Comparison Between Basal Insulin Analog and Insulin Analog Mid Mixture AS Starter Insulin for Chinese Patients With Type 2 Diabetes Mellitus (CLASSIC Study)
Phase: PHASE4
Conditions: Type 2 Diabetes Mellitus
Sponsor: Eli Lilly and Company

Protocol F3Z-GH-IOQR
Comparison Between Basal Insulin Analog and Insulin AnaLog Mid Mixture AS 
Starter Insulin for Chinese Patients With Type 2 Diabetes Mellitus (CLASSIC Study)
NCT03018938  
Approval Date: 26-Jun-2016

F3Z-GH-IOQR Clinical Protocol
Page 1
LY275585
Protocol F3Z-GH-IOQR
Comparison Between Basal Insulin Analog and Insulin 
AnaLog Mid Mixture AS Starter Insulin for Chinese Patients 
With Type 2 Diabetes Mellitus (CLASSIC Study)
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
basal insulin analog and insulin analog mid mixture, unless such persons are bound by a 
confidentiality agreement with Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Basal Insulin Analog and Insulin Analog Mid Mixture
Study F3Z-GH-IOQR is a multicenter, China-based, open label, 48-week, randomized,
parallel-design pragmatic study in Chinese patients with T2DM who have failed to achieve 
adequate glycemic control with oral anti-hyperglycemic medications (OAMs) with the aim to 
compare the effectiveness of basal insulin analog once daily and  insulin analog mid 
mixture twice daily treatments in real world setting
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 26-Jun-2016 GMT

F3Z-GH-IOQR Clinical Protocol
Page 2
LY275585
Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................11
3.
Introduction ......................................................................................................................13
3.1.
Background..................................................................................................................13
3.2.
Study Rationale............................................................................................................14
3.3.
Benefit/Risk Assessment..............................................................................................14
4.
Objectives and Endpoints..................................................................................................15
5.
Study Design.....................................................................................................................18
5.1.
Overall Design .............................................................................................................18
5.2.
Number of Participants.................................................................................................18
5.3.
End of Study Definition ...............................................................................................18
5.4.
Scientific Rationale for Study Design...........................................................................18
5.5.
Justification for Dose ...................................................................................................19
6.
Study Population...............................................................................................................20
6.1.
Inclusion Criteria..........................................................................................................20
6.2.
Exclusion Criteria ........................................................................................................20
6.3.
Lifestyle Restrictions....................................................................................................20
6.4.
Screen Failures.............................................................................................................20
7.
Treatments........................................................................................................................21
7.1.
Treatments Administered .............................................................................................21
7.1.1.
Packaging and Labelling ......................................................................................21
7.2.
Method of Treatment Assignment ................................................................................21
7.2.1.
Selection and Timing of Doses.............................................................................21
7.3.
Blinding .......................................................................................................................21
7.4.
Dosage Modification....................................................................................................21
7.5.
Preparation/Handling/Storage/Accountability...............................................................22
7.6.
Treatment Compliance .................................................................................................22
7.7.
Concomitant Therapy...................................................................................................22
7.8.
Treatment after the End of the Study............................................................................22
7.8.1.
Study Extensions..................................................................................................22
7.8.2.
Continued Access.................................................................................................22
7.8.3.
Special Treatment Considerations ........................................................................22
7.8.4.
Patient Follow-Up in Pragmatic Trials..................................................................22
8.
Discontinuation Criteria ....................................................................................................23

F3Z-GH-IOQR Clinical Protocol
Page 3
LY275585
8.1.
Discontinuation from Study Treatment.........................................................................23
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................23
8.1.2.
Temporary Discontinuation from Study Treatment...............................................23
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................23
8.2.
Discontinuation from the Study....................................................................................23
8.3.
Lost to Follow-Up........................................................................................................23
9.
Study Assessments and Procedures ...................................................................................24
9.1.
Efficacy Assessments...................................................................................................24
9.1.1.
Primary Effectiveness Assessments......................................................................24
9.1.2.
Secondary Effectiveness Assessments..................................................................24
9.1.3.
Exploratory Effectiveness Assessments................................................................24
9.1.4.
Appropriateness of Assessments ..........................................................................25
9.2.
Adverse Events ............................................................................................................25
9.2.1.
Serious Adverse Events........................................................................................26
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................27
9.2.2.
Complaint Handling.............................................................................................27
9.3.
Treatment of Overdose.................................................................................................27
9.4.
Safety...........................................................................................................................27
9.4.1.
Hypoglycemia......................................................................................................27
9.4.2.
Electrocardiograms ..............................................................................................29
9.4.3.
Vital Signs ...........................................................................................................29
9.4.4.
Clinical Laboratory Tests .....................................................................................29
9.4.5.
Other Tests...........................................................................................................29
9.4.6.
Safety Monitoring ................................................................................................29
9.5.
Pharmacokinetics .........................................................................................................29
9.6.
Pharmacodynamics ......................................................................................................29
9.7.
Pharmacogenomics ......................................................................................................29
9.8.
Biomarkers...................................................................................................................29
9.9.
Medical Resource Utilization and Health Economics ...................................................29
9.9.1.
Insulin Treatment Pattern.....................................................................................29
9.9.2.
Patient-Reported Outcomes..................................................................................30
9.9.3.
Healthcare Resource Utilization ...........................................................................31
10.
Statistical Considerations ..................................................................................................32
10.1. Sample Size Determination ..........................................................................................32
10.2. Populations for Analyses..............................................................................................32
10.3. Statistical Analyses ......................................................................................................32
10.3.1.
General Statistical Considerations ........................................................................32
10.3.2.
Treatment Group Comparability...........................................................................33

F3Z-GH-IOQR Clinical Protocol
Page 4
LY275585
10.3.2.1.
Patient Disposition..........................................................................................33
10.3.2.2.
Patient Characteristics ....................................................................................33
10.3.2.3.
Concomitant Therapy .....................................................................................33
10.3.2.4.
Treatment Compliance....................................................................................33
10.3.3.
Efficacy Analyses ................................................................................................33
10.3.3.1.
Primary Analyses ...........................................................................................33
10.3.3.2.
Secondary Analyses........................................................................................34
10.3.4.
Safety Analyses....................................................................................................35
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................35
10.3.6.
Other Analyses.....................................................................................................35
10.3.6.1.
Medical Resource Utilization and Health Economics......................................35
10.3.6.1.1.
Adherence and Insulin Treatment Pattern..................................................35
10.3.6.1.2.
Resource Utilization .................................................................................35
10.3.6.1.3.
Insulin Treatment Satisfaction Questionnaire (ITSQ)................................35
10.3.6.1.4.
SEITQ = Self-efficacy about Insulin Therapy 
Questionnaire (SEITQ).............................................................................35
10.3.6.2.
Subgroup Analyses.........................................................................................35
10.3.7.
Interim Analyses..................................................................................................36
11.
References ........................................................................................................................37
12.
Appendices .......................................................................................................................39

F3Z-GH-IOQR Clinical Protocol
Page 5
LY275585
List of Tables
Table
Page
Table IOQR.1.
Schedule of Activities for Prospective Cohorts ..............................................11
Table IOQR.2.
Objectives and Endpoints...............................................................................15

F3Z-GH-IOQR Clinical Protocol
Page 6
LY275585
List of Figures
Figure
Page
Figure IOQR.1.
Illustration of study design for Pragmatic Study F3Z-GH-IOQR....................18

F3Z-GH-IOQR Clinical Protocol
Page 7
LY275585
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................40
Appendix 2.
World Health Organization Classification of Diabetes ...................................43
Appendix 3.
Study Governance Considerations..................................................................44

F3Z-GH-IOQR Clinical Protocol
Page 8
LY275585
1.
Synopsis
Title of Study:
Comparison Between Basal Insulin Analog and Insulin Analog Mid Mixture As Starter Insulin for Chinese Patients 
With Type 2 Diabetes Mellitus (CLASSIC Study)
Rationale: 
The purpose of Study is to compare basal insulin analog once daily(QD) and insulin analog mid mixture twice daily 
(BID) as starter insulin regimen in Chinese patients with type 2 diabetes mellitus (T2DM) who have inadequate 
glycemic control with oral antihyperglycemic medications (OAMs) in real world settings.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary
1.  To compare change in HbA1c from baseline to 
24 weeks between insulin analog mid mixture BID and 
basal insulin analog QD treatments 
1. The change in HbA1c from baseline to 24 weeks
Secondary
2.  To compare change in HbA1c from baseline to 48 
weeks between insulin analog mid mixture BID and 
basal insulin analog QD treatments 
2. The change in HbA1c from baseline to 48 weeks
3. To compare the proportion of patients who achieve 
HbA1c <7% at 24 and 48 weeks between insulin analog 
mid mixture BID and basal insulin analog QD 
treatments
3. Proportion of patients who achieve HbA1c <7% at 24 
and 48 weeks
4. To compare the change in venous FPG from baseline 
to 24 and 48 weeks between insulin analog mid mixture 
BID and basal insulin analog QD treatments
4. Venous FPG change from baseline at 24 and 48 weeks
5. To compare the change in FSBG-based FBG and PPG 
from baseline to 24 and 48 weeks between insulin 
analog mid mixture BID and basal insulin analog QD 
treatments
5.FSBG-based FBG, PPG change from baseline at 24 
and 48 weeks
6. To compare the daily insulin dose at 24 and 48 weeks 
between insulin analog mid mixture BID and basal 
insulin analog QD treatments
6. Daily insulin dose at 24 and 48 weeks
7. To compare the change in body weight from baseline 
to 24 and 48 weeks between insulin analog mid mixture 
BID and basal insulin analog QD treatments
7. Body weight change from baseline at 24 and 48 weeks
8. To compare the severe, nocturnal and total 
hypoglycemia incidences and rates during the 24-week 
and 48-week treatment period between insulin analog 
mid mixture BID and basal insulin analog QD 
treatments
8. The severe, nocturnal and total hypoglycemia 
incidences and rates during the 24-week and 48-week 
treatment period 

