A Randomized Controlled Trial Comparing Glargine U300 and Glargine U100 for the Inpatient and Post-Hospital Discharge Management of Medicine and Surgery Patients With Type 2 Diabetes
Phase: PHASE4
Conditions: Type 2 Diabetes
Sponsor: Emory University

Glargine U300 vs U100_ Hospital Trial 
01/28/2019 
 
 
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IRB00091740 
 
NCT03013985 
 
A Randomized Controlled Trial Comparing Glargine U300 and Glargine U100 for the Inpatient and Post-
Hospital Discharge Management of Medicine and Surgery Patients with Type 2 Diabetes 
 
 
Principal Investigator: 
 
 
Guillermo E. Umpierrez, M.D. 
Professor of Medicine, Endocrinology  
Emory University School of Medicine 
Director, Diabetes and Endocrinology Section 
 
 
 
 
Grady Health System 
 
01/28/2019 
 
 
 

Glargine U300 vs U100_ Hospital Trial 
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Title:   
 
Glargine U300 Hospital Trial: A Randomized Controlled Trial Comparing Glargine U300 and Glargine 
U100 for the Inpatient and Post-Hospital Discharge Management of Medicine and Surgery Patients with 
Type 2 Diabetes  
 
Principal Investigator: 
 
 
Guillermo E. Umpierrez, M.D. 
Professor of Medicine, Endocrinology  
Emory University School of Medicine 
Director, Diabetes and Endocrinology Section 
 
 
 
 
Grady Health System 
 
Co-Principal Investigator: 
 
 
 
 
Francisco J Pasquel, MD, MPH 
Assistant Professor of Medicine, Endocrinology  
Emory University School of Medicine 
 
 
Investigators: 
Emory University, Atlanta  
  Priyathama Vellanki, MD   
  Maya Fayfman, MD 
  Sonya Haw, MD 
  Sol Jacobs, MD 
  Rodolfo J Galindo, MD 
 
 
Minneapolis Medical Research Foundation-Hennepin Medical Center, Minneapolis 
 Ameer Ali Khowaja, MD 
 
The Cleveland Clinic Foundation, Ohio 
 Cecilia Lansang, MD 

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I. 
RESEARCH OBJECTIVES AND SPECIFIC AIMS 
 
A. 
Introduction: 
The association between hyperglycemia and poor clinical outcomes in hospitalized patients with 
and without diabetes is well established (1-5). Extensive data from observational and prospective 
randomized controlled trials (RCT) in hospitalized patients have reported a strong association between 
hyperglycemia and poor clinical outcome, such as increased mortality, morbidity, hospital length of stay 
(LOS), infections and overall complications (1, 4, 6-8).  Clinical trials in both critically ill and in non-ICU 
medicine and surgery patients have shown that improvement of glycemic control in patients with 
hyperglycemia reduces LOS, systemic infections (9-11) and short- and long-term mortality (6, 11).   
 
Randomized multi-center trials have shown that basal bolus treatment with glargine U100 improve 
glycemic control and reduce the rate of hospital complications compared to sliding scale regular insulin 
(SSI) (12-14). In general surgery patients, the basal bolus approach results in significant reduction in a 
composite of hospital complications including postoperative wound infection, pneumonia, bacteremia, 
and acute renal and respiratory failure (15). The hospital hypoglycemia rate was reported in 3% in 
medicine (16) and 12% in surgery (17) patients treated with basal bolus regimen. Based on these results, 
clinical practice guidelines have recommended the use of basal bolus approach as the preferred insulin 
regimen for the management of non-ICU patients with diabetes (18-20).  
 
The Food and Drug Administration and the European Commission recently approved Glargine 
U300 insulin for the treatment of patients with diabetes. Glargine U300 is long-acting insulin with 
duration of action longer than 24 hours (21, 22). The results of the Edition clinical trials with more than 
3500 patients demonstrated that glargine U300 resulted in similar improvement in glycemic control and 
with a lower rate of nocturnal hypoglycemia compared to glargine U100 (23-27). The efficacy and safety 
of glargine U300 has been documented in patients with type 1 and type 2 diabetes (22-27); however, no 
previous studies have assessed the safety and efficacy of these new formulations in the inpatient (hospital) 
setting. In addition, certain features of glargine U300 needs to be investigated in the hospital including 1) 
prolonged duration of action, which may limit the ability to make day-to-day adjustments in insulin 
dosage; 2) a steady-state insulin concentration achieved after second or third day of therapy; and limited 
safety data in acutely ill patients with altered nutritional status. Accordingly, the present randomized 
clinical trial will compare the efficacy and safety of a basal bolus regimen with glargine U300 and 
glargine U100 (standard of care) in general medicine and surgery patients with T2D. 
 
B. 
Specific Aims:   
Aim 1.  To determine differences in inpatient glycemic control, as measured by mean daily blood 
glucose concentration and frequency of hypoglycemia, in general medicine and surgery patients 
with T2D treated with basal bolus regimen with glargine U300 and U100 plus glulisine insulin 
before meals. 
Hypothesis: Treatment with glargine U300 will result in equivalent glycemic control in hospitalized 
patients with T2D. Glargine U300 will result in lower number of hypoglycemia compared to glargine. 
 
Aim 2:  To determine differences in glycemic control after hospital discharge between treatment 
with glargine U300 and glargine U100 in medicine and surgery patients T2D.  Patients with poorly 
controlled diabetes (HbA1c ≥7.5%) enrolled in Aim 1 will be invited to participate in this open label 
prospective outpatient study. The total duration of the study is 3 months. Patients with an HbA1c between 
7.5% and 10% will be discharged on preadmission oral antidiabetic agents plus glargine U300 and U100 
once daily. Patients with an admission A1C ≥ 10% will be discharged on basal bolus regimen with 
glargine and glulisine insulin before meals.   

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Hypothesis: treatment with glargine U300 and U100 will result in a similar improvement in HbA1c levels 
after hospital discharge. Glargine U300 will result in lower number of hypoglycemia compared to U100. 
II. 
BACKGROUND AND CURRENT STATUS OF WORK IN THE FIELD. 
 
Inpatient glycemic control in non-ICU setting.  A large body of evidence has shown that in 
hospitalized patients, the presence of hyperglycemia and diabetes is associated with increased risk of 
complications and death (1-6, 28-31). Several randomized multi-center trials have shown that the use of 
basal bolus insulin regimen result in improved glycemic control and reduced rate of hospital 
complications compared to sliding scale regular insulin (SSI) in patients with T2D (12-14). We have 
reported that treatment with basal and basal bolus regimens using glargine U100 results in greater 
improvement in BG control and a reduction in the frequency of hospital complications including 
postoperative wound infection, pneumonia, bacteremia, and acute renal and respiratory failure compared 
to SSI treatment.(16, 17, 32, 33) In addition, the use of basal bolus regimen with glargine U100 is safe 
with low rate of hypoglycemic events. Based on these studies and others, clinical practice guidelines for 
the management of hyperglycemia in non-ICU setting have favored the use of basal prandial insulin 
regimens with insulin analogs for most inpatients with T2D (6, 19, 31).   
 
