or a non-serious AE.
664
665
The following AEs will be reported as an SAE using the important medical event criterion if no 
666
other seriousness criteria are applicable:
667
- Suspicion of transmission of infectious agents via the trial product
668
- Risk of liver injury defined as alanine aminotransferase (ALT) or aspartate aminotransferase 
669
(AST) >3 x UNL and total bilirubin >2 x UNL, where no alternative aetiology exists (Hy's law)
670
-Death
671
-A life-threatening event in which the subject was at risk of death at the time of the event
672
-Inpatient hospitalization and prolongation of existing hospitalization
673
-Persistent or significant disability or incapacity
674
-Important medical events that may not result in death, or a life threatening event but may 
675
require hospitalization
676
-Episodes of severe hypoglycemia will be captured as serious AEs.
677
- A planned hospitalization for pre-existing condition, or a procedure required by the protocol, 
678
without a serious deterioration in health, is not considered to be an SAE. 


Degludec Hospital Trial
November 17, 2020
18
679
680
Severity Assessment Definitions:
681
• Mild: Transient symptoms, no interference with the subject’s daily activities
682
• Moderate: Marked symptoms, moderate interference with the subject’s daily activities
683
• Severe: Considerable interference with the subject’s daily activities, unacceptable
684
685
Relationship to Trial Product Assessment Definitions:
686
• Probable: Good reasons and sufficient documentation to assume a causal relationship
687
• Possible: A causal relationship is conceivable and cannot be dismissed
688
• Unlikely: The event is most likely related to an aetiology other than the trial product
689
690
Adverse events will be actively collected from the signing of the informed consent and in all 
691
following contacts throughout the project. This includes events from all trial related activity after 
692
the subject has signed the informed consent, and until the post treatment follow-up period, as 
693
defined in the protocol. 
694
695
Outcome Categories and Definitions:
696
• Recovered: Fully recovered or by medical or surgical treatment the condition has returned to 
697
the level observed at the first trial related activity after the subject signed the informed consent
698
• Recovering: The condition is improving and the subject is expected to recover from the event. 
699
This term should only be used when the subject has completed the trial
700
• Recovered with sequelae: As a result of the AE, the subject suffered persistent and significant 
701
disability/incapacity (e.g. became blind, deaf, paralysed). Any AE recovered with sequelae 
702
should be rated as an SAE
703
• Not recovered
704
• Fatal
705
• Unknown
706
707
Reporting of adverse events:  All events meeting the definition of an AE must be collected and 
708
reported. The events must be recorded in the AE form in a timely manner.  During each contact 
709
with the trial site staff (site visits and telephone contacts), the subject will be asked about AEs. 
710
After the ICF is signed, all adverse events related to protocol procedures are to be reported. 
711
Suspected Unexpected Serious Adverse Reaction (SUSAR): An SAE which is unexpected and 
712
regarded as possibly or probably related to the trial/study product by the investigator. Serious 
713
adverse reaction (SAR): An Adverse event that fulfils both the criteria for a Serious Adverse 
714
Event and the criteria for an Adverse Reaction.An SAE report should be completed for any event 
715
where doubt exists regarding its seriousness.
716
If the investigator believes that an SAE is not related to study drug, but is potentially related to 
717
the conditions of the study (such as withdrawal of previous therapy or a complication of a study 
718
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
719
SAEs, whether related or not related to study drug, and pregnancies must be reported to Emory 
720
IRB and Novo Nordisk by fax or email. SAEs must be recorded on an SAE Report Form or 
721
similar form (e.g. CIOMS, MedWatch). 
722
Within 15 days of becoming aware, the PI/sponsor will notify the FDA and all participating 
723
investigators via IND safety reports of events that are unexpected, caused by the study 
724
drug, and meet the FDA definition of “serious.”