F3Z-GH-IOQR Clinical Protocol
Page 9
LY275585
Objectives
Endpoints
9. To compare time to insulin treatment change between 
insulin analog mid mixture BID and basal insulin analog 
QD treatments
9. Time to insulin treatment change: Defined as time to 
any of: insulin treatment discontinuation, switch, 
intensification or reduction in frequency
Discontinuation:  Defined as stopping insulin treatment 
for 30 days or more. 
Switch: Defined as stop the initial insulin therapy and 
started another insulin therapy of different class. 
Intensification: Defined as any of the following: adding 
meal time insulin in basal insulin analog QD group; 
changing from BID to TID in insulin analog mid mixture 
BID group
Reduction in frequency: Defined as any of the 
following: changing from BID to QD; changing from 
TID to BID or QD
10. To compare the proportion of patients who achieve 
the HbA1c  <7%   without switching and discontinuing 
study insulin, and without using rescue therapy between 
insulin analog mid mixture BID and basal insulin analog 
QD treatments
10. Proportion of patients who achieve the HbA1c  <7%  
without switching and discontinuing study insulin, and 
without using rescue therapy
11. To compare the patients-reported self-efficacy 
related to insulin therapy as assessed using SEITQ 
between insulin analog mid mixture BID and basal 
insulin analog QD treatments 
11. The change in SEITQ score form baseline at 48 
weeks 
Abbreviations:  BID = twice daily; FBG = fasting blood glucose; FPG = fasting plasma glucose; FSBG =finger stick
blood glucose; HbA1c = hemoglobin A1c; PPG = post prandial glucose; QD = once daily; SEITQ = Self-efficacy 
about Insulin Therapy Questionnaire; TID = three times a day.
Summary of Study Design:  
Study F3Z-GH-IOQR (IOQR) is a multicenter, open-label, randomized, 48-week, parallel, 2-arm pragmatic trial 
comparing the effectiveness of basal insulin analog QD and insulin analog mid mixture BID treatments in real world 
setting in adult Chinese patients (≥18 and ≤80 years) with T2DM who have failed to achieve adequate glycemic 
control with OAMs (hemoglobin A1c [HbA1c] ≥7.5%)
Treatment Arms and Duration:  
There are 2 arms in this 48 week study: basal insulin analog QD arm and insulin analog mid mixture BID arm
Number of Patients:
Approximately 830 participants will be randomized 1:1 into the 2 treatment groups such that there will be 
approximately 664 evaluable participants for primary analyses at Week 24.
Statistical Analysis:
General Considerations: Both efficacy and safety analyses will be performed on randomized patients. 

F3Z-GH-IOQR Clinical Protocol
Page 10
LY275585
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise stated.
The baseline value for measurements will be defined as the last non-missing observation on or before the 
randomization visit. If no data are available, the baseline value will be treated as missing.
For continuous measures, summary statistics will include at least number of patients with data, mean, standard 
deviation (SD), median, minimum, and maximum. For categorical measures, summary statistics will include at least 
number of patients with data, frequency counts, and percentages. For comparisons based on analysis models, the 
differences will be reported using least squares (LS) means, along with 95% confidence intervals (CIs) and p-value. 
Sometimes, treatment-wise comparison on the summary statistics may be performed and p-values provided, and 
such p-values should be viewed as a descriptive measure only. Unless specified otherwise, a two-sample t-test will 
be used for continuous measurements and Fisher’s exact test will be used for categorical measurements.
Primary Analysis: Missing measurements will not be imputed as HbA1c will be only measured once post-baseline 
at Week 24. In addition to common summary statistics for the change from baseline data, the comparison between 2 
treatment arms will be conducted using an analysis of covariate (ANCOVA) model, with change from baseline in 
HbA1c as response, treatment as fixed effect and baseline HbA1c as a covariate.  The 95% CI of LS means 
difference (insulin analog mid mixture BID – basal insulin analog QD) will be used to make conclusions for the 
comparison. 
Secondary Analyses:  For change from baseline in venous fasting plasma glucose (FPG), finger stick blood glucose 
(FSBG)-based fasting blood glucose (FBG), post prandial glucose (PPG) and blood glucose (BG) excursion, the 
analyses model will be similar to the primary analyses model, except that the comparison will be based on the 
treatment contrast p-value from the ANCOVA model. 
For percentages of patients reaching treatment goals (<7%) at Week 24 and Week 48, no missing data will be 
imputed. Count and percentages of patients reaching treatment goals will be summarized, and also be analyzed by a 
logistic regression model, with logit link function, treatment as fixed effect and baseline HbA1c as continuous 
covariate. 
Insulin dose at each visit will be descriptively summarized by treatment groups by total daily dose (IU and IU/kg).  
Safety:  The incidence rate of case report form (CRF) collected severe, nocturnal and total hypoglycemic events will 
be summarized by visit and for the overall study duration. Pairwise comparison between treatment arms will be 
performed by Fisher’s exact test. The overall yearly rates (events/patient/year) of those hypoglycemic events, 
calculated as, for each patient, the number of episodes times 365.25 and then divided by the patient’s treatment 
duration, will be summarized, and analyzed by a negative-binomial regression model with treatment as fixed effects 
and log of (patient’s treatment duration/365.25) as an offset variable.
Other Analyses:  For the medial resource utilization and patient-reported outcome measurements summary statistics 
will be provided and comparison will be performed by appropriate general test. 
Subgroup analysis will be performed for baseline HbA1c, baseline morning PPG, BG excursion, gender, and 
persistence levels in 2 treatment groups.

F3Z-GH-IOQR Clinical Protocol
Page 11
LY275585
2. Schedule of Activities
Table IOQR.1.
Schedule of Activities for Prospective Cohorts
eCRF Visit No.:
1
2
3
4
5
6
ETa
Week of treatment
0
4
12
24
36
48
ET
Visit Window (days)
−
±7
±7
±7
±14
±14
±14
Informed consent (before procedures/tests)
X
Demographics 
X
Weight
X
X
X
X
X
X
X
Height
X
Local urine pregnancy test b
X
Duration of diabetes
X
Anti-hyperglycemic medications(Non-insulin)
X
X
X
X
X
X
X
Insulin treatment c
X
X
X
X
X
X
X
Insulin dose d
X
X
X
X
X
X
X
Preexisting conditions/Adverse events e
X
X
X
X
X
X
X
Severe, nocturnal and total hypoglycemia events f
X
X
X
X
X
X
X
Other categories of hypoglycemia events (if 
available) g
X
X
X
X
X
X
X
HbA1c
Xh
Xi
Xi
Xi
Venous FPG j
X
X
X
X
2-point FSBG (pre-breakfast FBG and post-
breakfast PPG) k
X
X
X
X
Randomization 
X
SEITQ
X
X
X
X
ITSQ
X
X
X
Healthcare resource utilization 
X
X
X
X
X
X
Patient training
X
Dispense study diary and instruct to use
X
X
X
X
X
Review study diary 
X
X
X
X
X
X
Abbreviations:   eCRF = electronic case report form; ET = early termination; FBG = fasting blood glucose; FPG = fasting plasma glucose; FSBG = finger stick 
blood glucose; HbA1c = hemoglobin A1c; ITSQ = Insulin Treatment Satisfaction Questionnaire; No. = number; PPG = post prandial glucose; SEITQ = Self-
efficacy about Insulin Therapy Questionnaire.