Efficacy and safety of new glargine U-300 insulin:  
Glargine U300 insulin has a peakless pharmacodynamic profile with duration of action longer than 
24 hours. Several clinical trials in the Edition clinical program, which included more than 3500 patients 
with type 2 diabetes treated with basal insulin or with oral agents demonstrated that glargine U300 
treatment resulted in similar improvement in glycemic control (HbA1c reduction) compared to glargine 
U100 insulin (23-27). In addition, patients treated with glargine U300 experienced lower rates of 
hypoglycemia, in particular nocturnal hypoglycemia compared to glargine U100 (23-27).  The safety 
profile of glargine U300 makes these new insulin formulations an attractive alternative to glargine U100, 
as hypoglycemia has been associated with increased risk of complications and mortality in the hospital 
setting (34, 35). 
 
No previous studies have determined the safety and efficacy of glargine U300 compared to 
glargine U100 (current standard of care) in hospitalized patients with diabetes. Despite the benefit in 
improving glycemic control and in reducing hypoglycemia, there are potential concerns with the use of 
this new basal insulin formulation in the hospital due to its prolonged duration of action and time to 
achieve a steady-state concentration in patients with altered nutrition.  The anticipated large number of 
patients who will be treated with glargine U300 in the future, makes this proposal timely and of great 
clinical interest. 
 
Transition Care from Hospital to Home. Hospital discharge represents a critical time for ensuring a 
safe transition to the outpatient setting and reducing the need for emergency department visits and re-
hospitalization.  Few studies have addressed the management of patients with diabetes after hospital 
discharge in insulin treated patients with T2D.  The Endocrine Society guidelines for the management of 
hyperglycemia recently recommended the use of HbA1c concentration during the hospital stay in tailoring 
the glycemic management of diabetic patients at discharge (19). In a recent study we assessed the efficacy 
of an HbA1c based algorithm using glargine insulin for the management of patients with T2D (see 
preliminary results section) (36). Patients with an HbA1c between 7% and 9% were discharged on a 
combination of OADs and glargine insulin at 50% of total daily hospital dose. Patients with an admission 
HbA1c ≥ 9% were discharged on a combination of OAD and glargine insulin at 80% of total daily 
hospital dose or on a basal bolus regimen with glargine and rapid-acting insulin analog before meals. The 
admission HbA1c on admission of 8.75% decreased to 7.9% and 7.35% after 4 and 12 weeks of hospital 
discharge (p<0.01). The rate of hypoglycemia was ~30% in patients treated with oral agents plus basal 
insulin and greater than 40% in patients treated with basal bolus insulin regimen.  It is expected that 

Glargine U300 vs U100_ Hospital Trial 
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glargine U300, which is known to have lower rate of hypoglycemia compared to glargine U100, will 
reduce the rate of hypoglycemia after hospital discharge. 
 
Significance and Innovation. Glargine U300 is a new generation basal insulin analog with a longer 
duration of action compared to insulin glargine (21, 22). Several outpatient trials have reported that 
treatment with glargine U300 results in comparable improvement in HbA1c levels and in lower rates of 
hypoglycemia compared to glargine U100 insulin (23-27). No previous studies; however, have compared 
the safety and efficacy of the long-acting glargine U300 in the inpatient management of patients with 
diabetes. It is expected that a large number of patients with diabetes will be started or transitioned to this 
new insulin formulation; so acquiring knowledge on their safety and efficacy is of great clinical interest. 
Accordingly, the proposed study will provide novel and clinically useful information on the efficacy (BG 
control) and safety (hypoglycemia) of glargine U300 in the inpatient setting and after hospital discharge 
in general medicine and surgery patients with T2D.  
 
III. 
PRELIMINARY RESULTS: 
 
Our groups have reported the results of several 
observational and  prospective, randomized multi-center 
trials comparing the efficacy and safety of basal/bolus insulin 
regimens to sliding scale regular insulin (SSI) and split-
mixed regimen with NPH/regular in T2D patients admitted to 
general medicine services (16, 17).   
 
In the Rabbit trial (Fig 1), 130 nonsurgical insulin naïve 
patients were randomized to receive glargine once daily and 
glulisine before meals or SSRI before meals and at bedtime. 
Patients treated with glargine/glulisine had greater 
improvement in BG control than SSRI with a minimal risk of 
hypoglycemia patients (3% of patients in each group had a 
BG < 60 mg/dL). A BG target of <140 mg/dL was achieved 
in 66% of patients treated with glargine and glulisine whereas 
only 38% of those treated with SSRI achieved target glycemia.   
 
In the Rabbit-Surgery trial (Figure 2), 211 general non-cardiac 
surgery patients with T2D were randomized to a basal bolus 
(BB) with glargine once daily and glulisine before meals and to 
sliding scale regular insulin (SSI). Study outcomes included 
differences in daily BG levels and a composite of hospital 
complications including postoperative wound infection, 
pneumonia, respiratory failure, acute renal failure, and 
bacteremia. The mean daily glucose after the 1st day of BB and 
SSI was 145±32 mg/dl and 172±47 mg/dl, respectively, p<0.01. 
BG readings <140 mg/dl were recorded in 55% of patients in BB 
and 31% in the SSI group, p<0.001.  There were reductions with 
BB as compared with SSI in the composite outcome (24.3% and 
8.6%, OR: 3.39 (95% CI: 1.50-7.65); p=0.003).  We concluded 
that treatment with BB improved glycemic control and reduced 
complications compared to SSI in surgery patients with T2D. 
 
Basal insulin during Hospital Discharge.(36)  
Fig 1 
A1C < 7% 
Re-start 
outpatient 
treatment 
regimen 
(OAD and/or 
insulin) 
A1C 7%-9% 
Re-start 
outpatient oral 
agents and D/C 
on glargine once 
daily at 50% of 
hospital dose  
A1C >9% 
D/C on basal bolus at 
same hospital dose. 
Alternative: re-start 
oral agents and D/C 
on glargine once 
daily at 80% of 
hospital dose  
Discharge Treatment 
Umpierrez et al.  ADA Scientific Meeting, Philadelphia 2012 
Fig 3 
8.6
1.0
2.9
0.0
3.8
24.3
1.0
10.3
2.8
10.3
0
5
10
15
20
25
30
Composite
Mortality
Wound 
Infection
Pneumonia
Acute Renal 
Failure
Outcome Frequency, %
Figure 3.   Postoperative Complications
P=0.003
P=NS
P=0.05
P=0.10
P=0.24
Glargine+Glulisine
Sliding Scale Insulin
* Composite of hospital complications: wound infection, pneumonia, 
respiratory failure, acute renal failure, and bacteremia.

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In a recent preliminary study we assessed the efficacy of an HbA1c based algorithm for the management 
of non-ICU insulin treated patients with T2D (Fig. 4). A total 
of 214 general medicine and surgery patients with an 
admission HbA1c < 7% were discharged on their same 
outpatient antidiabetic regimen (oral antidiabetic drugs, 
OAD and/or insulin).  Patients with an HbA1c between 
7% and 9% were discharged on a combination of OADs 
and basal (glargine) insulin at 50% of total daily hospital 
dose. Patients with an admission HbA1c ≥ 9% were 
discharged on a combination of oral agents and basal 
insulin at 80-100% of total daily hospital dose or on a 
basal bolus regimen at the same hospital dosage. The admission HbA1c of 8.75% decreased to 7.9% and 
7.35% after 4 and 12 weeks of hospital discharge respectively (p<0.01, Fig 5).  Patients with higher 
HbA1c levels experienced a greater reduction as well as those treated with basal bolus insulin regimens. 
We concluded that the admission HbA1c concentration is beneficial in designing the discharge treatment 
algorithm after discharge in non-ICU patients with T2D. 
 