Degludec Hospital Trial
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19
725
 
726
Reporting of pregnancies:  Female subjects who are pregnant or breast-feeding will not be 
727
recruited in the study.  Female subjects will be instructed to notify the investigator immediately 
728
if they become pregnant during the trial. The investigator must report any pregnancy to the 
729
Emory IRB and Novo Nordisk. The pregnant subject will be asked to provide information about 
730
her pregnancy, delivery and the health of her infant until age one month. If the infant has a 
731
congenital anomaly/birth defect this must be reported and followed up as a serious adverse event.
732
 
733
Adverse events with additional data collection: Adverse events with additional data collection 
734
are those events thought to be [potentially] associated with the investigational compound or 
735
disease under study. The investigators will collect information on medical events of special 
736
interest including hypoglycemia, hyperglycemia (BG > 240 mg/dl), cardiovascular events (heart 
737
failure, acute myocardial infarction, and atrial fibrillation), and medication errors (e.g., incorrect 
738
dose of insulin). 
739
740
XIII.
LIABILITY AND SUBJECT INSURANCE:
741
Financial Obligation.
742
No additional cost to patients or to the institution will be incurred for research purposes. Patients 
743
will not be billed for the laboratory work or any test that is being done only for study purposes.  
744
Novo Nordisk will provide the study drugs (degludec, glargine and aspart insulin) at no cost to 
745
participants.  Patients will be responsible for the cost of their usual ongoing medical care, 
746
including procedures and/or non-study medications that their doctor requires as part of their 
747
usual medical care.
748
749
Payment for Participation.    
750
Participation in this study is voluntary.  Patients will receive one hundred dollars ($100.00) 
751
during the hospital stay and seventy- five dollars ($75.00) after each clinic visit at 1 and 3 
752
months after discharge. Total compensation will be two hundred and fifty dollars ($250.00).
753
754
755
Research Injuries.
756
If a patient is injured because of taking part in this study, Dr. Umpierrez and investigators at each 
757
institution, along with the medical facilities will make medical care available.  Emory University, 
758
however, has not set aside any money to pay participants or to pay for their medical treatment. 
759
The only exception is if it is proved that the injury or illness is directly caused by the negligence 
760
of an Emory/Grady employee.  “Negligence” is the failure to follow a standard duty of care. 
761
Financial compensation for such things as lost wages, disability or discomfort due to an injury 
762
related to the study is not available.  
763
764
XIV.
Publication Plan:
765
We anticipate completion of Aim 1 in September or October 2020 and Aim 2 in November 2020.  
766
Data will be analyzed in December 2020 (aim 1) and in March 2021(aim 2).  One abstract will 
767
be submitted to the 2021 American Diabetes Association meeting and one to EASD 2021.  Two 
768
manuscripts will be submitted during the first six months of 2021.
769
770


Degludec Hospital Trial
November 17, 2020
20
771
XV.
References
772
1.
Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. 
773
Hyperglycemia: an independent marker of in-hospital mortality in patients with 
774
undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87(3):978-982.
775
2.
Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill 
776
patients. Jama. 2003;290(15):2041-2047.
777
3.
Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefit of intensive insulin 
778
therapy in the critically ill: Insulin dose versus glycemic control. Crit Care Med. 
779
2003;31(2):359-366.
780
4.
Pomposelli JJ, Baxter JK, 3rd, Babineau TJ, et al. Early postoperative glucose control 
781
predicts nosocomial infection rate in diabetic patients. JPEN J Parenter Enteral Nutr. 
782
1998;22(2):77-81.
783
5.
Malmberg K, Ryden L, Efendic S, et al. Randomized trial of insulin-glucose infusion 
784
followed by subcutaneous insulin treatment in diabetic patients with acute myocardial 
785
infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 
786
1995;26(1):57-65.
787
6.
Clement S, Braithwaite SS, Magee MF, et al. Management of diabetes and 
788
hyperglycemia in hospitals. Diabetes Care. 2004;27(2):553-597.
789
7.
McAlister FA, Majumdar SR, Blitz S, Rowe BH, Romney J, Marrie TJ. The relation 
790
between hyperglycemia and outcomes in 2,471 patients admitted to the hospital with 
791
community-acquired pneumonia. Diabetes Care. 2005;28(4):810-815.
792
8.
Baker EH, Janaway CH, Philips BJ, et al. Hyperglycaemia is associated with poor 
793
outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive 
794
pulmonary disease. Thorax. 2006;61(4):284-289.
795
9.
Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces 
796
mortality in patients with diabetes undergoing coronary artery bypass grafting. J Thorac 
797
Cardiovasc Surg. 2003;125(5):1007-1021.
798
10.
Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin therapy in the medical 
799
ICU. N Engl J Med. 2006;354(5):449-461.
800
11.
van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically 
801
ill patients. N Engl J Med. 2001;345(19):1359-1367.
802
12.
Umpierrez GE, Smiley D, Zisman A, et al. Randomized study of basal-bolus insulin 
803
therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). 
804
Diabetes Care. 2007;30(9):2181-2186.
805
13.
Umpierrez GE, Smiley D, Jacobs S, et al. Randomized study of basal-bolus insulin 
806
therapy in the inpatient management of patients with type 2 diabetes undergoing general 
807
surgery (RABBIT 2 surgery). Diabetes Care. 2011;34(2):256-261.
808
14.
Umpierrez GE, Smiley D, Hermayer K, et al. Randomized study comparing a Basal-bolus 
809
with a basal plus correction insulin regimen for the hospital management of medical and 
810
surgical patients with type 2 diabetes: basal plus trial. Diabetes Care. 2013;36(8):2169-
811
2174.
812
15.
Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of Clinical 
813
Endocrinologists and American Diabetes Association consensus statement on inpatient 
814
glycemic control. Diabetes Care. 2009;32(6):1119-1131.