F3Z-GH-IOQR Clinical Protocol
Page 12
LY275585
a
Early termination (ET) visit is conducted within 14 days after the decision of discontinuation.  At ET visit, fasting laboratory samples will be collected if 
possible. 
b
A urine pregnancy test will be performed locally only for women of childbearing potential.
c
The current insulin treatment regimen, insulin treatment pattern change from last visit including insulin discontinuation, switch, intensification and reduction 
in frequency, and reason for insulin treatment pattern change will be recorded
d
For Visit 1, prescribed daily insulin dose by the physician will be recorded.  For the following visits, actual daily insulin dose of day prior to the visit will be 
recorded.  If the insulin treatment is temporarily suspended or discontinued before the visit, the actual daily insulin dose of the day in which the patient 
received his/her last insulin treatment will be recorded.
e
After the informed consent form (ICF) is signed, study site personnel will record the occurrence and nature of each patient’s preexisting conditions.  In 
addition, site personnel will record any change in the condition(s) and any new conditions as AEs.
f    Severe, nocturnal and total hypoglycemia events will be collected and analyzed as secondary endpoints.  
g
Other categories of hypoglycemia (documented symptomatic, asymptomatic, unspecified, probable symptomatic and relative hypoglycemia) events will be 
collected if available and analyzed as exploratory objectives 
h
Blood draw is not required for patients who already have measurement prior to study entry (value within 12 weeks).  
i
HbA1c will be drawn locally +/- 4 weeks of visit date
j
Venous FPG will be drawn locally after a fast of at least 8 hours without eating, drinking (except for water) or performing any significant physical activity 
+/- 2 weeks of visit date.  Missing venous FPG measurement will not be considered as a protocol violation.
k
Two-point FSBG [pre-breakfast (fasting) FBG and post-breakfast (approximately 2 hours after breakfast) PPG] should be measured on one day within 1 to 2 
weeks before or at Visit 1 (Week 0), Visit 4 (Week 24),Visit 6 (Week 48)or the ET visit (if possible).

F3Z-GH-IOQR Clinical Protocol
Page 13
LY275585
3.
Introduction
The International Diabetes Federation (IDF) reports that the number of people with type 2 
diabetes mellitus (T2DM) is going up in every country, particularly in Asian countries such as 
China due to multiple contributing factors, including diet, genes, and lifestyle (Hu 2011). By 
2035, the prevalence of diabetes is estimated to be 592 million globally, with an estimation of 
143 million in China alone (IDF Diabetes Atlas 2013).  A recent national survey in China 
estimated that about 9.7% of Chinese adults might have had diabetes, suggesting that China has 
the largest population of individuals with type 2 diabetes in the world (Yang et al. 2010).
3.1.
Background
Basal or premixed insulins are the recommended insulin starters following oral 
antihyperglycemic medication (OAM) failure in Chinese patients according to guidelines 
released by the Chinese Diabetes Society (CDS 2013). Premixed insulins contain rapid- and 
intermediate-acting insulin that control fasting (preprandial) and postprandial glucose (PPG) 
elevations, respectively. In many Asian countries, including China, patients initiate insulin 
therapy with premixed insulins (CDS 2013). In fact, over 50% of Chinese T2DM patients 
initiated insulin therapy with premixed insulin while less than 20% patients initiated with basal 
insulin (Ji et al. 2009; Ji et al. 2011).  Two main causes may contribute for this phenomenon. 
Firstly, in patients with high PPG, which is a characteristic of Asian patient population, treatment 
with mixtures provides additional benefits by controlling PPG elevation (Kalra et al. 2010). 
Secondly, a great proportion of Chinese patients need more aggressive insulin regimen due to 
delay in diagnosis or insulin initiation. Patients who require intensive insulin treatment may 
prefer premixed insulin with a less number of injections per day to basal bolus regimen (Jia et al. 
2015).  Generally speaking, although some physicians believe that basal insulin once daily is 
more suitable for patients with mild or moderate hyperglycemia following OAM failure while 
premixed insulin twice daily is more suitable for patients with moderate or even more severe
hyperglycemia, the perception about efficacy and safety profile between premixed insulin analog 
and basal insulin analog is comparable in China.
Currently, 2 classes of insulin analog mixtures are available in the China market based on 
different formulations: low mixtures with low ratio of rapid acting insulin like insulin lispro 
75/25 and insulin aspart 70/30, or mid mixtures with equal ratio of rapid acting insulin and 
intermediate acting insulin like insulin lispro 50/50 and insulin aspart 50/50. Most of the 
physicians selected low mixtures analog as start insulin in their practice. The reasons probably 
are that insulin analog mid mixtures went on the market after low mixtures and physicians are 
more familiar with premixed human insulins which are more commonly provided as low mixed 
formulation and have been used for a long time in China. At the same time, basal insulin analogs, 
including levermir and glargine, are also widely used in China. 
The F3Z-CR-IOQI (IOQI) (CLASSIFY) study is a Phase 4, randomized, open-label, 
multinational and multicenter trial (Watada et al. 2016). It showed that LM25 and LM50 were 
noninferior to each other in improving glycemic control in East Asian patients with T2DM. 
Additionally, LM50 was more efficacious than LM25 with respect to the percentage of subjects 

F3Z-GH-IOQR Clinical Protocol
Page 14
LY275585
reaching target hemoglobin A1c (HbA1c) levels. In China subgroup which accounts for around 
40% of the whole study population, LM50 is superior to LM25 in HbA1c change (-2.03% versus 
-1.55%) from baseline, and a significantly higher percentage of patients achieved HbA1c levels 
of <7% (72.4% versus 45.0%; P=0.001) levels in the LM50 treatment group compared to the 
LM25 treatment group, while no increased hypoglycemia incidence or more weight gain is 
observed in LM50 group as trade-off (Su et al. 2015a). The better response to LM50 in the 
Chinese population is probably due to the pronounced high PPG which reflects Chinese patient’s 
venerable beta cell function and high carbohydrate intake diet (Su et al. 2015b; Chen et al. 2016).  
This evidence is of great value in helping physician’s select insulin regimens, but it is the sole 
multicenter clinical trial supporting the use of insulin analog mid mixture as start insulin. More 
investigation is needed on mid mixtures as starter insulin in East-Asia patients.
3.2.
Study Rationale
Given the results of the IOQI randomized clinical trial (Section 3.1), the proposed pragmatic 
study is designed to compare these insulin initiation regimens in more generalizable populations 
and clinical settings.
Pragmatic clinical trials (PCTs) may be characterized by selection of relevant alternative 
interventions (including “usual care”) for comparison, inclusion of a diverse study population 
from heterogeneous practice settings, and/or collection of data on a broad range of health 
outcomes. Hence, PCTs address relative efficacy as well as provide a high degree of external 
validity. The concept of experimental versus pragmatic is not a dichotomy but a continuum, and 
any given trial may have experimental features (for example, narrow patient selection criteria) 
and pragmatic features (for example, liberal co-medication rules).
Premixed insulin analogs (including both insulin analog low mixture and mid mixture) and basal 
insulin analogs are both widely used in China. Many randomized clinical trials have compared 
efficacy and safety between insulin analog low mixture and basal insulin in Chinese population
(Yang et al. 2013; Li et al. 2014; Qin et al. 2014).
Generally speaking, the low mixture analog is either inferior or superior to basal insulin in 
Chinese patients with inadequate control under oral agent treatment.  The compliance rate 
between mixture and basal insulin also is comparable in some observational studies.
Nonetheless, little evidence is available to compare the insulin analog mid mixture and basal 
insulin analog as starter insulin in real world setting.
This study will provide information on whether the effectiveness of insulin analog mid mixture
twice daily (BID) is comparable with basal insulin analog once daily (QD) as starter insulin in 
real world setting (Primary objective).
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks of study insulin 
treatments may be found in the package inserts of these insulin products.  

F3Z-GH-IOQR Clinical Protocol
Page 15
LY275585
4.
Objectives and Endpoints
Table IOQR.2 shows the objectives and endpoints of the study.
Table IOQR.2.
Objectives and Endpoints
Objectives
Endpoints
Primary
1.  To compare change in HbA1c from baseline to 24 
weeks between insulin analog mid mixture BID and 
basal insulin analog QD treatments 
1. The change in HbA1c from baseline to 24 weeks
Secondary
2.  To compare change in HbA1c from baseline to 48 
weeks between insulin analog mid mixture BID and 
basal insulin analog QD treatments 
2. The change in HbA1c from baseline to 48 weeks
3. To compare the proportion of patients who achieve 
HbA1c <7% at 24 and 48 weeks between insulin analog 
mid mixture BID and basal insulin analog QD 
treatments
3. Proportion of patients who achieve HbA1c <7% at 24 
and 48 weeks
4. To compare the change in venous FPG from baseline 
to 24 and 48 weeks between insulin analog mid mixture 
BID and basal insulin analog QD treatments
4. Venous FPG change from baseline at 24 and 48 weeks
5. To compare the change in FSBG-based FBG and PPG 
from baseline to 24 and 48 weeks between insulin 
analog mid mixture BID and basal insulin analog QD 
treatments
5.FSBG-based FBG, PPG change from baseline at 24 
and 48 weeks
6. To compare the daily insulin dose at 24 and 48 weeks 
between insulin analog mid mixture BID and basal 
insulin analog QD treatments
6. Daily insulin dose at 24 and 48 weeks
7. To compare the change in body weight from baseline 
to 24 and 48 weeks between insulin analog mid mixture 
BID and basal insulin analog QD treatments
7. Body weight change from baseline at 24 and 48 weeks
8. To compare the severe, nocturnal and total 
hypoglycemia incidences and rates during the 24-week
and 48-week treatment period between insulin analog 
mid mixture BID and basal insulin analog QD 
treatments
8. The severe, nocturnal and total hypoglycemia 
incidences and rates during the 24-week and 48-week
treatment period 