Our preliminary studies indicate that in general medicine and surgery patients with T2D 1) basal bolus or 
basal plus supplement regimens with glargine U100 are effective in improving glycemic control during 
the hospital stay, and 2) treatment with glargine U100 alone or in combination with oral agents or rapid-
acting insulin (basal bolus) is effective in improving and maintain glucose control after hospital discharge.  
In addition, these results indicate our ability to design, recruit and complete clinical trials in hospitalized 
patients with T2D.   
 
 
IV. 
EXPERIMENTAL PLAN 
 
Aim 1.  To determine differences in inpatient glycemic control, as measured by mean daily blood 
glucose concentration and frequency of hypoglycemia, in general medicine and surgery patients 
with T2D treated with basal bolus regimen with glargine U300 and U100 plus glulisine insulin 
before meals. 
 
IV.a. Rationale.   Several studies have shown improved clinical outcome with improved glycemic 
control in hospitalized patients with T2D (4, 5, 9, 11, 28, 37, 38). RCTs in medicine and surgical patients 
with T2D have shown that basal bolus regimen with glargine results in a lower mean daily BG 
concentration compared to the sole use of SSI and in lower rate of hospital complications (see preliminary 
results section). Glargine U300 results in similar improvement but in lower rate of hypoglycemia than 
treatment with glargine U100. No previous studies; however, have compared the efficacy and safety of 
glargine U300 in the management of hyperglycemia and diabetes in hospital setting.  Determining the 
safety and efficacy of new insulin formulations in the hospital, an environment associated with reduced 
insulin sensitivity and altered nutritional intake, is an exceedingly important clinical question.  
 
IV.b. STUDY DESIGN AND METHODS 
We will consent about 300 patients (for a total of 180 randomized subjects) with T2D treated with 
diet, oral hypoglycemic agents or insulin therapy, except long-acting GLP1-RA (albiglutide, albiglutide 
and weekly exenatide), prior to admission will be included in this prospective, randomized, open label 
trial to compare the safety and efficacy of a basal bolus regimen with glargine U300 and U100 in patients 
with T2D admitted to general medicine and surgery services. 
 
IV.c. Primary and Secondary Research Outcomes: 
6.5$
7$
7.5$
8$
8.5$
9$
HbA1c$
Admission$
4$weeks$
12$weeks$
8.75% 
7.9% 
7.35% 
% 
Change in HbA1C levels after discharge 
Umpierrez et al.  ADA Scientific Meeting, Philadelphia 2012 
HbA1c Concentration   
Fig 4 

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The primary outcome of the study is to determine differences in glycemic control as measured by mean 
daily blood glucose concentration between treatment groups. For each subject, we will take the average of 
all pre-meal and bedtime glucose values collected after the first day of therapy during the hospital stay (up 
to 10 days).   
 
Secondary outcomes include differences between treatment groups in any of the following measures:  
1. Differences in mean daily glucose in patients admitted to medicine and surgery services. 
2. Differences in mean daily glucose in patients with admission HbA1c lower than and higher than 8%. 
3. Differences in mean daily glucose in patients with length of stay shorter and longer than 3 and 5 days. 
4. Proportion of BG readings within target of 80 mg/dl and 180 mg/dl before meals. 
5. Number of BG readings between 80 mg/dl and 180 mg/dl before meals without hypoglycemia. 
6. Number of patients with hypoglycemia (defined as a BG < 70 mg/dl) and number of events adjusted by 
length of stay (event rate). 
7. Number of patients with severe hypoglycemia (defined as a BG < 40 mg/dl) and number of events 
adjusted by length of stay (event rate). 
8. Length of hospital stay. 
9. Cardiac complications are defined as myocardial infarction, cardiac arrhythmia requiring medical 
treatment, or cardiac arrest. 
10. Acute renal failure defined as a clinical diagnosis with documented new-onset abnormal renal function 
(increment in serum creatinine > 0.5 mg/dL from baseline). 
11. Hospital mortality.  
 
IV.d. Plan.  This study will include male or female subjects > 18 years. Due to the design of this study, 
there will be no run-in period.  Upon arrival to the emergency department or medical or general surgical 
wards, subjects will be screened.  Patients with a known history of T2D treated with diet alone, any 
combination of OADs, and insulin prior to admission will be considered potential candidates for this 
study. Patients treated with degludec, glargine U300 or with long-acting GLP1-RA (dulaglutide, 
albiglutide and weekly exenatide) prior to admission will be excluded. Patients admitted with acute or 
chronic medical illnesses, emergency or elective surgical procedures and trauma would be included in the 
study. The goal of insulin therapy is to maintain fasting and pre-meal blood glucose levels between 80 
mg/dl and 180 mg/dL while avoiding hypoglycemia.   
 
A total of 180 patients with T2D with a blood glucose > 140 mg/dL and < 400 mg/dL will be randomized 
to receive: 
 
Group 1.  Basal bolus with glargine U300 once daily and glulisine insulin before meals (n=90).  
Group 2.  Basal bolus with glargine U100 once daily and glulisine insulin before meals (n=90). 
 
IV.d. Basal Bolus Insulin Protocol.   
 
Patients will be treated with a basal bolus insulin regimen as previously reported (15, 16, 39).  In brief, 
subjects treated with insulin prior to admission will receive 80% of the total daily outpatient insulin dose 
given. Insulin naïve patients will discontinue oral agents and will receive a starting total daily dose (TDD) 
of 0.4 U/kg/day for BG between 140 mg/dl and 200 mg/dL and 0.5 U/kg/day for BG between 201 mg/dl 
and 400 mg/dL. The starting TDD will be reduced to 0.3 U/kg/day in patients ≥ 70 years or with a GFR < 
60 ml/min. Both groups will be treated with bolus regimen given half of TDD as basal (glargine U300 or 
U100) once daily and half as insulin glulisine divided in three equal doses before meals. Patients with 
poor oral intake or to be kept NPO will receive the basal dose, but prandial dose will be held (32). Insulin 
dose will be adjusted daily to maintain a fasting and pre-dinner BG between 80 mg/dl and 180 mg/dl. 
 

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IV. e Treatment randomization.  This is an open label randomized controlled trial.  Patients will be 
randomized 1:1 consecutively using a computer generated randomization table provided by Dr. Limin 
Peng, statistician at the Emory School of Public Health.  The randomization table will be mailed to the 
research pharmacist at each institution who will be in charge of the randomization and group assignment. 
A research pharmacist at each institution will follow a computer-generated block randomization table 
based on prior insulin use (yes/no). 
 