Degludec Hospital Trial
November 17, 2020
21
815
16.
Umpierrez GE, Hellman R, Korytkowski MT, et al. Management of hyperglycemia in 
816
hospitalized patients in non-critical care setting: an endocrine society clinical practice 
817
guideline. J Clin Endocrinol Metab. 2012;97(1):16-38.
818
17.
Standards of medical care in diabetes--2012. Diabetes Care. 2012;35 Suppl 1:S11-63.
819
18.
Wang F, Surh J, Kaur M. Insulin degludec as an ultralong-acting basal insulin once a day: 
820
a systematic review. Diabetes Metab Syndr Obes. 2012;5:191-204.
821
19.
Garber AJ, King AB, Del Prato S, et al. Insulin degludec, an ultra-longacting basal 
822
insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in 
823
type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-
824
to-target non-inferiority trial. Lancet. 2012;379(9825):1498-1507.
825
20.
Zinman B, Philis-Tsimikas A, Cariou B, et al. Insulin Degludec Versus Insulin Glargine 
826
in Insulin-Naive Patients With Type 2 Diabetes: A 1-year, randomized, treat-to-target 
827
trial (BEGIN Once Long). Diabetes Care. 2012.
828
21.
Danne T, Bolinder J. New insulins and insulin therapy. Int J Clin Pract Suppl. 
829
2011(170):26-30.
830
22.
Ratner R, Gough SC, Mathieu C, et al. Hypoglycaemia Risk With Insulin Degludec 
831
Compared With Insulin Glargine in Type 2 and Type 1 Diabetes: A Pre-planned Meta-
832
Analysis of Phase 3 Trials. Diabetes Obes Metab. 2012.
833
23.
Nasrallah SN, Reynolds LR. Insulin Degludec, The New Generation Basal Insulin or Just 
834
another Basal Insulin? Clin Med Insights Endocrinol Diabetes. 2012;5:31-37.
835
24.
Umpierrez GE, Reyes D, Smiley D, et al. Hospital Discharge Algorithm Based on 
836
Admission HbA1c for the Management of Patients With Type 2 Diabetes. Diabetes Care. 
837
2014.
838
25.
Kellum JA, Lameire N, Group KAGW. Diagnosis, evaluation, and management of acute 
839
kidney injury: a KDIGO summary (Part 1). Crit Care. 2013;17(1):204.
840
26.
Heise T, Korsatko S, Nosek L, et al. Steady state is reached within 2-3 days of once-daily 
841
administration of degludec, a basal insulin with an ultralong duration of action. J 
842
Diabetes. 2016;8(1):132-138.
843
27.
Kaku K, Eid MA. Safety, efficacy, and early clinical experience of insulin degludec in 
844
Japanese people with diabetes mellitus: A first-year report from Japan. J Diabetes 
845
Investig. 2015;6(6):610-619.
846
28.
Swinnen SG, Simon AC, Holleman F, Hoekstra JB, Devries JH. Insulin detemir versus 
847
insulin glargine for type 2 diabetes mellitus. Cochrane Database Syst Rev. 
848
(7):CD006383.
849
29.
Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and 
850
prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke. 
851
2001;32(10):2426-2432.
852
30.
Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and increased risk 
853
of death after myocardial infarction in patients with and without diabetes: a systematic 
854
overview. Lancet. 2000;355(9206):773-778.
855
31.
Golden SH, Peart-Vigilance C, Kao WH, Brancati FL. Perioperative glycemic control 
856
and the risk of infectious complications in a cohort of adults with diabetes. Diabetes 
857
Care. 1999;22(9):1408-1414.
858
32.
Kitabchi AE, Umpierrez GE, Murphy MB, et al. Hyperglycemic crises in diabetes. 
859
Diabetes Care. 2004;27 Suppl 1:S94-102.