F3Z-GH-IOQR Clinical Protocol
Page 16
LY275585
Objectives and Endpoints
Objectives
Endpoints
9. To compare time to insulin treatment change between 
insulin analog mid mixture BID and basal insulin analog 
QD treatments
9. Time to insulin treatment change: Defined as time to 
any of: insulin treatment discontinuation, switch, 
intensification or reduction in frequency
Discontinuation:  Defined as stopping insulin treatment 
for 30 days or more. 
Switch: Defined as stop the initial insulin therapy and 
started another insulin therapy of different class.  
Intensification: Defined as any of the following: adding 
meal time insulin in basal insulin analog QD group; 
changing from BID to TID in insulin analog mid mixture 
BID group
Reduction in frequency: Defined as any of the 
following: changing from BID to QD; changing from 
TID to BID or QD
10. To compare the proportion of patients who achieve 
the HbA1c  <7% without switching and discontinuing 
study insulin, and without using rescue therapy between 
insulin analog mid mixture BID and basal insulin analog 
QD treatments
10. Proportion of patients who achieve the HbA1c <7% 
without switching and discontinuing study insulin, and 
without using rescue therapy
11. To compare the patients-reported self-efficacy 
related to insulin therapy as assessed using SEITQ 
between insulin analog mid mixture BID and basal 
insulin analog QD treatments 
11. The change in SEITQ score form baseline at 
48 weeks 
Tertiary/Exploratory
12. To compare the insulin treatment pattern for 

discontinuation

switch

intensification

reduction in frequency
between insulin analog mid mixture BID and basal 
insulin analog QD treatments
12. Time to insulin discontinuation, switch, 
intensification or reduction in frequency
       Proportion of patients who experience insulin 
discontinuation, switch, intensification or reduction in 
frequency during 48 weeks
13.  To compare healthcare resource utilization (all-
cause and T2DM-related; inpatient, outpatient and ER) 
between insulin analog mid mixture BID and basal 
insulin analog QD treatments 
13. Healthcare resource utilization (all-cause and 
T2DM-related;inpatient, outpatient and ER) during 48 
weeks
14. To compare patients’ perception of insulin treatment 
satisfaction, as assessed using the ITSQ at 24 and 48 
weeks between insulin analog mid mixture BID and 
basal insulin analog QD treatments
14. Domain and total ITSQ score at 24 and 48 weeks
15. To compare the patients-reported self-efficacy
related to insulin therapy as assessed using SEITQ 
between insulin analog mid mixture BID and basal 
insulin analog QD treatments 
15. The change in SEITQ score form baseline at 24 
weeks 

F3Z-GH-IOQR Clinical Protocol
Page 17
LY275585
Objectives and Endpoints
Objectives
Endpoints
16. To compare the incidences and rates of other 
categories of hypoglycemia (documented symptomatic, 
asymptomatic, unspecified, probable symptomatic and 
relative hypoglycemia), if available, during the 24-week 
and 48-week treatment period between insulin analog 
mid mixture BID and basal insulin analog QD 
treatments
16. The incidences and rates of other categories of 
hypoglycemia (documented symptomatic, 
asymptomatic, unspecified, probable symptomatic and 
relative hypoglycemia), if available, during the 24-week 
and 48-week treatment period 
Abbreviations:  BID = twice daily; FBG = fasting blood glucose; FPG = fasting plasma glucose; FSBG =finger stick
blood glucose HbA1c = hemoglobin A1c; ITSQ = Insulin Treatment Satisfaction Questionnaire; PPG = post 
prandial glucose; QD = once daily; SEITQ = Self-efficacy about Insulin Therapy Questionnaire; T2DM = type 2 
diabetes mellitus; TID = three times daily.

F3Z-GH-IOQR Clinical Protocol
Page 18
LY275585
5.
Study Design
5.1.
Overall Design
Study F3Z-GH-IOQR (IOQR) is a multicenter, randomized, 48-week, parallel, 2-arm pragmatic 
trial in Chinese patients with T2DM who have failed to achieve adequate glycemic control with 
OAMs comparing the effectiveness of insulin analog mid mixture BID and basal insulin analog 
QD treatments in real world setting. 
Figure IOQR.1 illustrates the study design.
Abbreviations:  BID = twice daily; QD = once daily; wks = weeks.
Figure IOQR.1.
Illustration of study design for Pragmatic Study F3Z-GH-IOQR.
5.2.
Number of Participants
Approximately 830 participants will be randomized 1:1into the 2 treatment groups such that 
there will be approximately 664 evaluable participants for primary analyses at Week 24 
5.3.
End of Study Definition
End of the trial is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
Given the results of the previous IOQI randomized clinical trial, this pragmatic study is designed 
to demonstrate that the results drawn from the randomized clinical trial can be applied in more 
generalizable populations and real world settings.
According to the scientific questions raised, instead of a randomized clinical trial (RCT) or a 
prospective observational study, a PCT is selected because the study aims to compare 
effectiveness in real world settings with minimal intervention while randomization is required to 
remove selection bias and other confounding factors between arms. 

F3Z-GH-IOQR Clinical Protocol
Page 19
LY275585
Two arms including basal insulin analog, and insulin analog mid mixture will be compared in a 
Chinese general T2DM population.  The following considerations have been incorporated into 
study design to ensure a robust study that represents real world situations:

Restriction on inclusion and exclusion criteria for patients in this study is minimal 
compared with a typical RCT. Patients enrolled will represent a general T2DM 
population with uncontrolled HbA1c levels under OAM.

There is also no restriction on insulin titration algorithm and OAM use. Also 
there is no restriction on switching or augmenting the initial insulin treatment. 
Physicians can pursue their general practice governed by local guideline.

The schedule of visits is aimed to reflect real-world practice. In general, the 
frequency of visits to physician offices after insulin initiation is weekly or 
biweekly in a real world setting for dose titration and adjustment (CDS 2013). 
Therefore, the potential intervention brought by the scheduled monthly or every 3 
month visits could be considered minimal. 

The duration of this study is 48 weeks which is relatively longer than a typical 
RCT with 24 or 26 weeks comparing 2 insulin regimens by measuring HbA1c. 
So adequate information from real world settings could be observed and collected.

In China, the community based primary care health system is not well developed, 
and most of the patients go to see the endocrinologists to start insulin treatment 
instead of general practitioners. Therefore in this study, no community based 
clinical center will be selected as study sites.
In summary, the study design presented is intended to provide a better understanding of the real-
world feasibility and performance of initiating insulin treatment with insulin analog mixtures. 
5.5.
Justification for Dose
No dose range assessment exists for this trial, therefore this is not applicable.  This is a pragmatic 
trial and insulin titration will be determined by individual investigator as would occur in clinical 
practice setting. 

F3Z-GH-IOQR Clinical Protocol
Page 20
LY275585
6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
enrollment:
[1]
have type 2 diabetes as defined by World Health Organization (WHO) criteria 
(Appendix 2) 
[2]
are ≥18 and ≤80 years of age at the time of Visit 1
[3]
are taking OAMs and are judged as OAM failure by the investigator 
[4]
most recent HbA1c value ≥7.5% within 12 weeks of study entry
[5]
in the opinion of the investigator, require to initiate premix analog or basal 
insulin analog treatment
[6]
willing to start with insulin treatment
[7]
are able and willing to give signed informed consent (Appendix 3)
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at
enrollment:
[8]
have a diagnosis of type 1 diabetes
[9]
have received any type of insulin within 24 months of study entry (except for 
intermittent use of insulin of less than 1 month each time)
[10] have serious preexisting medical or other conditions that, in the judgment of 
the investigator, would preclude participation in this study. 
[11] are pregnant or breastfeeding, or intend to become pregnant during the course 
of the study 
[12] are currently enrolled or have participated, within the last 30 days in any other 
clinical trial involving an investigational product or any other type of medical 
research judged not to be scientifically or medically compatible 
6.3.
Lifestyle Restrictions
Not applicable.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened.  