 
IV.f 
TREATMENT PROTOCOL - Basal Bolus Insulin Regimen with Glargine Once Daily plus 
Glulisine before Meals 
 
Patients Treated with Insulin Prior to Admission 
 Discontinue oral antidiabetic drugs on admission. 
Subjects treated with insulin prior to admission will receive 80% or 100% of the total daily dose 
(TDD) given as basal bolus regimen. Starting Insulin Doses: 
• 
Randomization BG <200mg/dl-give 80% of the TDD* 
• 
Randomization BG>200mg/dl-give 100% of the TDD* 
 Half of TDD will be given as basal (glargine U300 or U100) and half as rapid-acting insulin.   
 Glargine U300 and U100 will be given once daily, at the same time of the day.   
 Patients will receive the full-dose of glargine (even if NPO) the day of surgery or diagnostic 
procedure(s).     
 Glulisine insulin will be given in three equally divided doses before each meal.  To prevent 
hypoglycemia, if a subject is not able to eat, glulisine insulin dose will be held. 
* If patient was on basal only therapy consider adding prandial dose as calculated above.  
 
Insulin Naïve Patients Treated with Oral Agents or GLP1-RAs Prior to Admission 
 Discontinue oral antidiabetic drugs on admission. 
 Starting total daily insulin dose:  
 0.4 U/Kg/day when randomization BG between 140-200 mg/dL 
 0.5 U/Kg/day when randomization BG between 201-400 mg/dL   
 Reduce TDD to 0.3 units per kg in patients ≥ 70 years of age and/or with an eGFR < 60 
ml/min. 
 Half of TDD will be given as glargine U300 or U100 and half as glulisine.   
 Glargine will be given once daily, at the same time of the day.   
 Patients will receive the full-dose of glargine insulin (even if NPO) the day of surgery or 
diagnostic procedure(s).     
 Glulisine insulin will be given in three equally divided doses before meals. To prevent 
hypoglycemia, if a subject is not able to eat, the dose of glulisine will be held.  
 
Supplemental insulin. Glulisine insulin will be administered following the “supplemental/correction 
insulin scale” protocol (Appendix 1).   
 If a patient is able and expected to eat most of his/her meals, supplemental insulin will be 
administered before meals and at bedtime following the “usual” dose of the insulin scale protocol. 
 If a patient is not able to eat, supplemental insulin will be administered every 6 hours following 
the “sensitive” dose of the supplemental insulin scale protocol. 
 
Basal Insulin adjustment.   
 Daily basal (glargine U300 and U100) insulin dose will be adjusted as follow:  

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 If the fasting and pre-dinner BG is between 100 - 140 mg/dl in the absence of hypoglycemia 
the previous day: no change  
 If the fasting and pre-dinner BG is between 141 - 180 mg/dl in the absence of hypoglycemia: 
increase basal insulin by 10% every day  
 If the fasting and pre-dinner BG is 181- 299 mg/dl in the absence of hypoglycemia the 
previous day: increase basal insulin (glargine) dose by 20% every day  
 If the fasting and/or pre-dinner BG is ≥ 300 mg/dl in the absence of hypoglycemia the previous 
day: increase basal insulin (glargine) dose by 30% every day 
 If the fasting and pre-dinner BG is between 70 - 99 mg/dl in the absence of hypoglycemia: 
decrease TDD (basal and prandial) insulin dose by 10% every day  
 If a patient develops hypoglycemia (BG <70 mg/dL), the insulin TDD (basal and prandial) 
should be decreased by 20%.   
 If a patient develops severe hypoglycemia (BG <40 mg/dL), the insulin TDD (basal and 
prandial) should be decreased by 30-40%.   
 
IV.g. 
Data Analysis: 
Aim 1.  To determine differences in inpatient glycemic control, as measured by mean daily blood 
glucose concentration and frequency of hypoglycemia, in general medicine and surgery patients 
with T2D treated with basal bolus regimen with glargine U300 and U100 plus glulisine insulin 
before meals. 
 
Due to the lack of efficacy and safety data with the use of glargine U300 in the inpatient setting, periodic 
conduct interim analyses will be conducted every 6 months to monitor the primary outcome and rate of 
hypoglycemia, and to modify the study design regarding interval of administration and dosage adjustment 
for basal insulin (see page 9, Data Safety Monitoring Plan, sections IV. f. and IV.g.).       
 
Sample Size and Power Calculations:  
The primary endpoint in this study is glycemic control measured by mean daily BG concentration.  To 
show the non-inferiority of glargine U300 and U100 in terms of glycemic control, we set the equivalence 
margin as 18 mg/dl (1 mosm/l), from a view that a difference <18 mg/dl is usually not considered as 
clinically significant (12, 14, 16). Based on the results from Rabbit medicine and surgery trials, it is 
reasonable to assume the standard deviation of mean daily BG is bounded above by 45 mg/dl. Assuming 
the true BG difference between the treatment groups is zero, and using one-sided, two-sample t-tests, we 
require 78 subjects for each treatment group to achieve 80% power. Accounting for 10% attrition rate, we 
would need 90 patients per treatment group, which means 180 subjects in total, to achieve >80% power in 
Aim 1.  
 
Analysis of Primary Endpoint: 
The primary endpoint for Aim 1 is glycemic control measured by mean daily BG concentration among the 
two study groups. Blood glucose will be measured before each meal and at bedtime.  We will first 
perform cross-sectional analyses using nonparametric Krustal-Wallis tests (or Wilcoxon tests) or one-way 
ANOVA, followed by repeated measures ANOVA to estimate and test the difference between the two 
treatment groups while simultaneously examining mean daily BG across multiple days during treatment. 
A mixed effect model may be used to further account center effect or other potential confounders for the 
BG outcome. Stepwise, backward, or forward model selection strategy will be adopted to determine the 
variables to be included in the final model. Standard diagnostic and model checking procedures will be 
applied to examine the fit of the developed models. 
 
Analysis of Secondary Endpoints: 
Secondary endpoints for Aim 1in this study include incidence of hypoglycemia, number of hypoglycemic 

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events, number of severe hyperglycemia, mean daily fasting BG, daily insulin dose, length of hospital 
stay, acute renal failure and hospital mortality. Blood glucose will be measured before each meal and at 
bedtime.  For discrete outcomes (such as hypoglycemia outcomes), if the outcome is binary (e.g. with or 
without hypoglycemia), we will first conduct nonparametric comparisons based on a two-sided Chi-
square test (or Fisher’s exact test in the presence of low incidence rates), followed by the Cochran-
Mantel-Haenszel test, which adjusts for the potential center effect. If the discrete outcome is a count 
outcome (such as the number of hypoglycemic event), we will perform Poisson regression (or Negative 
Binomial regression) that adjusts for the length of hospital stay to assess the difference in the count 
outcome between the treatment groups. We also value the repeated measures analyses based on mixed 
effect models. This is because they will allow us to assess treatment effect fined tuned according to other 
confounders of the BG outcomes. By these considerations, we will conduct both types of analyses to 
provide a thorough evaluation of the hypothesis of interest. For continuous outcomes that are not repeated 
measures (such as length of hospital stay), we will use two-sample t-tests or nonparametric Wilcoxon 
tests to compare them between groups. Transformations will be applied if normality violation is detected.  
Multivariate linear regression will be further conducted to assess the difference in continuous secondary 
outcomes between the two groups while other relevant covariates. We will use standard model selection 
and model checking procedures for linear regression to decide the final models and assess their fits to the 
data. 
 