Degludec Hospital Trial
November 17, 2020
22
860
33.
Umpierrez GE. Basal versus sliding-scale regular insulin in hospitalized patients with 
861
hyperglycemia during enteral nutrition therapy. Diabetes Care. 2009;32(4):751-753.
862
34.
Umpierrez GE, Hor T, Smiley D, et al. Comparison of inpatient insulin regimens with 
863
detemir plus aspart versus neutral protamine hagedorn plus regular in medical patients 
864
with type 2 diabetes. J Clin Endocrinol Metab. 2009;94(2):564-569.
865
35.
Queale WS, Seidler AJ, Brancati FL. Glycemic control and sliding scale insulin use in 
866
medical inpatients with diabetes mellitus. Arch Intern Med. 1997;157(5):545-552.
867
36.
Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of Clinical 
868
Endocrinologists and American Diabetes Association consensus statement on inpatient 
869
glycemic control. Endocr Pract. 2009;15(4):353-369.
870
37.
Pasquel FJ, Gianchandani R, Rubin DJ, et al. Efficacy of sitagliptin for the hospital 
871
management of general medicine and surgery patients with type 2 diabetes (Sita-
872
Hospital): a multicentre, prospective, open-label, non-inferiority randomised trial. Lancet 
873
Diabetes Endocrinol. 2016.
874
38.
Vellanki P, Bean R, Oyedokun FA, et al. Randomized controlled trial of insulin 
875
supplementation for correction of bedtime hyperglycemia in hospitalized patients with 
876
type 2 diabetes. Diabetes Care. 2015;38(4):568-574.
877


Degludec Hospital Trial
November 17, 2020
23
879
Appendix 1.
Supplemental “sliding insulin scale” protocol
880
881
BEFORE MEAL, Supplemental Sliding Scale Insulin (number of units) - Add to scheduled 
882
insulin dose.  
883
884
885
886
**Check appropriate column and cross out other columns
887
BG (mg/dL)
        Insulin Sensitive                     Usual                    Insulin Resistant                              
< 141
                    No sliding scale (supplemental)insulin
141 – 180
2
3
4
181 – 220
3
4
6
221 – 260
4
5
8
261 – 300
5
6
10
301 – 350
6
8
12
351 – 400
7
10
14
> 400
8
12
16
888
889
BEDTIME sliding scale: Supplemental Sliding Scale Insulin dose at bedtime starting at BG 
890
> 220 mg/dL
891
  BG (mg/dL)          Insulin Sensitive                          Usual                    Insulin 
892
Resistant                                 
< 220
                    No sliding scale (supplemental) insulin
221 – 260
1
2
4
261 – 300
2
3
5
301 – 350
3
4
6
351 – 400
4
5
7
> 400
5
6
8
893
894
895
896
897
898
** Check appropriate column below and cross out other columns
899
900
The numbers in each column indicate the number of units of aspart insulin per dose.  
901
Supplemental” dose is to be added to the scheduled dose of aspart insulin.  If a patient is able and 
902
expected to eat all or most of his/her meals, supplemental insulin will be administered before 
903
each meal following the “usual” column dose.  
904
Supplemental insulin at bedtime will be given ONLY for BG > 220 mg/dl = half of premeal 
905
insulin dose38.  Example, a patient with blood glucose of 280 mg/dl will receive 5 U before a 
906
meal or 2 U at bedtime of supplemental insulin.    
907
If a patient is not able to eat (NPO), supplemental insulin will be administered every 6 hours (6-
908
12-6-12) following the “sensitive” column dose.  Example, a patient kept NPO with blood 
909
glucose of 181 mg/dl will receive 3 U of supplemental insulin.    
910