F3Z-GH-IOQR Clinical Protocol
Page 21
LY275585
7. Treatments
7.1.
Treatments Administered
This study involves a comparison of insulin analog mid mixture BID and basal insulin analog 
QD in routine care.
No drug will be provided, but drug treatments expected for this trial are: 

Insulin analog mid mixture:  for example, Humalog Mix50, Novorapid 50

Basal insulin analog:  for example, insulin glargine, insulin detemir
After randomization to initial insulin treatment regimen, treatment decisions will be solely at the 
discretion of the physician and the patient, and anti-hyperglycemia treatment will be conducted 
within the construct of the standard care according to CDS guideline (CDS 2013). 
Investigational products are defined as insulins being used in this study.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational products to the patient or care 
givers. 

verifying that instructions are followed properly
7.1.1. Packaging and Labelling
All study drugs are commercially available. Study drug will not be supplied to patients. 
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to treatment/intervention at 
Visit 1.  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an interactive voice-response system (IVRS) or interactive web-response system 
(IWRS) and then the site will be responsible for providing the treatment/intervention to the 
patients.
7.2.1. Selection and Timing of Doses
The dose will be initiated, titrated and maintained at the discretion of the investigator following 
the usual standard of care according to CDS guideline (CDS 2013).
The timing of doses will follow product labels. 
7.3.
Blinding
This is an open-label study.
7.4.
Dosage Modification
Dose adjustments are at the discretion of investigator following usual standard of care. 

F3Z-GH-IOQR Clinical Protocol
Page 22
LY275585
7.5.
Preparation/Handling/Storage/Accountability
The healthcare professionals (HCPs) are responsible to ensure the safe handling and appropriate 
storage of the investigational products. 
7.6.
Treatment Compliance
No patient-reported and HCP-perceived compliance of the treatment will be assessed.  
7.7.
Concomitant Therapy
All concomitant therapies that are part of routine care are allowed and can be used during the 
study.
Only anti-hyperglycemic concomitant therapy will be collected at baseline and throughout the 
study (Section 2).  
7.8.
Treatment after the End of the Study
7.8.1. Study Extensions
Not applicable. 
7.8.2. Continued Access
The insulin analogs used in this study are commercially available in China. 
7.8.3.Special Treatment Considerations
Rescue therapy for hyperglycemia and hypoglycemia will be determined by the investigator 
following usual standard of care.
7.8.4. Patient Follow-Up in Pragmatic Trials
Patient follow-up is dictated only by usual care, no additional visit is required by the protocol.

F3Z-GH-IOQR Clinical Protocol
Page 23
LY275585
8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Not applicable due to the pragmatic nature of this trial.
8.1.2. Temporary Discontinuation from Study Treatment
Not applicable due to the pragmatic nature of this trial.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
Not applicable due to the pragmatic nature of this trial.
8.2.
Discontinuation from the Study
Patients will be discontinued from study in the following circumstances:

Exclusion criteria: [10], [11] or [12] is/are observed or develop(s) after study entry or 
enrollment.
Some possible reasons that may lead to permanent discontinuation include:

enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study

participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

investigator decision
o
the investigator decides that the patient should be discontinued from the study

subject decision
o
the patient or the patient’s designee, for example, parents or legal guardian 
requests to be withdrawn from the study
Patients who discontinue from the study early will have end-of-study procedures performed as 
shown in the Schedule of Activities (Section 2).
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.  

F3Z-GH-IOQR Clinical Protocol
Page 24
LY275585
9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
9.1.
Efficacy Assessments
9.1.1. Primary Effectiveness Assessments
The primary efficacy measure is the change in HbA1c from baseline to 24 weeks.
9.1.2. Secondary Effectiveness Assessments
The following secondary effectiveness measures will be collected at the time shown in the 
Schedule of Activities (Section 2): 

the change in HbA1c from baseline to 48 weeks

proportion of patients who achieve HbA1c <7% at 24 and 48 weeks

venous fasting plasma glucose (FPG) change from baseline at 24 and 48 weeks

finger stick blood glucose (FSBG)-based fasting blood glucose (FBG), PPG 
change from baseline at 24 and 48 weeks

daily insulin dose at 24 and 48 weeks

body weight change from baseline at 24 and 48 weeks

the severe, nocturnal and total hypoglycemia incidences and rates during the 24-
week and 48-week treatment period 

time to insulin treatment change

proportion of patients who achieve the HbA1c <7% without switching and 
discontinuing study insulin, and without using rescue therapy

the change in Self-efficacy about Insulin Therapy Questionnaire (SEITQ) score 
from baseline at 48 weeks 
9.1.3. Exploratory Effectiveness Assessments

time to insulin discontinuation, switch, intensification or reduction in frequency

proportion of patients who experience insulin discontinuation, switch, 
intensification or reduction in frequency during 48 weeks

healthcare resource utilization (all-cause and T2DM-related; inpatient, outpatient 
and emergency room [ER]) during 48 weeks

domain and total Insulin Treatment Satisfaction Questionnaire (ITSQ) score at 24 
and 48 weeks

the change in SEITQ score form baseline at 24 weeks

F3Z-GH-IOQR Clinical Protocol
Page 25
LY275585

the incidences and rates of other categories of hypoglycemia (documented 
symptomatic, asymptomatic, unspecified, probable symptomatic and relative 
hypoglycemia), if available, during the 24-week and 48-week treatment period
9.1.4. Appropriateness of Assessments
All effectiveness and safety measures assessed in this study are all well-established measures for 
insulin treatment.
Patient-reported outcomes measures (SEITQ, ITSQ) included in this study have been designed to 
provide information from the patient and the HCP perspective. Healthcare resource utilization 
assessments included in this study are acceptable methods for determining the impact of 
treatment/intervention from the payer perspective.
If a patient is unable to complete the questionnaire without assistance, someone not affiliated 
with the study may assist the patient in completing the questionnaire.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
adverse events (AEs) that are serious or otherwise medically important, considered related to the 
investigational products or the study, or that caused the patient to discontinue the investigational 
products before completing the study.  The patient should be followed until the event resolves, 
stabilizes with appropriate diagnostic evaluation, or is reasonably explained.  The frequency of 
follow-up evaluations of the AE is left to the discretion of the investigator.
After the informed consent form (ICF) is signed, study site personnel will record via case report 
form (CRF) the occurrence and nature of each patient’s preexisting conditions, including 
clinically significant signs and symptoms of the disease under treatment in the study.  In 
addition, site personnel will record any change in the condition(s) and any new conditions as 
AEs. Investigators should record their assessment of the potential relatedness of each AE to 
protocol procedure and/or investigational product, via CRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease and concomitant treatment or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between 
investigational products and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.

F3Z-GH-IOQR Clinical Protocol
Page 26
LY275585
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via CRF, clarifying if possible, the circumstances leading 
to any dosage modifications, or discontinuations of treatment. 
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason:  important medical 
events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious, based upon appropriate medical judgment.
Although all AEs occurring after signing the ICF are recorded in the CRF, serious adverse event 
(SAE) reporting begins after the patient has signed the ICF and has received investigational 
product.  However, if an SAE occurs after signing the ICF, but prior to receiving investigational 
product, it needs to be reported ONLY if it is considered reasonably possibly related to study 
procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 24-
hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.
Pregnancy (during maternal or paternal exposure to investigational products) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient summary CRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.
Investigators or other study personnel are requested to report adverse reactions in temporal 
association with Lilly drugs not under evaluation and with any non-Lilly drugs to the appropriate 

F3Z-GH-IOQR Clinical Protocol
Page 27
LY275585
party (for example, regulators or local market authorization holder) as they would in normal 
practice as required by applicable laws, regulations, and practices.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the investigator’s brochure (IB) and that the investigator identifies as related to investigational 
products or procedure.  Lilly has procedures that will be followed for the recording and 
expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational products or drug delivery system so that the 
situation can be assessed.
Investigators are instructed to report product complaints related to marketed products directly to 
the manufacturer following package inserts.  
9.3.
Treatment of Overdose
Refer to the product label of study insulins for advice on overdose.
9.4.
Safety
9.4.1. Hypoglycemia
Patients will be trained about signs and symptoms of hypoglycemia, how to treat hypoglycemia, 
and how to collect appropriate information in the study diary according to the Schedule of 
Activities (Section 2).  Hypoglycemia will be classified as follows (ADA 2005) (Note:  the blood 
glucose (BG) concentrations listed below refer to values reported by a laboratory or obtained 
with FSBG meter):

Documented symptomatic hypoglycemia: An event during which typical symptoms of 
hypoglycemia are accompanied by BG ≤70 mg/dL (≤3.9 mmol/L).

Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
hypoglycemia but with BG ≤70 mg/dL (≤3.9 mmol/L).

Unspecified hypoglycemia: An event during which BG ≤70 mg/dL (≤3.9 mmol/L) but 
no information relative to symptoms of hypoglycemia was recorded

Severe hypoglycemia: An event requiring assistance of another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions. During these episodes 
the patient has an altered mental status and cannot assist in their care, is semiconscious or 

F3Z-GH-IOQR Clinical Protocol
Page 28
LY275585
unconscious or experienced coma with or without seizures, and may require parenteral 
therapy. Plasma glucose measurements may not be available during such an event, but 
neurological recovery attributable to the restoration of BG concentration to normal is 
considered sufficient evidence that the event was induced by a low BG concentration 
(BG ≤70 mg/dL [≤3.9 mmol/L]). 