IV.f.        Data and Safety Monitoring Board (DSMB): 
The Data and Safety Monitoring Board (DSMB) will review unblended data on safety, treatment 
compliance, and evaluate the efficacy of the intervention being studied in this clinical trial. The DSMB 
will meet at 6-month intervals and report on study progress to the IRB.  
IV.g. Interim Analysis and Stopping Rules:  We plan to perform one interim analysis on the primary 
endpoint every 6 months and when half of the subjects have been randomized. The trial will be stopped if 
there is evidence beyond a reasonable doubt of a difference in the rate of death and hospital complications 
(two-sided alpha level, <0.01) between the treatment groups.  
 
 
 
V. 
Aim 2:  To determine differences in glycemic control after hospital discharge between 
treatment with glargine U300 and glargine U100 in medicine and surgery patients T2D.   
 
V.a. 
Rationale.  Few studies have addressed the efficacy of insulin alone or in combination with oral 
agents after hospital discharge. In a recent study (see preliminary results section), patients were 
discharged on a combination of OADs and glargine U100 insulin or on a basal bolus regimen according to 
bA1c levels and achieved a marked reduction in HbA1c from 8.75% on admission to 7.9% and 7.35% 
after 4 and 12 weeks of hospital discharge. However, the use of glargine U100 alone or in combination to 
oral agents or as basal bolus insulin resulted in 30% and close to 40% incidence of hypoglycemia, 
respectively. In this study, we will compare the efficacy and safety of glargine U300 and U100 after 
hospital discharge. The total duration of the study is 3 months. Several outpatient insulin trials have 
shown that treatment with glargine U300 results in similar improvement in glycemic control, but in 
significant reduction in hypoglycemia compared to glargine U100 (23-27). Thus we expect that glargine 
U300 will be a safer alternative to current use of glargine U100 formulation. 
  
 V.b Insulin Discharge algorithm:  
Patients with poorly controlled diabetes (HbA1c ≥7.5%) enrolled in Aim 1 will be invited to participate in 
this open label prospective outpatient study. The total duration of the study is 3 months.  

Glargine U300 vs U100_ Hospital Trial 
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11
 Patients with admission Hba1c < 7.5% will be discharged on their preadmission antidiabetic 
regimen and will not be included in the Aim 2 outpatient study.  
 Patients with no previous pharmacological treatment prior to admission will be discharged on 50% 
of daily basal insulin (glargine U300 or glargine U100) hospital dose. 
 Patients on oral agents prior to admission with an HbA1c between 7.5% and <10% will be 
discharged on oral agents plus glargine U300 or glargine U100 at 50% of the daily hospital dose.  
 Patients on oral agents prior to admission with an admission A1C ≥ 10% will be discharged on 
their oral agents plus glargine U300 or glargine U100 at 80% of daily hospital dose.  If previous 
basal bolus only therapy or contraindications to previous oral therapy, discharge on basal bolus at 
100% of daily hospital dose. 
 Patients on oral agents plus basal insulin (NPH, glargine, detemir) prior to admission with HbA1C 
between 7.5% and <10% will be discharged on their oral agents plus glargine U300 or glargine 
U100 at 50% of daily hospital dose.   
 Patients on oral agents plus basal insulin (NPH, glargine, detemir) prior to admission with an 
admission A1C ≥ 10% will be discharged on their oral agents plus glargine U300 or glargine U100 
at 80% of daily hospital dose.  If contraindications to previous oral therapy, discharge on basal 
bolus at 100% of daily hospital dose. 
Patients treated with basal or basal bolus regimen prior to admission will be discharged on 50%-80% of 
their preadmission TDD with glargine once daily and glulisine before meals.   
 
 
Concomitant Medications: 
Background medications: 
 
Metformin.   Metformin is considered background medication (non-investigational medicinal product) 
and will not be provided during the trial.  The total daily dose of metformin prior to admission will be 
restarted at hospital discharge with no dose adjustments occurring during the trial. Patients with eGFR 
between 30-45 ml/min will be discharged at a max-dose of 500 mg twice daily.  Patients with eGFR < 30 
ml/min will not be allowed to receive metformin.   

Glargine U300 vs U100_ Hospital Trial 
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12
 
Sulfonylurea and Insulin secretagogues.  Sulfonylurea treatment is considered background medication 
(non-investigational medicinal product) and will not be provided during the trial.  The total daily dose of 
sulfonylurea prior to admission will be reduced by 50% or stopped at hospital discharge at the 
investigator’s discretion.    
 
Pioglitazone.  Pioglitazone is considered background medication (non-investigational medicinal product) 
and will not be provided during the trial. The total daily dose of pioglitazone prior to admission will be 
restarted at hospital discharge.  No dose adjustment or up-titration will occur during the trial; however, in 
the event of peripheral edema or signs of volume overload, the dose of pioglitazone can be reduced or 
stopped at the investigator’s discretion.    
 
DPP4-inhibitors.  DPP4-i treatment is considered background medication (non-investigational medicinal 
product) and will not be provided during the trial.  The total daily dose of DPP4-I will be adjusted as per 
renal function (eGFR). No dose adjustment or up-titration will occur during the trial. 
 
GLP1-RA.  GLP1-RA treatment is considered background medication (non-investigational medicinal 
product) and will not be provided during the trial.  No dose adjustment or up-titration will occur during 
the trial. 
 
SGLT2-i.  The use of SGLT2-I is considered background medication (non-investigational medicinal 
product) and will not be provided during the trial.  No dose adjustment or up-titration will occur during 
the trial. 
 
 
V.c. Hospital Diabetes Education.  Prior to discharge, participants will be trained in: 
1. Diabetes education if not received within 1 year of admission   
2. Recommended targets for fasting and premeal blood glucose between 90 to 130 mg/dL 
3. Use of glucose meters for home glucose self-monitoring 
4. Keeping BG records, and will receive a logbook to record glucose tests results. 
5. Hypoglycemia prevention, recognition and management 
6. Insulin administration 
 
V.d. 
Follow-up Care: 
 Provide glargine insulin 1-month supply at each clinic visit.  
 A member of the diabetes research team will contact patients via telephone call every 2 weeks for 
a total of 3 months.   
 Patients will be asked to attend outpatient visits at 1 and 3 month after hospital discharge.   
 Recommendation on insulin adjustment to be provided after each telephone contact and/or clinic 
visit by a licensed physician (fellow or study physician) (section V.f).     
 
V.e. 
During follow up we will collect the following information:   
1. Glycemic control: 
a. Mean daily fasting and premeal blood glucose levels 
b. HbA1C at 1 and 3 months after hospital discharge 
c. Hypoglycemic events (BG < 70 mg/dl and < 40 mg/dl) 
d. Hyperglycemic events (BG > 240 mg/dl) 
2. Diabetes treatment: 
a. Insulin dosage (unit/day) 
b. Use of oral agents 

Glargine U300 vs U100_ Hospital Trial 
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13
c. Protocol adherence  
3. Clinical Outcome: 
a. Hospital readmissions 
b. Emergency room visits 
c. Postoperative complications 
 
V.f.    Primary care physicians will be provided with the following algorithm for outpatient basal 
insulin dose adjustment every 2 weeks: 
 
Basal Insulin (glargine U300 and glargine U100) 
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 
no RBG <70 mg/dL 
Increase daily dose by 2 IU 
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% 
 
V.g.  Aim 2. Statistical Analysis: 
V.g.1. Sample Size and Power Calculations: The primary endpoint in Aim 2 is difference in glycemic 
control (mean daily BG) after hospital discharge. Under the same assumptions for equivalence margin and 
BG variability as in Aim 1, we have the same sample size requirement (i.e. 78 subjects per group after 
10% attrition). Accounting for 10% attrition rate, we would need 90 patients per treatment group (total # 
of patients to be recruited: 180 subjects, 90 per treatment group), to achieve >80% power.  
 
V.g.2. Analysis of Primary Endpoint: 
The primary endpoint in this study is glycemic control measured by mean daily BG concentration after 
hospital discharge. Secondary outcomes include rate of hypoglycemia during follow-up, change in 
HbA1c, body weight in kilograms, number of episodes of severe hyperglycemia, complications and 
emergency room visits or hospital readmissions at 12 weeks post-discharge. To analyze these outcomes, 
we will follow the same analytic strategy proposed for the secondary endpoints of Aim 1. We will first 
compare the primary outcome using two-sample t-tests (or Wilcoxon tests) or one-way ANOVA, 
followed by multivariate linear regression to estimate and test the difference between the two treatment 
groups while simultaneously accounting for other potential confounders. Transformations will be applied 
if normality violation is detected. Stepwise, backward, or forward model selection strategy will be 
adopted to determine the variables to be included in the final model. Standard diagnostic and model 
checking procedures will be applied to examine the fit of the developed models. 
 
DATA HANDLING AND RECORD KEEPING: 
Data collection records with personal identifiers will be stored in locked file cabinets.  Presentation of the 
study results at regional or scientific meetings or in publications will not identify subjects.  Access to 
research and confidential records will be limited to clinical investigators, research coordinators, and the 
IRB at Emory University.  
All data will be entered electronically in Redcap by participating sites. Sponsor site expects data to be 
entered in Redcap within 10 days of phone call or outpatient visit. 

Glargine U300 vs U100_ Hospital Trial 
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14
 
VI. 
Methods and Procedures Applied to Human Subjects: 
 
VI.a. Subject Population: 
 
We plan to study a total of 180 randomized patients with a known history of T2D, age > 18 years, 
treated with diet alone, any combination of oral antidiabetic agents, GLP1-RA (except long-acting agents: 
albiglutide, albiglutide and weekly exenatide) or insulin therapy (except degludec or glargine U300).  
Patients included within this study will be determined by the set of inclusion and exclusion criteria. 
 
VI.b. Inclusion Criteria: 
1. 
Males or females between > 18 years admitted to a general medicine or surgical service.   
2. 
Known histories of T2D treated with either diet alone, oral monotherapy, any combination of oral 
antidiabetic agents, short-acting GLP1-RA (exenatide, liraglutide) or insulin therapy with the 
exception of degludec and glargine U300.  
3. 
Subjects must have a randomization BG > 140 mg and < 400 mg/dL without laboratory evidence 
of diabetic ketoacidosis (bicarbonate < 18 mEq/L, pH < 7.30, or positive serum or urinary 
ketones). 
 
VI.c. Exclusion Criteria:  
1. 
Subjects with increased BG concentration, but without a known history of diabetes. 
2. 
Admission or pre-randomization BG≥400 mg/dl 
3. 
Patients treated with degludec or glargine U300, or with long-acting weekly GLP1-RA (weekly 
exenatide, dulaglutide or albiglutide).  
4. 
Patients with acute critical or surgical illness admitted to the ICU or expected to require admission 
to the ICU. 
5. 
Patients with clinically relevant hepatic disease (diagnosed liver cirrhosis and portal hypertension), 
corticosteroid therapy, or impaired renal function (eGFR< 30 ml/min). 
6. 
Mental condition rendering the subject unable to understand the nature, scope, and possible 
consequences of the study. 
7. 
Female subjects who are pregnant or breast-feeding at time of enrollment into the study. 
 
VI.d. Withdrawal Criteria 
1. The subject may withdraw at will at any time. 
2. The subject may be withdrawn from the trial at the discretion of the investigator due to a safety concern 
or if judged non-compliant with trial procedures or included in contravention to the inclusion and/or 
exclusion criteria. 
3. Subject admitted to the ICU who required continuous intravenous insulin infusion to maintain glycemic 
control. 
4. Pregnancy or intention to become pregnant.  
5. Treatment with oral or injectable corticosteroid (equivalent or higher than prednisone 5mg/day), 
parenteral nutrition and immunosuppressive treatment after randomization. 
 
Treatment Failure Criteria 
Subjects with persistent hyperglycemia (≥ 2 glucose readings ≥ 400 mg/dL, ≥ 3 consecutive glucose 
readings > 280 mg/dL, or with a mean daily blood glucose concentration ≥ 280 mg/dL) and no treatable 
intercurrent cause for the hyperglycemia has been identified, will be considered as treatment failure and 
discontinued from the study.  If needed, subjects will be started on continuous insulin infusion.   
 

Glargine U300 vs U100_ Hospital Trial 
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15
VII. 
Study Sites:  This study will be performed at Grady Memorial Hospital, Emory University 
Hospitals, Atlanta, GA, Minneapolis Medical Research Foundation-Hennepin Medical Center, 
Minneapolis, and The Cleveland Clinic Foundation, Ohio. 
 
 
 
 
 
 
VIII. CLINICAL MANAGEMENT GUIDELINES 
 
 
VIII.a.  Admission Laboratory Studies 
 
 
Standard of care laboratory studies including glucose, HbA1C, and chemistry will be measured on 
admission and as determined by the treating physician.   
For research purposes a blood sample will be obtained to measure HbA1C at 1 month and 3 months 
after discharge.  In addition, a urine pregnancy test will be performed, when clinically indicated prior to 
randomization (in female subjects of child bearing potential only).   
 
VIII.b.    Assessment and Monitoring of Hospital Mortality  
The investigators and research team will follow study subjects daily and the presumed cause of death will 
be recorded.  Information on the attending physician’s summary of events surrounding subject’s demise 
will also be documented.    
VIII.c. Assessment and Monitoring of Nosocomial Infections  
Nosocomial infections will be diagnosed based on standardized CDC criteria (40).  New nosocomial 
infections will not be diagnosed until 48 hours after study initiation to minimize the chance that the 
infection was actually present (but undiagnosed) prior to study initiation.   
The investigators will review each subject’s records regarding potential new infection diagnosis daily on 
each weekday from Monday to Friday. Data from the weekends will be collected on the following 
Monday.  The coded infection diagnosis and the presumed causative microorganism will be determined 
daily on a Monday to Friday basis, with weekend data entered on the following Monday.   
 