Nocturnal hypoglycemia: Any hypoglycemic event (documented hypoglycemia or 
probable symptomatic hypoglycemia, including severe hypoglycemia) that occurs 
between bedtime and waking. This is consistent with the ADA recommendations of 
reporting events that occur during sleep (ADA 2005). It is also important to collect the 
actual time when a hypoglycemic event occurred to allow further characterization of 
hypoglycemia timing (for example, to qualify the hypoglycemic events that are occurring 
between midnight to 6 AM or to look at frequency of events occurring across a 24-hour 
clock).

Probable symptomatic hypoglycemia: An event during which symptoms indicative of 
hypoglycemia are not accompanied by a BG determination (but that was presumably 
caused by BG ≤70 mg/dL [≤3.9 mmol/L]).

Relative hypoglycemia: An event during which typical symptoms of hypoglycemia, that 
do not require the assistance of another person, are accompanied by BG >70 mg/dL 
(>3.9 mmol/L), but these levels may be quickly approaching the 70 mg/dL (3.9 mmol/L) 
threshold. The BG level of patients with chronically poor glycemic control can decrease 
so rapidly that patients may report symptoms of hypoglycemia before their BG 
concentration is <70 mg/dL (<3.9 mmol/L). The evaluation of this category is optional. 
However, if a patient reports a relative hypoglycemia event where assistance from 
another person was received or the patient experienced significant symptoms, the study 
team should clarify the circumstances to ensure the event is not a severe hypoglycemia 
event, and report it appropriately.

Total hypoglycemia: This optional category combines all cases of hypoglycemia 
(documented hypoglycemia or probable symptomatic hypoglycemia, including severe 
hypoglycemia) excluding the events of relative hypoglycemia. Nocturnal and severe 
hypoglycemia are special cases of documented or probable hypoglycemia. If an event of 
hypoglycemia falls into multiple subcategories, that event should only be counted once in 
this category.
All episodes of hypoglycemia should be recorded in the “Hypoglycemic Episodes” section of the 
electronic case report form (eCRF). If a hypoglycemic event meets the criteria of SAE 
(Section 9.2.1), it should also be recorded on “Serious Adverse Events” section of the eCRF (that 
is, recorded as an SAE).  
Severe, nocturnal and total hypoglycemia events will be collected and analyzed as secondary 
endpoints. Other categories of hypoglycemia (documented symptomatic, asymptomatic, 
unspecified, probable symptomatic and relative hypoglycemia) events will be collected if 
available and analyzed as exploratory objectives.

F3Z-GH-IOQR Clinical Protocol
Page 29
LY275585
9.4.2. Electrocardiograms
Not applicable.
9.4.3. Vital Signs
For each patient, height and weight should be conducted according to the Schedule of Activities 
(Section 2). 
9.4.4. Clinical Laboratory Tests
For each patient, HbA1c and FBG should be obtained locally according to the Schedule of 
Activities (Section 2). 
Two-point FSBG [pre-breakfast (fasting) and post-breakfast (approximately 2 hours after 
breakfast)] should be measured on one day within 1 to 2 weeks before or at Visit 1 (Week 0), 
Visit 4 (Week 24), Visit 6 (Week 48), or the ET visit (if possible).
For each woman of childbearing potential (as assessed by the HCP), a urine pregnancy test 
should be obtained locally according to the Schedule of Activities (Section 2).
9.4.5. Other Tests
Not applicable.
9.4.6. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.5.
Pharmacokinetics
Not applicable.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Pharmacogenomics
Not applicable.
9.8.
Biomarkers
Not applicable.
9.9.
Medical Resource Utilization and Health Economics
9.9.1. Insulin Treatment Pattern
The insulin treatment patterns of interest during the 48-week period were defined as follows: 

F3Z-GH-IOQR Clinical Protocol
Page 30
LY275585

Discontinuation:  Defined as stopping insulin treatment for 30 days or more. 
Time to discontinuation will be calculated as the number of days from 
initiation of insulin to insulin discontinuation or censoring. Time to insulin 
discontinuation and proportion of patient discontinued insulin will be 
compared.  

Switch: Defined as stop the initial insulin therapy and started another insulin 
therapy of different class.  Proportion of patient switching and time to 
switching will be compared.
Note:  Switching to a different brand of the same class will not be considered as an 
insulin treatment pattern switch. 

Intensification: Defined as any of the following: adding meal time insulin in 
basal insulin analog QD group; changing from BID to TID in insulin analog 
mid mixture BID group. Time to insulin treatment intensification and 
proportion of patient undergone insulin treatment intensification will be 
compared.

Reduction in frequency: Defined as any of the following: changing from 
BID to QD; changing from TID to BID or QD. Time to insulin treatment 
reduction in frequency and proportion of patient undergone insulin treatment 
reduction in frequency will be compared.

Time to insulin treatment change: Defined as time to any of: insulin 
treatment discontinuation, switch, intensification, or reduction in frequency.
Insulin treatment change and reason for insulin treatment change will be collected in 
the CRF by investigator and study-site personnel for all participants throughout the
study. 
9.9.2. Patient-Reported Outcomes
The self-reported questionnaires will be administered according to the Schedule of Activities
(Section 2). These questionnaires have been translated into Chinese and linguistically validated.
Self-efficacy about Insulin Therapy Questionnaire (SEITQ). The SEITQ is designed to 
measure an individual’s self-efficacy related to insulin therapy.  The SEITQ consists of 5 items 
(that is, statements).  The first 4 statements imply confidence in completing the tasks needed to 
take insulin correctly and avoid both hyperglycemia and hypoglycemia, whereas the last 
statement is an outcome expectation and implies that performance of these tasks will lead to 
avoidance of complications.  The items are preceded by the stem “I am confident that I will be 
able to...”  The directions ask respondents to indicate their level of agreement with each 
statement on a 7-point scale ranging from “1” (Strongly disagree) to “7” (Strongly Agree).  The 
directions do not include a recall period nor do they refer to a specific insulin therapy or delivery 
system.
Insulin Treatment Satisfaction Questionnaire (ITSQ). The ITSQ is a validated measure 
consisting of 22 items that comprehensively assess treatment satisfaction for persons with 

F3Z-GH-IOQR Clinical Protocol
Page 31
LY275585
diabetes taking insulin.  Items are measured on a 7-point scale, where lower scores reflect better 
outcomes.  In addition to an overall score, the items that make up the 5 domains of satisfaction 
are categorized as: ·Inconvenience of Regimen (5 items), Lifestyle Flexibility (3 items), 
Glycemic Control (3 items), Hypoglycemic Control (5 items), and Insulin Delivery Device 
(6 items).  
9.9.3. Healthcare Resource Utilization
Medical resource utilization data, associated with medical encounters, will be collected in the 
CRF by the investigator and study-site personnel for all participants throughout the study.  
Protocol-mandated procedures, tests, and encounters are excluded. 
Healthcare resource utilization will be examined as all-cause and T2DM-related, and categorized 
as inpatient, outpatient, and ER utilizations: 

Inpatient hospital utilization will be identified using medical encounters where the place 
of service is an inpatient hospital facility.  

Outpatient utilization will be identified using medical encounters where the place of 
service is outpatient facility. 

Emergency room utilization will be identified using medical encounters where the place 
of service is an ER.  Emergency room claims that have the same service date as a 
hospitalization will not be counted as an ER visit. Emergency room visits adjacent to a
hospitalization will be considered a hospitalization and will not be counted as an ER visit.
The data collected may be used to conduct exploratory economic analyses and will include:

number and duration of medical care encounters, including surgeries, and other 
selected procedures (inpatient and outpatient)

reason and duration of hospitalization (total days length of stay, including 
duration by wards; for example, intensive care unit)

number and character of diagnostic and therapeutic tests and procedures

F3Z-GH-IOQR Clinical Protocol
Page 32
LY275585
10. Statistical Considerations
10.1. Sample Size Determination
The primary objective of the study will be evaluated using the classification method as proposed 
by Qu and colleagues (2011). With no prior hypothesis specified, the study will be considered a 
success if a conclusion may be reached by the classification method. With a 1:1 randomization 
ratio between insulin analog mid mixture BID and basal insulin analog QD, and assuming a non-
inferiority margin of 0.4%, no treatment difference between mid mixture BID and basal insulin 
analog QD, and a common SD of 1.5% for the change from baseline in HbA1c at Week 24, 332 
evaluable patients per arm will provide greater than 99% possibility for the study to reach a 
conclusion for primary analyses with 2-sided alpha level of 0.05.  If we assume 20% of the 
patients will drop out without providing an evaluable post-baseline HbA1c), 415 patients per arm 
need to be randomized.
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who signed informed consent.
Randomized
All participants who were enrolled and who were randomized to any one of the 
treatment groups.
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee. Any change to
the data analysis methods described in the protocol will require an amendment only if it changes a 
principal feature of the protocol. Any other change to the data analysis methods described in the 
protocol, and the justification for making the change, will be described in the statistical analysis plan 
(SAP) or the clinical study report (CSR). Additional exploratory analyses of data will be conducted, 
as deemed appropriate.
Given the nature of this pragmatic study, both efficacy and safety analyses will be performed on 
randomized patients. As sensitivity analyses, certain efficacy analyses may be repeated by 
censoring all efficacy data after patients changed the randomized treatment regimen.
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated.
The baseline value for measurements will be defined as the last non-missing observation on or 
before the randomization visit. If no data are available, the baseline value will be treated as 
missing. The Week 24 value for measurements will be the last non-missing post-baseline 
observation up to 24 weeks, and the Week 48 value for measurements will be the last non-
missing post-baseline observation up to 48 weeks.