Aim 1.  Inpatient Arm – Flow Chart 
 
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 signs1 
x 
 
 
 
 
 
 
 
 
x 
Phys Exam1 
x 
 
 
 
 
 
 
 
 
x 
Body weight 
x 
 
 
 
 
 
 
 
 
x 
BMI 
x 
 
 
 
 
 
 
 
 
x 
HbA1c 
x 
 
 
 
 
 
 
 
 
 
Fasting BG 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pre-meal BG 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Safety 
 
 
 
 
 
 
 
 
 
 

Glargine U300 vs U100_ Hospital Trial 
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16
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 
 
 
 
 
 
 
 
 
x 
Trial material 
 
 
 
 
 
 
 
 
 
 
Drug dispense2 
x 
 
 
 
 
 
 
 
 
 
1At time of study enrollment and hospital discharge 2As needed 
 
 
 
 
Flow Chart:  Aim 2, Outpatient Study 
 
Visit Type 
Hospital 
Day 1 
TC 
Clinic 
visit 
TC 
TC 
TC 
Clinic 
visit 
Visit # 
1 
2 
3 
4 
5 
6 
7 
Time-wks 
0 
2 
4 
6 
8 
10 
12 
Inf. consent  
x 
 
 
 
 
 
 
Incl/excl criteria 
x 
 
 
 
 
 
 
Randomization 
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 
 
 
 
x 
Fasting BG 
x 
 
x 
 
 
 
x 
Safety 
 
 
 
 
 
 
 
Adv events 
x 
x 
x 
x 
x 
x 
x 
Hypoglycemia 
x 
x 
x 
x 
x 
x 
x 
Urine pregnancy test 
x 
 
x 
 
 
 
 
CMP or BMP 
x 
 
x 
 
 
 
x 
Trial material 
 
 
 
 
 
 
 
Drug dispense 
x 
 
x 
 
 
 
 
Drug account 
x 
 
x 
 
 
 
x 
 
IX. 
Potential Risks to the Subject: 
IX.a. Hypoglycemia.   It is possible that following the proposed protocol, patients receiving insulin 
glargine U300 and U100 may develop hypoglycemia. The risk of hypoglycemia in non-ICU patients 
treated with subcutaneous insulin is between 5–30% (12, 17, 41, 42). The number of hypoglycemia will 
be analyzed statistically. For the purpose of this analysis, hypoglycemia is defined as a BG < 70 mg/dL. 
Severe hypoglycemia is defined as BG < 40 mg/dL. 
 
X. 
Protection against risks: 
 
We will follow safeguards to minimize the risk to our subjects: a) we will carefully monitor capillary BG 
at the bedside using a hand-held glucose meter, b) only experienced nurses/or phlebotomist will draw 
blood samples, and c) women of reproductive age who are sexually active will undergo a urine pregnancy 
tests prior to participation in the study.  To prevent significant clinical events, no patients with history of 
significant liver, renal impairment or cardiac failure will be recruited in this study.    
 
X.a. 
Hypoglycemia:  We expect that approximately 10% in the inpatient setting and ~20% in the 
outpatient (post-discharge) arm will experience one or more episodes of hypoglycemia.  To minimize the 
risk of hypoglycemia, the starting dose will be reduced in the basal bolus insulin regimen (TDD: 0.3 units 

Glargine U300 vs U100_ Hospital Trial 
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17
per kg of body weight) in patients ≥ 70 years of age and/or eGFR < 60 ml/min.  To avoid hypoglycemia, 
the total daily dose of insulin will be decreased by 10% for BG between 70-99 mg/dl and by 20% after 
each episode of hypoglycemia (BG < 70 mg/dl).  In addition, in patients treated with insulin at home, the 
TDD of insulin will be reduced by 20% on admission and the attending physician may further reduce 
insulin dose in the presence of severe hypoglycemia. 
 
Hypoglycemia will be treated with dextrose infusion.  Dextrose 50% solution will be given for glucose 
values < 70 mg/dl.  If the patient is awake, 25 ml (1/2 amp) will be given IV or oral juice/snack (crackers) 
as per protocol.  If the patient is not awake:  50ml (1 amp) will be given STAT.  Blood glucose levels will 
be repeated in 15 minutes and dextrose administration will be repeated as needed for values < 70 mg/dl.   
 
XI. 
Inclusion of women. 
We anticipate that ~50% of the study subjects will be female.  Absence of pregnancy must be 
demonstrated by blood or urine testing prior to randomization (in female subjects of child bearing 
potential only).  Glargine U300 and U100 have not been approved during pregnancy.   
 
XII. 
Inclusion of minorities. 
Patients will not be excluded based on race or ethnic origin.  We anticipate that approximately 
one-third of patients will be African Americans, Hispanics, and Caucasians.   
 
XIII. Inclusion of children. 
No patients under the age of 18 will be recruited in this study. 
 
XIV.   Payment for participation.     
Participation in this study is voluntary.  Patients will receive one hundred dollars ($100.00) during 
the hospital stay.  If a participant should stop participation before completion, the payment will be 
prorated at $10.00 per day. Participants will receive seventy- five dollars ($75.00) after each clinic visit at 
1 and 3 months after discharge. Total compensation will be two hundred and fifty dollars ($250.00). 
 
 
XV.   Financial conflict of interests. 
 
This study receives support from Sanofi. Dr. Umpierrez serves as a consultant to Sanofi and 
receives compensation for these services. The terms of this arrangement have been reviewed and 
approved by Emory University in accordance with its conflict of interest policies. 
 
 
XVI.    Pharmacovigilance specifications 
 
1. 
DEFINITIONS 
Serious adverse event (SAE): any untoward medical occurrence that at any dose:  
 Results in death, 
 Is life threatening, (Note: the term “life-threatening” refers to an event/reaction in which the patient 
was at risk of death at the time of the event/reaction; it does not refer to an event/ reaction which 
hypothetically might have caused death if it were more severe), 
 Requires inpatient hospitalization or results in prolongation of existing hospitalization, 
 Results in persistent or significant disability/incapacity, 
 Is a congenital anomaly/birth defect, or 

Glargine U300 vs U100_ Hospital Trial 
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 Is a medically important event or reaction. Medical and scientific judgment should be exercised in 
deciding whether other situations should be considered serious, such as important medical events 
that might not be immediately life-threatening or result in death or hospitalization, but might 
jeopardize the patient or might require intervention to prevent one of the other outcomes listed in 
the definition above. 
Related Adverse Event, i.e. Adverse Drug Reaction (ADR): There is a reasonable possibility according to 
the ISS sponsor that the product may have caused the event. 
 
Unexpected Adverse Event, i.e. Adverse Drug Reaction (ADR): An adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an 
unapproved investigational medicinal product or package insert/summary of product characteristics for an 
approved product). An expected ADR with a fatal outcome should be considered unexpected unless the 
local/regional product labelling specifically states that the ADR might be associated with a fatal outcome. 
 
Adverse Event of Special Interest (AESI): An adverse event of special interest (AESI) is an adverse event 
(serious or non-serious) of scientific and medical concern specific to the Sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the Investigator to the Sponsor may be appropriate. 
Such events may require further investigation in order to characterize and understand them. AESIs may be 
added or removed during a study by protocol amendment. 
 
New safety finding : Any (other than reportable individual case safety report (ICSR)) safety issue that may 
require expedited reporting because providing information that may lead to a change in the known risk-
benefit balance for the  product and as mentioned, but not limited to, in the following regulatory texts: 
Europe: Volume 9A of the Rules Governing Medicinal products in the European Union (September 2008) 
Section 4.1; and US: FDA: 21 CFR Parts 312 Investigational New Drug Application- Section 312.32, (c) 
(1) IND safety reports. 
 
2. 
OBLIGATIONS AND RESPONSIBILITIES OF THE ISS SPONSOR 
 The ISS sponsor warrants that the study will be performed in compliance with all applicable local 
and international laws and regulations, including without limitation ICH E6 guidelines for Good 
Clinical Practices.  
 The ISS sponsor shall be responsible for the respect of all obligations required by applicable local 
and international laws and regulations.  
 The sponsor shall be responsible for ensuring submission of required expedited and periodic reports 
to the appropriate Regulatory Authority (RA), the Ethics Committee and investigators of each 
country participating in the ISS (based on applicable regulations).  
 Any Periodic reports (e.g. Development Safety Update Report (DSUR)), submitted to Regulatory 
Authority must first be transmitted to Sanofi for review and comment. 
 The study reports of any ISS must contain a section describing safety review and conclusion and 
must be reviewed by Sanofi before finalization. 
 New Safety Findings in a study pertaining to safety of product must be transmitted within 1 business 
day. (e.g., Data Safety Monitoring Board recommendations) 
The ISS sponsor must provide to Sanofi upon request results of any relevant complementary exams 
performed to obtain the final diagnosis of any SAE (e.g., hospital discharge summary, autopsy, 
consultation). 
 The Institution must report the following information in English to the Sanofi group entity 
Pharmacovigilance contact: 

Glargine U300 vs U100_ Hospital Trial 
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19
 Routine transmission of all Serious Adverse Events (SAEs) including pregnancy, overdose and 
Adverse Events of Special Interest (AESI), if any. These events must be transmitted within 1 
business day of the Institution’s awareness or identification of the event. 
 Routine transmission of SAEs related to the use of the Sanofi product must be transmitted within 
1 business day of the Institution’s awareness or identification of the event. The reference safety 
information to be used by the Institution for evaluation of expectedness of adverse events shall 
be the current approved product label available in the country for an approved indication or the 
Investigator Brochure for an unapproved indication. 
 Any Periodic reports (e.g. Development Safety Update Report (DSUR)), submitted to 
Regulatory Authority must be transmitted to Sanofi at the time of submission. 
 New Safety Findings in a study pertaining to safety of product must be transmitted within 1 
business day. (e.g., Data Safety Monitoring Board recommendations) 
 The study reports of any ISS must contain a section describing safety review and conclusion and 
must be reviewed by Sanofi before finalization. 
 
 The reference safety information to be used by the ISS sponsor for evaluation of expectedness of adverse 
events shall be the current approved product label available in the country (for an approved indication) 
 
3. 
SANOFI GROUP ENTITY PHARMACOVIGILANCE CONTACT 
 
 
These reports may be sent by GPE-PV E-MAIL to:  
Reports by E-MAIL should be sent to: CL-CPV-Receipt@sanofi.com or Fax: 908-547-8000, 
within 24 hours of receipt by investigator/sponsor. E-Mail or Fax transmission should include 
the following:  
Investigator-Sponsored (IST #) study number: SA-2016-11517  
Study Title: _ Glargine U300 Hospital Trial: A Randomized Controlled Trial Comparing 
Glargine U300 and Glargine U100 for the Inpatient and Post-Hospital Discharge Management of 
Medicine and Surgery Patients with Type 2 Diabetes  
Name of Principal Investigator: Guillermo Umpierrez, MD, CDE. 
 

Glargine U300 vs U100_ Hospital Trial 
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XVI. References 
1. 
Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an 
independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin 
Endocrinol Metab. 2002;87(3):978-82. 
2. 
Finney SJ, Zekveld C, Elia A, Evans TW. Glucose control and mortality in critically ill patients. 
Jama. 2003;290(15):2041-7. 
3. 
Van den Berghe G, Wouters PJ, Bouillon R, Weekers F, Verwaest C, Schetz M, et al. Outcome 
benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Crit 
Care Med. 2003;31(2):359-66. 
4. 
Pomposelli JJ, Baxter JK, 3rd, Babineau TJ, Pomfret EA, Driscoll DF, Forse RA, et al. Early 
postoperative glucose control predicts nosocomial infection rate in diabetic patients. JPEN J 
Parenter Enteral Nutr. 1998;22(2):77-81. 
5. 
Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, et al. Randomized trial of 
insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute 
myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 
1995;26(1):57-65. 
6. 
Clement S, Braithwaite SS, Magee MF, Ahmann A, Smith EP, Schafer RG, et al. Management of 
diabetes and hyperglycemia in hospitals. Diabetes Care. 2004;27(2):553-97. 
7. 
McAlister FA, Majumdar SR, Blitz S, Rowe BH, Romney J, Marrie TJ. The relation between 
hyperglycemia and outcomes in 2,471 patients admitted to the hospital with community-acquired 
pneumonia. Diabetes Care. 2005;28(4):810-5. 
8. 
Baker EH, Janaway CH, Philips BJ, Brennan AL, Baines DL, Wood DM, et al. Hyperglycaemia is 
associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic 
obstructive pulmonary disease. Thorax. 2006;61(4):284-9. 
9. 
Furnary AP, Gao G, Grunkemeier GL, Wu Y, Zerr KJ, Bookin SO, et al. Continuous insulin 
infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. J 
Thorac Cardiovasc Surg. 2003;125(5):1007-21. 
10. 
Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, et al. Intensive 
insulin therapy in the medical ICU. N Engl J Med. 2006;354(5):449-61. 
11. 
van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive 
insulin therapy in the critically ill patients. N Engl J Med. 2001;345(19):1359-67. 
12. 
Umpierrez GE, Hor T, Smiley D, Temponi A, Umpierrez D, Ceron M, et al. Comparison of 
inpatient insulin regimens with detemir plus aspart versus neutral protamine hagedorn plus regular 
in medical patients with type 2 diabetes. J Clin Endocrinol Metab. 2009;94(2):564-9. 
13. 
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XV. Appendix 1. 
Supplemental “sliding insulin scale” protocol 
 
BEFORE MEAL, Supplemental Sliding Scale – Glulisine Insulin (number of units) - Add to 
scheduled insulin dose.   
 
**Check appropriate column and cross out other columns 
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 
 
 
 
 
 
BEDTIME sliding scale: Supplemental Sliding Scale Insulin dose at bedtime starting at BG > 220 
mg/dL 
  BG (mg/dL)          Insulin Sensitive                          Usual                    Insulin 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 
 
 
 
The numbers in each column indicate the number of units of glulisine insulin per dose.  Supplemental” 
dose is to be added to the scheduled dose of aspart insulin.  If a patient is able and expected to eat all or 
most of his/her meals, supplemental insulin will be administered before each meal following the “usual” 
column dose. Supplemental insulin at bedtime = half of premeal insulin dose.  Example, a patient with 
blood glucose of 260 mg/dl will receive 5 U before a meal or 2 U at bedtime of supplemental insulin.     
If a patient is not able to eat (NPO), supplemental insulin will be administered every 6 hours (6-12-6-12) 
following the “sensitive” column dose.  Example, a patient kept NPO with blood glucose of 200 mg/dl 
will receive 3 U of supplemental insulin.     
The patient’s inpatient primary medical or surgical team may change insulin dose at their discretion in the 
presence of hypoglycemia (BG <70 mg/dL) or severe hyperglycemia (BG >350 mg/dL).  In addition, the 
attending physician may consider using the total supplemental insulin dose, patient’s nutritional intake, 
and results of BG testing to adjust insulin regimen.