F3Z-GH-IOQR Clinical Protocol
Page 33
LY275585
For continuous measures, summary statistics will include at least the number of patients with 
data, mean, SD, median, minimum, and maximum. For categorical measures, summary statistics 
will include at least the number of patients with data, frequency counts, and percentages. For 
comparisons based on analysis models, the differences will be reported using LS means, along 
with 95% CIs and p-value. Sometimes, comparison on the summary statistics may be performed 
and p-values be provided, and such p-values should be viewed as a descriptive measure only. 
Unless specified otherwise, a two-sample t-test will be used for continuous measurements and 
Fisher’s exact test will be used for categorical measurements.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
The overall study disposition status will be summarized over all enrolled patients. Reasons for 
screen failures and study discontinuations will be tabulated for each treatment arm and overall 
population.
10.3.2.2. Patient Characteristics
Patient characteristics at baseline (for example, demographics, diabetes history, and comorbidity) 
will be summarized by treatment arm and overall population. No formal statistical comparisons 
will be performed.
10.3.2.3. Concomitant Therapy
Anti-hyperglycemic concomitant therapy will be summarized at baseline and throughout the 
study by treatment arm and overall population. General concomitant therapy will not be 
collected or summarized.
10.3.2.4. Treatment Compliance
No patient-reported and HCP-perceived compliance of the treatment will be collected and 
summarized.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary outcome of the study is the change from baseline in HbA1c at Week 24. In this 
study, HbA1c will be only measured once post-baseline at Week 24, so missing measurements 
will not be imputed. In addition to common summary statistics for the change from baseline 
data, the comparison between 2 treatment arms will be conducted using an analysis of covariate 
(ANCOVA) model, with change from baseline in HbA1c as response, treatment as fixed effect 
and baseline HbA1c as a covariate.  The 95% CI of LS means difference (insulin analog mid 
mixture BID – basal insulin analog QD) will be used to make conclusions for the comparison. 
Specifically, let L and U be the lower and upper limit of this CI. Then,

If L>-0.4%, the Non-inferiority (NI) of basal insulin analog QD to insulin analog 
mid mixture BID is established;

If L>0%, the superiority of basal insulin analog QD to insulin analog mid mixture 
BID is established;

F3Z-GH-IOQR Clinical Protocol
Page 34
LY275585

If U<0.4%, the NI of insulin analog mid mixture BID to basal insulin analog QD
is established;

If U<0%, the superiority of insulin analog mid mixture BID to basal insulin 
analog QD is established;
For more details, refer to the SAP and Qu and colleagues (2011). P-value for the treatment 
contrast from the ANCOVA may still be displayed, but should not be used to make a conclusion. 
As a sensitivity analyses, the primary analyses will be repeated by censoring all efficacy data 
after patients changed the randomized treatment regimen.
10.3.3.2. Secondary Analyses
For change from baseline in HbA1c at Week 48, the analyses model will be similar to the 
primary analyses model, and the sensitivity analyses will also be performed. Also, a mixed-
model repeated measures (MMRM) model will be employed to analyze the HbA1c change from 
baseline at Week 48. This MMRM model will have all post-baseline HbA1c as responses, 
baseline HbA1c as a continuous covariate, treatment group, Visit (Week 24 or Visit 48), and 
treatment by visit interaction as fixed effects and patient as a random effect. Treatment contrast 
at Week 48 will be used for making the inference.
For change from baseline in venous FPG, FSBG-based FBG, PPG, BG excursion and 
bodyweight at Week 24 and Week 48, the analyses will be done similarly to the primary analyses 
model (ANCOVA for Week 24 and Week 48, and MMRM for Week 48), except for the 
comparison will be based on the treatment contrast p-value from the corresponding analyses 
model. 
For percentages of patients reaching treatment goals (<7%) at Week 24 and Week 48, no missing 
data will be imputed. Count and percentages of patients reaching treatment goals will be 
summarized (when calculating percentages, the denominator will be the patients with non-
missing HbA1c data at Week 24 or Week 48), and also be analyzed by a logistic regression 
model, with logit link function, treatment as fixed effect and baseline HbA1c as continuous 
covariate. Same analyses strategy will be used for the composite endpoint of patients reaching 
treatment goals (<7%) and did not switch from or discontinue study treatment, and did not take 
rescue medication.
Insulin dose at each visit will be descriptively summarized by treatment groups by total daily 
dose (IU and IU/kg).  
Time to insulin treatment change (as defined in Section 9.9.1) will be compared between 
treatment arms by a log rank test at Week 48. Patients who did not have any insulin treatment 
change up to Week 48 (or up to early discontinuation) will be considered as censored at Week 48 
(or time of early discontinuation) with no event.

F3Z-GH-IOQR Clinical Protocol
Page 35
LY275585
10.3.4. Safety Analyses
General AEs will be collected in this study. Count and frequency of AEs will be summarized for 
overall study population and by treatment arm. Also, AEs as a cause for insulin treatment change 
will be collected, and summarized by treatment arm.
Serious adverse events will be collected and reported per Lilly standard operating procedure (SOP)
and local regulatory requirement. Count and frequency of SAEs will be summarized by treatment 
arm.  
The incidence rate of CRF-collected severe, nocturnal and total hypoglycemic events will be 
summarized by visit and for the overall study duration. Comparison between treatment arms will be 
performed by Fisher’s exact test. The overall yearly rates (events/patient/year) of those 
hypoglycemic events, calculated as, for each patient, the number of episodes times 365.25 and then 
divided by the patient’s treatment duration, will be summarized, and analyzed by a Negative-
binomial regression model with treatment as fixed effects and log of (patient’s treatment 
duration/365.25) as an offset variable.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
No pharmacokinetic/pharmacodynamics (PK/PD) analyses will be performed in this study.
10.3.6. Other Analyses
10.3.6.1. Medical Resource Utilization and Health Economics 
10.3.6.1.1.Adherence and Insulin Treatment Pattern
For these measurements, summary statistics will be provided, and comparison will be performed 
by appropriate general test (see Section 10.3.1).
10.3.6.1.2.Resource Utilization
Utilization data will be summarized descriptively by category across arms (for example, surgery, 
and hospitalization days) for a treatment arm, including a frequency table with tabular statistics.  
Tests for differences in proportions between treatment arms will be performed.  
10.3.6.1.3.Insulin Treatment Satisfaction Questionnaire (ITSQ) 
Overall and domain scores will be summarized and tabulated for ITSQ score at endpoint. 
10.3.6.1.4.SEITQ = Self-efficacy about Insulin Therapy Questionnaire (SEITQ)
Categorical responses for the each question will be summarized at baseline and endpoint. 
Comparisons will also be performed.
10.3.6.2. Subgroup Analyses
Subgroup analyses may be performed on selected outcomes in subgroups of interest. All 
subgroup analyses will be exploratory in nature. As the interest will be on how different 
treatment regimens work in a specific subgroup, instead of whether the treatment differences are 
the same across different subgroups, the subgroup analyses will be performed by analyzing the 
outcome data in different subgroups, instead of analyzing the outcome data in the whole 
population with subgroup factors included in the analyses model. 

F3Z-GH-IOQR Clinical Protocol
Page 36
LY275585
The following subgroups will be explored, and additional subgroups may be further explored if 
needed: 

baseline HbA1c (<8.4% and ≥8.4%)

baseline morning PPG (<13.5 mmol/L and ≥13.5 mmol/L)

baseline morning BG excursion (<4.4 mmol/L and ≥4.4 mmol/L)

baseline body mass index (BMI) (<25 and ≥25)

gender (male and female)

3-month persistence (discontinued insulin in the first 3 months of treatment or not)
10.3.7. Interim Analyses
An interim analysis may be conducted after all patients complete Visit 4.  The analysis will 
include the primary objective and key secondary objectives to be described in more detail in the 
SAP.  Although the study is open label, in order to avoid influencing study conduct in any way 
results will not be publicly disclosed until the last patient completes Visit 6.

F3Z-GH-IOQR Clinical Protocol
Page 37
LY275585
11.
References
[ADA] American Diabetes Association. Workgroup on Hypoglycemia. Defining and reporting
hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on
Hypoglycemia. Diabetes Care. 2005;28(5):1245-1249.
[CDS] Chinese Diabetes Society. Chinese guidelines for the management of type 2 diabetes 
mellitus (2013 edition). Chin J Diabetes Mellitus. 2014;6:447-498.
Chen W, Qian L, Watada H, Li P, Iwamoto N, Imori M, Yang W. Impact of diet on the efficacy 
of insulin lispro 25/75 and insulin lispro 50/50 as starter insulin in East Asian patients with 
type 2 diabetes: subgroup analysis of the CLASSIFY randomized trial. J Diabetes Investig.
2016; doi:10.1111/jdi.12547.
Hu FB. Globalization of diabetes: the role of diet, lifestyle, and genes. Diabetes Care. 
2011;34(6):1249-157.
International Diabetes Federation. IDF Diabetes Atlas, 6th edn. Brussels, Belgium: International 
Diabetes Federation, 2013.
Ji L, Feng B, Su Q, Lin J, Chen Y, Rong H, Zhuang X, Huang W, Wang A, Ma L, Pu X, Han Z, 
Jin H, Chen J, Jiang X, Zhou L, Xu Y, Lv X. The safety and efficacy of initiating insulin 
therapy in Chinese patients with type 2 diabetes mellitus inadequately controlled with previous 
oral antidiabetic drugs. Chin J Diabetes. 2011;19:746–751. 
Ji L, Jia W, Weng J. Glycemic control in insulinized type 2 diabetes patients in China: one-year 
results from IDMPS. American, Diabetes Association 69th Scientific Sessions, June 5–9, 
2009, New Orleans, Louisiana, USA.
Jia W, Xiao X, Ji Q, Ahn KJ, Chuang LM, Bao Y, Pang C, Chen L, Gao F, Tu Y, Li P, Yang J. 
Comparison of thrice-daily premixed insulin (insulin lispro premix) with basal-bolus (insulin 
glargine once-daily plus thrice-daily prandial insulin lispro) therapy in east Asian patients with 
type 2 diabetes insufficiently controlled with twice-daily premixed insulin: an open-label, 
randomised, controlled trial. Lancet Diabetes Endocrinol. 2015;3(4):254-262.
Kalra S, Plata-Que T, Kumar D, Mumtaz M, Søndergaard F, Kozlovski P, Bebakar WM.
Initiation with once-daily BIAsp 30 results in superior outcome compared to insulin glargine 
in Asians with type 2 diabetes inadequately controlled by oral anti-diabetic drugs. Diabetes 
Res Clin Pract. 2010;88(3):282-288.
Li C, Yu D, Li J, et al. Efficacy and safety of addition basal insulin in elderly patients with type 2 
diabetes poorly controlled on oral glucose-lowering drugs. Chin J Diabetes Mellitus.
2014;06(11): 813-816.
Qin J, Wang X, Zhang N, Chen Y. Superior efficacy and safety of glargine insulin plus acarbose 
as compared to twice-daily injection of premixed insulin with poorly control of blood glucose 
in type 2 diabetic patients. Chin J Diabetes. 2014;22(05):439-441.
Qu Y, Liu R, Dmitriento A, Offen W. A new classification approach for comparing two active 
treatments when there is no prior projection on which one is better. Stat Med. 
2011;30(30):3488-3495.

F3Z-GH-IOQR Clinical Protocol
Page 38
LY275585
Su Q, Qian L, Li P, Yang W. Insulin Mid Mixture Lispro Mix 50 (LM50) Showed Better 
Glycemic Control than Low Mixture Lispro Mix 25 (LM25) as Starter Insulin in Chinese 
Patients with Type 2 Diabetes Mellitus: a Subgroup Analysis of the CLASSIFY Study. 
American Diabetes Association 75th Scientific sessions, June 5-9, 2015a, Boston,
Massachusetts, USA
Su Q, Qian L, Li P, Yang W. The Overall Glycemic Control is Likely Attributed to Improvement 
in Post Prandial Glucose Levels in Chinese Patients with Type 2 Diabetes Mellitus: a 
Subgroup-Analysis of CLASSIFY Study. The 19th Scientific Meeting of the Chinese Diabetes 
Society, Dec 9-12, 2015b, Suzhou, Jiangsu, China
Watada H, Su Q, Li P, Iwamoto N, Qian L, Yang W. Comparison of insulin lispro mix 25 with 
insulin lispro mix 50 as an insulin starter in Asian patients with type 2 diabetes: a phase 4, 
open-label, randomized trial (CLASSIFY study). Diabetes Metab Res Rev. 2016; 
doi:10.1002/dmrr.2816.
Yang W, Lu J, Weng J, Jia W, Ji L, Xiao J, Shan Z, Liu J, Tian H, Ji Q, Zhu D, Ge J, Lin L, 
Chen L, Guo X, Zhao Z, Li Q, Zhou Z, Shan G, He J; China National Diabetes and Metabolic 
Disorders Study Group. Prevalence of diabetes among men and women in China. N Engl J 
Med. 2010;362(12):1090-1101.
Yang W, Xu X, Lv X. Comparison of once-daily biphasic insulin aspart 30 with insulin glargine 
in type 2 diabetes patients——Easymix study in China. Chin J Diabetes. 2013;21(11):1002-
1007.

F3Z-GH-IOQR Clinical Protocol
Page 39
LY275585
12.
Appendices

F3Z-GH-IOQR Clinical Protocol
Page 40
LY275585
Appendix 1.
Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ANCOVA
analysis of covariance
BG
blood glucose
BID
bwice daily
BMI
body mass index
CIOMS
Council for International Organizations of Medical Sciences
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
CRF/eCRF
case report form/electronic case report from
CSR
clinical study report
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ER
emergency room
ERB
ethical review board
FBG
fasting blood glucose
FPG 
fasting plasma glucose
FSBG
finger stick blood glucose
GCP
good clinical practice

F3Z-GH-IOQR Clinical Protocol
Page 41
LY275585
HbA1c
hemoglobin A1c
HCP
healthcare professional
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IDF
International Diabetes Federation
Investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
ITSQ
Insulin Treatment Satisfaction Questionnaire
IVRS/
interactive voice-response system
IWRS
interactive web-response system
MMRM
mixed-model repeated measures
NI
Non-inferiority
OAMs
oral antihyperglycemic medications
PCT
pragmatic clinical trial
PD
pharmacodynamic
PK
pharmacokinetic
PPG
post prandial glucose
PRO/ePRO
patient-reported outcomes/electronic patient-reported outcomes
QD
once daily
RCT
randomized clinical trial
SAE
serious adverse event
SAP
statistical analysis plan
SEITQ
Self-efficacy about Insulin Therapy Questionnaire
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
BG measured by Self-Monitoring Blood Glucose Device

F3Z-GH-IOQR Clinical Protocol
Page 42
LY275585
SUSARs
suspected unexpected serious adverse reactions
WHO
World Health Organization
T2DM
type 2 diabetes mellitus

F3Z-GH-IOQRClinical Protocol
Page 43
CCI
LY275585

F3Z-GH-IOQR Clinical Protocol
Page 44
LY275585
Appendix 3.
Study Governance Considerations
Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for ensuring:

that the patient understands the potential risks and benefits of participating in the 
study

that informed consent is given by each patient or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed consent 
form (ICF) prior to the performance of any protocol procedures and prior to the 
administration of investigational products.

answering any questions the patient may have throughout the study and sharing in 
a timely manner any new information that may be relevant to the patient’s 
willingness to continue his or her participation in the trial.
Appendix 3.1.2.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International 
Conference on Harmonisation (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current package inserts and updates during the course of the study

informed consent form 

relevant curricula vitae
Appendix 3.1.3.
Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations

F3Z-GH-IOQR Clinical Protocol
Page 45
LY275585
Some of the obligations of the sponsor will be assigned to a third-party.
Appendix 3.1.4.
Investigator Information
Physicians who work in teaching or nonteaching hospitals with a specialty in in endocrinology or 
internal medicine and over three years’ experience initiating premix or basal insulin in type 2 
diabetes mellitus (T2DM) patients, will be qualified to participate as investigators in this clinical 
trial.
Appendix 3.1.5.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.6.
Final Report Signature
The clinical study report (CSR) coordinating investigator will sign the final CSR for this study, 
indicating agreement that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the case report 
forms (CRFs), and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.

F3Z-GH-IOQR Clinical Protocol
Page 46
LY275585
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data will be encoded and stored in electronic data capture system.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect patient-
reported outcome (PRO) measures (for example, a rating scale), a daily dosing schedule, or an 
event diary.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.

PPD
Leo Document ID = 763ccf15-5bd0-4202-9602-56da0ea04270
Approver: 
Approval Date & Time: 26-Jun-2016 08:20:26 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 26-Jun-2016 08:22:04 GMT
Signature meaning: Approved
PPD